Hemophilia

The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Management is focused mainly on treatment of acute bleeding events and prevention of bleeding events via replacement of deficient factors.

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Overview

Definition

Hemophilias are a group of disorders of secondary hemostasis due to the deficiency of specific clotting factors.

Epidemiology

About 400 children per year are born with hemophilia in the United States.

3 different types have been described:

  • Hemophilia A:
    • Almost always affects males (X-linked recessive)
    • 1 in 5000 males
    • Most common: represents 80% of all cases
  • Hemophilia B: 
    • Almost always affects males (X-linked recessive)
    • 1 in 30,000 males
    • Clinically indistinguishable from hemophilia A 
  • Hemophilia C: 
    • Affects males and females equally
    • May be autosomal recessive or autosomal dominant depending on specific mutation
    • 1 in 1 million males and females

Etiology

Genetic mutation resulting in deficiency of clotting factors:

  • Hemophilia A:
    • Factor VIII: X-linked recessive mutations in the F8 gene
    • Located on the X chromosome
  • Hemophilia B (Christmas disease):
    • Factor IX: X-linked recessive mutations in the F9 gene
    • Located on the X chromosome
  • Hemophilia C: 
    • Factor XI: mutations in the F11 gene
    • Located on chromosome 4

Acquired hemophilia:

  • The patient has developed immune-mediated autoantibodies against clotting proteins (most commonly factor VIII).
  • Idiopathic in 50%
  • Can be secondary to autoimmune disorders such as lupus, rheumatoid arthritis, multiple sclerosis, Sjögren’s syndrome, and inflammatory bowel disease 
  • Other predisposing conditions include major trauma and pregnancy.

Pathophysiology

Genetics

  • Mutations of F8 gene on X chromosome:
    • 40%–45% of severe cases of hemophilia A are caused by a major inversion of the intron 22 section on the long arm of the X chromosome.
    • 1%–5% of severe cases of hemophilia A are caused by a major inversion of the intron 1 section on the long arm of the X chromosome.
    • Point mutations and small deletions/insertions are present in approximately 60% of cases of hemophilia A, but no specific mutation or deletion predominates.
  • Mutations of F9 gene on X chromosome:
    • Highly heterogeneous: include deletions, duplications, insertions, splice-site variants, missense variants, and nonsense variants
    • 40%–45% of severe cases of hemophilia B are caused by missense variants.
  • Mutations of F11 gene on chromosome 4:
    • > 200 distinct pathogenic variants in the F11 gene have been reported.
    • Phe283Leu missense mutation in exon 9 is responsible for a higher prevalence among those of Ashkenazi Jewish ancestry.

Location of F8 gene for coagulation factor VIII: Xq28, resulting in hemophilia A

Image: “F8 gene location” by Genome Decoration Page/NCBI. License: Public Domain

Clotting cascade

  • Produces stable fibrin clot at the site of injury
  • Two clotting pathways exist: intrinsic and extrinsic
  • The two pathways converge to a common pathway; the end result is formation of a fibrin clot.
  • Factors Ⅷ and Ⅸ are components of the intrinsic pathway.
  • Factor ⅩⅠ is a component of the common pathway.
  • Factor deficiencies result in the dysfunction of hemostasis:
    • Reduced activation of prothrombin to thrombin → reduced levels of thrombin
    • Decreased fibrin clot formation →  delayed hemostasis
  • Severity of disease is proportional to severity of deficiency:
    • Mild: > 5% of normal levels
    • Moderate: 1%–5% of normal levels
    • Severe: < 1% of normal levels

Clotting cascade

Image by Lecturio.

Clinical Presentation

Manifestations

Presentation is based mainly on the severity of the factor deficiency.

Mild to moderate deficiency:

  • Presents after trauma or surgery
  • Average age at onset > 10 months, when the child begins to crawl or walk
  • Bleeding out of proportion to expected tissue response given level of trauma
  • Hemarthrosis (bleeding into joints):
    • Joint effusion may lead to pain and ↓ range of motion.
    • Repetitive effusions may cause early joint destruction.
  • Hematoma (bleeding into muscle):
    • With or without excessive bruising
    • May lead to compartment syndrome

More severe deficiency:

  • Presents first in early infancy:
    • At birth: intracranial bleeding or cephalohematoma from cranial deformation due to normal vaginal birth trauma
    • 1–10 days: prolonged bleeding after circumcision
    • 1–4 weeks: bleeding from umbilical stump
  • May present with spontaneous bleeding at any age
  • Nosebleeds and bleeding gums after brushing teeth
  • CNS (intracranial bleeding):
    • May present with altered mental status, lethargy, vomiting
    • Warrants immediate medical attention 
  • GI  (bleeding into the GI tract):
    • May present with hematemesis, bloody stools if gross bleeding
    • May present with symptoms/signs of anemia, black stools if occult bleeding
  • Genitourinary (bleeding into the urinary tract):
    • May present with hematuria if gross bleeding
    • May present with symptoms/signs of anemia if occult bleeding

Long-term complications

  • Hemophilic arthropathy:
    • Components of blood are caustic to the synovium.
    • Causes progressive joint destruction, loss of range of motion
  • Infections associated with transfusion of blood products:
    • Rare with appropriate screening precautions, which were instituted in 1985
    • Many surviving adults who received transfusions prior to that are infected with bloodborne pathogens
  • Development of factor VIII autoantibodies (factor VIII inhibitors) after repetitive transfusions:
    • Patients develop an “allergy” to potentially lifesaving treatment → increased susceptibility to severe bleeding complications
    • Can indirectly lead to delayed growth, delayed sexual development

Diagnosis

The diagnosis of hemophilia is made on the basis of clinical suspicion (usually due to a bleeding event) followed by demonstration of deficient factor levels (< 40%).

History

  • Family history may be present in male ancestors.
  • Negative family history does not exclude the diagnosis.
  • Reports of bruising, spontaneous bleeding, or bleeding out of proportion to a given trauma  
  • Reports of hemarthrosis, hematuria, hematemesis, etc. 

Physical examination

  • Ecchymoses
  • Hemarthroses
  • Hematomas 

Laboratory evaluation

  • CBC:
    • Normal to decreased hemoglobin/hematocrit depending on occult or gross bleeding
    • Normal platelet count 
  • Coagulation studies: 
    • Normal bleeding time
    • Normal PT 
    • Elevated aPTT: intrinsic pathway
    • Low serum levels of factor VIII, IX, or XI (factor will be < 40% normal range)
    • Check von Willebrand’s factor (VWF) if factor VIII levels are low to rule out von Willebrand’s disease
  • Genetic testing:
    • Genetic testing is not needed to diagnose hemophilia.
    • Generally reserved for female first-degree relatives for the purposes of family planning/genetic counseling
  • Imaging: 
    • CT of brain: evaluate for intracranial bleeding 
    • CT of abdomen: evaluate for retroperitoneal bleeding/hematoma
    • Ultrasonography of abdomen: evaluate for retroperitoneal bleeding/hematoma
    • Ultrasonography of joint: evaluate for joint swelling/hemarthrosis

Management

General considerations

  • Genetic counseling
  • Careful surgical and/or obstetric planning
  • Avoid contact sports.
  • Avoid drugs that hamper platelet function (aspirin, NSAIDs).
  • Pain management in selected cases

Chronic prophylactic deficiency correction for patients with severe deficiency

  • Chronic infusions of deficient factor to maintain levels above the critical range:
    • 2–3 transfusions/week (though longer-acting formulations are available)
    • Goal is to maintain levels at > 1%.
    • Recombinant factor VIII concentrate for hemophilia A
    • Recombinant factor IX concentrate for hemophilia B
    • Factor XI concentrate or fresh frozen plasma (FFP) for hemophilia C 
  • Desmopressin for mild hemophilia A: Desmopressin increases endothelial release of factor VIII, but not factor IX, and VWF.
  • Antifibrinolytic agents: epsilon-amino caproic acid or tranexamic acid to control local bleeding (bleeding in the gums or GI tract and during oral surgery)
  • Monoclonal antibody emicizumab approved by the Food and Drug Administration (FDA) for prophylaxis of bleeding in hemophilia A:
    • Not associated with the development of factor VIII inhibitors
    • Limited coverage by 3rd-party payers, cost, and limited availability restrict usage.

Acute bleeding episodes

  • Immediate transfusion of the deficient factor: 
    • Recombinant factor VIII concentrate for hemophilia A
    • Recombinant factor IX concentrate for hemophilia B
    • Factor XI concentrate or FFP for hemophilia C
  • Co-transfusion with packed RBCs in the setting of hemodynamic instability

Surgical evaluation/intervention

  • Intracranial hemorrhage 
  • Compartment syndrome 
  • Hematoma debridement/debulking/evacuation 
  • Arthrocentesis, joint replacement

Prognosis

  • Severe hemophilia results in a limited life expectancy.
  • Availability of factor concentrates → dramatic improvement in life expectancy and in quality of life 
  • Life expectancy for hemophilia patients born after 1985 is around 65 years.
  • The most common cause of death is liver failure.
  • Complications of HIV and hepatitis C infection remain the most important cause of death in patients born prior to 1985.

Differential Diagnosis

  • Liver failure: The liver is the site for synthesis of coagulation factors; thus, a dysfunctional liver would result in deficiency in the clotting factors. Failure would be diagnosed clinically in the setting of liver disease with confirmation of the nature of the bleeding diathesis via laboratory workup. Treatment is aimed at controlling bleeding, replacing deficient clotting factors, and addressing the underlying cause of liver disease. 
  • Vitamin K deficiency: Vitamin K is needed for the activation of clotting factors II, VII, IX, and X; thus, a deficiency would lead to inactivation of these factors and present with bleeding complications. Diagnosis is made by laboratory workup demonstrating low vitamin K levels and downstream deficiency of associated clotting factors. Treatment is aimed at control of bleeding and correct vitamin K deficiency and/or deficient clotting factors.
  • Disseminated intravascular coagulation (DIC): Disseminated intravascular coagulation, an imbalance between native prothrombotic and antithrombotic factors, is a complication of many diseases. An inciting event causes widespread thrombosis (exhausting available clotting factor reserves) followed by uncontrolled bleeding. It has high morbidity and mortality and thus requires critical care intervention. Treatment is aimed at control of bleeding, resuscitation to maintain hemodynamic stability, and addressing the inciting event.  
  • Thrombotic thrombocytopenic purpura (TTP): a disorder due to a deficiency in the metalloproteinase responsible for breakdown of VWF, which can be congenital or acquired: Thrombotic thrombocytopenic purpura falls into the differential diagnosis with idiopathic thrombocytopenic purpura (ITP) and DIC, all presenting with thrombocytopenia. Thrombotic thrombocytopenic purpura is more acute than hemophilia and requires urgent plasmapheresis.
  • Henoch–Schönlein purpura: an autoimmune small-vessel vasculitis: Henoch–Schönlein purpura typically presents as a tetrad of abdominal pain, hematuria, purpuric rash, and hematuria. The disorder is diagnosed clinically and managed symptomatically.
  • Von Willebrand disease: an inherited autosomal bleeding disorder that can present with mild to moderate bleeding at any age: Diagnosis is made by demonstration of VWF deficiency on laboratory analysis. Treatment is with control of bleeding and administration of desmopressin and antifibrinolytic agents.

References

  1. Hoots W, Shapiro A. (2020). Hemophilia A and B: Routine management including prophylaxis. Retrieved March 6, 2021, from https://www.uptodate.com/contents/hemophilia-a-and-b-routine-management-including-prophylaxis
  2. Hoots W, Shapiro A, Heiman M. (2021). Genetics of hemophilia A and B. Retrieved March 6, 2021, from https://www.uptodate.com/contents/genetics-of-hemophilia-a-and-b
  3. Bérubé C. (2021). Factor XI (eleven) deficiency. Retrieved March 6, 2021, from https://www.uptodate.com/contents/factor-xi-eleven-deficiency
  4. Kasper D, Fauci A, Hauser S, Longo DL, Jameson J, Loscalzo J. (2012). Harrison’s Principles of Internal Medicine (18th ed.). New York: McGraw Hill Education, pp. 2180–2186.
  5. Duga S, Salomon O. (2013). Congenital factor XI deficiency: An update. Seminars in Thrombosis Hemostasis 39(6):621–631.

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