Hematology · Coagulation Disorders
The facts most likely to be tested
Hemophilia A is an X-linked recessive disorder caused by a deficiency of Factor VIII.
Patients present with hemarthrosis, deep tissue hematomas, and prolonged bleeding after minor trauma or surgery.
Laboratory evaluation reveals an isolated prolonged PTT with a normal PT and normal platelet count.
The mixing study will show correction of the prolonged PTT, confirming a factor deficiency rather than an inhibitor.
Definitive diagnosis is established by a low Factor VIII activity level.
First-line treatment for acute bleeding episodes is recombinant Factor VIII concentrate infusion.
Desmopressin (DDAVP) is used in mild cases to transiently increase Factor VIII levels by stimulating the release of von Willebrand factor.
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A 4-year-old boy is brought to the clinic after his parents noticed recurrent swelling and pain in his right knee following a minor fall. He has a history of prolonged oozing after a recent tooth extraction. Physical examination reveals a swollen, warm, and tender knee joint with limited range of motion. Laboratory studies show a prolonged PTT of 68 seconds, a normal PT, and a normal platelet count.
What is the most likely diagnosis?
Hemophilia A
The patient's presentation of hemarthrosis and isolated prolonged PTT is classic for Hemophilia A, which is confirmed by low Factor VIII activity.
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Etiology / Epidemiology
X-linked recessive deficiency of Factor VIII; primarily affects males.
Clinical Manifestations
Deep tissue bleeding, hemarthrosis, and delayed post-traumatic bleeding.
Diagnosis
Prolonged aPTT that corrects with mixing study; low Factor VIII activity.
Treatment
First-line is Factor VIII concentrate; use desmopressin for mild cases.
Prognosis
Risk of inhibitor development; monitor for intracranial hemorrhage.
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Epidemiology & Etiology
This is an X-linked recessive disorder caused by mutations in the F8 gene. It is the most common severe hereditary coagulation disorder, occurring in approximately 1 in 5,000 live male births. One-third of cases arise from de novo mutations with no prior family history.
Pertinent Anatomy
The coagulation cascade relies on the intrinsic pathway, where Factor VIII acts as a critical cofactor for Factor IXa to activate Factor X. Deficiencies localize bleeding to joints, muscles, and deep soft tissues rather than superficial mucosal surfaces.
Pathophysiology
The absence of functional Factor VIII prevents the formation of the tenase complex, leading to impaired thrombin generation. This results in an inability to form a stable fibrin clot, causing persistent or recurrent bleeding. Clinical severity correlates with residual factor activity: severe is <1%, moderate is 1-5%, and mild is 5-40%.
Clinical Manifestations
Patients present with hemarthrosis (bleeding into joints), which leads to chronic arthropathy and joint deformity. Deep muscle hematomas and compartment syndrome are significant risks. Unlike platelet disorders, mucosal bleeding and petechiae are rare; however, intracranial hemorrhage is a leading cause of mortality.
Diagnosis
The aPTT is characteristically prolonged, while the PT and platelet count remain normal. A mixing study will show correction of the aPTT, confirming a factor deficiency rather than an inhibitor. The definitive diagnosis is established by a Factor VIII activity assay showing levels below the normal range.
Treatment
For acute bleeding or prophylaxis, Factor VIII concentrate is the standard of care. In mild cases, desmopressin (DDAVP) can be used to transiently increase endogenous Factor VIII levels. Avoid aspirin and NSAIDs due to their antiplatelet effects, which exacerbate bleeding risk.
Prognosis
The primary long-term complication is the development of alloantibody inhibitors against infused factor, rendering standard therapy ineffective. Patients require lifelong monitoring for joint health and blood-borne pathogens. Intracranial hemorrhage remains the most feared acute complication.
Differential Diagnosis
Hemophilia B: clinically indistinguishable, requires Factor IX assay
Von Willebrand Disease: usually presents with mucosal bleeding and normal aPTT
Vitamin K deficiency: presents with prolonged PT and aPTT
DIC: associated with systemic illness and abnormal platelet count/fibrinogen
Acquired Hemophilia: sudden onset in elderly patients with positive inhibitor screen