A 35-year-old man of Indian origin presents with a 3-month history of recurrent epistaxis, gum bleeding, and spontaneous bruising. He reports a similar bleeding tendency in his mother and maternal uncle. Physical examination reveals petechiae and ecchymoses on the forearms and legs. Laboratory investigations show: Hemoglobin 12.8 g/dL, Platelet count 250,000/μL (normal), PT 12 s (normal), aPTT 58 s (normal 25–35 s), bleeding time 3 min (normal <9 min), thrombin time 18 s (normal 14–16 s). Prothrombin time-based mixing study corrects the aPTT. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Factor VIII Deficiency (Hemophilia A) ### Key Laboratory Pattern **Key Point:** The isolated prolonged aPTT that corrects on mixing study indicates a **deficiency of a factor in the intrinsic pathway**. Combined with X-linked inheritance pattern (mother and maternal uncle affected) and normal PT, this is diagnostic of hemophilia A (Factor VIII deficiency). ### Laboratory Interpretation | Test | Result | Interpretation | |------|--------|----------------| | Platelet count | 250,000/μL | Normal — rules out thrombocytopenia | | PT | 12 s (normal) | Normal extrinsic pathway (Factors II, V, VII, X) | | aPTT | 58 s (prolonged) | Defect in intrinsic pathway (Factors VIII, IX, XI, XII) | | Bleeding time | 3 min (normal) | Normal platelet function | | Thrombin time | 18 s (prolonged) | Mild fibrinogen abnormality OR Factor VIII deficiency effect | | Mixing study | Corrects aPTT | Confirms **factor deficiency** (not inhibitor) | ### Pathophysiology of Hemophilia A **Mnemonic: COAGULATION CASCADE — Intrinsic Pathway** - **Contact phase:** Factor XII → Factor XI → Factor IX - **Tenase complex:** Factor IX + Factor VIII (cofactor) + Factor X → Factor Xa - **Common pathway:** Factor Xa → Thrombin → Fibrin **Key Point:** Factor VIII is a **cofactor** in the intrinsic tenase complex. Its deficiency causes prolonged aPTT but does NOT affect PT (which tests extrinsic pathway via Factor VII). ### Inheritance Pattern: X-Linked Recessive ```mermaid flowchart TD A[X-linked recessive inheritance<br/>Factor VIII gene on Xq28]:::outcome --> B[Affected males<br/>Hemizygous]:::outcome A --> C[Carrier females<br/>Heterozygous]:::outcome B --> D[Severe bleeding<br/>in childhood]:::action C --> E[Mild symptoms<br/>or asymptomatic]:::action E --> F[Can transmit to<br/>50% of sons]:::action ``` **Clinical Pearl:** In this case, the **mother and maternal uncle are affected**, suggesting the patient inherited the mutation from his mother (who is a carrier or mildly affected due to skewed X-inactivation). ### Severity Classification | Severity | Factor VIII Level | Clinical Presentation | |----------|-------------------|----------------------| | **Severe** | <1% | Spontaneous bleeding (joints, muscles, CNS); bleeding in infancy | | **Moderate** | 1–5% | Bleeding with minor trauma; epistaxis, hematuria | | **Mild** | 5–40% | Bleeding with significant trauma or surgery; prolonged bleeding | **High-Yield:** This patient's presentation (recurrent epistaxis, gum bleeding, spontaneous bruising at age 35) suggests **mild-to-moderate hemophilia A**. ### Why This Is NOT the Other Options **Factor V deficiency:** - Rare autosomal recessive disorder - Causes **both prolonged PT AND aPTT** (Factor V is in both extrinsic and common pathways) - This patient has normal PT, ruling out Factor V deficiency **Vitamin K deficiency:** - Affects Factors II, VII, IX, X (vitamin K–dependent factors) - Causes **prolonged PT** (Factor VII has shortest half-life) - aPTT may be prolonged if severe (Factors II, IX, X deficient) - This patient has normal PT, ruling out vitamin K deficiency **von Willebrand disease:** - Autosomal dominant (not X-linked) - Causes **prolonged bleeding time** (platelet dysfunction) and variable aPTT - This patient has **normal bleeding time**, ruling out vWD - Typically presents with mucosal bleeding (epistaxis, menorrhagia) but NOT joint/muscle bleeding ### Confirmatory Test **Key Point:** **Factor VIII assay** (one-stage or chromogenic) will show reduced Factor VIII activity (<40% of normal). This is the gold standard for diagnosis. ### Management **High-Yield:** Treatment is **Factor VIII replacement therapy:** - **Acute bleeding:** Factor VIII concentrate (recombinant or plasma-derived) to achieve 50–100% factor level - **Prophylaxis:** Regular Factor VIII infusions (2–3 times weekly) to maintain trough level >1% - **Adjunctive:** Desmopressin (DDAVP) may increase endogenous Factor VIII in mild cases (but NOT in severe hemophilia A) [cite:Harrison 21e Ch 139]