Coagulation Disorders – Comprehensive Study Notes

Hemostasis: Core Concepts

Physiology: From Vessel Injury to Stable Clot

  • Vascular spasm: Immediate local vasoconstriction (↑ prostaglandins)
  • Primary hemostasis (platelet plug)
    • Exposure of sub-endothelial matrix → platelet adhesion (GpIb–FvW)
    • Activation (shape change, granule release, surface phospholipid flip)
    • Aggregation via fibrinogen bridges (GpIIb/IIIa) → unstable “white thrombus”
  • Secondary hemostasis (coagulation cascade) stabilises plug with fibrin mesh
    • Intrinsic pathway: XII→XIIa→XIa→IXa+VIIIaXII \rightarrow XIIa \rightarrow XIa \rightarrow IXa + VIIIa
    • Extrinsic pathway: Tissue factor ((III)) + VIIaVIIa
    • Common pathway: Xa+Va⇒II (prothrombin)⇒IIa (thrombin)⇒I (fibrinogen)⇒Ia (fibrin)Xa + Va \Rightarrow II \,(\text{prothrombin}) \Rightarrow IIa\,(\text{thrombin}) \Rightarrow I \,(\text{fibrinogen}) \Rightarrow Ia\,(\text{fibrin}); XIIIaXIIIa cross-links → stable clot
  • “CR7 mnemonic”: III(3)+VII(7)=X(10)III(3)+VII(7)=X(10); special numbers 3 & 13
  • Physiological inhibitors / fibrinolysis
    • Antithrombin III: inactivates IIa, Xa > IXa, XIa, XIIa
    • Protein C + co-factor Protein S: degrade Va & VIIIa
    • Tissue plasminogen activator (tPA) → plasmin → fibrin ⇒ fibrin→D-dimers\text{fibrin} \rightarrow \text{D-dimers}

Laboratory Evaluation of Coagulation

Global Screening Tests

  • aPTT (intrinsic + common: XII, XI, IX, VIII, X, V, II, I)
  • PT / INR (extrinsic + common: VII, X, V, II, I); INR=PT<em>patientPT</em>control\text{INR}=\dfrac{\text{PT}<em>{\text{patient}}}{\text{PT}</em>{\text{control}}}
  • Thrombin Time (TT): conversion of I → Ia; ↑ with heparin or dys/afibrinogenemia
  • Reptilase Time: same step as TT but not affected by heparin
  • D-dimers: sensitive marker of recent fibrin turnover; high NPV for VTE
  • Specific factor assays ± fibrinogen quantification

Typical Causes of Prolongation

Isolated ↑ aPTT
  • Severe liver disease, DIC, Hemophilia A (VIII) or B (IX), von Willebrand (2N,3), other rare factor deficits, heparin, direct Xa inhibitors, lupus anticoagulant, factor inhibitors, vit K lack (late, mild)
Isolated ↑ PT
  • Vit K antagonists/deficiency, liver disease (early), DIC, isolated VII deficiency, factor inhibitors, DOACs
↑ TT
  • Quantitative/qualitative fibrinogen defect, heparin, direct IIa inhibitors, liver disease, DIC

Approach to the Bleeding Patient

Step 1 – Primary vs Secondary Hemostasis Pattern

Primary defect (platelets / vessel wall)

  • Immediate bleeding after trauma
  • Mucocutaneous pattern: petechiae, purpura, epistaxis, gingival bleed, menorrhagia
    Secondary defect (coagulation factors)
  • Delayed bleeding (minutes–hours)
  • Deep tissue & joint bleeds (hematomas, hemarthroses); petechiae rare

Step 2 – Congenital vs Acquired

  • Family history, age of onset; most disorders are acquired (drugs, acute/chronic disease)

First-line Panel

  • CBC + platelet count & smear
  • aPTT, PT/INR, TT, fibrinogen
  • Additional tests guided by abnormalities

Congenital Hemorrhagic Disorders

Factor-Deficiency Patterns

PT/INRaPTTProbable deficit
↑↑Common pathway (X, V, II, I ± others)
N↑Intrinsic (VIII, IX, XI, XII) = Hemophilias
↑NFactor VII
NNFactor XIII (only abnormal clot solubility)
TT/Reptilase ↑Fibrinogen defect

Hemophilia A (VIII) & B (IX)

  • X-linked recessive; 1⁄3 de novo; females usually carriers
  • Severity correlates with residual activity
    • Mild 6!–!40%6!\text{–}!40\% – bleeds with major trauma/surgery
    • Moderate 1!–!5%1!\text{–}!5\% – occasional deep bleeds ± spontaneous
    • Severe <1%<1\% – early-onset spontaneous hemarthroses & hematomas
  • Typical presentations: cephalohematoma / ICH at birth, prolonged post-venipuncture bleed, joint bleeds after crawling, dental eruption bleeds
Diagnosis Algorithm
  1. Isolated ↑ aPTT with normal PFA, platelets
  2. 1:1 mixing study → correction ⇒ factor assay (VIII/IX)
  3. If low VIII, exclude von Willebrand (antigen + ristocetin cofactor)
  4. Genetic testing ((F8, F9)) for severity & carrier screening
Management

Prophylaxis

  • Goal: maintain factor ≥ 1%1\%
  • Severe: routine factor infusion from childhood (VIII or IX concentrates)
  • Alternatives Hemophilia A: DDAVP (mild–mod; test response), emicizumab (bispecific Ab mimicking VIII, effective with inhibitors)
    Acute bleeding
  • Start treatment at first symptom
  • Target factor levels: slight bleed 30!–!50%30!\text{–}!50\%; hemarthrosis 40!–!50%40!\text{–}!50\%; major >50%>50\%; life-threatening 80!–!100%80!\text{–}!100\%
  • Adjuvants: tranexamic/aminocaproic acid for mucosal bleeds (contra kidney clots);
    avoid IM inj. & NSAIDs
Development of Inhibitors
  • Allo-antibodies (30 % in Hemophilia A) ⇒ poor response
  • Diagnose: lack of recovery → mixing study non-corrective → Bethesda assay titre
  • Treatment: bypass agents (rVIIa, activated PCC/FEIBA); long-term immune tolerance induction (daily factor) ± immunosuppression

Other Congenital Factor Deficits

  • Much rarer, often AR; hemarthroses uncommon (except VIII/IX)
  • Treat with specific concentrates, PCC, rVIIa, fibrinogen, FXIII as available

von Willebrand Disease (overview vs Hemophilia)

  • AD inheritance; equal sexes; mucocutaneous bleeding + ↑ bleeding time/PFA; aPTT ↑ in types 1, 2N, 3 via ↓ VIII; hemarthroses rare

Acquired Hemorrhagic Disorders

Drug-Related Coagulopathy

Vitamin-K Antagonists (VKA: warfarin, acenocoumarol)
  • Block VKORC1\text{VKORC1} ⇒ ↓ synthesis of II,VII,IX,XII, VII, IX, X + Proteins C/S
  • Bridging with heparin 5 days to avoid transient hyper-coagulable Pc/S drop (risk: warfarin skin necrosis, esp. congenital Pc deficit)
  • Monitoring: PT/INR; teratogenic
  • Reversal
    • Life-threatening bleed or urgent surgery: stop VKA + IV vit-K + 4-factor PCC (or PFC)
    • INR >10 no bleed: vit-K PO; 4.5-10: hold dose ± vit-K; <4.5: skip/reduce dose
DOACs
  • Dabigatran (IIa); Rivaroxaban/Apixaban/Edoxaban (Xa)
  • No routine monitoring; if needed: TT (dabigatran) or anti-Xa assay
  • Contra: mechanical valves, valvular AF, CrCl <30 mL/min, pregnancy, APS
  • Reversal: idarucizumab (dabigatran); andexanet alfa (Xa); PCC ± supportive care
Heparins & Fondaparinux
  • Unfractionated (IV/SC): monitor aPTT/anti-Xa; safe in pregnancy & renal failure; antidote — protamine
  • LMWH: SC, predictable; monitor anti-Xa if needed; avoid CrCl ≤30; lower HIT risk
  • Fondaparinux: selective Xa; no protamine reversal
  • HIT: immune PF4 Abs ⇒ thrombocytopenia + thrombosis

Vitamin K Deficiency

  • Causes: malnutrition, antibiotics, cholestasis/fat malabsorption, liver disease, neonatal (prevented by IM vit-K), VKA therapy
  • Earliest lab change: ↑ PT (VII short half-life) > aPTT
  • Treat: PO/IV vit-K ± PCC/PFC for active bleed

Liver Disease Coagulopathy

  • ↓ most factors except VIII & FvW (↑); ↓ AT III, Pc/S; thrombocytopenia
  • Labs: ↑ PT, aPTT, TT; normal/elevated VIII; low fibrinogen late; consider concomitant DIC if VIII ↓
  • Manage bleed: IV vit-K, platelets <50×10950\times10^9/L, cryoprecipitate if fibrinogen <100 mg/dL100\,\text{mg/dL}; PCC rarely (thrombosis risk); definitive: liver transplant

Disseminated Intravascular Coagulation (DIC)

  • Trigger: sepsis (G-), trauma, malignancy, obstetric comps, etc.
  • Path: systemic TF activation → microthrombi + consumption of platelets & factors → bleeding & MODS
  • Labs: ↓ PLT, ↑ PT/aPTT/TT, ↓ fibrinogen, ↑ D-dimer, schistocytes
  • Treat cause + support: PRBC if Hb<77, platelets <5050 with bleed, PFC, cryo (fibrinogen), anticoagulation (heparin) in some chronic/ thrombotic forms

Dilutional & Fibrinogen Deficiency

  • Massive transfusion / crystalloids deplete platelets & factors; follow 1:1:1 (PRBC:PFC:PLT) + fibrinogen (cryo or concentrate)

Acquired Factor Inhibitors (Autoantibodies)

  • Most common: anti-VIII in elderly, postpartum, autoimmune, malignancy
  • Presentation resembles hemophilia without hemarthroses; aPTT ↑, no correction on mixing; confirm Bethesda
  • Treat bleed: FEIBA or rVIIa; eradicate inhibitor: prednisone ± immunosuppressant

Thrombotic Disorders

Virchow Triad & Risk Landscape

  • Stasis (immobility, HF, varicose veins, obesity, pregnancy)
  • Endothelial injury / activation (atherosclerosis, trauma, surgery, catheters, smoking)
  • Hypercoagulability
    • Hereditary thrombophilias (FVL, Prothrombin 20210A, AT III, Pc, Ps deficits)
    • Acquired: APS, malignancy, OCP/estrogen, pregnancy/puerperium, nephrotic, liver, HIT, MPN, PV, SCD, hyperhomocysteinemia

Venous vs Arterial Thrombosis

  • Arterial: platelet-rich white clots; endothelium dysfunction; treat with antiplatelets
  • Venous: fibrin-rich red clots; factor imbalance + stasis; treat with anticoagulants

When to Investigate for Thrombophilia

  • 1st unprovoked TEV <45 yrs, recurrent/unusual site (Budd-Chiari, cerebral, portal), strong FHx

Hereditary Thrombophilias

Factor V Leiden (FVL)
  • AR missense in F5F5 → Va resistant to Protein C
  • Most common hereditary TEV; heterozygotes 5–7×, homozygotes 50–80× baseline risk
  • Dx: Activated Protein C Resistance Test (aPTT fails to prolong) → genetic confirmation
Prothrombin G20210A
  • 3′ UTR mutation ⇒\Rightarrow ↑ prothrombin (~30 %) → 2–3× TEV risk
  • Dx: DNA test (factor II level not reliable)
Natural Anticoagulant Deficiencies (AT III, Protein C, Protein S)
  • AD, rarer but earlier & more severe TEV (20–40 yrs), usually leg DVT
  • AT III deficiency: heparin resistance; measure AT activity; treat with concentrates if needed
  • Homozygous Pc/S ⇒ neonatal purpura fulminans; warfarin without heparin may induce necrosis in Pc deficit

Acquired Thrombophilias

Antiphospholipid Syndrome (APS)
  • Clinical: venous/arterial thrombosis or obstetric losses + persistent (≥12 wk) auto-Abs
    • Lupus anticoagulant: prolongs aPTT & dRVVT, does not correct on mixing, corrects with excess phospholipid (hexagonal test); causes false + VDRL
    • Anti-cardiolipin IgG/IgM, Anti-β2-GPI
  • SLE with APS: aPTT ↑ despite thrombosis risk (key in Case 4)
Malignancy-Associated
  • Trousseau migratory thrombophlebitis (pancreas, stomach); screen >50 yrs with unprovoked/recurrent TEV
Estrogen / Pregnancy
  • Estrogens ↑ fibrinogen & prothrombin, ↓ Protein S, acquired Pc resistance → 5× TEV risk; synergy with other RFs. CHC contraindications graded (MEC 3-4) in thrombophilias/APS
Loss/Reduced Synthesis of Anticoagulants
  • Nephrotic (AT III urinary loss), liver disease (↓ AT III, Pc, Ps), early VKA (Pc/S drop), DIC consumption

Management Principles

Acute Venous Thrombo-Embolism (VTE)

  • Start anticoagulation promptly (heparin → VKA/DOAC) unless contraindicated
  • Minimum 3 months; extended therapy if unprovoked, recurrent, or persistent RFs

Arterial Events

  • Revascularisation ± lysis; long-term antiplatelet + RF modification; anticoagulation for APS-related arterial events

Asymptomatic Thrombophilia

  • Routine primary prophylaxis not recommended; consider short-term anticoagulation in high-risk periods (surgery, pregnancy, multiple defects)

Clinical Case Pearls

  • Case 1 (18-mo boy, 1 % FVIII, knee hemarthrosis) → Immediate FVIII concentrate (option A)
  • Case 2 (5-yo severe Hem A on prophylaxis, FVIII 3 %) → Suspect inhibitor ⇒ order mixing study (option E)
  • Case 3 (71-yo, mucosal bleed, isolated ↑ aPTT, no correction) → Acquired inhibitor → next step Bethesda assay (option C)
  • Case 4 (SLE pt with DVT) → Likely APS; lab hallmark prolonged aPTT despite thrombosis (option C)

High-Yield Recaps

  • Intrinsic factors: XII,XI,IX,VIIIXII, XI, IX, VIII; Extrinsic: VIIVII
  • ↑ PT causes: vit-K lack/antagonist, liver disease, factor VII/II/X/V/I deficits, DIC
  • Hemophilia A prophylaxis: FVIII <1%1\%, frequent bleeds, peri-procedure
  • DDAVP treats only mild-moderate Hem A bleeds/prophylaxis; ineffective in severe or Hem B
  • Bypass agents for FVIII inhibitors: FEIBA (aPCC) & rVIIa
  • DOAC targets: dabigatran – IIa; “-xaban” – Xa
  • Vitamin-K–dependent factors: II,VII,IX,X,Protein C, Protein SII, VII, IX, X, \text{Protein C, Protein S}
  • DIC smear hallmark: schistocytes
  • FVL: most common hereditary TEV; diagnosed by APC resistance test