Hemophilia

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Basics

Description

  • Deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) coagulation proteins leading to bleeding tendencies in affected individuals. The majority of cases are due to inherited genetic mutations in factor VIII or factor IX coagulation proteins. However, an estimated 30% of all hemophilia cases result from spontaneous mutations.
  • Hemophilia A and B are clinically indistinguishable but can be differentiated by assays that detect levels of factors VIII and IX, respectively.
  • Disease severity correlates with the relative levels of coagulation factors present in serum analysis:
    • Severe: frequent spontaneous bleeding (factor activity <1%)
    • Moderate: occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery (factor activity 1–5%)
    • Mild: rare spontaneous bleeding, severe bleeding with major trauma, or surgery (factor activity 5–40%)
  • Bleeding frequency is similar in hemophilia A and B with similar levels of factor deficiency (1)[A].

Epidemiology

  • Worldwide, an estimated 1,125,000 people are affected with hemophilia (1)[A].
  • Hemophilia A represents 80–85% of the total hemophilia population; hemophilia B comprises the remaining 15–20%.

Prevalence
  • Estimated prevalence of hemophilia A at birth is 24.6 per 100,000 males (9.5 cases for severe hemophilia A).
  • Estimated prevalence of hemophilia B at birth is 5 cases per 100,000 males (1.5 cases for severe hemophilia B) (1)[A].

Etiology and Pathophysiology

  • Damage to vascular endothelium leads to exposure of subendothelial tissue factors, which interact with platelets, plasma proteins, and coagulation factors to produce a localized platelet plug contributing to hemostasis. Complexes involving factors VIII and IX participate in the intrinsic coagulation pathway to activate factor X, FXa. Downstream interactions involving FXa culminate in the conversion of prothrombin to thrombin, mediating platelet activation and fibrin deposition necessary for stabilization of the platelet plug.
  • Deficiencies of factor VIII or factor IX result in decreased production of FXa, leading to an unstable platelet plug and impaired hemostasis.

Genetics
  • Exhibits an X-chromosome linked inheritance pattern. Males are almost exclusively affected; females are usually asymptomatic carriers. Females with hemophilia have both X chromosomes affected, or one X chromosome is affected and the other is inactivated.
  • Carriers may have symptomatically low clotting factor levels:
    • May bleed at the time of surgery
  • Males within the same family share similar deficiencies and level of severity owing to the same genetic defect.

General Prevention

  • Patients should carry medical ID tags listing their factor deficiency, inhibitor status, type of treatment products used, and initial treatment doses for mild, moderate, or severe bleeding.
  • Immediate family members of affected patients should have factor VIII and IX levels checked prior to invasive procedures, childbirth, and if bleeding tendencies occur.
  • Genetic testing should be offered to at-risk female family members to facilitate genetic counseling.
  • Regular dental care and good oral hygiene are recommended to prevent gum bleeding.

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Basics

Description

  • Deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) coagulation proteins leading to bleeding tendencies in affected individuals. The majority of cases are due to inherited genetic mutations in factor VIII or factor IX coagulation proteins. However, an estimated 30% of all hemophilia cases result from spontaneous mutations.
  • Hemophilia A and B are clinically indistinguishable but can be differentiated by assays that detect levels of factors VIII and IX, respectively.
  • Disease severity correlates with the relative levels of coagulation factors present in serum analysis:
    • Severe: frequent spontaneous bleeding (factor activity <1%)
    • Moderate: occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery (factor activity 1–5%)
    • Mild: rare spontaneous bleeding, severe bleeding with major trauma, or surgery (factor activity 5–40%)
  • Bleeding frequency is similar in hemophilia A and B with similar levels of factor deficiency (1)[A].

Epidemiology

  • Worldwide, an estimated 1,125,000 people are affected with hemophilia (1)[A].
  • Hemophilia A represents 80–85% of the total hemophilia population; hemophilia B comprises the remaining 15–20%.

Prevalence
  • Estimated prevalence of hemophilia A at birth is 24.6 per 100,000 males (9.5 cases for severe hemophilia A).
  • Estimated prevalence of hemophilia B at birth is 5 cases per 100,000 males (1.5 cases for severe hemophilia B) (1)[A].

Etiology and Pathophysiology

  • Damage to vascular endothelium leads to exposure of subendothelial tissue factors, which interact with platelets, plasma proteins, and coagulation factors to produce a localized platelet plug contributing to hemostasis. Complexes involving factors VIII and IX participate in the intrinsic coagulation pathway to activate factor X, FXa. Downstream interactions involving FXa culminate in the conversion of prothrombin to thrombin, mediating platelet activation and fibrin deposition necessary for stabilization of the platelet plug.
  • Deficiencies of factor VIII or factor IX result in decreased production of FXa, leading to an unstable platelet plug and impaired hemostasis.

Genetics
  • Exhibits an X-chromosome linked inheritance pattern. Males are almost exclusively affected; females are usually asymptomatic carriers. Females with hemophilia have both X chromosomes affected, or one X chromosome is affected and the other is inactivated.
  • Carriers may have symptomatically low clotting factor levels:
    • May bleed at the time of surgery
  • Males within the same family share similar deficiencies and level of severity owing to the same genetic defect.

General Prevention

  • Patients should carry medical ID tags listing their factor deficiency, inhibitor status, type of treatment products used, and initial treatment doses for mild, moderate, or severe bleeding.
  • Immediate family members of affected patients should have factor VIII and IX levels checked prior to invasive procedures, childbirth, and if bleeding tendencies occur.
  • Genetic testing should be offered to at-risk female family members to facilitate genetic counseling.
  • Regular dental care and good oral hygiene are recommended to prevent gum bleeding.

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