Pathophysiology

Pathophysiology

I-15. Conditions associated with coagulation system dysfunction

凝固系の機能低下に関連する病態

Hemostasis — Stages

Goal: stop bleeding at the site of injury.

  1. Primary hemostasis: white thrombus (platelet plug) — stops bleeding but unstable.
  2. Secondary hemostasis: red thrombus — stabilizes clot via full coagulation cascade (fibrin deposition + cross-linking).
  3. Tertiary hemostasis: normalizes blood flow (fibrinolysis, vessel recanalization).

Primary hemostasis (platelet clumping)

  1. Vasoconstriction (endothelin) → ↓blood flow.
  2. Platelet adhesion: platelets bind exposed collagen via vWF and surface GP-Ib.
  3. Platelet activation: shape change, granule secretion (↑vasoconstriction + initiates cascade), GP-IIb/IIIa activation.
  4. Platelet aggregation: GP-IIb/IIIa links platelets via fibrinogen.
  5. Primary hemostatic plug (white thrombus).

Secondary hemostasis

  • Cascade initiated by extrinsic (tissue factor — thrombosis) or intrinsic (platelet activation — hemostasis) pathway; both converge on thrombin → fibrin → stable plug (red thrombus).
  • Thrombin is dual-acting:
    • Procoagulant: activates platelets, converts fibrinogen → fibrin.
    • Anticoagulant: binds thrombomodulin → activates protein C → limits the cascade (negative feedback/fibrinolysis).
  • Remodeling restores the vessel.

Coagulopathy (Bleeding Disorders)

Impaired clotting ability:

  • Coagulation-cascade disorders → large bleeds; platelet disorders → small bleeds.
  • Inherited: hemophilia A & B, von Willebrand disease, thrombocytopenia.
  • Acquired: thrombocytopenia/thrombocytopathy, vitamin K deficiency (malabsorption, iatrogenic), liver disease, uremia.

Hemophilia A & B

  • Deficiency of clotting factors: A = factor VIII, B = factor IX.
  • X-linked: women carriers, affects male children; A and B clinically indistinguishable.
  • Features: deep hematomas, hemarthrosis (joint bleeding).

Von Willebrand Disease

  • Low/impaired vWF. vWF is produced by endothelium, subendothelial CT, megakaryocytes, placenta; cleaved by ADAMTS13.
  • Functions: platelet adhesion to injured wall (initiates activation); stabilizes factor VIII in plasma.
  • Affects males and females equally; mostly genetic (acquired in aortic stenosis).
  • Symptoms: nosebleeds, prolonged bleeding after extraction/surgery, menorrhagia.

Thrombocytopenia

  • = low platelet count.
  • Reduced production: bone marrow conditions (aplastic anemia, marrow metastasis, acute leukemia).
  • Excessive consumption: ITP, heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC). (HIT/TTP/DIC feature both bleeding and ↑thrombosis.)

Immune thrombocytopenic purpura (ITP)

  • Autoantibodies against GP-IIb/IIIa (or GP-Ib); from loss of immune tolerance or platelet-antigen exposure (mimicry, infection, inflammation).
  • Three mechanisms:
    1. Bind megakaryocytes → ↓platelet production.
    2. Bind platelets → ↑splenic removal.
    3. Accelerated hepatic uptake via premature desialylation (liver mistakes young platelets for old ones).

一問一答

▶What are the three stages of hemostasis?

Primary hemostasis (platelet plug/white thrombus), secondary hemostasis (fibrin-stabilized red thrombus), and tertiary hemostasis (fibrinolysis and vessel recanalization).

▶What are the steps of primary hemostasis?

Vasoconstriction (endothelin) → platelet adhesion (vWF + GP-Ib to collagen) → platelet activation (shape change, granule secretion, GP-IIb/IIIa activation) → aggregation (fibrinogen bridges) → primary hemostatic plug (white thrombus).

▶Which molecules mediate platelet adhesion to exposed collagen?

Von Willebrand factor (vWF) bridges platelets to collagen via the platelet surface receptor GP-Ib.

▶How do platelets aggregate during primary hemostasis?

Activated GP-IIb/IIIa receptors link platelets to one another using fibrinogen as a bridge.

▶What are the two pathways of secondary hemostasis and where do they converge?

The extrinsic pathway (tissue factor) and the intrinsic pathway (platelet activation); both converge on thrombin → fibrin → stable red thrombus.

▶How is thrombin dual-acting?

Procoagulant: activates platelets and converts fibrinogen to fibrin. Anticoagulant: binds thrombomodulin to activate protein C, providing negative feedback that limits the cascade.

▶Name common inherited and acquired coagulopathies.

Inherited: hemophilia A & B, von Willebrand disease, thrombocytopenia. Acquired: thrombocytopenia/thrombocytopathy, vitamin K deficiency, liver disease, uremia.

▶Which clotting factors are deficient in hemophilia A and B?

Hemophilia A = factor VIII deficiency; hemophilia B = factor IX deficiency.

▶How do bleeding patterns differ between coagulation-cascade disorders and platelet disorders?

Coagulation-cascade disorders cause large bleeds; platelet disorders cause small bleeds.

▶What is the inheritance pattern of hemophilia A and B?

X-linked — women are carriers and male children are affected; A and B are clinically indistinguishable.

▶What are the characteristic bleeding features of hemophilia?

Deep hematomas and hemarthrosis (joint bleeding).

▶Which acquired condition can cause von Willebrand disease?

Aortic stenosis (mechanical destruction of vWF), though most cases are genetic.

▶What are the typical symptoms of von Willebrand disease?

Nosebleeds, prolonged bleeding after tooth extraction/surgery, and menorrhagia; it affects males and females equally.

▶Which enzyme cleaves von Willebrand factor?

ADAMTS13.

▶What are the two main functions of von Willebrand factor?

It mediates platelet adhesion to the injured wall (initiating activation) and stabilizes factor VIII in plasma.

▶What causes thrombocytopenia from reduced platelet production?

Bone marrow conditions such as aplastic anemia, marrow metastasis, and acute leukemia.

▶Which conditions cause thrombocytopenia by excessive consumption?

ITP, heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC).

▶What is the autoantibody target in immune thrombocytopenic purpura (ITP)?

Autoantibodies against platelet GP-IIb/IIIa (or GP-Ib).

▶What are the three mechanisms of platelet loss in ITP?

Antibodies (1) bind megakaryocytes → ↓platelet production, (2) bind platelets → ↑splenic removal, and (3) accelerate hepatic uptake via premature desialylation.

▶What is the goal and end product of secondary hemostasis?

To stabilize the clot via the full coagulation cascade, producing fibrin deposition and cross-linking (the red thrombus).