Pathophysiology

Pathophysiology

I-16. Conditions with excessive activation of the coagulation system

凝固系の過剰活性化に関連する病態

Inherited Thrombophilias

Features suggesting inherited thrombophilia: thrombosis at a young age, recurrent thrombosis, unusual location, thrombosis despite prophylaxis, thrombosis from mild stimuli.

Causes:

  • Factor V Leiden mutation (3–7%) → activated protein C (APC) resistance.
  • Prothrombin gene mutation (1–3%) → hyperprothrombinemia (↑thrombin).
  • Deficiency of natural anticoagulants (<1%): antithrombin III, protein C + S.

APC Resistance

  • Most common congenital thrombophilia.
  • Normally APC (made by endothelium via thrombomodulin, protein C receptor, thrombin) cleaves activated factors V and VIII → stops the cascade.
  • Diagnosis: adding APC normally shortens clotting time — no shortening → APC resistance.
  • Factor V Leiden is the main cause: point mutation alters factor V conformation → resists APC → slower inactivation → prothrombotic state.
  • Acquired APC resistance: anti-phospholipid antibodies.

Antiphospholipid Syndrome

  • Immune disorder → ↑clot risk via anti-phospholipid antibodies.
  • Clinical: deep vein thrombosis, ischemic stroke, accelerated atherosclerosis, plus pregnancy complications (recurrent abortions, early fetal death).
  • In blood vessels: antibodies target circulating/endothelial glycoproteins → pro-coagulant + pro-inflammatory endothelium → complement activation + coagulation → thrombus.
  • In placenta: glycoprotein-antibody complexes activate complement → trophoblast destruction + PMNC activation → release of ROS (cell damage), TNF (inflammation), sVEGFR (↓vessel formation), tissue factor (coagulation).

Virchow’s Triad

1. Endothelial injury (most dominant — can cause thrombosis alone)

  • Healthy endothelium (antithrombotic): thrombomodulin, TFPI + heparan sulfate (inhibit cascade), tPA (→ plasmin → fibrinolysis), and prostacyclin + NO (vasodilation, ↓platelet activation).
  • Dysfunctional endothelium (prothrombotic): ↑tissue factor, ↑PAI (↓fibrinolysis), inflammatory phenotype (P-/E-selectin, VCAM-1, ICAM-1) → activates leukocytes/mononuclear cells → express tissue factor + release TF microvesicles. Activated PMNCs form NETs → promote platelet activation/coagulation. Subendothelial CT exposure initiates platelet activation + cascade.

2. Abnormal blood flow

  • Normal laminar flow keeps platelets central (antithrombotic). Disruption → thrombus:
    • Stasis: slowed flow.
    • Turbulence: platelets contact endothelium → injury, and prevents dilution of activated clotting factors.

3. Hypercoagulability

  • ↑Procoagulant or ↓anticoagulant proteins → promotes thrombus.

(Primary/white/arterial thrombi vs. secondary/red/venous thrombi.)

Risk Factors for Thrombosis

  • High (10–100×): trauma/surgery, homozygous Factor V Leiden, limb immobilization.
  • Moderate (2–10×): inherited (Leiden, prothrombin, anticoagulant mutations), acquired (obesity → endothelial inflammation, smoking, long flights).
  • Low (<2×): other genetic variants. (Combined factors greatly raise risk.)

COVID-19 & Thrombosis

  • Normal: ANGII → ACE-2 → ANG 1-7 → NO (vasodilation, ↓platelet aggregation, feedback against ANGII).
  • COVID-19: virus binds/blocks ACE-2 → ↑ANGII → vasoconstriction + platelet aggregation (loss of NO), ↑tissue factor, suppressed protein C → pro-thrombotic endothelial phenotype.

一問一答

▶What is the most common congenital thrombophilia?

Activated protein C (APC) resistance, most often due to the Factor V Leiden mutation.

▶What features suggest an inherited thrombophilia?

Thrombosis at a young age, recurrent thrombosis, unusual location, thrombosis despite prophylaxis, and thrombosis from mild stimuli.

▶What is the mechanism of the Factor V Leiden mutation?

A point mutation alters factor V conformation so it resists APC cleavage → slower inactivation → a prothrombotic state.

▶How is APC resistance diagnosed?

Adding APC normally shortens clotting time; if there is no shortening, APC resistance is present.

▶What is the normal function of activated protein C (APC)?

Made by endothelium (via thrombomodulin, the protein C receptor, and thrombin), APC cleaves activated factors V and VIII to stop the coagulation cascade.

▶Besides Factor V Leiden, what other inherited causes of thrombophilia exist?

Prothrombin gene mutation (hyperprothrombinemia → ↑thrombin) and deficiency of natural anticoagulants (antithrombin III, protein C, protein S).

▶What causes acquired APC resistance?

Anti-phospholipid antibodies.

▶What are the clinical features of antiphospholipid syndrome?

Deep vein thrombosis, ischemic stroke, accelerated atherosclerosis, and pregnancy complications (recurrent abortions, early fetal death).

▶How do antiphospholipid antibodies damage the placenta?

Glycoprotein-antibody complexes activate complement → trophoblast destruction and PMNC activation → release of ROS (cell damage), TNF (inflammation), sVEGFR (↓vessel formation), and tissue factor (coagulation).

▶What are the three components of Virchow's triad?

Endothelial injury, abnormal blood flow, and hypercoagulability.

▶Which element of Virchow's triad is most dominant?

Endothelial injury — it can cause thrombosis on its own.

▶What antithrombotic factors does healthy endothelium provide?

Thrombomodulin, TFPI + heparan sulfate (inhibit the cascade), tPA (→ plasmin → fibrinolysis), and prostacyclin + NO (vasodilation, ↓platelet activation).

▶What makes dysfunctional endothelium prothrombotic?

Increased tissue factor, increased PAI (↓fibrinolysis), and an inflammatory phenotype (P-/E-selectin, VCAM-1, ICAM-1) that activates leukocytes to express tissue factor and form NETs.

▶How does abnormal blood flow promote thrombosis?

Normal laminar flow keeps platelets central (antithrombotic). Stasis (slowed flow) and turbulence (platelet-endothelium contact, no dilution of activated clotting factors) both promote thrombus.

▶What is hypercoagulability in Virchow's triad?

An imbalance of increased procoagulant or decreased anticoagulant proteins that promotes thrombus formation.

▶What are the high-risk (10–100×) factors for thrombosis?

Trauma/surgery, homozygous Factor V Leiden, and limb immobilization.

▶What are the moderate-risk (2–10×) factors for thrombosis?

Inherited (Factor V Leiden, prothrombin, anticoagulant mutations) and acquired factors (obesity → endothelial inflammation, smoking, long flights).

▶How does the normal ACE-2 pathway protect against thrombosis?

ANGII → ACE-2 → ANG 1-7 → NO, producing vasodilation, reduced platelet aggregation, and negative feedback against ANGII.

▶How do arterial and venous thrombi differ?

Arterial thrombi are primary/white (platelet-rich); venous thrombi are secondary/red (fibrin- and RBC-rich).

▶How does COVID-19 cause a prothrombotic state?

The virus binds/blocks ACE-2 → ↑ANGII → vasoconstriction and platelet aggregation (loss of NO), ↑tissue factor, and suppressed protein C → prothrombotic endothelial phenotype.