case study of severe anemia

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• Published: 13 September 2021

Critical iron deficiency anemia with record low hemoglobin: a case report

• Audrey L. Chai   ORCID: orcid.org/0000-0002-5009-0468 1 ,
• Owen Y. Huang 1 ,
• Rastko Rakočević 2 &
• Peter Chung 2  

Journal of Medical Case Reports volume  15 , Article number:  472 ( 2021 ) Cite this article

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Anemia is a serious global health problem that affects individuals of all ages but particularly women of reproductive age. Iron deficiency anemia is one of the most common causes of anemia seen in women, with menstruation being one of the leading causes. Excessive, prolonged, and irregular uterine bleeding, also known as menometrorrhagia, can lead to severe anemia. In this case report, we present a case of a premenopausal woman with menometrorrhagia leading to severe iron deficiency anemia with record low hemoglobin.

Case presentation

A 42-year-old Hispanic woman with no known past medical history presented with a chief complaint of increasing fatigue and dizziness for 2 weeks. Initial vitals revealed temperature of 36.1 °C, blood pressure 107/47 mmHg, heart rate 87 beats/minute, respiratory rate 17 breaths/minute, and oxygen saturation 100% on room air. She was fully alert and oriented without any neurological deficits. Physical examination was otherwise notable for findings typical of anemia, including: marked pallor with pale mucous membranes and conjunctiva, a systolic flow murmur, and koilonychia of her fingernails. Her initial laboratory results showed a critically low hemoglobin of 1.4 g/dL and severe iron deficiency. After further diagnostic workup, her profound anemia was likely attributed to a long history of menometrorrhagia, and her remarkably stable presentation was due to impressive, years-long compensation. Over the course of her hospital stay, she received blood transfusions and intravenous iron repletion. Her symptoms of fatigue and dizziness resolved by the end of her hospital course, and she returned to her baseline ambulatory and activity level upon discharge.

Conclusions

Critically low hemoglobin levels are typically associated with significant symptoms, physical examination findings, and hemodynamic instability. To our knowledge, this is the lowest recorded hemoglobin in a hemodynamically stable patient not requiring cardiac or supplemental oxygen support.

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Anemia and menometrorrhagia are common and co-occurring conditions in women of premenopausal age [ 1 , 2 ]. Analysis of the global anemia burden from 1990 to 2010 revealed that the prevalence of iron deficiency anemia, although declining every year, remained significantly high, affecting almost one in every five women [ 1 ]. Menstruation is considered largely responsible for the depletion of body iron stores in premenopausal women, and it has been estimated that the proportion of menstruating women in the USA who have minimal-to-absent iron reserves ranges from 20% to 65% [ 3 ]. Studies have quantified that a premenopausal woman’s iron storage levels could be approximately two to three times lower than those in a woman 10 years post-menopause [ 4 ]. Excessive and prolonged uterine bleeding that occurs at irregular and frequent intervals (menometrorrhagia) can be seen in almost a quarter of women who are 40–50 years old [ 2 ]. Women with menometrorrhagia usually bleed more than 80 mL, or 3 ounces, during a menstrual cycle and are therefore at greater risk for developing iron deficiency and iron deficiency anemia. Here, we report an unusual case of a 42-year-old woman with a long history of menometrorrhagia who presented with severe anemia and was found to have a record low hemoglobin level.

A 42-year-old Hispanic woman with no known past medical history presented to our emergency department with the chief complaint of increasing fatigue and dizziness for 2 weeks and mechanical fall at home on day of presentation.

On physical examination, she was afebrile (36.1 °C), blood pressure was 107/47 mmHg with a mean arterial pressure of 69 mmHg, heart rate was 87 beats per minute (bpm), respiratory rate was 17 breaths per minute, and oxygen saturation was 100% on room air. Her height was 143 cm and weight was 45 kg (body mass index 22). She was fully alert and oriented to person, place, time, and situation without any neurological deficits and was speaking in clear, full sentences. She had marked pallor with pale mucous membranes and conjunctiva. She had no palpable lymphadenopathy. She was breathing comfortably on room air and displayed no signs of shortness of breath. Her cardiac examination was notable for a grade 2 systolic flow murmur. Her abdominal examination was unremarkable without palpable masses. On musculoskeletal examination, her extremities were thin, and her fingernails demonstrated koilonychia (Fig. 1 ). She had full strength in lower and upper extremities bilaterally, even though she required assistance with ambulation secondary to weakness and used a wheelchair for mobility for 2 weeks prior to admission. She declined a pelvic examination. No bleeding was noted in any part of her physical examination.

Koilonychia, as seen in our patient above, is a nail disease commonly seen in hypochromic anemia, especially iron deficiency anemia, and refers to abnormally thin nails that have lost their convexity, becoming flat and sometimes concave in shape

She was admitted directly to the intensive care unit after her hemoglobin was found to be critically low at 1.4 g/dL on two consecutive measurements with an unclear etiology of blood loss at the time of presentation. Note that no intravenous fluids were administered prior to obtaining the hemoglobin levels. Upon collecting further history from the patient, she revealed that she has had a lifetime history of extremely heavy menstrual periods: Since menarche at the age of 10 years when her periods started, she has been having irregular menstruation, with periods occurring every 2–3 weeks, sometimes more often. She bled heavily for the entire 5–7 day duration of her periods; she quantified soaking at least seven heavy flow pads each day with bright red blood as well as large-sized blood clots. Since the age of 30 years, her periods had also become increasingly heavier, with intermittent bleeding in between cycles, stating that lately she bled for “half of the month.” She denied any other sources of bleeding.

Initial laboratory data are summarized in Table 1 . Her hemoglobin (Hgb) level was critically low at 1.4 g/dL on arrival, with a low mean corpuscular volume (MCV) of < 50.0 fL. Hematocrit was also critically low at 5.8%. Red blood cell distribution width (RDW) was elevated to 34.5%, and absolute reticulocyte count was elevated to 31 × 10 9 /L. Iron panel results were consistent with iron deficiency anemia, showing a low serum iron level of 9 μg/dL, elevated total iron-binding capacity (TIBC) of 441 μg/dL, low Fe Sat of 2%, and low ferritin of 4 ng/mL. Vitamin B12, folate, hemolysis labs [lactate dehydrogenase (LDH), haptoglobin, bilirubin], and disseminated intravascular coagulation (DIC) labs [prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, d -dimer] were all unremarkable. Platelet count was 232,000/mm 3 . Peripheral smear showed erythrocytes with marked microcytosis, anisocytosis, and hypochromia (Fig. 2 ). Of note, the patient did have a positive indirect antiglobulin test (IAT); however, she denied any history of pregnancy, prior transfusions, intravenous drug use, or intravenous immunoglobulin (IVIG). Her direct antiglobulin test (DAT) was negative.

A peripheral smear from the patient after receiving one packed red blood cell transfusion is shown. Small microcytic red blood cells are seen, many of which are hypochromic and have a large zone of pallor with a thin pink peripheral rim. A few characteristic poikilocytes (small elongated red cells also known as pencil cells) are also seen in addition to normal red blood cells (RBCs) likely from transfusion

A transvaginal ultrasound and endometrial biopsy were offered, but the patient declined. Instead, a computed tomography (CT) abdomen and pelvis with contrast was performed, which showed a 3.5-cm mass protruding into the endometrium, favored to represent an intracavitary submucosal leiomyoma (Fig. 3 ). Aside from her abnormal uterine bleeding (AUB), the patient was without any other significant personal history, family history, or lab abnormalities to explain her severe anemia.

Computed tomography (CT) of the abdomen and pelvis with contrast was obtained revealing an approximately 3.5 × 3.0 cm heterogeneously enhancing mass protruding into the endometrial canal favored to represent an intracavitary submucosal leiomyoma

The patient’s presenting symptoms of fatigue and dizziness are common and nonspecific symptoms with a wide range of etiologies. Based on her physical presentation—overall well-appearing nature with normal vital signs—as well as the duration of her symptoms, we focused our investigation on chronic subacute causes of fatigue and dizziness rather than acute medical causes. We initially considered a range of chronic medical conditions from cardiopulmonary to endocrinologic, metabolic, malignancy, rheumatologic, and neurological conditions, especially given her reported history of fall. However, once the patient’s lab work revealed a significantly abnormal complete blood count and iron panel, the direction of our workup shifted towards evaluating hematologic causes.

With such a critically low Hgb on presentation (1.4 g/dL), we evaluated for potential sources of blood loss and wanted to first rule out emergent, dangerous causes: the patient’s physical examination and reported history did not elicit any concern for traumatic hemorrhage or common gastrointestinal bleeding. She denied recent or current pregnancy. Her CT scan of abdomen and pelvis was unremarkable for any pathology other than a uterine fibroid. The microcytic nature of her anemia pointed away from nutritional deficiencies, and she lacked any other medical comorbidities such as alcohol use disorder, liver disease, or history of substance use. There was also no personal or family history of autoimmune disorders, and the patient denied any history of gastrointestinal or extraintestinal signs and/or symptoms concerning for absorptive disorders such as celiac disease. We also eliminated hemolytic causes of anemia as hemolysis labs were all normal. We considered the possibility of inherited or acquired bleeding disorders, but the patient denied any prior signs or symptoms of bleeding diatheses in her or her family. The patient’s reported history of menometrorrhagia led to the likely cause of her significant microcytic anemia as chronic blood loss from menstruation leading to iron deficiency.

Over the course of her 4-day hospital stay, she was transfused 5 units of packed red blood cells and received 2 g of intravenous iron dextran. Hematology and Gynecology were consulted, and the patient was administered a medroxyprogesterone (150 mg) intramuscular injection on hospital day 2. On hospital day 4, she was discharged home with follow-up plans. Her hemoglobin and hematocrit on discharge were 8.1 g/dL and 24.3%, respectively. Her symptoms of fatigue and dizziness had resolved, and she was back to her normal baseline ambulatory and activity level.

Discussion and conclusions

This patient presented with all the classic signs and symptoms of iron deficiency: anemia, fatigue, pallor, koilonychia, and labs revealing marked iron deficiency, microcytosis, elevated RDW, and low hemoglobin. To the best of our knowledge, this is the lowest recorded hemoglobin in an awake and alert patient breathing ambient air. There have been previous reports describing patients with critically low Hgb levels of < 2 g/dL: A case of a 21-year old woman with a history of long-lasting menorrhagia who presented with a Hgb of 1.7 g/dL was reported in 2013 [ 5 ]. This woman, although younger than our patient, was more hemodynamically unstable with a heart rate (HR) of 125 beats per minute. Her menorrhagia was also shorter lasting and presumably of larger volume, leading to this hemoglobin level. It is likely that her physiological regulatory mechanisms did not have a chance to fully compensate. A 29-year-old woman with celiac disease and bulimia nervosa was found to have a Hgb of 1.7 g/dL: she presented more dramatically with severe fatigue, abdominal pain and inability to stand or ambulate. She had a body mass index (BMI) of 15 along with other vitamin and micronutrient deficiencies, leading to a mixed picture of iron deficiency and non-iron deficiency anemia [ 6 ]. Both of these cases were of reproductive-age females; however, our patient was notably older (age difference of > 20 years) and had a longer period for physiologic adjustment and compensation.

Lower hemoglobin, though in the intraoperative setting, has also been reported in two cases—a patient undergoing cadaveric liver transplantation who suffered massive bleeding with associated hemodilution leading to a Hgb of 0.6 g/dL [ 7 ] and a patient with hemorrhagic shock and extreme hemodilution secondary to multiple stab wounds leading to a Hgb of 0.7 g/dL [ 8 ]. Both patients were hemodynamically unstable requiring inotropic and vasopressor support, had higher preoperative hemoglobin, and were resuscitated with large volumes of colloids and crystalloids leading to significant hemodilution. Both were intubated and received 100% supplemental oxygen, increasing both hemoglobin-bound and dissolved oxygen. Furthermore, it should be emphasized that the deep anesthesia and decreased body temperature in both these patients minimized oxygen consumption and increased the available oxygen in arterial blood [ 9 ].

Our case is remarkably unique with the lowest recorded hemoglobin not requiring cardiac or supplemental oxygen support. The patient was hemodynamically stable with a critically low hemoglobin likely due to chronic, decades-long iron deficiency anemia of blood loss. Confirmatory workup in the outpatient setting is ongoing. The degree of compensation our patient had undergone is impressive as she reported living a very active lifestyle prior to the onset of her symptoms (2 weeks prior to presentation), she routinely biked to work every day, and maintained a high level of daily physical activity without issue.

In addition, while the first priority during our patient’s hospital stay was treating her severe anemia, her education became an equally important component of her treatment plan. Our institution is the county hospital for the most populous county in the USA and serves as a safety-net hospital for many vulnerable populations, most of whom have low health literacy and a lack of awareness of when to seek care. This patient had been experiencing irregular menstrual periods for more than three decades and never sought care for her heavy bleeding. She, in fact, had not seen a primary care doctor for many years nor visited a gynecologist before. We emphasized the importance of close follow-up, self-monitoring of her symptoms, and risks with continued heavy bleeding. It is important to note that, despite the compensatory mechanisms, complications of chronic anemia left untreated are not minor and can negatively impact cardiovascular function, cause worsening of chronic conditions, and eventually lead to the development of multiorgan failure and even death [ 10 , 11 ].

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Department of Medicine, University of Southern California, Los Angeles, CA, USA

Audrey L. Chai & Owen Y. Huang

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA

Rastko Rakočević & Peter Chung

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AC, OH, RR, and PC managed the presented case. AC performed the literature search. AC, OH, and RR collected all data and images. AC and OH drafted the article. RR and PC provided critical revision of the article. All authors read and approved the final manuscript.

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Correspondence to Audrey L. Chai .

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Chai, A.L., Huang, O.Y., Rakočević, R. et al. Critical iron deficiency anemia with record low hemoglobin: a case report. J Med Case Reports 15 , 472 (2021). https://doi.org/10.1186/s13256-021-03024-9

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Received : 25 March 2021

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Published : 13 September 2021

DOI : https://doi.org/10.1186/s13256-021-03024-9

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Chapter 6-1:  Approach to the Patient with Anemia - Case 1

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Chief complaint, constructing a differential diagnosis.

• RANKING THE DIFFERENTIAL DIAGNOSIS
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Mrs. A is a 48-year-old white woman who has had fatigue for 2 months due to anemia.

Figure 6-1.

Diagnostic approach: anemia.

Anemia can occur in isolation, or as a consequence of a process causing pancytopenia, the reduction of all 3 cell lines (white blood cells [WBCs], platelets, and red blood cells [RBCs]). This chapter focuses on the approach to isolated anemia, although a brief list of causes of pancytopenia appears in Figure 6-1 . The first step in determining the cause of anemia is to identify the general mechanism of the anemia and organize the mechanisms using a pathophysiologic framework:

Acute blood loss: this is generally clinically obvious.

Underproduction of RBCs by the bone marrow; chronic blood loss is included in this category because it leads to iron deficiency, which ultimately results in underproduction.

Increased destruction of RBCs, called hemolysis.

Signs of acute blood loss

Hypotension

Tachycardia

Large ecchymoses

Symptoms of acute blood loss

Hematemesis

Rectal bleeding

Vaginal bleeding

After excluding acute blood loss, the next pivotal step is to distinguish underproduction from hemolysis by checking the reticulocyte count:

Low or normal reticulocyte counts are seen in underproduction anemias.

High reticulocyte counts occur when the bone marrow is responding normally to blood loss; hemolysis; or replacement of iron, vitamin B 12 , or folate.

Reticulocyte measures include:

The reticulocyte count: the percentage of circulating RBCs that are reticulocytes (normally 0.5–1.5%).

The absolute reticulocyte count; the number of reticulocytes actually circulating, normally 25,000–75,000/mcL (multiply the percentage of reticulocytes by the total number of RBCs).

The reticulocyte production index (RPI)

Corrects the reticulocyte count for the degree of anemia and for the prolonged peripheral maturation of reticulocytes that occurs in anemia.

Normally, the first 3–3.5 days of reticulocyte maturation occurs in the bone marrow and the last 24 hours in the peripheral blood.

When the bone marrow is stimulated, reticulocytes are released prematurely, leading to longer maturation times in the periphery, and larger numbers of reticulocytes are present at any given time.

For an HCT of 25%, the peripheral blood maturation time is 2 days, and for an HCT of 15%, it is 2.5 days; the value of 2 is generally used in the RPI calculation.

The normal RPI is about 1.0.

However, in patients with anemia, RPI < 2.0 indicates underproduction; RPI > 2.0 indicates hemolysis or an adequate bone marrow response to acute blood loss or replacement of iron or vitamins.

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Patient Case Presentation

Patient  Overview

M.J. is a 25-year-old, African American female presenting to her PCP with complaints of fatigue, weakness, and shortness of breath with minimal activity. Her friends and family have told her she appears pale, and combined with her recent symptoms she has decided to get checked out. She also states that she has noticed her hair and fingernails becoming extremely thin and brittle, causing even more concern. The patient first started noticing these symptoms a few months ago and they have been getting progressively worse. Upon initial assessment, her mucosal membranes and conjunctivae are pale. She denies pain at this time, but describes an intermittent dry, soreness of her tongue.

Vital Signs:

Temperature – 37 C (98.8 F)

HR – 95

BP – 110/70 (83)

Lab Values:

Hgb- 7 g/dL

Serum Iron – 40 mcg/dL

Transferrin Saturation – 15%

Medical History

• Diagnosed with peptic ulcer disease at age 21 – controlled with PPI pharmacotherapy
• IUD placement 3 months ago – reports an increase in menstrual bleeding since placement

Surgical History

• No past surgical history reported

Family History

• Diagnosis of iron deficiency anemia at 24 years old during pregnancy with patient – on daily supplement
• Otherwise healthy
• Diagnosis of hypertension – controlled with diet and exercise
• No siblings

Social History

• Vegetarian – patient states she has been having weird cravings for ice cubes lately
• Living alone in an apartment close to work in a lower-income community
• Works full time at a clothing department store

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INTRODUCTION

An approach to the evaluation of the adult with anemia is presented here. Diagnosis of specific conditions is discussed in separate topic reviews referenced below. Evaluation of anemia in children is discussed separately. (See "Approach to the child with anemia" .)

BASIC PRINCIPLES

Anemia definitions  —  Anemia is defined for patient care as a reduction in one or more of the major red blood cell (RBC) measurements obtained as a part of the complete blood count (CBC): hemoglobin concentration, hematocrit, or RBC count. A low hemoglobin concentration and/or low hematocrit are the parameters most widely used to diagnose anemia.

The reference range depends on age and sex of the patient, as well as other factors such as altitude, prevalence of smoking in the normative population, and other factors ( table 1 ):

Adherence to a strict cutoff should not supersede clinical judgment. We generally use the following cutoffs:

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A case study of an older adult with severe anemia refusing blood transfusion

Research output : Contribution to journal › Article › peer-review

Purpose: To discuss the diagnosis and treatment of severe anemia in an older adult who presents the challenge of declining blood transfusion in a real-world scenario where critical thinking, evidence-based care, and collaboration with other providers must come together to serve this patient's unique needs. Data sources: Extensive review of the scientific literature on anemia and the situation in which a patient refuses blood transfusion presented in a case study format. Conclusions: A thorough physical assessment, complete health history, and appropriate diagnostic workup should be used to distinguish the normal effects of senescence from the signs and symptoms of anemia. Common conditions that cause anemia in the elderly include chronic disease, iron deficiency, and gastro-intestinal bleeding. These conditions may result in profound anemia. The challenge can be compounded when, because of religious tenets, a patient, does not accept a blood transfusion. This case study challenges nurse practitioners to apply knowledge, seek guidance, and make appropriate referrals to care for a patient in order to render care within the parameters of the patient's belief system. Implications for practice: The astute primary care provider recognizes that anemia is not an expected physiological change associated with aging but a manifestation of an underlying disease process. Fatigue, weakness, and dyspnea are all symptoms of anemia that, may be overlooked and attributed to the aging process. Further, in keeping with the principles of autonomy and self-determination, it. is the clinician's duty to work with all patients to restore them to a state of optimal health while respecting deeply held, spiritual beliefs.

• Blood management
• Iron deficiency
• Jehovah's witness

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• Blood Transfusion Medicine & Life Sciences 100%
• Anemia Medicine & Life Sciences 89%
• Personal Autonomy Medicine & Life Sciences 19%
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• Information Storage and Retrieval Medicine & Life Sciences 13%
• Dyspnea Medicine & Life Sciences 13%
• Signs and Symptoms Medicine & Life Sciences 13%

T1 - A case study of an older adult with severe anemia refusing blood transfusion

AU - Thomas, C. Michelle

AU - Coleman, Harriet R.

AU - Taub, Leslie Faith Morritt

PY - 2007/1

Y1 - 2007/1

N2 - Purpose: To discuss the diagnosis and treatment of severe anemia in an older adult who presents the challenge of declining blood transfusion in a real-world scenario where critical thinking, evidence-based care, and collaboration with other providers must come together to serve this patient's unique needs. Data sources: Extensive review of the scientific literature on anemia and the situation in which a patient refuses blood transfusion presented in a case study format. Conclusions: A thorough physical assessment, complete health history, and appropriate diagnostic workup should be used to distinguish the normal effects of senescence from the signs and symptoms of anemia. Common conditions that cause anemia in the elderly include chronic disease, iron deficiency, and gastro-intestinal bleeding. These conditions may result in profound anemia. The challenge can be compounded when, because of religious tenets, a patient, does not accept a blood transfusion. This case study challenges nurse practitioners to apply knowledge, seek guidance, and make appropriate referrals to care for a patient in order to render care within the parameters of the patient's belief system. Implications for practice: The astute primary care provider recognizes that anemia is not an expected physiological change associated with aging but a manifestation of an underlying disease process. Fatigue, weakness, and dyspnea are all symptoms of anemia that, may be overlooked and attributed to the aging process. Further, in keeping with the principles of autonomy and self-determination, it. is the clinician's duty to work with all patients to restore them to a state of optimal health while respecting deeply held, spiritual beliefs.

AB - Purpose: To discuss the diagnosis and treatment of severe anemia in an older adult who presents the challenge of declining blood transfusion in a real-world scenario where critical thinking, evidence-based care, and collaboration with other providers must come together to serve this patient's unique needs. Data sources: Extensive review of the scientific literature on anemia and the situation in which a patient refuses blood transfusion presented in a case study format. Conclusions: A thorough physical assessment, complete health history, and appropriate diagnostic workup should be used to distinguish the normal effects of senescence from the signs and symptoms of anemia. Common conditions that cause anemia in the elderly include chronic disease, iron deficiency, and gastro-intestinal bleeding. These conditions may result in profound anemia. The challenge can be compounded when, because of religious tenets, a patient, does not accept a blood transfusion. This case study challenges nurse practitioners to apply knowledge, seek guidance, and make appropriate referrals to care for a patient in order to render care within the parameters of the patient's belief system. Implications for practice: The astute primary care provider recognizes that anemia is not an expected physiological change associated with aging but a manifestation of an underlying disease process. Fatigue, weakness, and dyspnea are all symptoms of anemia that, may be overlooked and attributed to the aging process. Further, in keeping with the principles of autonomy and self-determination, it. is the clinician's duty to work with all patients to restore them to a state of optimal health while respecting deeply held, spiritual beliefs.

KW - Anemia

KW - Blood management

KW - Iron deficiency

KW - Jehovah's witness

UR - http://www.scopus.com/inward/record.url?scp=33847261490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847261490&partnerID=8YFLogxK

U2 - 10.1111/j.1745-7599.2006.00188.x

DO - 10.1111/j.1745-7599.2006.00188.x

M3 - Article

C2 - 17214867

AN - SCOPUS:33847261490

SN - 1041-2972

JO - Journal of the American Academy of Nurse Practitioners

JF - Journal of the American Academy of Nurse Practitioners

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Severe anemia: a case report

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Purpose: To investigate the frequency and types of severe unknown anemia in patients referred to the Baqiyatallah Hospital (Tehran) for six months. Methods: In this descriptive cross-sectional study, the patients with severe unknown anemia referred to the Baqiyatallah Hospital (Tehran, Iran) were selected over six months. Following consideration of inclusion and exclusion criteria, 230 patients with severe anemia (hemoglobin (Hb) > 8gr/dl) were included. Complete medical history was obtained from the patients and additional biochemical blood analyses were applied to determine the frequency and type of anemia. SPSS (v.19) software was used to analyze the findings and the significance level was defined as a p-value <0.05. Results: In chronic disease anemia (47.5%), gastrointestinal bleeding-associated anemia (29%), bleeding malignancies anemia (21.5%), and aplastic anemia (2%). There were significant differences (p<0.05) in the frequency of different types of normocytic anemia. The highest frequency was detected in folate deficiency anemia (46%), hypothyroidism anemia (34%), and B12 deficiency anemia (20%), respectively. The hemolytic anemia represented a significant difference (p<0.05) in comparison with sickle cell anemia (95%). Also, sickle cell anemia showed a significant difference (p<0.05) between thalacemia-associated anemia (95%) and malignancy-related anemia (95%) Conclusion: Respectively, the highest frequency of anemia in patients was found in chronic diseases and gastrointestinal bleeding. It is suggested that more attention should be paid to the type of anemia of patients referred to the urgency of hospitals.

Digestive Diseases

Tomica Milosavljevic

Background: Anemia is present in almost 5% of adults worldwide and accompanies clinical findings in many diseases. Diseases of the gastrointestinal (GI) tract and liver are a common cause of anemia, so patients with anemia are often referred to a gastroenterologist. Summary: Anemia could be caused by various factors such as chronic bleeding, malabsorption, or chronic inflammation. In clinical practice, iron deficiency anemia and the combined forms of anemia due to different pathophysiological mechanisms are most common. Esophagogastroduodenoscopy, colonoscopy, and the small intestine examinations in specific situations play a crucial role in diagnosing anemia. In anemic, GI asymptomatic patients, there are recommendations for bidirectional endoscopy. Although GI malignancies are the most common cause of chronic bleeding, all conditions leading to blood loss, malabsorption, and chronic inflammation should be considered. From a gastroenterologist’s perspective, the clinical spectrum o...

The American Journal of Medicine

Gerson Greenburg

Northern Clinics of Istanbul

Sinan Kazan

Dr suman akula

Elyns Group

Background: Anemia profoundly impairs bodily health, prolongs hospital stay, heightens healthcare costs and reduces overall quality of life. Very severe ane mia (particularly acute cases) portends a critical state, may progress to irreversible vital organ damage, thereby increasing mortalities. Thus, it is worthwhile to evaluate the occurrence of very severe anemia cases, its clinical/laboratory features, prevalent causes/associations and survival patterns in Benin City, Nigeria.

Journal of B.U.ON.: official journal of the Balkan Union of Oncology

John Griniatsos

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shaurya mehta

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Preoperative Blood Transfusion Requirements for Hemorrhoidal Severe Anemia: A Retrospective Study of 128 Patients

Affiliations.

• 1 Department of Anorectal Surgery, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China (mainland).
• 2 Chinese Medicine Professional Doctorate Program, First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, Anhui, China (mainland).
• 3 Department of Anorectal Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China (mainland).
• 4 Department of Anorectal Surgery, The Third Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China (mainland).
• PMID: 38704632
• DOI: 10.12659/MSM.943126

BACKGROUND Severe anemia caused by hemorrhoidal hematochezia is typically treated preoperatively with reference to severe anemia treatment strategies from other etiologies. This retrospective cohort study included 128 patients with hemorrhoidal severe anemia admitted to 3 hospitals from September 1, 2018, to August 1, 2023, and aimed to evaluate preoperative blood transfusion requirements. MATERIAL AND METHODS Of 5120 patients with hemorrhoids, 128 (2.25%; male/female: 72/56) experienced hemorrhoidal severe anemia, transfusion, and Milligan-Morgan surgery. Patients were categorized into 2 groups based on their preoperative hemoglobin (PHB) levels after transfusion: PHB ≥70 g/L as the liberal-transfusion group (LG), and PHB <70 as the restrictive-threshold group (RG). The general condition, bleeding duration, hemoglobin level on admission, transfusion volume, length of stay, immune transfusion reaction, surgical duration, and hospitalization cost were compared between the 2 groups. RESULTS Patients with severe anemia (age: 41.07±14.76) tended to be younger than those with common hemorrhoids (age: 49.431±15.59 years). The LG had a significantly higher transfusion volume (4.77±2.22 units), frequency of immune transfusion reactions (1.22±0.58), and hospitalization costs (16.69±3.31 thousand yuan) than the RG, which had a transfusion volume of 3.77±2.09 units, frequency of immune transfusion reactions of 0.44±0.51, and hospitalization costs of 15.00±3.06 thousand yuan. Surgical duration in the LG (25.69±14.71 min) was significantly lower than that of the RG (35.24±18.72 min). CONCLUSIONS Patients with hemorrhoids with severe anemia might require a lower preoperative transfusion threshold than the currently recognized threshold, with an undifferentiated treatment effect and additional benefits.

• Anemia* / etiology
• Anemia* / therapy
• Blood Transfusion* / methods
• Gastrointestinal Hemorrhage / etiology
• Gastrointestinal Hemorrhage / surgery
• Gastrointestinal Hemorrhage / therapy
• Hemoglobins / analysis
• Hemoglobins / metabolism
• Hemorrhoids* / complications
• Hemorrhoids* / surgery
• Length of Stay
• Middle Aged
• Preoperative Care* / methods
• Retrospective Studies
• Hemoglobins

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Case report article, old woman with sheehan's syndrome suffered severe hyponatremia following percutaneous coronary intervention: a case report and review of literature.

• 1 School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
• 2 Cardiology Department and Experimental Animal Center, Liaocheng People’s Hospital of Shandong University and Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng, Shandong, China
• 3 Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng, Shandong, China
• 4 Department of Cardiology, Shandong Corps Hospital of Chinese People’s Armed Police Forces, Jinan, China

Glucocorticoid deficiency can lead to hypoglycemia, hypotension, and electrolyte disorders. Acute glucocorticoid deficiency under stress is very dangerous. Here, we present a case study of an elderly patient diagnosed with Sheehan's syndrome, manifesting secondary adrenal insufficiency and secondary hypothyroidism, managed with daily prednisone and levothyroxine therapy. She was admitted to our hospital due to acute non-ST segment elevation myocardial infarction. The patient developed nausea and limb twitching post-percutaneous coronary intervention, with subsequent diagnosis of hyponatremia. Despite initial intravenous sodium supplementation failed to rectify the condition, and consciousness disturbances ensued. However, administration of 50 mg hydrocortisone alongside 6.25 mg sodium chloride rapidly ameliorated symptoms and elevated blood sodium levels. Glucocorticoid deficiency emerged as the primary etiology of hyponatremia in this context, exacerbated by procedural stress during percutaneous coronary intervention. Contrast agent contributed to blood sodium dilution. Consequently, glucocorticoid supplementation emerges as imperative, emphasizing the necessity of stress-dose administration of glucocorticoid before the procedure. Consideration of shorter intervention durations and reduced contrast agent dosages may mitigate severe hyponatremia risks. Moreover, it is crucial for this patient to receive interdisciplinary endocrinologist management. In addition, Sheehan's syndrome may pose a risk for coronary atherosclerotic disease.

Introduction

In developed countries, studies have revealed varying prevalence rates of Sheehan's syndrome (SHS) among women, ranging from 0.0051% ( 1 ) to 3.1% ( 2 ). There were also studies showing that the prevalence of SHS ranged from 1% to 2% among women who experienced hypotension due to blood loss of 1–2 L ( 3 , 4 ). Contrastingly, in undeveloped nations, the prevalence varies from 3.1% to 27.6% ( 5 – 7 ). The diagnostic journey for SHS patients spans a considerable duration of 7–19 years from symptom onset to definitive diagnosis ( 8 ). Sheehan's syndrome arises from ischemic necrosis of the anterior pituitary gland triggered by postpartum hemorrhage ( 8 ), leading to pituitary hormone dysfunction, including insufficient secretion of growth hormone, thyroid stimulating hormone, gonadotropin, prolactin, and adrenocorticotropin (ACTH) ( 7 , 9 ). Predominant symptoms are associated with dysfunction of the gonads, thyroid, and adrenal cortex due to insufficient secretion of gonadotropins, thyroid stimulating hormones, and ACTH, respectively. The latter is the most prominent and sometimes life-threatening. Supplementing various deficient hormones is the primary treatment for SHS.

Glucocorticoids, pivotal adrenal cortex hormones, play crucial roles in regulating glucose metabolism, blood pressure, and electrolyte balance. Deficiency in glucocorticoids can lead to hypoglycemia, hypotension, and electrolyte disturbances. Lifetime glucocorticoid replacement therapy stands as a cornerstone in managing SHS patients. Fluctuations in neuroendocrine system activity necessitate adjustments in glucocorticoid supplementation, while metabolic disruptions from other etiologies also dictate dosage alterations. Inadequate comprehension of these dynamics among healthcare professionals may impact the prognosis of SHS patients and predispose them to risks. Surgical treatments, including interventional procedures, represent significant stressors in medical care. Failure to administer preoperative stress doses of glucocorticoids to SHS patients can engender serious consequences. To our knowledge, this article represents the first documented case of severe hyponatremia in an SHS patient following percutaneous coronary intervention (PCI).

Case presentation

A 70-year-old female patient presented with paroxysmal exertional chest tightness persisting for one month, alleviated by a few minutes of rest. Forty years ago, the patient suffered from postpartum hemorrhage, without blood transfusion, subsequently developing lactation failure and amenorrhea. Five years later, she was diagnosed with SHS at the Affiliated Hospital of Shandong University. Management included 5 mg of prednisone acetate in the morning for secondary adrenal insufficiency, and 50 ug of levothyroxine for secondary hypothyroidism. Apart from medication adherence, the patient lacked awareness regarding adrenal insufficiency. The patient had a decade-long history of hypertension, controlled with 5 mg of telmisartan and 5 mg of amlodipine daily. This patient had a weight of 46 kl, a height of 1.57 m, and a BMI of 18.66 kg/m 2 . Upon hospital admission, her vital signs were stable with a blood pressure of 122/58 mmHg, and a heart rate of 65 beats per minute. Physical examination revealed no pulmonary rales, cardiac murmurs, lower limb edema. Laboratory finding indicated elevated blood troponin I (0.5487 ng/ml, 0–0.0175 ng/ml), normal blood sodium (141.5 mmol/L, 137 mmol/L–147 mmol/L), and elevated fasting total cholesterol (6.28 mmol/L, 3 mmol/L–5.7 mmol/L). Thyroid function tests revealed low level of free thyroxine (FT4) (6.77 pmol/L, 7.98 pmol/L–16.02 pmol/L), with normal levels of free triiodothyronine (FT3) and thyroid stimulating hormone. Electrocardiogram indicated sinus bradycardia. We diagnosed the patient with acute non-ST segment elevation myocardial infarction (NSTEMI) and performed percutaneous coronary angiography (CAG) and intravascular ultrasound (IVUS) examination. We found that the stenosis degree was 40%, 80%, and 60%, 98%, and almost completely occluded, respectively, in the left main trunk (LM), the proximal and middle segments of the left anterior descending branch (LAD), the proximal segments of the left circumflex branch (LCX), and the middle segment of the right coronary artery (RCA) ( Figures 1A–C ). The minimum lumen area at the distal stenosis of the LM was 4.51 mm 2 ( Figure 1E ), the plaque load at the most severe stenosis of the proximal LAD was 80%, with a minimum lumen area of 2.88 mm 2 ( Figure 1F ). Due to the patient's refusal to undergo coronary artery bypass grafting, two stents were inserted in the middle segment of the RCA ( Figure 1D ). The intervention lasted for 2 h, including coronary angiography, bilateral intravascular ultrasound examination, patient involvement in treatment decision-making based on examination results, and subsequent coronary intervention treatment, utilizing 130 ml of iodixanol. The patient did not experience any chest discomfort, but was nervous and had a blood pressure rise to 190/100 mmHg, managed with sublingual nifedipine tablets and intravenous isosorbide nitrate. Following percutaneous intervention (PCI), the patient experienced a sequence of symptoms from the 12th to the 50th h, including nausea and loss of appetite, profuse sweating, mild limb twitching, and drowsiness in sequence ( Table 1 ). Limb twitching persisited for 18 h from the 38th to the 56th h post-PCI. On the 24th h post-PCI, the patient was diagnosed with hyponatremia ( Table 1 ), and 2%−3% sodium chloride was intermittently administered intravenously. Despite increased sodium chloride supplementation, symptoms persisted until administration of hydrocortisone, leading to symptom resolution and rapid improvement in blood sodium levels ( Table 1 ). By the 62nd h post-PCI, symptoms of hyponatremia completely resolved, with blood sodium level increasing from 114.2 mmol/L to 132 mmol/L ( Table 1 ). At the 86th h post-PCI, blood sodium level returned to normal. After 40 h, blood tests revealed low levels of cortisol (2.76 ug/dl, 6.7ug/dl–22.6 ug/dl), ACTH (4.26 pg/ml, 10.1 pg/ml–57.6 pg/ml), FT3 (3.41 pmol/L, 3.53 pmol/L−7.37 pmol/L), and FT4 (7.12 pmol/L, 7.98 pmol/L–16.02 pmol/L). Following discharge, the patient continued oral medication with 2.5 mg prednisone acetate and 50 ug levothyroxine sodium daily, as well as dual antiplatelet drugs, statins, and antihypertensive agents. During the next nine-month follow-up period, the patient did not experience ischemic symptoms or hyponatremia.

Figure 1 . Coronary angiography ( A – D ) and intravascular ultrasound examination ( E and F ) in an elderly patient with Sheehan's syndrome. ( A ) The stenosis degree is 40%, 80%, and 60%, respectively, at the end of the left main trunk, the proximal and middle segments of the left anterior descending branch. ( B ) The stenosis degree is 98% at the proximal segments of the left circumflex branch. ( C ) The stenosis degree is almost completely occluded at the middle segment of the right coronary artery. ( D ) Two stents are inserted in the middle segment of the RCA. ( E ) The minimum lumen area at the distal stenosis of the left main trunk is 4.51 mm 2 . ( F ) The plaque load at the most severe stenosis of the proximal left anterior descending branch is 80%, and the minimum lumen area is 2.88 mm 2 .

Table 1 . Timeline of changes in symptoms, blood sodium titers, and hyponatremia treatment in this patient at 12, 24, 38, 50, 56, 62 and 86 h after percutaneous intervention. normal titer blood sodium reference value: 137 mmol/L to 147 mmol/L.

SHS and hyponatremia

Sheehan's syndrome is characterized by insufficient secretion of ACTH due to pituitary necrosis, resulting in decreased synthesis and secretion of adrenocortical hormones, particularly glucocorticoids. Glucocorticoids play a vital role in regulating sodium and water excretion and maintaining electrolyte balance in the body. Insufficient glucocorticoid levels lead to diminished renal free water clearance, causing water retention and dilutional hyponatremia, resulting in reduced plasma osmolality. Furthermore, despite low osmolality, there is inappropriate secretion of antidiuretic hormone (vasopressin) due to the absence of cortisol's tonic inhibition ( 10 ).

Clinical presentation and management

In this case, the patient had a medical history of a SHS diagnosis, presenting with secondary adrenal insufficiency and secondary thyrotrophin deficiency necessitating hormone replacement therapy. Secondary adrenal insufficiency arises from pituitary impairment, causing decreased production of ACTH and subsequent reduction in adrenal stimulation, leading to decreased cortisol production. Glucocorticoid deficiency emerged as the primary mechanism of hyponatremia in this patient. During the 2-h of coronary diagnosis and treatment, the patient was anxious, had high blood pressure, and was in a severe stress state, which required additional cortisol to cope with. The specific amount could be evaluated by a specialist doctor. However, due to secondary adrenal insufficiency, the patient could not suddenly increase the secretion of glucocorticoids to copy with the stress. Additionally, glucocorticoids were not pre increased before the procedure. Therefore, the patient was at risk of acute and severe adrenal cortical hormone deficiency, leading to excessive sodium loss, water retention, and subsequent hyponatremia.

Treatment response

Despite intravenous supplementation of 24.05 g sodium chloride within 26 h, hyponatremia persisted, accompanied limb twitching and drowsiness, indicating an exacerbation of hyponatremia and the formation of hypotonic brain edema. Administration of 50 mg hydrocortisone effectively relieved excessive sodium excretion and water retention. Even with 6.25 g sodium chloride treatment, the patient's symptoms almost disappeared after 6 h, and blood sodium increased from 114.2 mmol/L to 132 mmol/L after 12 h. The subsequent increase in blood sodium levels highlights the importance of glucocorticoid replacement therapy in managing hyponatremia secondary to SHS.

Management considerations

The case underscores the importance of preoperative stress dose glucocorticoid therapy in SHS patients undergoing procedures such as PCI. However, we were unaware the importance. Additionally, awareness of the potential for contrast agents to induce dilutional hyponatremia and stress response caused by PCI is crucial. Lack of endocrinologist consultation before the procedure and inadequate patient education regarding adrenal insufficiency contributed to the suboptimal management of this patient. Inappropriately administered sublingual nifedipine treatment, intended to manage transient hypertension, not only increased the risk of acute cardiovascular and cerebrovascular disease, but also increased the risks of further activating the sympathetic nervous ( 11 ) and exacerbating stress. Therefore, the interdisciplinary management involving endocrinologists is crucial for optimizing the treatment for patients with complex endocrine disorders like SHS, facilitating appropriate examinations, treatment and health education to prevent adrenal crisis and improve long-term outcomes ( 12 , 13 ).

Prolonged limb twitching and sodium correction

Unlike the transient symptoms of epilepsy, the patient experienced persistent limb twitching for up to 18 h, possibly due to prolonged lower blood sodium levels. This prolonged imbalance could have led to sustained electrical instability in brain cells, resulting in repetitive abnormal electro-discharge and impaired brain function, posing significant risks to the patient. However, our approach to correcting hyponatremia may not have followed optimal guidelines. Our method of correcting hyponatremia may not have followed the best guidelines. The target value for increasing serum sodium was not set to not exceed 8–10 mmol/L/24 h ( 14 ). Our treatment rapidly increased the patient's blood sodium from 114 mmol/L to 132 mmol/L in 12 h, and then continued to supplement with hypertonic sodium chloride. Within 26 h after identifying hyponatremia, 24.05 g of sodium chloride was administered intravenously. These treatments are unreasonable, and the overly rapid correction of hyponatremia may be a risk factor for osmotic demyelination syndrome. Proper management should aim to increase blood sodium concentration gradually, with close monitoring to prevent such complications.

Other proposed mechanisms of hyponatremia

Contrast agents have been implicated in inducing hyponatremia, particularly in women ( 15 – 18 ). Following administration, the contrast agents elevate the osmotic pressure of extracellular fluid, leading to passive water transfer of intracellular to extracellular compartments and resultant diluted hyponatremia ( 15 , 16 ). Sweating caused by sympathetic nerve stimulation and sweating caused by adverse reactions to iodixanol injection may also contribute to sodium loss.

Role of hypothyroidism

The patient's thyroid hormone levels were low before and after the procedure, indicating the presence of secondary hypothyroidism. Hypothyroidism may have contributed to hyponatremia mainly through the reduced ability to excretal free water, caused by higher levels of ADH. The elevation in ADH levels is largely due to the decrease in cardiac output that stimulates the carotid sinus baroreceptors, prompting the release of ADH. In addition, hypothyroidism can promote hyaluronic acid deposition in extravascular tissues, leading to increased water retention and reduced blood volume. This not only reduces glomerular filtration, but also increases the secretion of antidiuretic hormone, thereby increasing the risk of diluted hyponatremia ( 19 – 22 ). Therefore, optimizing levothyroxine therapy to restore normal thyroid hormone levels may help mitigate the risk of hyponatremia in such cases.

SHS and coronary artery disease

Previous studies have indicated a higher mortality rate in patients with pituitary dysfunction, primarily attributed to cardiovascular diseases ( 23 – 25 ). Due to chronic inflammation, dyslipidemia, and abdominal obesity, patients with SHS tend to develop coronary artery disease (CAD) ( 26 ). This NSTEMI patient suffered from severe coronary atherosclerosis, with traditional risk factors including hypertension and hypercholesterolemia. Long-term oral administration of glucocorticoids may be associated with hypertension and hyperlipidemia in such patients ( 27 , 28 ). In addition, hypothyroidism, which is common in SHS, can also contribute to hyperlipidemia ( 29 ).

Although severe hyponatremia following PCI in SHS patients is not extensively reported, there are cases of female patients exhibiting life-threatening adrenal dysfunction post-PCI ( 30 , 31 ). The lowest blood sodium level in these cases is 122 mmol/L, and there is no hypoglycemia. Glucocorticoids have good therapeutic effects. The difference is that these patients exhibit significant hypotension, shock, and even Takotsubo syndrome ( 30 , 31 ).

Conclusions

The deficiency of glucocorticoids caused by secondary adrenal insufficiency is the primary mechanism for severe hyponatremia in this patient with SHS. The stress induced by PCI exacerbates glucocorticoid deficiency. The contrast agent further contributes to dilutional hyponatremia. The preoperative stress dose of glucocorticoid is crucial to avoid this complication. Glucocorticoids were crucial in correcting severe hyponatremia in this SHS patient with secondary adrenal insufficiency. Shortening the duration of PCI and minimizing the dosage of contrast agents may be beneficial for preventing severe hyponatremia. Meanwhile, it is also crucial for this SHS patient to receive interdisciplinary management involving endocrinologists before and after the procedure. Additionally, SHS may serve as a potential risk factor for CAD.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Ethics Committee of Liaocheng People's Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

JG: Data curation, Writing – review & editing. YW: Data curation, Formal Analysis, Investigation, Writing – original draft, Writing – review & editing, Software, Methodology, Project administration, Supervision. AZ: Writing – review & editing. HP: Writing – review & editing, Data curation. FW: Writing – review & editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article.

The work was supported by Shandong Province Traditional Chinese Medicine Science and Technology Development Plan Project (No. 20190906).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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27. Khan NA, Donatelli CV, Tonelli AR, Wiesen J, Ribeiro Neto ML, Sahoo D, et al. Toxicity risk from glucocorticoids in sarcoidosis patients. Respir Med . (2017) 132:9–14. doi: 10.1016/j.rmed.2017.09.003

28. Hemmer MC, Wierer M, Schachtrup K, Downes M, Hübner N, Evans RM, et al. E47 modulates hepatic glucocorticoid action. Nat Commun . (2019) 10(1):306. doi: 10.1038/s41467-018-08196-5

29. Matlock CL, Vanhoof AR, Rangrej SB, Rathore R. Comparison between levothyroxine and lifestyle intervention on subclinical hypothyroidism in women: a review. Cureus . (2023) 15(4):e38309. doi: 10.7759/cureus.38309

30. Kumar B, Kodliwadmath A, Singh A, Duggal B. Acute adrenal insufficiency as a mysterious cause of shock following percutaneous coronary intervention: a cardiologist’s nightmare. BMJ Case Rep . (2020) 13(3):e233585. doi: 10.1136/bcr-2019-233585

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Keywords: Sheehan’s syndrome, percutaneous coronary intervention, severe hyponatremia, glucocorticoid deficiency, stress, contrast agent, coronary atherosclerotic disease

Citation: Gao J, Wang Y, Zhang A, Pang H and Wang F (2024) Old woman with Sheehan's syndrome suffered severe hyponatremia following percutaneous coronary intervention: a case report and review of literature. Front. Cardiovasc. Med. 11:1353392. doi: 10.3389/fcvm.2024.1353392

Received: 15 December 2023; Accepted: 17 April 2024; Published: 29 April 2024.

Reviewed by:

© 2024 Gao, Wang, Zhang, Pang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yuehai Wang [email protected]

† These authors have contributed equally to this work

This article is part of the Research Topic

Case Reports in General Cardiovascular Medicine: 2023

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Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia

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A 44-year-old man presents with fever, abdominal pain, and fatigue. His physical examination shows splenomegaly. His laboratory results are as follows:

The patient is transfused several units of packed red blood cells without significant correction of his anemia, and instead, his pancytopenia worsens. Peripheral smear shows pancytopenia without blasts, tear drop cells, or dysplasia. A bone marrow biopsy demonstrates the following:

• Aplastic anemia
• Acute promyelocytic leukemia
• Myelofibrosis
• Hemophagocytic lymphohistiocytosis
• Myelodysplastic syndrome

Explanation

The most likely diagnosis is hemophagocytic lymphohistiocytosis (HLH). The patient fulfills at least five of the main nine diagnostic criteria of HLH including fever, splenomegaly, cytopenia, elevated ferritin, low fibrinogen, and evidence of hemophagcytosis on bone marrow, as demonstrated in the pictures that a histiocytes engulfing a nucleated red cell (Figure 1) and a neutrophil (Figure 2).

Myelofibrosis can be associated with splenomegaly, but is less likely here since no marrow fibrosis or tear drop cells reported. Myelodysplastic syndrome is a possible cause of pancytopenia, but no dysplasia was noted on peripheral smear or in the bone marrow. Acute promyelocytic leukemia can be associated with DIC and low fibrinogen on presentation, but should have a hypercellular bone marrow with predominance of promyelocytes. Patients with aplastic anemia are found to have profound hypocellular bone marrow, but no hemophagocytes should be found.

Case study submitted by Tzu-Fei Wang, MD, The Ohio State University, Columbus, OH

American Society of Hematology. (1). Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia .

American Society of Hematology. "Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia (label-accessed May 08, 2024).

"American Society of Hematology." Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia, 08 May. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia .

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Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study

• Emily L. Graul 1 ,
• Clementine Nordon 2 ,
• Kirsty Rhodes 2 ,
• Shruti Menon 3 ,
• Mahmoud Al Ammouri 1 ,
• Constantinos Kallis 1 ,
• Anne E. Ioannides 1 ,
• Hannah R. Whittaker 1 ,
• Nicholas S. Peters 4 &
• Jennifer K. Quint 1  

BMC Pulmonary Medicine volume  24 , Article number:  221 ( 2024 ) Cite this article

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An immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation.

We conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization.

Odds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45).

Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).

Conclusions

Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

Peer Review reports

Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are associated with an increased risk of cardiovascular disease (CVD) [ 1 ] likely due to linked pathophysiology, hypoxic state, and an amplified systemic inflammatory response [ 2 , 3 ]. Previous studies have demonstrated an increased, immediate period of risk for hospitalized cardiovascular events following a COPD exacerbation compared with non-exacerbating patients, [ 1 , 4 ] with the risk highest within the first month and following a severe (hospitalized) exacerbation [ 1 , 5 , 6 ]. The 30 day risk of arrhythmias and heart failure (HF) following an exacerbation, [ 6 , 7 , 8 ] approach [ 4 , 6 ] or even surpass [ 7 , 9 ] 3-fold, compared to those who did not have an exacerbation.

Globally, the prevalence of HF in COPD is high, [ 10 ] and, of patients hospitalized for exacerbation, 20% have existing, undertreated HF [ 11 ]. Incident HF attributed to exacerbations is thought to come from the increase in pulmonary arterial pressures, low blood oxygen levels [ 12 ] and activation of adrenoceptors of the autonomic nervous system [ 12 , 13 ]. However, shared symptomology of HF and COPD exacerbations makes new HF diagnosis difficult, with HF often missed [ 3 , 12 , 14 ] or occurring in tandem; approximately 8% of people primarily diagnosed with HF also have a secondary diagnosis of exacerbation [ 15 ]. Studies have investigated COPD progression in HF [ 12 ] and conversely, HF progression across COPD phenotypes, [ 12 , 16 ] but few have focused on exacerbating COPD alone [ 15 ] and no studies have examined factors associated with hospitalization with a HF diagnosis following a COPD exacerbation.

Arrhythmias are also common among people with COPD, with prevalence ranging from 5 to 15% globally, [ 10 ] and atrial fibrillation (AF) is the most common arrhythmia [ 17 ]. AF diagnoses at the time of an exacerbation are also common, with estimates around 17% [ 18 ], but due to shared, nonspecific symptoms between AF and COPD, differential diagnosis can be difficult [ 19 ]. During a COPD exacerbation, changes in blood gases from hypoxia and rising pulmonary pressure can lead to electrophysiological and structural changes of the atrium, and together are thought to contribute to exacerbation-related disturbances in rhythm and progression of AF [ 6 , 10 , 19 , 20 , 21 ] The understanding of COPD progression alongside AF progression is unclear [ 19 ]. Few studies have examined factors associated with hospitalization for incident AF after an exacerbation, with the focus on the short-term [ 21 , 22 ]. Several have however investigated factors associated with concurrent AF at time of an exacerbation [ 18 , 23 ].

Therefore, using a primary-care defined COPD cohort from the Clinical Practice Research Datalink (CPRD) Aurum database linked with hospital, mortality, and socioeconomic deprivation data, we explored factors associated with incident hospitalization for non-fatal HF, or AF or atrial flutter, within the 30 days following a COPD exacerbation.

Study design and methods

Data source.

We obtained pseudonymized, routinely-collected electronic healthcare record data from CPRD Aurum, [ 24 ] a primary care database broadly representative by age, sex, deprivation, and regional distribution, [ 25 ] and covering approximately 20% of GP-registered patients in England [ 24 ]. Primary care data from the May 2022 build [ 24 ] were linked to the Office for National Statistics (ONS) for mortality, socioeconomic data from the 2015 Index of Multiple Deprivation (IMD), and secondary care data from NHS England’s Hospital Episode Statistics (HES) Admitted Patient Care (APC) database.

Source population

The source population were people with a COPD diagnosis who had been included in the Exacerbations of COPD and their OutcomeS on CardioVascular diseases (EXACOS-CV) observational open cohort study [ 4 ]. People were eligible for inclusion in that original cohort study if they met the following criteria: 1) aged 40 years or older, 2) had a COPD diagnosis using a validated algorithm (86.5% PPV) [ 26 ] 3) were eligible for linkage with HES, ONS, and IMD data, 4) had a smoking history (i.e., current or ex-smoker), 5) had continuous GP practice registration with acceptable quality data in the year before start of follow up, and 6) had data recorded after 1 st of January 2014.

Study design and population

We conducted two nested-case control studies, in parallel. The study population for each study consisted of COPD patients in the EXACOS-CV source population, who 1) experienced an exacerbation within cohort follow-up, 2) among the pool of eligible controls had at least 30 days of contributing data post-exacerbation, and 3) had no evidence of HF or arrhythmias in the year before exacerbation. People were excluded from the AF/flutter study population if, within the 30 days post-exacerbation, they had evidence of other non-AF arrhythmias (e.g., cardiac arrest) (Fig. 1 for study designs; Supplementary Figures 1 and 2 for HF and AF/flutter eligibility diagram respectively).

Study design for the parallel, nested case control studies. Abbreviations: HF=heart failure, AF/f = atrial fibrillation/flutter, GP=general practice, CV=cardiovascular. Two nested case control studies, for HF and AF/f respectively, were conducted among all patients who experienced an exacerbation at start of cohort follow up. Full definitions of demographic and clinical factors of interest are in the Supplementary materials

Cases were individuals with a hospitalized, cardiovascular event (HF or AF/flutter, respectively) within 1-30 days post COPD exacerbation. Cases were determined in the HES database using ICD-10 codes in the primary diagnostic position across all episodes in a single hospitalization. The date of admission was the date of the case (index date, HF or AF/flutter, respectively). Extended case definitions are in Supplementary Table 3 .

The set of controls per case was drawn among individuals in the study population who had no in-hospital diagnosis of the cardiovascular event-of-interest (HF or AF/flutter, respectively) and who had 30 days of contributing data post-exacerbation. Controls were assigned a pseudo-end date (i.e., 30 days post-exacerbation) on which to match. Controls were individually matched to cases on GP practice to account for unmeasurable potential clinical differences in disease management by clinicians, within a 30-day window of the index date, and could be used as a control for more than one case. For the HF analysis, controls were matched 2:1 and for the AF/flutter analysis, 3:1.

The choice of matching factors and ratios were chosen based on considerations of 1) maximizing the ratio itself for reasons of power and precision while 2) minimizing cases lost without a full set of controls. Only case sets with the full ratio of controls per case were included for analysis.

We examined factors potentially associated with hospitalization for HF or AF/flutter in the 30 days following an exacerbation of COPD. Factors included demographic characteristics: age (categorized into four age bands; 40-69, 70-74, 75-79, ≥80), sex, IMD quintiles, and ethnicity; and smoking status. Comorbidities included (hypertension, anxiety, depression and depressive symptoms, type II diabetes, chronic kidney disease (CKD), BMI [body mass index; using World Health Organization classification]). COPD factors included GOLD grade of airflow limitation (defined as 1 mild, 2 moderate, 3-4 severe/very severe), Medical Research Council (MRC) dyspnea score (1-2; 3; 4-5), exacerbation severity at cohort entry (moderate/severe) prior exacerbation frequency (infrequent (≤1) versus frequent (≥2) history in a year window preceding one year to cohort entry). Prior CVD history was evidence of the following anytime preceding the year before exacerbation date [acute coronary syndrome (ACS), arrhythmias, HF, ischemic stroke, pulmonary hypertension PH], COPD inhaled therapies, and major classes of cardiovascular medications (prescriptions defined two years before cohort entry). Covariate definitions are in Supplementary Table 4 .

We used validated definitions for COPD exacerbations. A moderate exacerbation was defined as a COPD-related primary care (GP) visit with either a code for exacerbation (including Lower Respiratory Tract Infection (LRTI) SNOMED-CT codes) and/or prescription for respiratory antibiotics and oral systemic corticosteroids not on the same day as an annual review, as validated in CPRD [ 27 ]. A severe exacerbation was defined as a hospitalization with an acute respiratory event code including COPD or bronchitis as a primary diagnosis, or a secondary diagnosis of COPD, as validated in HES [ 28 ]. We considered exacerbations to be the same event if recorded within 14 days in which case the highest level of severity was chosen.

We checked covariate missingness to assess use in adjusted models. Imputation was not considered for covariates with missing data, given the missingness mechanism was Missing-Not-At-Random (MNAR), violating the Missing-Completely-At-Random (MCAR) assumption premising imputation [ 29 ].

Codelists for primary care factors were generated using SNOMED-CT and British National Formulary ontologies; we used our standardizable, reproducible methodology, available on GitHub: for drug [ 30 ] and medical/phenotype codelists , respectively. Codelists for hospitalizations used ICD-10 codes. Codelists are available on our EXACOS-CV GitHub repository .

Statistical analysis

We compared separately the odds of hospitalization for HF or AF/flutter between the comparator groups for each factor, using conditional logistic regression. Our final model was adjusted for all covariates without substantial amount of missing data, including demographic factors, comorbidities, and COPD inhaled therapies and cardiovascular medications. In three sensitivity analyses, we repeated main analyses additionally adjusting for variables-of-interest with substantial missing data, respectively: GOLD, MRC, and CKD.

Analyses were performed using STATA v17.

These data were collected and provided by CPRD. Ethical approval was obtained through CPRD’s Research Data Governance Process (protocol number: 22_002377). The RECORD checklist for observational studies is in Supplementary Table 5 .

Characteristics of study participants

The HF dataset consisted of 1,569 cases experiencing an HF event within the first 30 days post-exacerbation, matched to 3,138 controls. The AF/flutter dataset consisted of 841 cases experiencing an AF/flutter event within the first 30 days post-exacerbation, matched to 2,523 controls. Tables 1 and 2 show the characteristics of the participants for HF and AF/flutter, respectively.

Across both study populations, cases tended to have had a severe exacerbation, were more likely to be older, male, an ex-smoker, have comorbidities including prior prevalent cardiovascular disease, and be prescribed cardiovascular medications. Cases and controls both tended to have infrequent exacerbation history, have prescriptions for long-acting therapies, but tended to not have prescriptions for short-acting inhaled therapies.

Factors associated with HF hospitalization 1-30 days post exacerbation

Age, type II diabetes, obesity, prior HF diagnosis, prior arrhythmia diagnosis, having a severe exacerbation, and most cardiovascular medications were associated with increased odds of being hospitalized for HF within 30 days of a COPD exacerbation (Table 1 ). The factors most strongly associated with HF were exacerbation severity (aOR=6.25, 95%CI 5.10-7.66), a prior HF diagnosis (aOR=2.57, 95%CI 1.73-3.83), age at least 80 years (≥80 vs. 40-69; aOR=2.41, 95%CI 1.88-3.09), and, of the cardiovascular medications, diuretics (aOR=2.81, 95%CI 2.29-3.45).

In sensitivity analyses, GOLD grade, MRC score, and history of CKD were all associated with an increased odds of being hospitalized for HF within the month post exacerbation.(Supplementary Table 1 ) The strongest associations were for CKD (aOR=1.85, 95%CI 1.46-2.35) and higher levels of airflow limitation and breathlessness (GOLD grade 3-4 Severe/Very Severe aOR=1.83, 95%CI 1.32-2.54, versus GOLD grade 1 Mild) (Score 4-5 MRC aOR=1.87, 95%CI 1.42-2.46, versus MRC 1-2).

Factors associated with AF/flutter hospitalization 1-30 days post exacerbation

Age, male sex, prior arrhythmia, prior PH, and having a severe exacerbation were associated with AF/flutter in the 30 days following an exacerbation. Most cardiovascular medications were also associated with AF/flutter (Table 2 ). The factors most strongly associated with AF were exacerbation severity (aOR=5.78 95%CI 4.45-7.50), age ≥80 years (aOR=3.15 95%CI 2.26-4.40), prior arrhythmia and PH (aOR=3.55, 95%CI 2.53-4.98; aOR=3.05, 95%CI 1.21-7.68), and of the cardiovascular medications, anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).

In sensitivity analyses, GOLD grade, MRC score, and CKD had no association with AF/flutter (Supplementary Table 2 ).

In a primary care defined COPD population, this study examined the clinical profiles of people hospitalized for HF and for AF within a month post exacerbation. We observed that the odds of HF and of AF hospitalization were higher for people with severe, hospitalized exacerbations and with cardiovascular-related history. For HF analyses only, the odds of HF were also higher for people with microvascular factors (i.e., type II diabetes; obesity; CKD) and for people with pulmonary factors, namely those with worse GOLD grade of airflow limitation and higher levels of MRC breathlessness scores.

Heart failure

The pathophysiological links between COPD exacerbations and HF are recognized [ 31 , 32 , 33 ]. Upon exacerbation, dynamic lung hyperinflation from airflow limitation alongside heightened inflammation and hypoxia, can lead to increased strain on both the lungs and heart. The increased cardiopulmonary pressure can then lead to impaired contraction or filling of the left ventricle, namely HF with preserved or with reduced ejection fraction, respectively [ 31 , 32 , 33 ].

Few studies have investigated factors associated with HF in COPD alone, [ 15 , 34 , 35 , 36 ] of which only one [ 15 ] investigated hospitalized exacerbation with concurrent HF, but did not quantify this relationship with ORs, and was conducted in the US National Inpatient Sample (NIS) database. The remaining were post-hoc analyses of trials focused on stable COPD [ 34 , 35 , 36 ].

The strong magnitude of the association for exacerbation severity (hospitalization) but not for exacerbation frequency, suggests two points. First, from a healthcare service-level standpoint, patients hospitalized for exacerbations are more likely to be hospitalized for a future HF (i.e., re-admission) compared with patients whose exacerbation was managed in primary care. Second, clinically, exacerbation severity (e.g., greater intensity of inflammation) has a greater indication of a patients’ future cardiac state, rather than past exacerbation occurrence and management. Findings for older age were anticipated and align with previous studies [ 15 , 34 , 35 , 36 ].

The associations for history of HF, arrhythmia, type II diabetes, and CKD with post-exacerbation HF are unsurprising given their known independent relationships each with HF and exacerbations alone. Chronic, unmanaged HF can lead to future health service utilization for HF [ 16 , 37 ]. Arrhythmia-attributed cardiac remodeling can contribute to development of cardiomyopathy [ 38 ]. Diabetes is a risk factor for substantial HF progression [ 16 , 39 ], and separately a population-based study in COPD patients demonstrated an increased risk of cardiovascular mortality with type II diabetes [ 40 ]. Impaired renal hemodynamics and activation of the renin-angiotensin-aldosterone system (RAAS) can lead to HF, [ 41 ] and separately reduced kidney function is associated with future HF [ 42 ].

Our findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation HF hospitalization. The strongest association for diuretics suggests that leading up to future HF, patients perhaps are receiving treatment indicated for uncontrolled edema from existing HF, diabetic cardiomyopathy, or CKD for example.

GOLD and MRC as factors for post-exacerbation HF likewise were expected. Increased breathlessness and reduced lung function are not only symptoms of an imminent exacerbation or HF; equally, these factors can also indicate delayed diagnosis of unstable COPD or HF, [ 16 , 43 ] given their shared symptomology [ 3 , 12 , 14 ]. Reduced lung function can contribute to worsening prognosis and precipitate a future exacerbation or HF [ 16 , 43 ].

Atrial fibrillation

The pathophysiological mechanisms implicating AF post COPD exacerbation are also established [ 19 , 44 ]. At time of exacerbation, drastic increases in lung hyperinflation and impaired intrathoracic pressures can cause increased pulmonary vascular resistance and damage, leading to alterations to atrial electrophysiology [ 19 , 44 ]. Compromised gas exchange in the lungs can induce systemic inflammation and oxidative stress too, and also put strain on pulmonary vasculature, leading to abnormal atrial structure and ion-channel remodeling, [ 19 , 44 ] while certain treatments prescribed upon exacerbation are arrhythmogenic [ 19 , 44 ].

Only four studies have investigated patient profiles for AF development in unstable COPD, all hospital-based [ 18 , 21 , 22 , 23 ], of which two conducted in the US National Inpatient Sample (NIS) database [ 18 , 22 ]. Two examined factors associated with AF diagnosis after exacerbation [ 21 , 22 ] one of which patients had existing AF [ 21 ]. Two failed to quantify with ORs, only comparing baseline characteristics of exacerbating patients by status of concurrent AF [ 18 , 23 ].

Our findings for older age and male gender are not unexpected; studies similarly found these associations in exacerbating [ 18 , 22 ] and in stable COPD [ 45 ]. Unsurprisingly, exacerbation severity associated with future AF, again adding to the existing evidence of stronger associations for hospitalized exacerbation [ 1 , 6 ] and again, likewise to HF, suggests a distinction between healthcare service-level patient pathways, and intensity versus frequency.

The associations we found for history of PH and arrhythmias aligns with what was anticipated clinically. Electrophysiological and structural changes to the atrium over time, from either AF itself [ 20 ] or from chronic atrial stretching and fibrosis attributed to PH, [ 46 ] can lead to future AF. While a study using Euro Heart Survey data showed COPD as a factor for progression of paroxysmal to persistent AF (aOR=1.51, 95%CI 0.95-2.39) [ 20 ], neither of the two studies looking at patient profiles for post-exacerbation AF, looked at chronic, prevalent arrhythmias itself as a factor [ 21 , 22 ]. No studies have looked at PH, although the study among end-stage COPD patients in the NIS database found a weak association for pulmonary circulatory disorders (aOR=1.44, 95%CI 1.37-1.52) [ 22 ], compared the OR of about 3 for PH. A study found raised pulmonary artery pressure to be associated with AF (p<0.05), but failed to quantify, and it was small, underpowered, and not generalizable as it restricted to hospitalized COPD patients with existing AF [ 21 ].

The lack of associations for prior ACS, ischemic stroke, HF, and hypertension somewhat contradict the study among hospitalized, end-stage COPD patients, [ 22 ] where an association was found for HF (aOR=2.42; 95%CI: 2.36-2.48) and coagulopathy (aOR=1.23; 95%CI:1.16-1.31), but again this may reflect the more severe prognosis of these patients versus those in our study.

Likewise to HF, findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation AF hospitalization. Although we were unable to adjudicate by specific subtype of AF,(e.g., paroxysmal, persistent) the strongest associations for positive inotropes, anti-arrhythmic drugs, and anticoagulants may suggest that leading up to future AF, patients perhaps are receiving treatment to manage abnormal heart rate and/or rhythm, and/or to prevent clotting. Future research could investigate the respective treatment profile relative to paroxysmal AF and to persistent AF [ 47 ] to confirm and extend our findings.

Our null results for other comorbidities (i.e., depression and depressive symptoms, anxiety, BMI, CKD, and type-II diabetes) goes against studies finding an association for diabetes, [ 18 , 22 ] mixed findings for depression, [ 18 , 22 ] among other comorbidities. Yet these observed associations could be due to differing context; using the NIS database in a study population of only hospitalized, exacerbating, insured payors. GOLD airflow obstruction and MRC dyspnea score were not associated with post-exacerbation AF hospitalization, possibly as AF is often associated with vague symptoms of onset and not necessarily immediately thought about as a cause of increasing breathlessness in someone with COPD [ 44 , 48 , 49 ].

Methodological considerations

A key strength is our generalizable COPD cohort, defined within the electronic healthcare record with detailed data to examine and adjust for a range of factors. Unlike other studies, this allowed us to look at two patient pathways: cardiovascular-related hospitalizations post primary-care exacerbation, and re-admissions post hospitalized exacerbation. Our exclusion criteria allowed us to quantify the odds of new onset HF and AF hospitalizations following exacerbation, by ensuring no evidence of AF or HF in the year prior to exacerbation. We chose to study two common cardiovascular conditions in COPD, AF and HF. We could not subdivide HF and AF more granularly, because of insufficient statistical power and the inability to obtain electrocardiogram or echocardiogram results to adjudicate.

We used validated codes to define COPD [ 26 ] and COPD exacerbations [ 27 , 28 ] so misclassification is unlikely. Where possible, we used previously tested methods [ 30 ] and codes to define our factors-of-interest and codes were checked by a pulmonologist and/or cardiologist. The nested case control matched design allowed us to control for unmeasurable potential clinical differences in disease management by clinicians, by matching patients on GP practice.

To minimize selection bias among patients with measured factors only, we adjusted only for covariates without substantial missing data. We reserved GOLD, MRC, and CKD for sensitivity analyses; the associations of these factors with HF are generalizable only to patients with measurements (e.g., patients with greater healthcare monitoring, provision, or access). For this reason, the relationship for ethnicity could not be quantified, and given the data sparsity. For the HF analysis, we were unable to quantify B-type natriuretic peptide testing as a factor (BNP or NT-proBNP) because of 90% missing data for BNP (data not shown).

Confounding by indication is possible, particularly for the associations observed for cardiovascular medications (cases could have been more likely prescribed cardiovascular medications to manage a prevalent co-morbidity (perhaps with delayed diagnosis) that posed future cardiovascular risk, compared with controls) [ 50 ]. For example, although 12.8% of HF cases had prevalent HF diagnoses at baseline (201/1569), over 70% of HF cases were prescribed diuretics (1122/1569). Diuretics, particularly extended use of loop diuretics, can indicate possible, pre-HF diagnoses [ 51 ], given HF diagnoses tend to be delayed in COPD patients [ 14 , 37 , 51 ]. Taking this information together, this suggests a substantial proportion of cases could have been prescribed diuretics to manage possible-yet-undiagnosed HF, in which case, the later case-defining hospitalization was the delayed, first-time diagnosis of HF.

Our results for cardiovascular medications do not imply these medications are increasing the cardiovascular risk, rather they add to an understanding of the exacerbating patient profile. Furthermore, although these medications could indicate delayed CVD diagnosis, alternatively they could be medically indicated for management of a co-morbidity we did not adjust for, e.g., beta-blockers can be prescribed for thyroid conditions [ 52 ].

Implications for clinical practice

Within the month-window following an exacerbation, largely exacerbation intensity and cardiovascular-related management and disease history were associated with odds of incident HF and AF. For HF specifically, existing type II diabetes, CKD, lung function (GOLD grade), and levels of breathlessness (MRC) had an association too—but not for AF. These factors can help better identify patients most at-risk for HF and AF, to streamline efforts to allocate screening, vigilant monitoring, and prevention.

At the time of a COPD exacerbation, particularly hospitalized exacerbation, we recommend preemptively monitoring markers of possible HF, through taking medication history of loop diuretics, [ 51 ] and through BNP testing [ 53 ]. At present however, HF prevention is narrow in scope, with guidelines for early identification of HF not explicitly considering unstable COPD [ 53 , 54 ]. Our results suggest that HF monitoring should widen to include patients with COPD exacerbations.

Upon exacerbation, particularly hospitalized exacerbation, we recommend proactively screening for AF (e.g., electrocardiogram) [ 19 ] as AF commonly presents subclinically [ 17 ]. Still, at present, AF screening is narrow in scope; it is primarily conducted in patients with existing or suspected AF with the goal of preventing stroke, with AF guidelines not explicitly considering unstable COPD [ 17 , 55 ]. Our results suggest that AF screening should widen to include patients with COPD exacerbations, to help prevent future AF—even before stroke.

Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding risk factors will help to target people for prevention. Future studies with the intent of improving risk prediction for HF and AF should consider exacerbations of COPD.

Availability of data and materials

Data are available on request from the CPRD. Their provision requires the purchase of a license, and this license does not permit the authors to make them publicly available to all. This work used data from the CPRD Aurum version collected in May 2022 and have clearly specified the data selected within the Methods section, and linked data in the Supplementary Materials . To allow identical data to be obtained by others, via the purchase of a license, the code lists will be provided upon request. Licenses are available from the CPRD ( http://www.cprd.com ): The Clinical Practice Research Datalink Group, The Medicines and Healthcare products Regulatory Agency, 10 South Colonnade, Canary Wharf, London E14 4PU.

Abbreviations

Chronic Obstructive Pulmonary Disease

Clinical Practice Research Datalink

• Cardiovascular Disease

General practice

Hospital Episode Statistics

Index of Multiple Deprivation

Medical Research Council

• Heart Failure
• Atrial Fibrillation

Chronic Kidney Disease

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Acknowledgements

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the National Health Service (NHS) as part of their care and support. The interpretation and conclusions contained in this study are those of the author/s alone.

This study was funded by AstraZeneca UK. CN, KR, and SM of the funding source took part in initial conceptualization and protocol design and the interpretation of results.

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JQ takes responsibility for the content of the manuscript, including the data and analysis. EG, JQ, CN, KR, and SM conceptualized the study and designed the protocol. JQ, NP and EG contributed to the development of the codelists that defined the study variables. EG, CK contributed to the methodology. EG, HW, CK and AI accessed and verified the data. EG, CK and AI were responsible for data curation and management. EG, CK were responsible for formal analysis. EG wrote the original draft of the manuscript. EG, MA, JQ contributed to the literature review and clinical implications. All authors contributed and approved the final manuscript. All authors had final responsibility for the decision to submit for publication.

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CPRD has NHS Health Research Authority (HRA) Research Ethics Committee (REC) approval to allow the collection and release of anonymized primary care data for observational research [NHS HRA REC reference number: 05/MRE04/87]. Each year CPRD obtains Section 251 regulatory support through the HRA Confidentiality Advisory Group (CAG), to enable patient identifiers, without accompanying clinical data, to flow from CPRD contributing GP practices in England to NHS Digital, for the purposes of data linkage [CAG reference number: 21/CAG/0008]. The protocol for this research was approved by CPRD’s Research Data Governance (RDG) Process (protocol number: 22_002377 ) and the approved protocol is available upon request. Linked pseudonymized data was provided for this study by CPRD. Data is linked by NHS Digital, the statutory trusted third party for linking data, using identifiable data held only by NHS Digital. Select general practices consent to this process at a practice level with individual patients having the right to opt-out.

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JQ reports grants from GlaxoSmithKline, Health Data Research UK, MRC, Asthma+Lung UK, Bayer, BI, AZ and Chiesi, outside this work and AZ for the conduct of this study. JQ has received personal fees for advisory board participation, consultancy or speaking fees from GlaxoSmithKline, Evidera, AstraZeneca, and Insmed. CN, KR, and SM are employees of AZ and hold stock and/or options in the company. HW reports grants from Health Data Research UK outside the submitted work. EG, CK, AI, and MA have nothing to disclose.

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Graul, E.L., Nordon, C., Rhodes, K. et al. Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study. BMC Pulm Med 24 , 221 (2024). https://doi.org/10.1186/s12890-024-03035-4

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• Chronic Obstructive Pulmonary Disease Exacerbations
• Electronic Health Records
• Epidemiology

BMC Pulmonary Medicine

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Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium

• Maximilian Feth 1 ,
• Natasha Weaver 2 , 3 ,
• Robert B. Fanning 4 , 5 ,
• Sung-Min Cho 6 , 7 ,
• Matthew J. Griffee 8 , 9 ,
• Mauro Panigada 10 ,
• Akram M. Zaaqoq 11 ,
• Ahmed Labib 12 ,
• Glenn J. R. Whitman 6 ,
• Rakesh C. Arora 13 , 14 ,
• Bo S. Kim 6 ,
• Nicole White 2 ,
• Jacky Y. Suen 15 , 16 , 19 ,
• Gianluigi Li Bassi 15 , 17 , 18 , 19 ,
• Giles J. Peek 20 ,
• Roberto Lorusso 21 ,
• Heidi Dalton 22 ,
• John F. Fraser 15 , 16 , 17 , 18 , 19 ,
• Jonathon P. Fanning   ORCID: orcid.org/0000-0002-1675-0522 15 , 16 , 17 , 23 , 24 on behalf of

the COVID-19 Critical Care Consortium

Journal of Intensive Care volume  12 , Article number:  18 ( 2024 ) Cite this article

11 Accesses

3 Altmetric

Metrics details

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy in patients with severe acute respiratory distress syndrome (ARDS) secondary to COVID-19. While bleeding and thrombosis complicate ECMO, these events may also occur secondary to COVID-19. Data regarding bleeding and thrombotic events in COVID-19 patients on ECMO are sparse.

Using the COVID-19 Critical Care Consortium database, we conducted a retrospective analysis on adult patients with severe COVID-19 requiring ECMO, including centers globally from 01/2020 to 06/2022, to determine the risk of ICU mortality associated with the occurrence of bleeding and clotting disorders.

Among 1,248 COVID-19 patients receiving ECMO support in the registry, coagulation complications were reported in 469 cases (38%), among whom 252 (54%) experienced hemorrhagic complications, 165 (35%) thrombotic complications, and 52 (11%) both. The hazard ratio (HR) for Intensive Care Unit mortality was higher in those with hemorrhagic-only complications than those with neither complication (adjusted HR = 1.60, 95% CI 1.28–1.99, p  < 0.001). Death was reported in 617 of the 1248 (49.4%) with multiorgan failure ( n  = 257 of 617 [42%]), followed by respiratory failure ( n  = 130 of 617 [21%]) and septic shock [ n  = 55 of 617 (8.9%)] the leading causes.

Conclusions

Coagulation disorders are frequent in COVID-19 ARDS patients receiving ECMO. Bleeding events contribute substantially to mortality in this cohort. However, this risk may be lower than previously reported in single-nation studies or early case reports.

Trial registration ACTRN12620000421932 ( https://covid19.cochrane.org/studies/crs-13513201 ).

Clinical Perspective

Coagulation disorders such as thrombotic or hemorrhagic events are frequent in COVID-19 ARDS patients receiving ECMO.

While older age, pre-existing cardiac disease, and diabetes were independently associated with bleeding, prone positioning and a longer time from admission to ECMO were associated with a higher percentage of thrombotic events.

A longer duration of ECMO was linked to an increased rate of combined hemorrhagic and thrombotic events.

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary support technique that can be lifesaving in patients suffering from severe respiratory and/or circulatory failure [ 1 , 2 , 3 ]. However, ECMO exposes patients to complications such as bleeding and thrombosis [ 4 , 5 , 6 ]. Coagulation disorders in critically ill patients supported with ECMO result from a complex interplay between the underlying illness and both ECMO-related (e.g., shear stress, artificial circuit surface–blood interaction) and iatrogenic factors (e.g., systemic anticoagulation) [ 7 , 8 , 9 ]. These complications are associated with increased morbidity and mortality [ 5 , 10 ]. However, the mechanisms behind coagulation disorders during ECMO are not yet fully understood, and prevention strategies are lacking.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease-2019 (COVID-19), can result in acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission and advanced respiratory failure management [ 11 , 12 ]. Despite optimal medical management, including mechanical ventilation and prone positioning, mortality and morbidity rates due to refractory respiratory failure among these patients are high [ 13 , 14 ]. A rescue therapy in these patients is ECMO [ 15 , 16 ]. The mechanisms and clinical implications of thrombotic and hemorrhagic events in COVID-19 patients supported with ECMO are areas of ongoing research. This study aimed to define the global frequency, outcomes of, and risk factors for thrombotic and hemorrhagic disorders in COVID-19 patients with refractory ARDS supported with ECMO.

All data for this study were extracted from the global COVID-19 Critical Care Consortium (CCCC) prospective database, which was established to collect and analyze data on patients admitted to intensive care units for the treatment of severe COVID-19 [ 17 ]. The rationale and design have been previously published (Trial registration ACTRN12620000421932) [ 17 ]. Institutional Review Board (IRB) approval was obtained for each participating institution. A waiver of informed consent was granted for all patients. Additional file 1 : Table S1 summarizes all the recruiting sites, including IRB approvals, contributors, and collaborators.

The CCCC database was examined for patients referred to the ICUs of 229 collaborating institutions spanning 32 countries, from January 1, 2020, through June 30, 2022. Patients who satisfied all the following criteria were entered into the registry: (1) age ≥ 16 years; (2) COVID-19 pneumonia with laboratory confirmation (real-time PCR and/ or next-generation sequencing); and (3) admission to ICU due to severe COVID-19 pneumonia. Patients admitted to critical care for conditions unrelated to COVID-19 were excluded.

Data were collected from ICU admission to either in-hospital death or hospital discharge. Data collection followed guidelines for the International Severe Acute Respiratory IncideNce sTudy of Severe Acute and Emerging Infection Consortium (ISARIC), Short-Period Incidence Study for Severe Acute Respiratory Infection (SPRINT-SARI), and the CCCC. All data obtained were de-identified and stored at a Research Electronic Data Capture (REDCap) database hosted at one of the following institutions: Oxford University, United Kingdom; University College Dublin, Ireland; or Monash University, Australia.

According to the ISARIC and the Extracorporeal Membrane Oxygenation for 2019 novel Coronavirus Acute Respiratory Distress Disease (ECMOCARD study) case report forms (CRF), adverse coagulation events included (1) thrombotic events including ischemic stroke, myocardial ischemia, myocardial infarction, deep vein thrombosis (DVT), and pulmonary embolism (PE); (2) hemorrhagic events were classified according to the bleeding site or the two predominant bleeding sources, in cases involving multiple bleeding sites; and (3) disseminated intravascular coagulation (DIC). Adverse coagulation events were diagnosed by treating physicians. The study focused on the following four patient groups treated with ECMO: (1) patients without hemorrhage or thrombosis (controls); (2) patients with both a hemorrhagic and thrombotic event; (3) patients with a hemorrhagic event only; and (4) patients with a thrombotic event only.

The study's primary outcome was mortality in COVID-19 patients supported with ECMO who suffered thrombotic and bleeding events. Secondary outcomes were the incidence of thrombotic and bleeding complications and the duration of ICU requirement (days). Additionally, we investigated risk factors for hemorrhagic or thrombotic events in COVID-19 patients on ECMO. Laboratory assessments were obtained according to the CRFs. ‘First value’ refers to a specific parameter's first recorded value in the CRFs. Minimum and maximum values are the minimum/maximum level of a parameter from enrolling in the study throughout the follow-up period.

Statistical analysis

The study cohort was limited to patients who were treated with ECMO. Patients without thrombotic or hemorrhagic complications were compared to the following subgroups: patients with a hemorrhagic event only, a thrombotic event only, or a combination of hemorrhagic and thrombotic events. Demographic characteristics, medical history, critical care treatment, and outcomes were described and checked for missing data (Additional file 1 : Table S2). Continuous data were summarized as mean with standard deviation or median with interquartile range. Categorical variables were summarized as frequency count and percentage. Differences between groups were evaluated using Pearson's chi-squared test for categorical variables and the Wilcoxon–Mann–Whitney U test for continuous variables.

Survival analysis was used to estimate the effect of coagulation complications (combined and for thrombotic and hemorrhagic complications separately) on the time between ICU admission and mortality. The survival analysis cohort was limited to patients with non-missing discharge status and a valid ICU discharge date. The effect of coagulation complications on the instantaneous mortality hazard was estimated using Cox regression, assuming patients ‘discharged alive’ (alive, home, palliative care, hospitalized, or transferred to another facility) were censored independently. The proportional hazards assumption was verified with log–log plots and a test of Schoenfeld residuals. Parametric Weibull regression also was performed as a sensitivity analysis. Each survival analysis method was used to produce crude estimates and estimates adjusted a priori for patient age, sex, body mass index (BMI), and country of hospitalization. Due to a large proportion of missing BMI data, all analyses were repeated without adjusting for BMI. Regression results were presented as hazard ratios with 95% confidence intervals and p values.

Analysis was performed in SAS 9.4 (SAS Institute Inc., Cary, NC, USA), apart from survival analyses performed in Stata 15 (StataCorp, College Station, TX, USA).

During the study period, 1,248 patients receiving VV- or VA-ECMO support due to COVID-19-related critical illness were included in the CCCC database. Table 1 summarizes baseline patient characteristics, including pre-existing health and management conditions. A hemorrhagic or thrombotic event was documented in 469 (38%). Among these 469 patients, 52 (11%) experienced at least one hemorrhagic and one thrombotic complication, while 252 (54%) patients experienced a hemorrhagic event only and 165 (35%) a thrombotic event only (Fig.  1 ),

Study Cohort, Flow Chart. CCCC Covid Critical Care Consortium, ECMO extracorporeal membrane oxygenation

Outcomes and causes of death

The adjusted hazard ratio (HR) for ICU mortality was higher among patients who experienced only a hemorrhagic complication than in patients who had neither type of complication (adjusted HR = 1.60, 95% CI 1.28–1.99, p  < 0.001, Table  2 ). No statistically significant differences in ICU mortality were observed in patients with both types of complication (adjusted HR = 1.02, 95% CI 0.67–1.57, p  = 0.918) or thrombotic events only (adjusted HR 0.79, 95% CI 0.59–1.05, p  = 0.103) relative to patients with neither type of complication. Figure  2 depicts the survival of COVID-19 patients supported with ECMO over time in the four study groups.

Kaplan–Meier Curve comparing patients with a thrombotic event, a hemorrhagic event, both events and neither event. NB Log rank test for equality of survivor functions p  < 0.0001

The length of stay (days) within the ICU was longer for patients with both types of complication (42.0 days, 27.5–52.5, p  = 0.009) and for those with a thrombotic event only (37.0 days, 24.0–57.0, p  = 0.010) than in patients with neither type of complication (30.0 days, 17.0–52.0). Hospital length of stay was longer for those with both types of complication (45.0 days, 29.0–72.0, p  = 0.017) and those with thrombotic events (44.0 days, 26.0–69.0, p  = 0.003), but shorter among those with hemorrhagic events (28.0 days, 14.0–50.0, p  = 0.001) compared to patients with neither type of complication (35.0 days, 19.0–59.0).

Overall, 617 of 1248 patients (49.4%) died in the ICU. The leading cause of death was multiorgan failure (257, 42%), followed by respiratory failure (130, 21%) and septic shock (55, 8.9%) (Table  3 ).

Coagulation complications (Table  4 )

Thrombotic complications were documented in 217 (17.4%) of the 1248 patients with pulmonary embolism being the most common ( n  = 86 or 39.6%). Hemorrhagic complications occurred in 304 (24%) of all patients with the most common source being gastrointestinal (112, 36.8%). Note that bleeding severity was not part of the case report forms and, therefore, cannot be commented on.

The most common anticoagulation prophylaxis method was unfractionated heparin (UFH), followed by low molecular weight heparin (LMWH). Other anticoagulation strategies were rarely used (Table  5 ). Table 6 summarizes laboratory assessments.

Advanced ARDS management and ECMO

Clinical management of COVID-19 patients supported with ECMO is shown in Table  5 , while Additional file 1 : Table S3 provides ECMO specific data. Prone positioning during mechanical ventilation was more common in patients with thrombotic events than in controls (111, 81% vs. 354, 69%, p  = 0.006). Furthermore, in patients with both types of complication (36/52, 71%, p  = 0.004) as well as in patients with just a thrombotic event (112/165, 69%, p  < 0.001), tracheostomy was more commonly performed than in controls (289/779, 50%).

Most patients received venovenous (864, 93.8%) rather than venoarterial ECMO (57, 6.2%). Time to admission for ECMO was statistically longer for patients with thrombotic events than in controls ( p  = 0.043). Duration of ECMO support also was statistically longer among patients with both complication types ( p  = 0.015). Maximum and mean daily ECMO blood flow was significantly less in patients with only thrombotic events than in patients with either hemorrhage events only, as well as among those with either, both, or neither type of complication (maximum daily blood flow p  = 0.010, mean daily blood flow rate p  = 0.015). However, there was no statistically significant difference in mean daily blood flow rates once adjusted for patient body weight. Circuit changes were most frequent in patients with both types of complications (26%), followed by those with hemorrhage complications (22%) and those with neither type of complication (16%). The incidence of any circuit change was the least frequent in patients with a thrombotic event (12%).

When considering venovenous ECMO only, we found a higher adjusted HR for ICU mortality for patients with hemorrhagic complications (adjusted HR 1.42, 95% CI 1.10–1.84, p  = 0.008) compared to those without either type of complication. In contrast to the entire cohort, we observed a statistically significant reduction in HR for ICU mortality for venovenous ECMO patients with thrombotic complications only (HR, 0.64, 95% CI 0.46–0.89, p  = 0.008) compared to venovenous ECMO patients without either type of complication (Table  2 ).

International comparison

This study involved participants mainly from the United States ( n  = 354), Colombia ( n  = 215), Spain ( n  = 140), Italy ( n  = 140), Kuwait ( n  = 126) and Australia ( n  = 12). Mortality was highest in Italy (64%), lowest in Australia (33%), and comparable (47–56%) among the other countries. However, ICU length of stay was not significantly different between regions. Table 7 summarizes further parameters by the host nation.

In this international registry, we found that coagulation-related complications occurred in 38% of patients with severe COVID-19 requiring ECMO (hemorrhagic 20.2%; thrombotic 13.2%, and both < 5%). Hemorrhagic events were associated with increased mortality, whereas thrombotic events, alone or combined with hemorrhagic events, did not significantly impact mortality. In a recent study by Mansour et al., 66% of 620 critically ill COVID-19 patients receiving ECMO in France experienced coagulation disorders: 29% had bleeding, 16% thrombotic events, and 20% had both. Compared to this French cohort, our global CCCC study observed a lower incidence of bleeding and combined complications, with thrombotic events being comparable (13.2 vs. 16%). Differences in the choice of anticoagulant agent and/or the therapeutic target level might have contributed to the lower rate of bleeding events we observed in CCCC registry patients. Another potential explanation for the difference in the incidence of bleeding events might be how bleeding events were defined and captured. Nevertheless, both our study and that of Mansour et al. identified an association between coagulation disorders and increased mortality.

Within our population, those experiencing only hemorrhagic but not thrombotic event (alone or in combination) experienced a greater hazard of ICU mortality. This might be due to the high rates of mortality associated with certain types of bleeding, such as intracranial hemorrhage and severe bleeding requiring massive transfusion. Our finding of a reduced hazard of ICU mortality for patients experiencing thrombotic events contrasts with the reports of patients requiring ECMO due to non-Covid-19 conditions who undergo thrombosis. This might either be due to the differences of prothrombotic tendencies of different COVID-19 phenotypes or to the already increased risk of thrombosis resulting from prolonged critical care. Unfortunately, due to missing data, we could not adjust our survival analysis for other factors that might have contributed to mortality in this group. Therefore, though hypothesis generating, our mortality findings should be interpreted with caution.

In our cohort, multi-organ as well as respiratory failure and septic shock were the leading causes of death. This mirrors results reported by Peek et al. in 2009, who found that multi-organ failure accounted for 42% of the deaths in patients treated with ECMO [ 18 ]. Death due to hemorrhagic shock or cerebrovascular events was rare, even though bleeding was identified as a risk factor for mortality. Ischemic stroke and cerebrovascular accidents, generally considered frequent causes of permanent impairment after ECMO, occurred in nine patients in our study (4.1% among patients with a thrombotic event and 0.72% of the entire cohort), which is comparable to the incidence of stroke in a non-COVID ECMO group investigated in the EOLIA trial [ 2 ].

Our study identified several factors independently associated with coagulation disorders: older age, pre-existing cardiac disease, and diabetes were associated with bleeding events, while White ethnicity was associated with an increased risk of all coagulation disorders. Extended ECMO duration was associated with an increased incidence of bleeding but not thrombotic events, diverging from past reports in both in COVID and non-COVID patient populations. Longer mechanical ventilation was associated with both thrombotic and combined complications, but not with bleeding events alone. Both prone positioning during mechanical ventilation and longer time from admission to ECMO were associated with a higher incidence of thrombotic events. This aligns with Gebhard et al.’s 2021 study, which found extended prone positioning increased DVT risk in a small cohort [ 19 ]. These findings suggest a need for vigilance and close monitoring for thrombosis in ECMO patients undergoing prone positioning, awaiting further studies to clarify this relationship.

Subcutaneous administration of anticoagulation was associated with thrombotic complications (both combined and individual), suggesting that this route might not be suitable for preventing thrombosis in COVID-19 ECMO patients. This finding contrasts with Wiegele et al.’s single-center study, where ECMO patients treated with subcutaneous enoxaparin experienced fewer thrombotic or major bleeding events than those receiving unfractionated heparin [ 20 ].

Blood product transfusion was frequent in patients with either or both complications. Transfusion of packed red blood cells was independently associated with both forms of complication (alone or combined). However, platelets, fresh frozen plasma, and cryoprecipitate transfusions occurred more in patients with bleeding events, regardless of whether they were combined with thrombotic complications, but not in patients with only thrombotic events.

Strengths and limitations

This study has several limitations, including missing data and the retrospective nature of data extraction. Despite using standardized case report forms to minimize variations in data reporting, data entry depended on the discretion of physicians and research staff at each participating center and consequently, data completeness was heterogeneous. In addition, variability in ECMO and critical care management across centers, coupled with the voluntary nature of site participation, may have skewed representation to those with sufficient resources to enter the data. This variability hinders the precise assessment of potentially outcome-impacting factors such as the anticoagulation practices and ECMO management protocols.

On the other hand, extensive international collaboration offers valuable insights into thrombotic and bleeding events in COVID-19 ECMO patients globally. The pandemic’s evolving nature and the consequent adaptations in patient management strategies across different COVID waves add complexity to our analysis, particularly as our data collection tools could not be updated to reflect these changes, omitting potentially significant factors like immunomodulatory treatments and vaccination impacts on thrombotic and hemorrhagic complications. Additionally, the case report forms did not define bleeding severity, which might have led to heterogeneous reporting of bleeding events.

Notably, our study found no link between thrombotic events and mortality, possibly due to the lack of a detailed thrombosis severity assessment and the inclusion of minor thrombotic events. Future research should aim for clear definitions and severity grading of hemorrhagic and thrombotic events to enhance understanding and management of these complications.

In an international registry for critically ill COVID-19 patients receiving ECMO, the incidence of bleeding and thrombotic complications were high, albeit lower than previously reported. Bleeding significantly elevated mortality risk, with multi-organ failure and sepsis as the primary causes of death. Factors such as older age and White ethnicity were associated with an increased incidence of bleeding. Extended ECMO duration corresponded with higher bleeding rates but did not affect the occurrence of thrombotic events.

Availability of data and materials

The datasets used and/ or analyzed during the current study are available from the corresponding author in reasonable request.

Abbreviations

Acute respiratory distress syndrome

Body mass index

COVID critical care consortium

Disseminated intravascular coagulation

Deep vein thrombosis

• Extracorporeal membrane oxygenation

Intensive care unit

International severe acute respiratory and emerging infection consortium

Low molecular weight heparin

Polymerase chain reaction

Pulmonary embolism

Research electronic data capture

Severe acute respiratory syndrome coronavirus 2

Short-period incidence study of severe acute respiratory infection

Unfractionated heparin

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Acknowledgements

We recognize the crucial importance of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) and Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) networks in developing and expanding the global Coronavirus Disease 2019 Critical Care Consortium (COVID-19– CCC). We thank the generous support we received from the Extracorporeal Life Support Organization and the International Extracorporeal Membrane Oxygenation Network. We owe Li Wenliang, MD from the Wuhan Central Hospital, an eternal debt of gratitude for reminding the world that doctors should never be censored during a pandemic. Finally, we acknowledge all members of the COVID-19–CCC and various collaborators.

Steering Committee

Gianluigi Li Bassi MD 1,3, 4,5, 7, 8 , PhD; Jacky Y. Suen BSc 1, 2 , PhD; Heidi J. Dalton MD, MCCM 9 ; John Laffey, MA, MD 10 ; Daniel Brodie, MD 11 ; Eddy Fan, MD, PhD 12 ; Antoni Torres, MD, PhD, FERS ATS Fellow 4, 13 36 37 ; Davide Chiumello, MD 14 ; Alyaa Elhazmi 15 ; Carol Hodgson, PT, PhD 16,31 ; Shingo Ichiba, MD 17 ; Carlos Luna, MD18; Srinivas Murthy, MD 19 ; Alistair Nichol, MD, PhD 16, 21,31 ; Pauline Yeung Ng, MD 22 ; Mark Ogino, MD 23 ; Eva Marwali, MD, PhD 35 ; Giacomo Grasselli MD 33, 34 , PhD; Robert Bartlett, MD 25 ; Aidan Burrell, MBBS, PhD 26,27 ; Muhammed Elhadi MBBCh 38 ; Anna Motos 39,40 ; Ferran Barbé MD, PhD 41,42 ; Alberto Zanella MD 33 ; and John F. Fraser MBChB, PhD, FRCP(Glas), FFARCSI, FRCA, FCICM 1, 3, 5, 7, 8 on behalf of the COVID-19 Critical Care Consortium.

Affiliations

1. Critical Care Research Group, The Prince Charles Hospital, Brisbane, Australia

2. Faculty of Medicine, The University of Queensland, Brisbane, Australia

3. University of Queensland, Brisbane, Australia

4. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

5. Queensland University of Technology, Brisbane, Australia

6. School of Public Health, Queensland University of Technology, Brisbane, Australia

7. St Andrew’s War Memorial Hospital, UnitingCare Hospitals, Brisbane Australia

8. Wesley Medical Research, Brisbane, Australia

9. INOVA Fairfax Medical Center, Heart and Vascular Institute, Falls Church VA, USA

10. Anaesthesia and Intensive Care Medicine, Galway University Hospitals, and School of Medicine, National University of Ireland, Galway, Ireland

11. Department of Medicine, Columbia University College of Physicians and Surgeons, New York-Presbyterian Hospital, NY, NY, USA

12. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada

13. Servei de Pneumologia. Hospital Clinic de Barcelona, Barcelona, Spain

14. Ospedale San Paolo, Milan, Italy

15. Dr. Sulaiman Alhabib Medical Group—Research Center, Riyadh, Saudi Arabia

16. Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health, Monash University, Melbourne, Australia

17. Department of Clinical Engineering / Department of Intensive Care Medicine, Tokyo Women’s Medical University Hospital, Japan

18. División Neumonología, Hospital de Clínicas, UBA, Buenos Aires, Argentina

19. Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada

20. Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health, Monash University, Melbourne, Australia

21. University College Dublin-Clinical Research Centre at St Vincent’s University Hospital, Dublin

22. Division of Respiratory and Critical Care Medicine, The University of Hong Kong, Hong Kong, China

23. Nemours Alfred I duPont Hospital for Children, Wilmington, DE, USA

24. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

25. University of Michigan Medical Center, Ann Arbor, Michigan, USA

26. Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

27. Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, VIC, Australia.

28. Australian Centre for Health Services Innovation (AusHSI) and Centre for Healthcare Transformation, School of Public Health & Social Work, Queensland University of Technology (QUT), Brisbane, Queensland, Australia

29. Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

30. ISARIC, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK

31. Department of Physiotherapy, Alfred Hospital, Melbourne, Australia

32. Department of Intensive Care, Alfred Hospital, Melbourne, Australia

33. Department of Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

34. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

35. National Cardiovascular Center Harapan Kita, Jakarta, Indonesia

36. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

37. Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid, Spain

38. Faculty of Medicine, University of Tripoli, Tripoli, Libya

39. Centro de Investigación Biomedica En Red—Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

40. Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Universitat de Barcelona, Barcelona, Spain.

41. Translational Research in Respiratory Medicine, Respiratory Dept, Hospital Universitari Aranu de Vilanova and Santa Maria; IRBLleida, Lleida, Spain.

42. Centro de Investigación Biomedica En Red—Enfermedades Respiratorias (CIBERES), Barcelona, Spain

43. School of Medicine, Griffith University, Brisbane, Australia

The Bill & Melinda Gates Foundation, Grant number INV-034765; Queensland Health; The Prince Charles Hospital Foundation; The Wesley Medical Research; Fisher & Paykel Healthcare; The University of Queensland; The Health Research Board of Ireland. Jacky Y Suen is funded by the Advance Queensland fellowship program, Queensland Government, Australia. Gianluigi Li Bassi is a recipient of the BITRECS fellowship; the “BITRECS” project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 754550 and from the “La Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN18/50310006.

Author information

Authors and affiliations.

Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain Medicine, German Armed Forces Hospital Ulm, Ulm, Germany

Maximilian Feth

Queensland University of Technology, Brisbane, QLD, Australia

Natasha Weaver & Nicole White

School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia

Natasha Weaver

St. Vincent’s Hospital, Melbourne, VIC, Australia

Robert B. Fanning

Faculty of Medicine, University of Melbourne, Victoria, Australia

Division of Cardiac Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

Sung-Min Cho, Glenn J. R. Whitman & Bo S. Kim

Division of Neuroscience Critical Care, Department of Neurology and Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

Sung-Min Cho

Department of Anesthesiology and Perioperative Medicine, Sections of Critical Care and Perioperative Echocardiography, University of Utah, Salt Lake City, UT, USA

Matthew J. Griffee

Anesthesiology Service, Veteran Affairs Medical Center, Salt Lake City, UT, USA

Department of Anesthesia, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Di Milano, Intensive Care and Emergency, Milano, Lombardia, Italy

Mauro Panigada

Department of Anaesthesiology, Division of Critical Care Medicine, University of Virginia, Charlottesville, VA, USA

Akram M. Zaaqoq

Medical Intensive Care Unit, Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar

Ahmed Labib

Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

Rakesh C. Arora

Case Western Reserve University School of Medicine, Cleveland, OH, USA

Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, ChermsideBrisbane, QLD, 4032, Australia

Jacky Y. Suen, Gianluigi Li Bassi, John F. Fraser & Jonathon P. Fanning

Faculty of Medicine, University of Queensland, Brisbane, Australia

Jacky Y. Suen, John F. Fraser & Jonathon P. Fanning

Intensive Care Unit, St Andrew’s War Memorial Hospital, UnitingCare Health, Spring Hill, QLD, Australia

Gianluigi Li Bassi, John F. Fraser & Jonathon P. Fanning

Intensive Care Unit, The Wesley Hospital, UnitingCare Health, Auchenflower, QLD, Australia

Gianluigi Li Bassi & John F. Fraser

Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia

Jacky Y. Suen, Gianluigi Li Bassi & John F. Fraser

Congenital Heart Centre, University of Florida, Gainesville, FL, USA

Giles J. Peek

Cardiothoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, and Cardiovascular Research Institute Maastricht, Maastricht, Netherlands

Roberto Lorusso

Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA, USA

Heidi Dalton

Nuffield Department of Population Health, University of Oxford, Oxford, UK

Jonathon P. Fanning

The George Institute for Global Health, Sydney, NSW, Australia

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• Gianluigi Li Bassi
• , Jacky Y. Suen
• , Heidi J. Dalton
• , John Laffey
• , Daniel Brodie
• , Antoni Torres
• , Davide Chiumello
• , Alyaa Elhazmi
• , Carol Hodgson
• , Shingo Ichiba
• , Carlos Luna
• , Srinivas Murthy
• , Alistair Nichol
• , Pauline Yeung Ng
• , Mark Ogino
• , Eva Marwali
• , Giacomo Grasselli
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• , Anna Motos
• , Ferran Barbé
• , Alberto Zanella
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Contributions

Study concept and design: Jonathon P. Fanning, Maximilian Feth, Gianluigi Li Bassi, Jacky Y. Suen, John F. Fraser, Acquisition, analysis, or interpretation of data: Maximilian Feth, Jonathon P. Fanning, Robert B. Fanning, Natasha Weaver Statistical analysis: Natasha Weaver, Nicole White Tables and figures: Natasha Weaver, Maximilian Feth, Jonathon P. Fanning, First drafting of the manuscript: Maximilian Feth, Jonathon Fanning. Critical revision for important intellectual content and final approval of the manuscript: Maximilian Feth, Jonathon P. Fanning, Natasha Weaver, Robert B. Fanning, Matthew J. Griffee, MD, Sung-Min Cho, Mauro Panigada, Akram M. Zaaqoq, Yew Woon Chia, Bingwen Eugene Fan, Davide Chiumello, Silvia Coppola, Ahmed Labib, Glenn JR Whitman, Rakesh C. Arora, Bo S. Kim, Anna Motos, Nicole White, Jacky Suen, Gianluigi Li Bassi, Roberto Lorusso, John F. Fraser, Giles J. Peek, Heidi Dalton. Guarantors: Maximilian Feth, Jonathon P. Fanning.

Corresponding author

Correspondence to Jonathon P. Fanning .

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Feth, M., Weaver, N., Fanning, R.B. et al. Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium. j intensive care 12 , 18 (2024). https://doi.org/10.1186/s40560-024-00726-2

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Houston’s flood problems offer lessons for cities trying to adapt to a changing climate

Professor Emeritus of Climate and Space Sciences and Engineering, University of Michigan

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Richard Rood receives funding from the National Oceanographic and Atmospheric Administration and the National Science Foundation. He is a co-principal investigator at the Great Lakes Integrated Sciences and Assessment Center at the University of Michigan.

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Scenes from the Houston area looked like the aftermath of a hurricane in early May after a series of powerful storms flooded highways and neighborhoods and sent rivers over their banks north of the city.

Hundreds of people had to be rescued from homes, rooftops and cars, according to The Associated Press. Huntsville registered nearly 20 inches of rain from April 29 to May 4, 2024.

Floods are complex events, and they are about more than just heavy rain. Each community has its own unique geography and climate that can exacerbate flooding. On top of those risks, extreme downpours are becoming more common as global temperatures rise.

I work with a center at the University of Michigan that helps communities turn climate knowledge into projects that can reduce the harm of future climate disasters. Flooding events like the Houston area experienced provide case studies that can help cities everywhere manage the increasing risk.

Flood risks are rising

The first thing recent floods tell us is that the climate is changing.

In the past, it might have made sense to consider a flood a rare and random event – communities could just build back. But the statistical distribution of weather events and natural disasters is shifting.

What might have been a 1-in-500-years event may become a 1-in-100-years event , on the way to becoming a 1-in-50-years event. When Hurricane Harvey hit Texas in 2017, it delivered Houston’s third 500-year flood in the span of three years.

Basic physics points to the rising risks: Global greenhouse gas emissions are increasing global average temperatures. Warming leads to increasing precipitation and more intense downpours, and increased flood potential, particularly when storms hit on already saturated ground.

Communities aren’t prepared

Recent floods are also revealing vulnerabilities in how communities are designed and managed.

Pavement is a major contributor to urban flooding, because water cannot be absorbed and it runs off quickly. The Houston area’s frequent flooding illustrates the risks. Its impervious surfaces expanded by 386 square miles between 1997 and 2017, according to data collected by Rice University . More streets, parking lots and buildings meant more standing water with fewer places for rainwater to sink in.

If the infrastructure is well designed and maintained, flood damage can be greatly reduced. However, increasingly, researchers have found that the engineering specifications for drainage pipes and other infrastructure are no longer adequate to handle the increasing severity of storms and amounts of precipitation. This can lead to roads being washed out and communities being cut off . Failures in maintaining infrastructure, such as levees and storm drains, are a common contributor to flooding.

In the Houston area, reservoirs are also an essential part of flood management, and many were at capacity from persistent rain. This forced managers to release more water when the storms hit.

For a coastal metropolis such as the Houston-Galveston area, rapidly rising sea levels can also reduce the downstream capacity to manage water. These different factors compound to increase flooding risk and highlight the need to not only move water but to find safe places to store it.

The increasing risks affect not only engineering standards, but zoning laws that govern where homes can be built and building codes that describe minimum standards for safety, as well as permitting and environmental regulations.

By addressing these issues now, communities can anticipate and avoid damage rather than only reacting when it’s too late.

Four lessons from case studies

The many effects associated with flooding show why a holistic approach to planning for climate change is necessary, and what communities can learn from one another. For example, case studies show that:

Floods can damage resources that are essential in flood recovery, such as roads, bridges and hospitals . Considering future risks when determining where and how to build these resources enhances the ability to recover from future disasters . Jackson, Mississippi’s water treatment plant was knocked offline by flooding in 2022, leaving people without safe running water. Houston’s Texas Medical Center famously prepared to manage future flooding by installing floodgates, elevating backup generators and taking other steps after heavy damage during Tropical Storm Allison in 2001.

Flood damage does not occur in isolation. Downpours can trigger mudslides , make sewers more vulnerable and turn manufacturing facilities into toxic contamination risks . These can become broad-scale dangers, extending far beyond individual communities.

It is difficult for an individual or a community to take on even the technical aspects of flood preparation alone – there is too much interconnectedness. Protective measures like levees or channels might protect one neighborhood but worsen the flood risk downstream . Planners should identify the appropriate regional scale, such as the entire drainage basin of a creek or river, and form important relationships early in the planning process.

Natural disasters and the ways communities respond to them can also amplify disparities in wealth and resources. Social justice and ethical considerations need to be brought into planning at the beginning.

Learning to manage complexity

In communities that my colleagues and I have worked with , we have found an increasing awareness of the challenges of climate change and rising flood risks.

In most cases, local officials’ initial instinct has been to protect property and persist without changing where people live. However, that might only buy time for some areas before people will have little option but to move .

When they examine their vulnerabilities, many of these communities have started to recognize the interconnectedness of zoning, storm drains and parks that can absorb runoff, for example. They also begin to see the importance of engaging regional stakeholders to avoid fragmented efforts to adapt that could worsen conditions for neighboring areas.

This is an updated version of an article originally published Aug. 25, 2022 .

• Climate change
• Infrastructure
• Extreme weather
• Extreme rainfall
• Disaster mitigation
• Flash flooding

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