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.
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.
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.
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.
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.
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.
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.
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.
With the confirmation of the diagnosis of hemophilia A 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.
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.