Hemophilia A


Article Author:
Philip Salen


Article Editor:
Hani Babiker


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
6/9/2019 10:58:33 PM

Introduction

Hemophilia, which means love (philia) of blood (hemo), manifests with prolonged and excessive bleeding either spontaneously or after insignificant trauma. Hemophilia encompasses a group of inherited ailments that alter the body's normal blood coagulation. A hereditary hemorrhagic disorder resulting from congenital deficit or scarcity of factor VIII, hemophilia A, which is known as classical hemophilia, manifests as protracted and excessive bleeding either spontaneously or secondary to trauma.[1][2][3]

Etiology

A X-linked, recessive hemorrhagic trait or gene induces Hemophilia A.  Hemophilia A's X-linked trait manifests as a congenital absence or decrease in plasma clotting Factor VIII, a pro-coagulation cofactor and robust initiator of thrombin that is essential for the generation of adequate amounts of fibrin to form a platelet-fibrin plug at sites of endothelial disruption.  Female Hemophilia A gene carriers will transmit the gene to 50% of their male offspring, who will inherit the disorder. Female hemophilia gene carriers do not manifest symptoms of Hemophilia A but may have lower than usual quantities of Factor VIII. Male Hemophilia A patients do not transmit hemophilia to male offspring, but their female offsprings will carry the hemophilia gene.  [4][5][6][7]

Epidemiology

Hemophilia A, the most common hereditary disorder of hemostasis, occurs in one out of 5000 males and accounts for 80% of hemophilia cases. Hemophilia A occurs in more than 400,000 males worldwide, many of whom remain undiagnosed in the developing world.

Pathophysiology

When the vascular endothelium sustains an injury, the hemostatic process initiates the coagulation cascade to restore vascular integrity and prevent further bleeding. Platelet activation occurs at the site of vascular rupture initiating promulgation of clotting factors and fibrin formation resulting in a platelet-fibrin plug to inhibit further bleeding. Factor VIII, the deficit of which causes hemophilia A, provides essential enhancement of thrombin generation and promulgation of fibrin formation to inhibit further bleeding. Factor VIII adheres to von Willebrand factor to protect it from proteolytic degradation. Bleeding in hemophilia results from defective fibrin stabilization secondary to inadequate fibrin generation which results in a failure of secondary hemostasis. Insufficient thrombin in the coagulation cascade results in a dearth of fibrin.

History and Physical

Severe hemophilia often manifests in the first months of life, whereas mild or moderate hemophilia will present later in childhood or adolescence often incidentally or following trauma. In two-thirds of cases, confirmation of the hemophilia diagnosis occurs shortly after delivery of an affected son to a mother who carries the susceptible gene. In spontaneous mutation scenarios that occur in one-third of cases, hemophilia A diagnostic confirmation proceeds after bleeding symptoms occur spontaneously or after insignificant trauma. Characteristic hemophilia bleeding symptoms can manifest as spontaneous intracranial bleeding in neonates, excessive postoperative bleeding after circumcision, atraumatic painful hemarthrosis, inexplicable bruising when the infant begins crawling or walking, and inordinate musculocutaneous hemorrhage, either spontaneously or after intramuscular vaccination. Frequent falls or impacts from furniture while learning to ambulate can induce extensive soft tissue contusions and hemorrhage that can mimic the appearance of child abuse in the young hemophiliac. Hemarthrosis manifests as the most common hemorrhagic symptom in adolescents and adults. Recurrent hemarthrosis eventually causes erosion of joint cartilage and results in the painful Charcot joints of hemophilic arthropathy. Intracranial hemorrhage represents the most immediately life-threatening manifestation of hemophilia A with potential for chronic neurological disability and long-term neurological sequelae.

Evaluation

Diagnostic evaluation for hemophilia occurs in the setting of known family history, excessive bleeding out of proportion to the traumatic injury, or abnormally activated partial thromboplastin time. Normal hemogram and prothrombin time in the setting of elevated activated partial thromboplastin time heightens the suspicion of hemophilia and should prompt factor VIII and IX determination. Determining residual plasma concentration of factor VIII represents the keystone of diagnosis, classification, and treatment of hemophilia A as therapy and prognosis will vary depending factor VIII deficiency. Most hemophilia A patients have a prolonged activated partial thromboplastin time; however, a normal result does not rule out mild hemophilia. Hemorrhage severity in hemophilia A correlates scarcity of factor VIII. Factor VIII concentration, expressed in international units (IU); 1 IU is defined as the concentration of factor VIII in 1 mL of pooled plasma or percentages of normal pooled plasma with normal levels ranging between 50% to 150%. Severe Hemophilia A will have no measurable factor VIII, less than 0.01 IU/mL or less than 1%, and will bleed spontaneously. Moderate or mild hemophilia, 0.02 to 0.05 IU/mL (2% to 5%) or 0.06 IU/mL to 0.40 IU/mL (6% to 40%) respectively, will bleed excessively after relatively insignificant trauma.

Treatment / Management

Administration of recombinant factor VIII replacement for the treatment of acute bleeding in severe hemophilia A patients should occur promptly with initiation before completion of the patient assessment. Calculation of factor VIII replacement for bleeding in severe hemophilia A is dose of factor VIII = percentage desired of factor x bodyweight (kg) x 0.5.[8][9][10]

For severe, life-threatening hemorrhage, administer factor VIII to achieve a 100% desired factor VIII level; for mild to moderate hemorrhage, administer factor VIII to achieve a 30% to 50% desired factor VIII level. Accounting for the hemophilia A patient’s native factor VIII levels should be factored into factor VIII repletion if known. The combination of effective blood product screening with viral inactivation protocols and recombinant production of Factor VIII have enhanced factor VIII replacement products safety from the viral transmission, such as HIV and hepatitis C.

Other pharmaceutical adjuvant therapies for hemophilia A-induced bleeding include desmopressin, tranexamic acid, epsilon aminocaproic acid, and management of factor VIII inhibitors. Intravenous, subcutaneous, or intranasal desmopressin (DDAVP) has utility for treatment of bleeding in mild to moderate hemophilia A patients by triggering the release of complexes von Willebrand’s factor and factor VIII from vascular endothelial cells.

Periodic, prophylactic Factor VIII concentrates infusions for severe Hemophilia A patients have benefit in preventing spontaneous bleeding. The intent of factor VIII prophylaxis aims to modify severe hemophilia to a milder form by keeping the nadir level of factors more than 1% of normal. The World Federation of Hemophilia recommends factor VIII prophylaxis initiation in hemophiliac children after their first or second episode of hemarthrosis to prevent joint destruction and preserve musculoskeletal function. Mild and moderate hemophilia A patients receive factor VIII concentrates or desmopressin to prevent hemorrhage in anticipation from trauma or surgery.[11][12]

Pearls and Other Issues

Defects in the binding of factor VIII and von Willebrand factor, characterizing type 2N or “Normandy type” von Willebrand disease, will manifest like hemophilia-induced bleeding, but unlike hemophilia, inherited manifestation occurs in an autosomal pattern, thereby also affecting female patients. Establishing the diagnosis of type 2N von Willebrand disease utilizes molecular genetic testing.

Many severe hemophilia A patients, nearly 30%, develop alloantibodies against administered factor VIII. Inhibitor development represents a major complication and challenge in hemophilia treatment because these alloantibodies inactivate the procoagulant effect of infused factor VIII thereby inhibiting the response to factor VIII replacement.

Enhancing Healthcare Team Outcomes

Hemophilia A is best managed by an interprofessional team that includes hematology nurses. Once the diagnosis is confirmed based on plasma factor VIII levels, patient and family referral for genetic screening and counseling for factor VIII gene mutation analysis to establish carrier status.

The outlook for most patients with hemophilia A is guarded. Repeated transfusions of blood products and related factors is not a benign event. In addition, these patients are prone to bleeding, which can be life threatening.


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Hemophilia A - Questions

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A patient with known hemophilia A has refractory bleeding after a tooth extraction. Hemoglobin is found to be 9.8 g/dL. What is the next treatment?



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In which of these conditions is the partial thromboplastin time (PTT) characteristically increased?



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A patient with hemophilia needs factor VIII but is worried about the risk of acquiring HIV. What is the risk?



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A patient newly diagnosed with hemophilia A will most likely be treated with which of the following?



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What is the inheritance pattern for factor VIII deficiency, hemophilia A?



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What are the laboratory findings associated with hemophilia A?



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Which of the following would be the best treatment for hemophilia A?



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In patients with hemophilia A, what clotting factor is absent?



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A 13-month-old boy is seen by the clinician for a well-child check-up. His mother says that she has no current complains and feels that he has been developing normally similar to his elder siblings. Upon physical examination, a 3 cm scalp hematoma is palpated. His mother says that he sustained it while bumping his head on a table while standing and cruising. The mother states the size of the lesion is somewhat surprising given the child was not phased by the minor trauma. Blood work reveals thrombocytopenia and decreased levels of factor VII. Which of the following mechanism of inheritance is found in the child's most likely disorder?



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A patient with severe hemophilia A presents with hemarthrosis of the knee. Which of the following is the best initial treatment?



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A 14-year-old male with hemophilia A is undergoing surgery to remove his tonsils. Which of the following is the best option for preventing bleeding complications?



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Which of the following statements about hemophilia A is true?



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Which of the following is identified by abnormalities in the partial thromboplastin times?



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A patient has a lifelong history of bleeding and has low factor VIII levels. What is the diagnosis?



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Which of the following is the proper treatment for bleeding in a severe hemophilia A patient?



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A 28-year old man is brought to the emergency department following a history of a hit by a wooden stick by an unknown person an hour ago. On physical examination, he has a subgaleal hematoma of 10 x 3 cm size in the right parietal region, and his Glasgow coma scale score is E3V2M5, and pupils are equal in size and reactive. The paramedic who brought him in shows a hemophilia A card which was retrieved from the patient's pocket, which indicates that he is suffering from severe hemophilia. How much recombinant factor VIII replacement would be required for him?



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A 17-year-old male with a history of a severe bleeding disorder presents to the emergency department for evaluation and treatment of the abrupt, atraumatic onset of tingling, swelling, and pain of his right knee. He has a maternal uncle with similar complaints of easy bruising and prolonged bleeding after minor cuts. Which of the following therapeutic interventions will provide him with the most benefit?



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A 14-year-old male with a history of mild hemophilia A presents for evaluation of bleeding from a right knee abrasion after an inadvertent fall. Which of the following is the best initial therapy for this patient?



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Hemophilia A - References

References

López Fernández MF, Limitations of prophylactic treatment in patients with hemophilia. Blood coagulation     [PubMed]
Mahlangu J, Emicizumab for the Prevention of bleeds in Hemophilia A. Expert opinion on biological therapy. 2019 May 31;     [PubMed]
Oldenburg J,Hay CRM,Jiménez-Yuste V,Peyvandi F,Schved JF,Szamosi J,Winding B,Lethagen S, Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: the A-SURE study. BMJ open. 2019 May 30;     [PubMed]
Ulrich-Merzenich G,Hausen A,Zeitler H,Goldmann G,Oldenburg J,Pavlova A, The role of variant alleles of the mannose-binding lectin in the inhibitor development in severe hemophilia A. Thrombosis research. 2019 May 9;     [PubMed]
Tegenge MA,Mahmood I,Forshee R, Clinical Pharmacology Review of Plasma-derived and Recombinant Protein Products: CBER Experience and Perspectives on Model-Informed Drug Development. Haemophilia : the official journal of the World Federation of Hemophilia. 2019 May 26;     [PubMed]
Miesbach W,O'Mahony B,Key NS,Makris M, How to discuss gene therapy for haemophilia? A patient and physician perspective. Haemophilia : the official journal of the World Federation of Hemophilia. 2019 May 21;     [PubMed]
Schep SJ,Boes M,Schutgens REG,van Vulpen LFD, An update on the 'danger theory' in inhibitor development in hemophilia A. Expert review of hematology. 2019 May;     [PubMed]
Samuelson Bannow B,Recht M,Négrier C,Hermans C,Berntorp E,Eichler H,Mancuso ME,Klamroth R,O'Hara J,Santagostino E,Matsushita T,Kessler C, Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood reviews. 2019 May;     [PubMed]
Top O,Geisen U,Decker EL,Reski R, Critical Evaluation of Strategies for the Production of Blood Coagulation Factors in Plant-Based Systems. Frontiers in plant science. 2019;     [PubMed]
Preijers T,Schütte LM,Kruip MJHA,Cnossen MH,Leebeek FWG,van Hest RM,Mathôt RAA, Strategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and B. Therapeutic drug monitoring. 2019 Apr;     [PubMed]
Lasne D,Pouplard C,Nougier C,Eschwege V,Duchez VLC,Proulle V,Smahi M,Harzallah I,Voisin S,Toulon P,Sobas F,Galinat H,Flaujac C,Ternisien C,Jeanpierre E, Factor VIII assays in treated hemophilia A patients. Annales de biologie clinique. 2019 Feb 1;     [PubMed]
Emicizumab for haemophilia A. Australian prescriber. 2019 Feb;     [PubMed]

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