Pathophysiology

Pathophysiology

I-17. Simultaneous under- & overacting coagulation disorders (TTP, HIT, DIC)

凝固系の低下と亢進が併存する病態（TTP・HIT・DIC）

Overview

TTP, HIT, and DIC all combine simultaneous overactivation and insufficiency of hemostasis: overactivation consumes platelets and clotting factors → secondary thrombocytopenia + bleeding alongside thrombosis.

Thrombotic Thrombocytopenic Purpura (TTP)

(Moschcowitz syndrome)

  • Normally ADAMTS13 cleaves large vWF multimers into smaller anticoagulant fragments.
  • Pathomechanism: autoantibodies inhibit ADAMTS13 (or ↑its clearance) → uncleaved ultra-large vWF → microthrombi that occlude vessels and shred RBCs; microthrombi also activate complement → vessel-wall damage.
  • Clinical pentad:
    1. Thrombocytopenia with purpura.
    2. Microangiopathic hemolytic anemia (fragmentocytes/schistocytes).
    3. Fever (complement).
    4. Neurological symptoms (headache, focal deficits, seizures, coma).
    5. Renal failure.
  • Acute treatment: plasma infusion (ADAMTS13 replacement), plasmapheresis (remove autoantibodies), or plasma exchange (both). Untreated → multi-organ failure.

Heparin-Induced Thrombocytopenia (HIT)

  • Type 1 (pharmacological): minor drug-induced platelet drop within minutes; not severe.
  • Type 2 (immune-mediated): develops in 4–14 days, severe (mortality ~20%, amputation ~10%); both thrombosis + thrombocytopenia. Most common drug-induced thrombocytopenia (incidence 1–5%; antibodies don’t always cause HIT).
  • Pathomechanism: heparin + platelet (PF4) forms an immunogenic complex → antibodies.
    1. Antibodies bind platelet Fc receptors + the immune complex → platelet aggregation; antibody-bound platelets cleared by spleen → thrombocytopenia (worsened by thrombus consumption).
    2. Immune complexes activate monocytes (via Fc) → coagulation cascade.
    3. Endothelium turns pro-coagulant/pro-inflammatory → more thrombi.

Disseminated Intravascular Coagulation (DIC)

  • Causes: infectious (sepsis); non-infectious (trauma, surgery, delivery/abortion).
  • Pathomechanism:
    1. Cascade activation: PAMPs/DAMPs/cytokines → ↑tissue factor on monocytes + TF microvesicles; NETs (DNA + histones) activate cascade & platelets; ↑vWF release.
    2. Anticoagulant inhibition: ↓anticoagulant release; neutrophil elastase cleaves anticoagulants.
    3. Fibrinolysis inhibition: ↑PAI-1.
  • Clinical: widespread microthrombi, endothelial dysfunction (impaired vasoregulation/barrier), hemorrhage (consumed platelets/factors) → tissue ischemia, edema, multi-organ dysfunction syndrome.

一問一答

▶What feature do TTP, HIT, and DIC share?

Simultaneous overactivation and insufficiency of hemostasis — overactivation consumes platelets and clotting factors, causing secondary thrombocytopenia and bleeding alongside thrombosis.

▶What is the normal role of ADAMTS13?

It cleaves large von Willebrand factor multimers into smaller, anticoagulant fragments.

▶What is the pathomechanism of TTP?

Autoantibodies inhibit ADAMTS13 (or increase its clearance) → uncleaved ultra-large vWF → microthrombi that occlude vessels and shred RBCs; microthrombi also activate complement → vessel-wall damage.

▶What is the clinical pentad of TTP?

(1) Thrombocytopenia with purpura, (2) microangiopathic hemolytic anemia (schistocytes), (3) fever, (4) neurological symptoms, and (5) renal failure.

▶What is the acute treatment of TTP?

Plasma infusion (ADAMTS13 replacement), plasmapheresis (remove autoantibodies), or plasma exchange (both); untreated TTP leads to multi-organ failure.

▶How do Type 1 and Type 2 HIT differ?

Type 1 is pharmacological — a minor platelet drop within minutes, not severe. Type 2 is immune-mediated, develops in 4–14 days, and is severe (mortality ~20%, amputation ~10%) with both thrombosis and thrombocytopenia.

▶What is the pathomechanism of immune-mediated HIT?

Heparin binds platelet factor 4 (PF4) forming an immunogenic complex → antibodies bind platelet Fc receptors and the complex → platelet aggregation; antibody-bound platelets are cleared by the spleen → thrombocytopenia (worsened by thrombus consumption).

▶How do HIT immune complexes amplify coagulation beyond platelets?

They activate monocytes (via Fc receptors) to trigger the coagulation cascade, and turn the endothelium pro-coagulant/pro-inflammatory → more thrombi.

▶What are the infectious and non-infectious causes of DIC?

Infectious: sepsis. Non-infectious: trauma, surgery, and delivery/abortion.

▶How is the coagulation cascade activated in DIC?

PAMPs/DAMPs/cytokines increase tissue factor on monocytes plus TF microvesicles; NETs (DNA + histones) activate the cascade and platelets; and vWF release increases.

▶How are anticoagulant mechanisms inhibited in DIC?

Decreased anticoagulant release, and neutrophil elastase cleaves anticoagulant proteins.

▶How is fibrinolysis inhibited in DIC?

By increased PAI-1.

▶What is the clinical picture of DIC?

Widespread microthrombi, endothelial dysfunction (impaired vasoregulation/barrier), and hemorrhage (from consumed platelets/factors) → tissue ischemia, edema, and multi-organ dysfunction syndrome.

▶Why does thrombocytopenia develop in TTP, HIT, and DIC?

Overactivation of hemostasis consumes platelets (and clotting factors) faster than they are produced.

▶What is the eponym for TTP?

Moschcowitz syndrome.

▶Why does microangiopathic hemolytic anemia occur in TTP?

vWF microthrombi mechanically shred red blood cells, producing fragmentocytes/schistocytes.

▶What is the incidence of HIT, and does the antibody always cause disease?

Incidence is about 1–5%; the antibodies do not always cause clinical HIT.

▶What are NETs and their role in DIC?

Neutrophil extracellular traps (DNA + histones) that activate the coagulation cascade and platelets.

▶Which is the most common drug-induced thrombocytopenia?

Heparin-induced thrombocytopenia (Type 2 HIT).

▶What is the consequence of untreated TTP?

Multi-organ failure.