IV. PATHOPHYSIOLOGY

Pathophysiologic Mechanism: Accelerated Destruction of Platelets

Click on the image to review effect of Platelet destruction.

Causes: Destruction of platelets can be broadly categorized into immune mediated and non-immune mediated.

Immune Mediated Platelet Destruction

• Auto-immune thrombocytopenic purpura (ITP)
  ITP is caused by an auto-antibody directed against glycoproteins on the platelet membrane. Platelets that are coated with antibody are cleared by macrophages in the spleen*, liver, and bone marrow (reticulo-endothelial system).
  
  
  Click image to view animation.
  
  *Normally platelets move through the spleen without hindrance. However, when they are coated by antibodies they bind to and are phagocitized by splenic macrophages, removing them from circulation.
  
  The spleen is the major site of platelet destruction in ITP. Platelet survival in the circulation is decreased. Despite increased numbers of megakaryocytes, platelet production may also be decreased. Decreased platelet production is probably due to multiple mechanisms including megakaryocyte damage by the antibody, rapid destruction of young platelets in the marrow, and failure to increase thrombopoietin levels much above normal levels. ITP can be acute or chronic.
  
  Historically "ITP" stood for "Idiopathic Thrombocytopenic Purpura" because before the mechanism of thrombocytopenia was understood, the presence of megakaryocytes in the bone marrow was confusing. Once investigators were able to detect anti-platelet antibodies, the pathophysiology became clearer. Although the name ITP has continued in common usage. AITP might be a more accurate acronym.
  
  
• Drug-induced Thrombocytopenia
  • Heparin Induced Thrombocytopenia (HIT)
    HIT is due to an antibody against the Heparin-Platelet Factor 4 complex. This antibody can activate platelets and patients can become paradoxically hypercoagulable despite the thrombocytopenia. This is a life and limb threatening condition requiring immediate discontinuation of heparin and institution of alternative anticoagulation therapy.
  • Glycoprotein IIb/IIIa Receptor Antagonists
    Drugs such as eptifibatide and abciximab may cause a rapid onset severe thrombocytopenia in up to 2% of patients.
  • Drugs that induce an autoantibody or lupus-like syndrome
  • Procainamide
  • Alpha methyl dopa
  • Non-steroidal anti-inflammatory agents (NSAID)
  • Gold (Induction of chronic, sometimes refractory, ITP like state)
  • Anti-epileptics (V-alproic acid)
  • Sulfonylurea hypoglycemic agents
  • Retinoids
  • Danazol
  • Desferrioxamine
  • Drugs that cause Drug Antibody Complex – Hapten (Drug and platelet component forms a new antigen recognized by the immune system.  The drug must be present for ab binding and platelet destruction to occur.)
  • Quinidine/quinine
  • Antimicrobials (penicillin, cephalosporins)
  • Anti-inflammatory agents (salicylates, acetaminophen, NSAID)
  • Digoxin
  • Alpha methyl dopa
  • Diuretics (hydrochlorathiazide, furosemide)
  • Antiepileptics (carbamazepine, diphenylhydantoin)
  • H2 antagonists (cimetidine, ranitidine)
  • Antihistamines
  • Tricyclic antidepressants (imipramine, desipramine)
  • Lidocaine
  • Morphine
  • Ticlodipine
• Secondary to Other Disorders
• Connective tissue disorders (e.g. Systemic Lupus Erythematosis)
• Lymphoproliferative disorders
• Solid tumors
• Infection (viral, bacterial, parasitic)
• Alloimmune Thrombocytopenia
• Neonatal Alloimmune Thrombocytopenic Purpura (NATP)
• Post-transfusion Purpura (PTP)

Non-immune Mediated Platelet Destruction

• Disseminated Intravascular Coagulation (DIC)
• Thrombotic Thrombocytopenic Purpura (TTP)
  (Although TTP may be caused by an antibody against ADAMTS-13, the resultant thrombocytopenia is a secondary phenomenon caused by platelet consumption in microthrombi.)
• Hemolytic Uremic Syndrome
• Vasculitis
• Disruption of laminar flow (such as cardiopulmonary bypass, intravascular prosthetic devices)
• Drug-induced platelet consumption (platelet activating agents such as L-asparaginase)