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Case Report: A 19-Years Old Patient with Haemophilia a with High Response Inhibitor Screening and Quantitation and the Bethesda Method

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Marianela Trejos Herrera , Alicia Lopez Campos; Case Report: A 19-Years Old Patient with Haemophilia a with High Response Inhibitor Screening and Quantitation and the Bethesda Method. Blood 2016; 128 (22): 4956. doi: https://doi.org/10.1182/blood.V128.22.4956.4956

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A severe haemophiliac patient, high response inhibitors, 19 years, who was diagnosed at 8 months old and since then he begins to administer factor VIII concentrates. However, a year later after the start of treatment, they were detected inhibitors that behave as high response inhibitors from the start.

He discontinues treatment with Factor VIII concentrate and instead he begins to administer Factor IX concentrate and prothrombin complex as an alternative treatment.

Through his illness, the patient has made significant bleeding at the level of joint and other muscles such as the psoas. It is a bleeding patient at rest up for what is currently administered prophylactically Prothrombin Concentrate 3 times a week.

This case, the comment will be directed towards laboratory diagnosis and its evolution since he was diagnosed in 1994 to date.

From 2013, screening protocols and quantification of both factors and inhibitors were modified in the Specialized Hematology laboratory of Hospital México, due to problems in the sensitivity and specificity of the method and reagents we were using. The results from these patient specific inhibitors are described in the following paragraphs.

Observations

With the experience and current knowledge of the following it is concluded, according to a literature review that was performed (see Table 1):

1) This time period has persisted inhibitor high title, which is evidenced of the study of mixtures which do not clearly show a potentiation by incubating 2 hours at 37 ° C, since the values of the Control Mix and patient give very similar high values.

2) We were shown only on the date of 14.02.2013, there was a real interference Lupic Anticoagulant (LA), which is confirmed by the method of Russel viper venom.

3) The dates high titer inhibitors were reported against factor VIII (from 6 November 2013 to date), both screening and for the Bethesda, aPTT reagent was used with Kaolin activator which is low sensitivity to LA.

4) On November 20, 2015 there was an error in the interpretation and anti factor VIII inhibitors as negative were reported as potentiation at 37 ° C is not evidenced, but rather was interpreted as interference of an LA, which was communicated to the medical and preventive measures cited in paragraph corrections were made.

5) The last date that the sample was processed, on February 1, 2016, the inhibitor against factor VIII did not affect dilution of silica APTT, so the index ROSNER was not affected (<12) and it was not necessary to mount the LA test, according to the request in identifying protocols inhibitors.

6) Factor VIII deficient plasma is currently being used, which contains von Willebrand factor, as recommended by international guidelines quantization factors.

Conclusions

According to an experience as support center Reference Center in our country, we conclude and recommend the following:

1) Registration of haemophiliac patients with high antibody titer is essential as the description of the protocol to be followed in these patients.

2) The behavior of this inhibitor in the screening test of time and temperature dependence, it was decided to directly mount the Bethesda assay, following the recommendations of the literature on when the use of a reagent with low sensitivity to lupus inhibitor.

3) Within the protocol and as far as we can, we will process the purchase for quantification of factor VIII chromogenic by ELISA methodology, as a confirmatory method.

No relevant conflicts of interest to declare.

Author notes

Asterisk with author names denotes non-ASH members.

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A 24-Year-Old Man with Previously Diagnosed Hemophilia

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Francesca Khani, Mikhail Roshal, A 24-Year-Old Man with Previously Diagnosed Hemophilia, Clinical Chemistry , Volume 58, Issue 7, 1 July 2012, Pages 1086–1089, https://doi.org/10.1373/clinchem.2011.166728

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A 24-year-old Middle Eastern man diagnosed with hemophilia at the age of 4 or 5 years presented to the hematology clinic for follow-up after a recent hospitalization for excessive bleeding from an accidental knife cut. The patient reported a history of prolonged bleeding after teeth extractions, an upper gastrointestinal bleed 3 years previously, and excessive bruising since childhood. He denied hemarthroses but reported chronic pain in his ankles and joints. The patient reported having been treated for episodes of excessive bleeding with fresh frozen plasma (FFP) 3 and factor VIII during past hospitalizations. Because of poor continuity of care, his disease had not been monitored or treated on an ongoing outpatient basis. The patient's family history is noteworthy for consanguineous parents (first cousins) and a sister who also experienced excessive bleeding, although her diagnosis was uncertain. Initial laboratory test results included a normal complete blood count, including platelets, a prolonged activated partial thromboplastin time (aPTT), and a prolonged prothrombin time (PT) ( Table 1 ). Fibrinogen activity was normal. A 1:1 mixture of the patient's plasma with pooled normal plasma demonstrated full correction of the PT and aPTT, a result consistent with factor deficiency.

Patient's laboratory results (citrated plasma).

Additional patient data and differential diagnosis.

Patients with isolated hemophilia A, B, or C (due to deficiencies in factors VIII, IX, and XI, respectively) or factor VIII deficiency due to von Willebrand disease typically have a prolonged aPTT but a normal PT. In the absence of anticoagulation therapy or suspected vitamin K deficiency, a prolonged PT in this patient's initial workup should raise clinical suspicion for a bleeding disorder of a different etiology. Given the patient's clinically notable bleeding symptoms since childhood, a genetic disorder should be considered. The differential diagnosis includes dysfibrinogenemia, prothrombin deficiency, factor V deficiency, combined deficiency of factors V and VIII (F5F8D), factor X deficiency, and hereditary combined deficiency of the vitamin K–dependent clotting factors. All of these conditions feature prolongation of both the PT and the aPTT ( 1 ). Given the results of the mixing studies, we subsequently evaluated factor activities ( Table 1 ).

How do the coagulation studies for this patient differ from those typically seen for patients with hemophilia?

What are possible causes of simultaneous prolonged PT and prolonged aPTT?

What further coagulation studies would you recommend in evaluating this patient?

The results of additional coagulation studies strongly suggested a diagnosis of F5F8D, because activities of factors V and VIII activities were markedly decreased. Also, factor VII activity appeared to be slightly increased, but this finding was considered unlikely to be of clinical consequence. F5F8D is a genetic condition that is often misdiagnosed as a single-factor deficiency condition such as hemophilia A, particularly in institutions with limited diagnostic resources in hematology ( 2 ). The inheritance pattern and pathogenesis of these 2 genetic disorders are distinct and are important for both therapeutic and genetic-counseling purposes. This scenario underscores the importance of further laboratory investigation when initial testing appears to be inconsistent with the patient's supposed diagnosis.

In the coagulation cascade, factors V and VIII are glycoprotein cofactors for the proteolytic activation of prothrombin (factor II) by factor X and of factor X by factor IX, respectively, and thus are essential for clot formation. F5F8D is a rare autosomal recessive disorder in which plasma concentrations of factors V and VIII are both decreased, thus leading to the symptoms of excessive bleeding. The incidence of this condition is approximately 1 in 1 000 000 in the general population but reportedly is more prevalent among Middle Eastern Jewish and non-Jewish Iranian populations, for which the incidence is estimated to be 1 in 100 000. The higher degree of consanguinity in these populations is thought to partially explain the higher prevalence of this autosomal recessive disorder ( 3 ).

F5F8D is genetically distinct from isolated inherited deficiencies of factor VIII (hemophilia A) and factor V (parahemophilia). Although having hemophilia A and a concurrent factor V deficiency is possible, such a combination is much less probable given the distinct inheritance patterns of the 2 conditions. Family history is also important to onsider. Because this patient also has a sister with a similar bleeding disorder, it is unlikely that hemophilia A, which typically affects only males because of its X-linked inheritance, is the etiology ( 3 ). Clinically, patients with hemophilia A present in childhood similarly to those with F5F8D—easy bruising, nosebleeds, and severe bleeding after surgical procedures, dental extractions, and trauma. Menorrhagia and postpartum hemorrhage are common in affected women ( 1 ). Autosomal recessive factor V deficiency, which also presents in childhood and is associated with parental consanguinity, presents with easy bruising, nosebleeds, and mucous membrane bleeding, particularly within the oral cavity ;( 1 ). Hemarthroses, muscle hematomas, and spontaneous bleeding are less likely to be observed in patients with factor V deficiency and in those with F5F8D compared to patients with severe hemophilia A ( 1 ). The bleeding severity in patients with F5F8D is ultimately similar to that experienced by patients with similar deficiency levels of either of these factors alone ( 4 ). The results of the coagulation studies, the clinical presentation, and the family history for the patient described in this case indicate F5F8D as the most likely diagnosis. Molecular genetic testing would be needed to absolutely confirm this diagnosis. For diagnostic and treatment purposes, however, assays of factors V and VIII assays are sufficient ( 2 ).

Currently, mutations in either of 2 genes, LMAN1 4 (lectin, mannose-binding, 1) and MCFD2 (multiple coagulation factor deficiency 2), are believed to account for all cases of F5F8D. LMAN1 and MCFD2 encode proteins that form a calcium-dependent complex essential for transporting factors V and VIII from the endoplasmic reticulum to the Golgi apparatus in coat protein II–coated vesicles ( Fig. 1 ). Interestingly, factors V and VIII are the only cargo proteins known to be affected in patients with F5F8D. If the transport of other cargo proteins is affected, the deficiency likely is not large enough to produce a clinical phenotype ( 2 ), ( 5 ).

Illustration of factor V (FV) and factor VIII (FVIII) transport from the endoplasmic reticulum to the Golgi apparatus, facilitated by the calcium-dependent LMAN1–MCFD2 complex.

FV and FVIII leave the endoplasmic reticulum in coat protein II (COPII)-coated vesicles and are further modified in the Golgi apparatus before exiting the cell.

CLINICAL MANAGEMENT

As in most bleeding conditions, the guidelines for the clinical management of F5F8D are dictated by the severity of the disease. In F5F8D, both the nature of the bleeding and the activities of factors V and VIII activities are used to guide therapy. Regular prophylaxis is not usually necessary unless the patient has recurrent severe hematomas and hemarthroses ( 2 ). For minor bleeding episodes, factor VIII activity should be increased to 30%–50% of normal; for more-severe bleeding episodes, factor VIII activity should be increased to 50%–70%. For bleeding episodes in general, factor V activity should be increased to 25% ( 1 ). Sources of both factors are required for adequate hemostasis. Because no factor V concentrates are available at this time, FFP is the only product available for factor V replacement. Although FFP theoretically may be used to replace both factors, it is important to remember that factors V and VIII differ in the recommended concentrations needed for hemostasis and have different plasma half-lives (36 h for factor V and 10–14 h for factor VIII) ( 5 ). Thus, replacing factor VIII with FFP alone would necessitate substantially more exposure to blood products. Factor VIII concentrates can be used to supplement FFP to achieve an adequate factor VIII concentration. Numerous types of factor VIII concentrates are available and are in widespread use for patients with hemophilia A. Desmopressin has been reported to be useful for minor bleeding episodes in F5F8D to further increase the factor VIII concentration ( 6 ). Patients undergoing surgical procedures require appropriate prophylactic therapy: administration of factor VIII concentrates every 12 h to maintain the factor VIII activity at >50% and FFP every 12 h to achieve the factor V activity at >25%, until wound healing occurs ( 1 )

Clinical and family histories pertaining to bleeding abnormalities are extremely important in evaluating hereditary coagulation disorders.

Further laboratory investigation is necessary when supposed diagnoses, family history, and the results of initial laboratory studies are inconsistent.

Although rare, F5F8D should be suspected in patients who claim to have hemophilia and have a prolonged PT and a prolonged aPTT, particularly if they are of Middle Eastern heritage and/or have a family history of consanguinity. It is therefore necessary to include factors V and VIII in testing for unexplained factor deficiencies in the setting of prolongation of both PT and aPTT.

In patients with F5F8D and an acute bleeding episode, both factor V and factor VIII need to be replaced. FFP must be given to replace factor V because no other source of factor V is currently available.

Human genes: LMAN1 , lectin, mannose-binding, 1; MCFD2 , multiple coagulation factor deficiency 2.

fresh frozen plasma

activated partial thromboplastin time

prothrombin time

combined deficiency of factors V and VIII

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Bolton-Maggs PHB , Perry DJ , Chalmers EA , Parapia LA , Wilde JT , Williams MD et al . The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation . Haemophilia 2004 ; 10 : 593 – 628 .

Google Scholar

Zhang B . Recent developments in the understanding of the combined deficiency of FV and FVIII . Br J Haematol 2009 ; 145 : 15 – 23 .

Spreafico M , Peyvandi F . Combined FV and FVIII deficiency . Haemophilia 2008 ; 14 : 1201 – 8 .

Peyvandi F , Tuddenham EG , Akhtari AM , Lak M , Mannucci PM . Bleeding symptoms in 27 Iranian patients with the combined deficiency of factor V and factor VIII . Br J Haematol 1998 ; 100 : 773 – 6 .

Spreafico M , Peyvandi F . Combined factor V and factor VIII deficiency . Semin Thromb Hemost 2009 ; 35 : 390 – 9 .

Mannucci PM , Duga S , Peyvandi F . Recessively inherited coagulation disorders . Blood 2004 ; 104 : 1243 – 52 .

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Hemophilia Case Study

The mother of six-month-old Steven cannot stop his bleeding after he hits his mouth on the kitchen floor. Find out what happens to this infant who has a disease that is credited for bringing down the last tsar of Russia.

Module 8: Hemophilia

Steven had just turned 6 months old.   He had recently discovered the freedom of being mobile...

Hemophilia - Page 1

The pediatrician ordered the following tests: platelet count, bleeding time, protime...

Hemophilia - Page 2

The hematologist reviewed Steven's case, and recommended that he be treated with recombinant...

Hemophilia - Page 3

The geneticist interviewed Steven's mother and grandmother. The grandmother indicated...

Hemophilia - Page 4

Case Summary

Summary of the Case

Hemophilia - Summary

Answers to the Case Questions

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Case Study: Emerging Therapies in Hemophilia

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A 27-year-old man with a history of severe hemophilia A presents for follow-up after a recent hospitalization for a bleeding episode in his knee. His hospitalization was complicated by the presence of a high-titer factor VIII inhibitory antibody measured at 13 Bethesda units (BU), prompting the use of recombinant factor VIIa to control his bleeding.

On examination, his titer remains elevated at 9 BU. Options to best control further bleeding episodes are being considered, including initiation of immune tolerance induction (ITI) to eliminate his inhibitor.The patient asks if there are newer therapies that are on the horizon to prevent bleeding in hemophilia A. Data from the recently published phase III HAVEN 1 Trial report that patients with hemophilia A treated with weekly emicizumab prophylaxis, compared to no prophylaxis, had a lower rate of annualized bleeding events.

What is the mechanism of action of emicizumab?

• A bispecific monoclonal antibody binding activated factor IX and factor X
• Monoclonal antibody that blocks the tissue factor pathway inhibitor (TFPI)
• Monoclonal antibody that inhibits anti-thrombin III by a linked small interference RNA
• Recombinant fusion protein that binds activated factor IX and factor X

Explanation

Emicizumab (answer A) is a bispecific monoclonal antibody binding factor X and activated factor IX, effectively restoring the function of the missing factor VIII. The HAVEN 1 Trial was a phase III open-label, multicenter trial primarily assessing annualized bleeding rates with use of weekly prophylactic emicizumab versus no prophylaxis in hemophilia A patients who were previously receiving episodic factor VIII bypassing agents. At 24 weeks, annualized bleeding rate in the emicizumab prophylaxis group was 2.9 events compared to 23.3 events in the no prophylaxis group( p<0.001). This represents an 87 percent decrease in annualized bleeding rates with use of emicizumab. Quality of life scores were also significantly higher in the emicizumab group. However, approximately 47 percent of subjects on emicizumab prophylaxis required activated prothrombin complex concentrate (aPCC) and/or recombinant factor VIIa.

Conicizumab (answer B) is a monoclonal antibody that blocks TFPI. TFPI helps regulate initiation of thrombin generation and has three separate domains that bind to tissue factor-factor VIIa, bind and inhibit factor Xa, and interact with protein S, respectively. Conicizumab interferes with factor Xa binding domain, and patients are currently being enrolled in a phase II trial.

Fitusiran is an investigational small RNA interference (RNAi) agent that targets antithrombin messenger RNA to improve thrombin generation and promote hemostasis in patients with hemophilia. It is not a monoclonal antibody (answer C). In a phase I dose escalation trial, once-monthly subcutaneous fitusiran injections resulted in increased thrombin generation. Of note, the population studied did not have inhibitory antibodies. Fitusiran resulted in decreased bleeding episodes and appeared to be well tolerated. Further enrollment of subjects onto this study has been put on hold due to the death of a subject, related to cerebral sinus venous thrombosis.

Recombinant factor VIII Fc fusion protein (answer D) has a half-life that is 1.5 times longer than standard recombinant factor VIII (18.8 hours vs. 11 hours). The efficacy of recombinant factor VIII Fc fusion protein was demonstrated in two phase III studies: A-LONG in adults and Kids A-LONG in children. It is dosed prophylactically one to two times a week, with 30 percent of patients in the trial achieving a five-day dosing interval. 1-6

References 

• Arruda VR, Doshi BS, Samelson-Jones BJ. Novel approaches to hemophilia therapy: successes and challenges . Blood. 2017;doi: 10.1182/blood-2017-08-742312. [Epub ahead of print].
• Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial . J Thromb Haemost. 2015;13:743-754.
• Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A . Blood. 2014;123:317-325.
• Nolan B, Mahlangu J, Perry D, et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with hemophilia A . Haemophilia. 2016;22:72-80.
• Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors . N Engl J Med. 2017;377:809-818.
• Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy . N Engl J Med. 2017;377:819-828.

Case study submitted by Gemlyn George, MD, and Arun K Singavi, MD, of Medical College of Wisconsin, Milwaukee, WI.

American Society of Hematology. (1). Case Study: Emerging Therapies in Hemophilia. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/emerging-therapies-hemophilia .

American Society of Hematology. "Case Study: Emerging Therapies in Hemophilia." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/emerging-therapies-hemophilia (label-accessed June 01, 2024).

"American Society of Hematology." Case Study: Emerging Therapies in Hemophilia, 01 Jun. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/emerging-therapies-hemophilia .

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• Diseases & Conditions

Severe cases of hemophilia usually are diagnosed within the first year of life. Mild forms might not be apparent until adulthood. Some people learn they have hemophilia after they bleed excessively during a surgical procedure.

Clotting-factor tests can reveal a clotting-factor deficiency and determine how severe the hemophilia is.

For people with a family history of hemophilia, genetic testing might be used to identify carriers to make informed decisions about becoming pregnant.

It's also possible to determine during pregnancy if the fetus is affected by hemophilia. However, the testing poses some risks to the fetus. Discuss the benefits and risks of testing with your doctor.

• Care at Mayo Clinic

Our caring team of Mayo Clinic experts can help you with your hemophilia-related health concerns Start Here

The main treatment for severe hemophilia involves replacing the clotting factor you need through a tube in a vein.

This replacement therapy can be given to treat a bleeding episode in progress. It can also be given on a regular schedule at home to help prevent bleeding episodes. Some people receive continuous replacement therapy.

Replacement clotting factor can be made from donated blood. Similar products, called recombinant clotting factors, are made in a laboratory, not from human blood.

Other therapies include:

• Desmopressin. In some forms of mild hemophilia, this hormone can stimulate the body to release more clotting factor. It can be injected slowly into a vein or used as a nasal spray.
• Emicizumab (Hemlibra). This is a newer drug that doesn't include clotting factors. This drug can help prevent bleeding episodes in people with hemophilia A.
• Clot-preserving medications. Also known as anti-fibrinolytics, these medications help prevent clots from breaking down.
• Fibrin sealants. These can be applied directly to wound sites to promote clotting and healing. Fibrin sealants are especially useful for dental work.
• Physical therapy. It can ease signs and symptoms if internal bleeding has damaged your joints. Severe damage might require surgery.
• First aid for minor cuts. Using pressure and a bandage will generally take care of the bleeding. For small areas of bleeding beneath the skin, use an ice pack. Ice pops can be used to slow down minor bleeding in the mouth.

More Information

Hemophilia care at Mayo Clinic

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Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

To avoid excessive bleeding and protect your joints:

• Exercise regularly. Activities such as swimming, bicycle riding and walking can build muscles while protecting joints. Contact sports — such as football, hockey or wrestling — are not safe for people with hemophilia.
• Avoid certain pain medications. Drugs that can make bleeding worse include aspirin and ibuprofen (Advil, Motrin IB, others). Instead, use acetaminophen (Tylenol, others), which is a safer alternative for mild pain relief.
• Avoid blood-thinning medications. Medications that prevent blood from clotting include heparin, warfarin (Jantoven), clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) and dabigatran (Pradaxa).
• Practice good dental hygiene. The goal is to prevent tooth and gum disease, which can lead to excessive bleeding.
• Get vaccinations. People with hemophilia should receive recommended vaccinations at the appropriate ages, as well as hepatitis A and B. Requesting use of the smallest gauge needle and having pressure or ice applied for 3 to 5 minutes after the injection can reduce the risk of bleeding.
• Protect your child from injuries that could cause bleeding. Kneepads, elbow pads, helmets and safety belts all help prevent injuries from falls and other accidents. Keep your home free of furniture with sharp corners.

Coping and support

To help you and your child cope with hemophilia:

• Get a medical alert bracelet. This lets medical personnel know that you or your child has hemophilia, and the type of clotting factor that's best in case of an emergency.
• Talk with a counselor. Striking the right balance between keeping your child safe and encouraging as much activity as possible can be tricky. A social worker or therapist with knowledge of hemophilia can help identify the least amount of limitations your child needs.
• Let people know. Be sure to tell anyone who will be taking care of your child — babysitters, child care workers, relatives, friends and teachers — about your child's condition. If your child plays noncontact sports, be sure to tell coaches, too.

Preparing for your appointment

If you or your child has signs or symptoms of hemophilia, you might be referred to a doctor who specializes in blood disorders (hematologist).

What you can do

Make a list of:

• Symptoms and when they began
• Key medical information, including other conditions, and a family history of bleeding disorders
• All medications, vitamins and supplements, including doses

Questions to ask your doctor

• What's the most likely cause of these signs and symptoms?
• What tests are needed? Do they require special preparation?
• What treatment do you recommend?
• What activity restrictions are recommended?
• What is the risk of long-term complications?
• Do you recommend that our family meet with a genetic counselor?

Don't hesitate to ask other questions, as well.

What to expect from your doctor

Your doctor is likely to ask you a number of questions, including:

• Have you noticed any unusual or heavy bleeding, such as nosebleeds or prolonged bleeding from a cut or vaccination?
• If you or your child has had surgery, did the surgeon mention excessive bleeding?
• Are you or your child prone to developing large, deep bruises?
• Do you or your child have pain or warmth around joints?

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• Bleeding disorders. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health-topics/bleeding-disorders. Accessed June 10, 2021.
• AskMayoExpert. Hemophilia. Mayo Clinic; 2021.
• Hoots WK, et al. Hemophilia A and B: Routine management including prophylaxis. https://www.uptodate.com/contents/search. Accessed June 10, 2021.
• Hemophilia. Merck Manual Professional Version. https://www.merckmanuals.com/professional/hematology-and-oncology/coagulation-disorders/hemophilia?query=hemophilia#. Accessed June 10, 2021.
• Weyand AC, et al. New therapies for hemophilia. Blood. 2019; doi:10.1182/blood-2018-08-872291.
• What is hemophilia? Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed June 10, 2021.
• Hoots WK, et al. Treatment of bleeding and perioperative management in hemophilia A and B. https://www.uptodate.com/contents/search. Accessed June 10, 2021.
• Morrow ES. Allscripts EPSi. Mayo Clinic. April 14, 2021.

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Key Findings: Study of Hemophilia Care Outcomes over 50 Year Span Reveals Progress, Ongoing Health Challenges

Medical care, treatment and support services for men and boys with hemophilia have improved over the last five decades. Yet people affected by this disorder still experience significant health challenges throughout their lifetime.

To continue the medical care for this population, it’s important to keep systems in place to monitor and learn more about the health of people with hemophilia. This knowledge can then be used to develop programs to improve health and quality of life for those living with hemophilia.

About This Study

Researchers from the Centers for Disease Control and Prevention (CDC) and the U.S. Hemophilia Treatment Center Network conducted a study of the health of men (19 years or older) with hemophilia in the United States (U.S). The study aimed to find out the links between

• Changes in hemophilia treatment and healthcare delivery over the last fifty years, and
• Factors that affect health (such as access to care, physical and social functioning, health problems, and death)

Researchers analyzed information collected from 4,899 men with severe and 2,587 men with mild hemophilia. These men received care at U.S. hemophilia treatment centers from 1998-2011. Data were organized into four time periods (called Eras) that reflected major developments in therapies and health care for people with hemophilia. Listed below are these Eras from oldest to youngest:

• Era A included men born prior to 1958 (oldest participants)
• Era B included men born 1958-1975
• Era C included men born 1976-1982
• Era D included men born 1982-1993 (youngest participants)

Hemophilia is an inherited bleeding disorder in which the blood does not clot properly. This can lead to spontaneous bleeding as well as prolonged bleeding following injuries or surgery.

The condition predominantly affects males.

For men with severe versus mild hemophilia within each Era, study researchers compared

• Demographic information, such as race and ethnicity;
• Healthcare access information, such as age at diagnosis and type of health insurance;
• Hemophilia-related and treatment-related health problems; and
• Number and causes of death.

Read the hemophilia study’s manuscript

Main Findings From This Study

• In the youngest age group (Era D) more than 1 in 3 men with severe hemophilia reported frequent bleeds (more than 5 bleeds in six months) despite being treated with the most modern therapies. One in 4 of these men also reported a recurrent bleed in a target joint (a bleed that occurs often or repeatedly in a particular joint).
• Across all Eras, compared to men with mild disease, those with severe hemophilia were about three times more likely to report activity limitations, and twice as likely to report some use of devices to help them move around, such as a cane or wheelchair.
• In every Era, the proportion of men with severe hemophilia that missed at least 10 days of work or school in the last year due to upper or lower joint problems was two or three times that of men with mild hemophilia.
• Nearly half of the men in the oldest age group (Era A) were disabled and unable to work. Moreover, men with severe hemophilia were about three times more likely to be disabled as their mild hemophilia counterparts in every Era.
• Infection-related health problems due to Hepatitis B, Hepatitis C, and HIV are common among men with severe hemophilia, particularly in the older Eras.
• Of the 551 deaths reported during the study period, liver failure was the most commonly reported cause of death, regardless of hemophilia severity or Era. Hemophilia-related deaths (bleeds) accounted for 14.6 percent of deaths in men with severe hemophilia and 10.7 percent of deaths in men with mild hemophilia across all Eras.

Critical Gaps & Future Directions

A number of observations from this study need further investigation

• Joint bleeding among men with hemophilia is more common than expected given widespread availability of proven therapies that are accessible for home use.
• Treatment of hemophilia through the regular infusion or injection of clotting factor concentrates into a vein to prevent bleeding (called prophylaxis), has been shown to result in better joint outcomes. However, this study found that men with hemophilia in all Eras tended to under-utilize prophylaxis.
• The differences in overall health between men with mild and severe hemophilia has not changed over time.
• There are subgroups of men in all Eras with mild hemophilia who experience higher levels of bleeding than expected.

Future directions

Research is needed to understand the reasons for the apparent underutilization of prophylaxis by some men with hemophilia, and to develop strategies that are successful in changing behavior.

More work is needed to understand the factors that contribute to joint bleeds and to develop treatment strategies for men with hemophilia who have a higher risk for joint disease.

Focused studies are needed on men with mild hemophilia who have unusually high rates of bleeding in order to identify the reasons behind their increased bleeding tendency.

More Information

Please visit the following links for more information about

https://www.cdc.gov/ncbddd/hemophilia/index.html

https://www.cdc.gov/ncbddd/hemophilia/inhibitors.html

Research on inhibitors

https://www.cdc.gov/ncbddd/hemophilia/articles.html#features and https://www.cdc.gov/ncbddd/hemophilia/research.html

Inhibitor testing

https://www.hemophilia.org/news/cdc-hosts-inhibitor-testing-webinar

Key Findings Reference

Mazepa MA, Monahan PE, Baker JR, Riske BK, and Soucie JM. Men with severe hemophilia in the United States: Birth cohort analysis of a large national database. Blood. Jan 2016, DOI: 10.1182/blood-2015-10-675140

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Gabriela Salinas and Jeeva Somasundaram

Roula Khalaf, Editor of the FT, selects her favourite stories in this weekly newsletter.

In April this year, Hein Schumacher, chief executive of Unilever, announced that the company was entering a “new era for sustainability leadership”, and signalled a shift from the central priority promoted under his predecessor , Alan Jope.

While Jope saw lack of social purpose or environmental sustainability as the way to prune brands from the portfolio, Schumacher has adopted a more balanced approach between purpose and profit. He stresses that Unilever should deliver on both sustainability commitments and financial goals. This approach, which we dub “realistic sustainability”, aims to balance long- and short-term environmental goals, ambition, and delivery.

As a result, Unilever’s refreshed sustainability agenda focuses harder on fewer commitments that the company says remain “very stretching”. In practice, this entails extending deadlines for taking action as well as reducing the scale of its targets for environmental, social and governance measures.

Such backpedalling is becoming widespread — with many companies retracting their commitments to climate targets , for example. According to FactSet, a US financial data and software provider, the number of US companies in the S&P 500 index mentioning “ESG” on their earnings calls has declined sharply : from a peak of 155 in the fourth quarter 2021 to just 29 two years later. This trend towards playing down a company’s ESG efforts, from fear of greater scrutiny or of accusations of empty claims, even has a name: “greenhushing”.

Test yourself

This is the fourth in a series of monthly business school-style teaching case studies devoted to the responsible business dilemmas faced by organisations. Read the piece and FT articles suggested at the end before considering the questions raised.

About the authors: Gabriela Salinas is an adjunct professor of marketing at IE University; Jeeva Somasundaram is an assistant professor of decision sciences in operations and technology at IE University.

The series forms part of a wider collection of FT ‘instant teaching case studies ’, featured across our Business Education publications, that explore management challenges.

The change in approach is not limited to regulatory compliance and corporate reporting; it also affects consumer communications. While Jope believed that brands sold more when “guided by a purpose”, Schumacher argues that “we don’t want to force fit [purpose] on brands unnecessarily”.

His more nuanced view aligns with evidence that consumers’ responses to the sustainability and purpose communication attached to brand names depend on two key variables: the type of industry in which the brand operates; and the specific aspect of sustainability being communicated.

In terms of the sustainability message, research in the Journal of Business Ethics found consumers can be less interested when product functionality is key. Furthermore, a UK survey in 2022 found that about 15 per cent of consumers believed brands should support social causes, but nearly 60 per cent said they would rather see brand owners pay taxes and treat people fairly.

Among investors, too, “anti-purpose” and “anti-ESG” sentiment is growing. One (unnamed) leading bond fund manager even suggested to the FT that “ESG will be dead in five years”.

Media reports on the adverse impact of ESG controversies on investment are certainly now more frequent. For example, while Jope was still at the helm, the FT reported criticism of Unilever by influential fund manager Terry Smith for displaying sustainability credentials at the expense of managing the business.

Yet some executives feel under pressure to take a stand on environmental and social issues — in many cases believing they are morally obliged to do so or through a desire to improve their own reputations. This pressure may lead to a conflict with shareholders if sustainability becomes a promotional tool for managers, or for their personal social responsibility agenda, rather than creating business value .

Such opportunistic behaviours may lead to a perception that corporate sustainability policies are pursued only because of public image concerns.

Alison Taylor, at NYU Stern School of Business, recently described Unilever’s old materiality map — a visual representation of how companies assess which social and environmental factors matter most to them — to Sustainability magazine. She depicted it as an example of “baggy, vague, overambitious goals and self-aggrandising commitments that make little sense and falsely suggest a mayonnaise and soap company can solve intractable societal problems”.

In contrast, the “realism” approach of Schumacher is being promulgated as both more honest and more feasible. Former investment banker Alex Edmans, at London Business School, has coined the term “rational sustainability” to describe an approach that integrates financial principles into decision-making, and avoids using sustainability primarily for enhancing social image and reputation.

Such “rational sustainability” encompasses any business activity that creates long-term value — including product innovation, productivity enhancements, or corporate culture initiatives, regardless of whether they fall under the traditional ESG framework.

Similarly, Schumacher’s approach aims for fewer targets with greater impact, all while keeping financial objectives in sight.

Complex objectives, such as having a positive impact on the world, may be best achieved indirectly, as expounded by economist John Kay in his book, Obliquity . Schumacher’s “realistic sustainability” approach means focusing on long-term value creation, placing customers and investors to the fore. Saving the planet begins with meaningfully helping a company’s consumers and investors. Without their support, broader sustainability efforts risk failure.

Questions for discussion

Read: Unilever has ‘lost the plot’ by fixating on sustainability, says Terry Smith

Companies take step back from making climate target promises

The real impact of the ESG backlash

Unilever’s new chief says corporate purpose can be ‘unwelcome distraction ’

Unilever says new laxer environmental targets aim for ‘realism’

How should business executives incorporate ESG criteria in their commercial, investor, internal, and external communications? How can they strike a balance between purpose and profits?

How does purpose affect business and brand value? Under what circumstances or conditions can the impact of purpose be positive, neutral, or negative?

Are brands vehicles by which to drive social or environmental change? Is this the primary role of brands in the 21st century or do profits and clients’ needs come first?

Which categories or sectors might benefit most from strongly articulating and communicating a corporate purpose? Are there instances in which it might backfire?

In your opinion, is it necessary for brands to take a stance on social issues? Why or why not, and when?

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A Case of Hemophilia A Presenting in a Neonate and a Review of the Literature

Esther kisseih.

1 Children’s Hospital of Michigan, Detroit, MI, USA

Neeraja Yerrapotu

Deepak yadav, melissa february, introduction.

Hemophilia A is an X-linked hereditary condition caused by decreased factor VIII activity, which predominately occurs in males. 1 Severe hemophilia occurs when circulating levels of a factor are less than 1% of normal activity in the blood and is typically diagnosed in the first 2 years of life. 2 Early identification of these patients is essential since they are at risk for spontaneous life- or limb-threatening bleeding and disability resulting from repeated joint bleeding. 3 Hemophilia A and B are X-linked recessive disorders, which explains their preponderance in males. Genetic studies reveal that majority of hemophilia A cases are due to an inversion of the long arm of chromosome X. 4 Hemophilia A, which is the deficiency of factor VIII, occurs with an incidence of 1 in 500 to 10 000 males. 5 Diagnostic criteria for hemophilia include confirmation of a factor activity level below 40% of normal (below 0.40 IU/mL), or a hemophilia gene mutation. A normal von Willebrand factor antigen should also be documented in patients with reduced factor VIII activity levels, to eliminate the possibility of von Willebrand disease. Severe hemophilia is a relatively uncommon condition in the newborn period and usually manifests within the first year to 1½ years of life with easy bruising, hemarthrosis, bleeding due to oral injury, or after an invasive procedure. 6 Hemophilia can also be diagnosed in the absence of a family history with the initial presentation of bleeding in the neonatal period. Moderate and mild hemophilia, on the other hand, are defined as factor 8 levels >1% to <5% and >5% to <40%, respectively. 7 , 8

Final Diagnosis

We report a case of severe hemophilia presenting in a newborn after circumcision.

Hospital Course

An African American male infant born via vaginal delivery to a 23-year-old gravida 3 para 1 woman at 40 weeks gestation. Pregnancy was unremarkable.

The infant’s APGARs were 9 at 1 and 5 minutes, with no complications.

Birth parameters were birth weight of 2.94 kg, the birth length of 50 cm, and head circumference of 34 cm. Examination revealed a small for gestational age (SGA) baby with caput succedaneum and an extra digit on the right hand. The neonate was monitored in the newborn nursery. Baby received 1 mg of vitamin K with no feeding issues noted. Blood was drawn for complete blood count (due to SGA status) as well as blood typing.

Laboratory workup on day 1 revealed a white cell count of 11.5 k/mm 3 , hemoglobin of 21.7 gm/dL, hematocrit of 61.3%, with a platelet count of 32 k/mm 3 ; on repeat, platelets were 183 k/mm 3 . The infant’s blood type was B positive, and the antibody screen was negative.

On the second day of life, the patient was circumcised after which there was bleeding noted from postcircumcision frenulum tears. Pressure dressing was applied. Over the next 5 hours, the bleeding worsened with staff having to change 3 soaked pressure dressings. During that time the patient was also noted to have prolonged bleeding from prior heel sticks. The patient was transferred to the neonatal intensive care unit, and due to concerns of bleeding diathesis labs were sent for coagulation studies: factor VIII activity, factor IX activity, factor XIII activity, von Willebrand factor antigen/activity, platelet function assays along with a complete blood count. Hematology and urology were consulted.

Results were significant for a partial thromboplastin time of >200 seconds (23.1-33.1), D-dimer of >35.2 mg/L, and a fibrinogen level of 103 mg/dL (186-486 mg/dL). The patient was given cryoprecipitate for the presumed diagnosis of hemophilia as well as due to low fibrinogen while awaiting the remaining test results.

Remaining lab work showed factor VIII level <1%, factor IX activity 9%, von Willebrand factor activity level 134% (43% to 138%), and von Willebrand antigen of 102% (60% to 153%). Platelet function testing with screening epinephrine was 119 seconds (100-163), and a platelet factor ADP of 78 seconds (57-114).

Once factor VIII deficiency was established, recombinant factor VIII was provided to the baby and bleeding subsided after replacement. Due to an increased risk of intracranial hemorrhage in patients with hemophilia, an ultrasound of the head was performed, which did not show any evidence of intracranial hemorrhage.

The clinical care team went back and elicited further history from the family. On further questioning of the family, it became apparent that the maternal grandfather had hemophilia, which the mother was unaware.

In any child with bleeding symptoms, initial evaluation should include a complete blood count, prothrombin time, and activated partial thromboplastin time. Testing factor levels, platelet function, and fibrinogen can also be considered based on the initial lab testing. Consultation with a hematologist should occur with the slightest concern for an inheritable coagulation defect. While interpreting the test results during the newborn period, it is important to remember that normal ranges for newborns vary from adult values. The exception to this is factor VIII, which is at the normal adult range or mildly increased at birth. 9 Adult levels are also achieved in preterm infants, thusit is therefore possible to diagnose most cases of hemophilia A at birth. 10 Prenatal diagnosis of hemophilia via chorionic villus sampling is the most widely used method, 11 but amniotic fluid, fetal blood, and pre-implantation genetic diagnostics can also be used in selected cases. Prenatal diagnosis must be preceded by adequate genetic counseling and risk assessment of the potential carrier and subsequent support during the diagnostic process.

As per the United Kingdom Hemophilia Centre Doctors’ Organization Guideline approved by the British Committee for Standards in Hematology, the treatment of choice for both hemophilia A and B are recombinant factor VIII and recombinant factor IX concentrates, which carry the lowest risk of transmitting viral infection. 12 In a neonate with clinically significant ongoing hemorrhage, where hemophilia is suspected based on a prolonged activated partial thromboplastin time, it may be appropriate to administer fresh frozen plasma while the results of appropriate factor assays are awaited. In the event of a low fibrinogen level, as in this case, cryoprecipitate is considered the best choice.

In newborns with hemophilia, intracranial hemorrhage is the most life-threatening complication. 13 The cranial ultrasound should be undertaken before discharge in all neonates with severe or moderate hemophilia. 14

Severe hemophilia is not an absolute contraindication to circumcision. However, there is a wide range of variation in approaching this clinical scenario among pediatric hematologist with the major concern of inhibitor development. 15 Circumcision has to be deferred in a male neonate of carrier mother until hemophilia A is confirmed or ruled out.

Author Contributions

Esther Kisseih contributed to conception, design and drafting of the manuscript. Neeraja Yerrapotu contributed to data acquisition and drafting of the manuscript. Deepak Yadav and Melissa February reviewed and critically appraised the manuscript.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.