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Platelet Disorder / Thrombocytopenia (TTP, ITP, HIT)

Classification of Platelet Disorders

Quantitative Disorder
Qualitative Disorder
  • Abnormally shaped Platelet Disorder, consider May-Hegglin anomaly, Wiskott-Aldrich syndrome (eczema, thrombocytopenia, immunodeficiency syndrome)
  • Functional Platelet Disorder
    • Glycoprotein Disorders
      • Bernard-Soulier syndrome, Glanzmann thrombasthenia, 
    • Storage pool disease, 
    • von Willebrand’s disease 
Misc Platelet issues

ThrombocytopeniaHypersplenism, DIC,  TTP/HUS, ITP, Drug-Induced, HIT are common / important causes and are discussed below 


  • Pathophysiology:
    • Some important concepts to understand in DIC are (see figure below)
      • It is a prothrombotic state with in vivo thrombin generation
      • This mechanism of prothrombotic state also causes dissemination
      • Endothelial microvasculature are involved
      • Concomitant and parallel activation of innate immunity and inflammatory system 
Note: Pathophysiologically hemostatic activation and thrombin generation is the key point in DIC 
Current consideration and management of disseminated intravascular coagulation ASH Hematology 2013

Note: Pathophysiologically DIC is state of Thrombin generation. This table shows the mechanisms that sustain such thrombin generation 
  • Causes:
    • Infection
    • Cancer 
  • Diagnosis: 
  • DDx of DIC 
    • Chronic, Stable, Severe Hepatic Insufficiency
    • Dilutional Coagulopathy
Note: Appreciate the difference in pathophysiology of these three clinical situations


  • Deficiency of vWD-cleaving-protease i.e ADAMTS 13. 


HIT: Note: HIT is a highly thrombotic state 

  • Type:
    • HIT -1(antibody present but not clinically significant) 
    • HIT - 2 (true HIT)
    • Autoimmune HIT (Rare; usually after major surgery) 
  • Pathogenesis: Figure 1 of NEJM 2015
    • Activated Platelet (by surgery or infection) release PF4 from alpha-granule 
      • PF4/Heparin polyanion complex is formed OR 
      • PF4/ Bacteria polyanion complex is formed
    • This complex activates B cell and produce Ig G against PF4
    • Ig G ab - PF4/Polyanion complex is formed
    • This complex binds with 
      • Platelet and activates more platelets - causes increased thrombosis. 
      • Monocytes and activates them - causes thrombosis 
      • Platelet bound with Anti-PF4 ab are removed by splenic macrophages 
    • Thrombosis and Splenic clearing causes Thrombocytopenia
      • Hence, unlike all other cause of thrombocytopenia that causes bleeding, HIT paradoxically causes thrombosis. 
  • Scoring System: 
    • 4T scoring (0-2 point for each) NEJM 2015
      • Acute Thrombocytopenia (usually >20K)
        • 10 % have decrease in platelet count of 30-50% 
      • Timing of Onset (Day 5-10, <5 days, >10 days)
        • Typically takes 5 days for antibody production
        • Only exception is if patient was on heparin in near past. 
          • Rapid-onset HIT (within 30 min) 
          • Delayed-onset HIT (unto 3 weeks after)
        • Other exceptions are there.  NEJM 2015

      • New Thrombosis
        • VTE occurs in 50% of confirmed HIT
      • other cause of thrombocytopenia (DIC, Drugs etc) 
    • Score: 
      • 6-8: High probability. Order further tests.
      • 4-5: Intermediate score.  
      • <3 : 5% probability. Do not order ab test as it has HIGH NEGATIVE PREDICTIVE VALUE 
  • Diagosis:
    • Screen: ELISA ab. 
      • If positive, reflexively, optical density test for quantification.  
    • If that is positive, Serotonin Release Assay (SRA)
      • Gold standard for diagnosis.
      • Negative SRA does not exclude HIT 
  • Treatment:
    • Direct Thrombin Inhibitor
      • Lepirudin (FDA approved)
      • Argatroban (FDA approved)
      • Bivalidurdin (off label use)
    • Off label use of Fondaparinaux as Fondaperinaux does not have moiety to cause antibody production, yet can activate anti-thrombin. 
    • Use therapeutic dose anti-coagulation until platelet > 150K for 2 consecutive days. 
    • Avoid the use of warfarin.
  • Reference: 
  • Clinical question to understand pathophysiology and MOA?
    • Despite same MOA why can you use  Fondaparinaux in HIT, but not LMWH? 
    • Why do avoid the use of warfarin in HIT? 
      • Warfarin use causes initial drop in APC, thus increasing the ratio toward procoagulant due to loss of APC 
Appreciate the Pathogenesis of HIT from this Figure below and compare it to thrombocytopenia in infection 

Appreciate How to Calculate Pretest probability of HIT by 4T scoring system 

Appreciate the work up algorithm for HIT based on Pretest Probability