Coagulation Disorders

Inherited defects (non-modifiable)

• Hemophilia A and B: X-linked recessive loss-of-function mutations in F8 or F9; an intron 22 inversion accounts for a large share of severe hemophilia A. Roughly a third of cases arise from de novo mutation, so absence of family history does not exclude hemophilia — a classic stem trap.
• von Willebrand disease: autosomal, the most common inherited bleeding disorder; type 1 (partial quantitative) predominates, type 2 variants are qualitative, type 3 is near-complete deficiency. Type 2N (Normandy) mimics hemophilia A because vWF cannot chaperone factor VIII.
• Thrombophilias: factor V Leiden, prothrombin G20210A, and deficiencies of protein C, protein S, or antithrombin — inherited, unmodifiable, and additive with acquired triggers.

Acquired defects (largely modifiable)

• Vitamin K deficiency: newborns (sterile gut, poor placental transfer — the AAP recommends universal IM vitamin K prophylaxis at birth), fat malabsorption (cholestasis, cystic fibrosis, celiac), prolonged broad-spectrum antibiotics, and warfarin. Factor VII's short half-life makes PT/INR prolong first.
• Liver disease: synthetic failure of all factors except factor VIII (endothelially produced), plus dysfibrinogenemia and thrombocytopenia from portal hypertension.
• Drugs: warfarin, heparins, DOACs, and antiplatelet agents; alcohol, which impairs both synthesis and platelet function.
• Acquired hemophilia A: autoantibody to factor VIII in the elderly, postpartum patients, and those with malignancy or autoimmune disease.
• Acquired vWD: shear-mediated cleavage of high-molecular-weight multimers in aortic stenosis (Heyde syndrome), LVADs, and myeloproliferative neoplasms.

• Factor deficiencies: Inherited (hemophilia A/B, factor VII deficiency) or acquired (liver disease, vitamin K deficiency, DIC) result in impaired thrombin generation; hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) account for 80-85% of inherited factor deficiencies and show X-linked recessive inheritance
• Fibrinogen abnormalities: Quantitative deficiency (afibrinogenemia, hypofibrinogenemia) or qualitative dysfunction (dysfibrinogenemia) impairs fibrin polymerization and clot stabilization; can be congenital or acquired (sepsis, liver disease, malignancy)
• Platelet disorders: Quantitative defects (thrombocytopenia from bone marrow failure, immune destruction, or sequestration) or qualitative dysfunction (Bernard-Soulier syndrome, Glanzmann thrombasthenia) compromise primary hemostasis
• Inhibitor pathways: Vitamin K-dependent factors (II, VII, IX, X) become deficient when vitamin K is unavailable or blocked; protein C and S (natural anticoagulants) when deficient predispose to thrombophilia
• Thrombophilic defects: Factor V Leiden (resistance to protein C inactivation), prothrombin G20210A mutation, antithrombin III deficiency, protein C/S deficiency, and antiphospholipid syndrome create a hypercoagulable state through loss of anticoagulant function or enhanced thrombin generation
• Disseminated intravascular coagulation (DIC): Widespread activation of coagulation consumes platelets and clotting factors while generating excessive plasmin, resulting in simultaneous bleeding and thrombosis through tissue factor pathway activation in sepsis, malignancy, or trauma

• Bleeding manifestations in factor deficiencies: Spontaneous bleeding into joints (hemarthrosis—classic in hemophilia), muscles, and mucous membranes; delayed bleeding hours to days after trauma distinguishes factor deficiencies from platelet disorders; severe factor deficiency (levels <1%) presents with spontaneous bleeding, while moderate deficiency (1-5%) manifests after minor trauma, and mild deficiency (>5%) only after significant injury
• Hemophilia A/B presentation: Male infants with prolonged bleeding after circumcision or umbilical cord bleeding; toddlers with excessive bruising and hemarthrosis; spontaneous bleeds into CNS (devastating) or GI tract; repeated joint bleeding leads to hemophilic arthropathy with chronic pain and reduced mobility
• Fibrinogen disorders: Severe hypofibrinogenemia or afibrinogenemia present with umbilical cord bleeding in neonates, spontaneous abortion (placental abruption), and severe mucosal bleeding; dysfibrinogenemia may present with thrombotic rather than bleeding manifestations
• Thrombophilic presentations: Unprovoked or provoked venous thromboembolism (DVT, PE) in patients <50 years without atherosclerotic risk factors; recurrent thrombosis despite anticoagulation; thrombosis in unusual sites (mesenteric, cerebral, portal veins); family history of early VTE strongly suggests hereditary thrombophilia
• DIC presentation: Acute phase shows hemorrhagic diathesis (bleeding from lines, mucous membranes, surgical sites) concurrent with microvascular thrombosis (acral necrosis, organ dysfunction); chronic DIC progresses slowly with compensatory fibrinogen production
• Important clinical pearl: Pattern of bleeding differentiates coagulopathies—easy bruising and hemarthrosis suggest factor deficiency, while petechiae and mucosal bleeding indicate platelet disorder; bleeding from multiple sites in setting of sepsis or malignancy raises DIC concern

• Prothrombin time (PT): Tests extrinsic pathway (factors II, V, VII, X, fibrinogen); prolonged PT indicates deficiency of factor VII, X, II, V, or fibrinogen or presence of inhibitors; used to monitor warfarin therapy; INR standardizes PT reporting
• Activated partial thromboplastin time (aPTT): Tests intrinsic and common pathways (factors VIII, IX, XI, XII, II, V, X, fibrinogen); prolonged aPTT with normal PT suggests factor VIII/IX deficiency (hemophilia), factor XI/XII deficiency, or lupus anticoagulant; corrects when normal plasma is added (indicates factor deficiency) but remains prolonged with inhibitor (anticoagulant present)
• Thrombin time (TT): Tests fibrinogen function; prolonged TT occurs with hypofibrinogenemia, dysfibrinogenemia, or high heparin levels; normal PT and aPTT with prolonged TT suggests fibrinogen disorder
• Fibrinogen level: Direct measurement of plasma fibrinogen; normal >100 mg/dL; levels <50 mg/dL cause bleeding symptoms; obtained when TT abnormal or clinical picture suggests fibrinogen disorder
• Specific factor assays: Factor VIII and IX levels are gold standard for hemophilia; factor levels correlate with bleeding risk—levels <1% have spontaneous bleeding, 1-5% have bleeding with minor trauma, >5% bleed only after significant trauma; activated protein C resistance (APCR) screening followed by factor V Leiden genotyping confirms most common thrombophilia
• Mixing studies: Normal plasma added to patient plasma; if aPTT/PT corrects, indicates factor deficiency; if remains prolonged, indicates inhibitor (autoantibody or acquired anticoagulant like lupus anticoagulant)
• Important diagnostic considerations: Factor levels vary with stress and estrogen use (oral contraceptives elevate VIII, IX); hemophilia carrier females can manifest symptoms if X-inactivation is skewed; DIC diagnosis requires constellation of findings—low platelets, low fibrinogen, elevated PT/aPTT, elevated D-dimer, elevated fibrin degradation products (FDP)—not single test

Hemophilia A and B

• First-line: Factor VIII/IX replacement targeting 30-50% factor levels for minor bleeding (hemarthrosis, muscle hematoma), 50-100% for major bleeds (CNS, GI), or perioperatively; dosing calculated as: units needed = (desired % - baseline %) × weight (kg) × 0.5 for factor VIII or 1.0 for factor IX; dosed every 8-12 hours (factor VIII half-life 8-12 hours) or every 18-24 hours (factor IX half-life 18-24 hours)
• Recombinant versus plasma-derived: Recombinant factors preferred due to viral safety; extended half-life products (pegylated, Fc-fusion) allow less frequent dosing (every 3-4 days for factor VIII, weekly for factor IX)
• Non-factor replacement strategies: Bypassing agents (activated prothrombin complex concentrate [

Complications of the disease

• Intracranial hemorrhage (emergency): the leading cause of bleeding death in hemophilia. Headache, vomiting, or altered mental status after even trivial head trauma mandates factor replacement to 80–100% activity BEFORE imaging — do not delay for the CT (WFH guidance).
• Airway/retropharyngeal or neck hematoma (emergency): expanding mass compresses the airway; give factor and secure the airway early.
• Iliopsoas hematoma (emergency): presents with groin/flank pain, hip held in flexion, and femoral neuropathy (numb anteromedial thigh, weak knee extension); can sequester liters of blood.
• Compartment syndrome: forearm/calf muscle bleeds cause pain out of proportion and pain with passive stretch; pulses are preserved until late.
• Hemophilic arthropathy: repeated hemarthrosis drives iron-induced synovitis, cartilage destruction, and fixed target joints — the chief cause of long-term disability.
• Hemophilic pseudotumor: encapsulated chronic hematoma that erodes bone.
• DIC sequelae (emergency): microvascular thrombosis producing purpura fulminans, acral gangrene, AKI, and ARDS, occurring alongside oozing from every line and puncture site; falling fibrinogen with rising D-dimer signals progression (ISTH DIC score).
• Anemia and iron deficiency from heavy menstrual bleeding in vWD and in symptomatic hemophilia carriers.

Complications of treatment

• Alloantibody inhibitors: neutralizing antibodies to infused factor VIII (or IX) in a substantial minority of severe hemophilia A patients. Signal: a bleed that stops responding to adequate factor dosing; confirm with a Bethesda assay and mixing study. Managed with bypassing agents and immune tolerance induction per WFH.
• Anaphylaxis and nephrotic syndrome: characteristic of factor IX inhibitors during immune tolerance induction.
• DDAVP toxicity: free-water retention causing hyponatremia and seizures, particularly in young children; tachyphylaxis limits repeat dosing.
• Thrombotic microangiopathy/thrombosis: reported with emicizumab given together with activated prothrombin complex concentrate — a boxed safety concern.
• Transfusion-transmitted HIV/HCV: historical, from pre-1985 plasma-derived concentrates; a favorite stem detail in older patients.
• Warfarin-induced skin necrosis: early protein C depletion in protein C–deficient patients; heparin-induced thrombocytopenia with heparin exposure.

• Isolated prolonged aPTT with normal PT and normal platelets should trigger a mixing study: correction implies factor deficiency; failure to correct implies an inhibitor (acquired hemophilia or lupus anticoagulant). The deficiency differential is hemophilia A/B, von Willebrand disease (especially type 2N and type 3), and factor XI deficiency — then send specific factor assays plus vWF studies. Conversely, a normal aPTT does not exclude mild factor deficiency or mild vWD.
• vWD is the most common inherited bleeding disorder and the answer for a young woman with heavy menses, epistaxis, and easy bruising. The aPTT is prolonged only when factor VIII is sufficiently reduced (marked in type 3 and type 2N); in type 1, factor VIII is often only mildly low and the aPTT is frequently normal. Diagnosis rests on vWF antigen, ristocetin cofactor/platelet-binding activity, and multimer analysis. DDAVP works for type 1; avoid DDAVP in type 2B, where it worsens thrombocytopenia by promoting platelet clumping.
• Vitamin K deficiency vs. liver disease: check factor V — normal in vitamin K deficiency, low in liver disease (both show low II, VII, IX, X). Liver disease vs. DIC: check factor VIII — normal or high in liver failure (endothelial origin, not hepatocyte-derived), low in DIC from consumption. Low fibrinogen with high D-dimer and schistocytes points to DIC; the definitive move is treating the underlying trigger — antibiotics for sepsis, delivery for obstetric DIC, ATRA started on clinical suspicion of APL per NCCN.
• Factor XII deficiency prolongs the aPTT but causes no bleeding — the classic distractor. Similarly, lupus anticoagulant prolongs aPTT in vitro yet causes thrombosis in vivo.
• A normal PT/aPTT does not exclude a bleeding disorder: factor XIII deficiency (delayed umbilical stump bleeding, poor wound healing) and mild platelet function defects have normal screens.
• For major warfarin-associated bleeding, give 4-factor PCC plus IV vitamin K, not FFP alone (ACC expert consensus on anticoagulant reversal; ASH guidance) — FFP is slower and volume-heavy.
• The one association to memorize: Heyde syndrome — aortic stenosis, acquired vWD from shear-cleaved high-molecular-weight multimers, and GI angiodysplasia bleeding; AVR reliably resolves the acquired vWD and typically stops the angiodysplasia bleeding.
• New head trauma in hemophilia: factor first, imaging second.