Lec 6: Coagulation Disorders

Coagulation Disorders — Comprehensive Study Notes

• Coagulation disorders are bleeding disorders caused by problems in the body’s blood clotting process. They can be inherited or acquired.

  • Except for Factor XI (FXI) deficiency, all other factor deficiencies can cause bleeding.
  • Distinguish from platelet deficiencies: spontaneous petechiae are uncommon in coagulation disorders.
  • Manifestations include large hematomas or ecchymoses, prolonged bleeding after trauma, surgery, or tooth extraction; bleeding into muscles, joints, body cavities, gastrointestinal tract, and urinary tract.

• Relative causes of excessive bleeding: increased fragility of blood vessels, platelet deficiency or dysfunction, or derangements in the coagulation mechanism.

• Key inheritance and acquisition themes:

  • Some disorders are inherited (e.g., vWD, Hemophilia A/B, FXI deficiency, factor deficiencies, TTP/HUS as syndromes with genetic predispositions).
  • Others are acquired (e.g., vitamin K deficiency, liver disease–related coagulopathy, disseminated intravascular coagulation).

Pathways of Coagulation (Overview)

• Intrinsic Pathway

  • Initiated by contact factors: XII (Hageman factor) → kallikrein-HMWK → XI → IX → VIII
  • Requires Ca²⁺ and phospholipid surface for activation at multiple steps.
  • End point: activation of factor X (Xa).

• Extrinsic Pathway

  • Initiated by tissue injury exposing tissue factor (thromboplastin): VII → VIIa with Tissue Factor (III) to activate X (Xa).
  • Requires Ca²⁺ for activation.

• Common Pathway (convergence of intrinsic and extrinsic)

  • Xa (with Va on a phospholipid surface and Ca²⁺) converts Prothrombin (II) to Thrombin (IIa).
  • Thrombin (IIa) converts Fibrinogen (I) to Fibrin; thrombin also activates Factor XIII to cross-link fibrin, stabilizing the clot.
  • Core sequence in the common pathway: II → IIa, I → fibrin, with XIII cross-linking.

• Important factors (names and roles)

  • I: Fibrinogen
  • II: Prothrombin
  • III: Tissue factor (thromboplastin) – membrane-bound glycoprotein released on vascular injury
  • IV: Calcium (Ca²⁺)
  • V: Labile factor – cofactor for the Xa-Va complex
  • VII: Stable factor
  • VIII: Anti-hemophilic factor A
  • IX: Anti-hemophilic factor B (Christmas factor)
  • X: Stuart-Prower factor
  • XI: Plasma thromboplastin antecedent
  • XII: Hageman factor
  • XIII: Fibrin-stabilizing factor

• Quick notes on clinical significance of deficiencies (per clinic statements)

  • Deficiencies of factors XI, IX, VIII, VII, X, V, Prothrombin (II), and fibrinogen (I) are clinically significant (bleeding risk).
  • Deficiency of Factor XII (XII) and the presence of lupus anticoagulant are not always clinically significant for bleeding risk.

• Factor III and Factor IV notes

  • Factor III (tissue factor) is a membrane-bound glycoprotein on subendothelial cells and is released upon vascular injury.
  • Factor IV is calcium (Ca²⁺).

Laboratory Investigations (Overview)

• Bleeding Time

  • Time to stop a standardized skin puncture bleeding.
  • Measured in minutes; reflects in vivo platelet function.
  • Normal range: approximately 2–10 minutes.

• Platelet Count

  • Measured from a blood sample with an electronic counter.
  • Normal range: 150–450 × 10³/μL.
  • Spontaneous bleeding risk increases when platelets fall below ~20,000/μL.

• Prothrombin Time (PT)

  • Assesses the extrinsic and common pathways (VII, X, V, II, I).
  • Normal range: 10–13 seconds.
  • INR (normal range for someone not on anticoagulants): ~0.8–1.2.
  • Prolongation suggests deficiencies in factors VII, X, V, II, or fibrinogen (I), or vitamin K–dependent effects.
  • Typical associations: deficiency of VII, X, V, II, or fibrinogen; warfarin effect; liver disease.

• Partial Thromboplastin Time (PTT)

  • Assesses the intrinsic and common pathways (XII, XI, IX, VIII; and factors in the common pathway).
  • Normal range: ~20–34 seconds.
  • Prolongation suggests deficiencies of XII, XI, IX, VIII; may also be prolonged with deficiencies in II or X or fibrinogen in certain contexts or with inhibitors.

• Thrombin Time (TT)

  • Measures the conversion of fibrinogen to fibrin by thrombin.
  • Useful for evaluating fibrinogen abnormalities or presence of inhibitors (e.g., heparin) affecting thrombin activity.

• D-dimers

  • Reflect fibrin degradation products; used to assess fibrinolysis and clot breakdown.

• von Willebrand Disease (vWD) testing

  • Included in PT/PTT interpretation because vWF affects platelet adhesion and stabilizes factor VIII.

The PT and PTT Pathways: Mnemonics and Conceptual Aids

• The PT and PTT pathways converge at factor X (Xa).

  • The phrase: “X marks the spot.”

• The PTT pathway mnemonic and Roman numeral cues

  • The PTT pathway includes XII, XI, IX, VIII (roman numerals).
  • The PTT mnemonic emphasizes the sequence of intrinsic factors before reaching X.

• The PT pathway mnemonic and factor V influence

  • The PT pathway emphasizes VII and tissue factor (III) leading to X activation, then the common pathway.
  • The PT has “one less letter” than PTT in a mnemonic sense; the pathway is considered shorter with fewer steps, which aligns with the idea that the PT pathway is