Heparin-Induced Thrombocytopenia (HIT)


Heparin Exposure and Prevalence


Risk Factors

Dose/Route of Heparin Exposure

  • HIT Can Occur with Any Heparin Dose, Schedule, or Route of Administration (Subcutaneous or Intravenous)
  • Therapeutic Heparin Dosing Has a Higher Risk of HIT (0.76% of Cases), as Compared to Prophylactic Heparin Dosing (<0.1% of Cases) (Chest, 2007) [MEDLINE]
  • However, HIT Can Occur with Any Dose of Heparin: cases of HIT have been reported in patients with heparin-coated catheters
  • Very High Doses of Heparin May Be Associated with Lower Risk of HIT (As Occurs During Cardiopulmonary Bypass), as Compared to Therapeutic Heparin Dosing

Type of Heparin Exposure

  • HIT Can Occur with Any Heparin Dose, Schedule, or Route of Administration (Subcutaneous or Intravenous)
    • Patients treated with low molecular weight heparin can develop HIT with prior exposure to either unfractionated or low molecular weight heparin: frequency of HIT was higher in those previously exposed to heparins of any type (Blood, 2005) [MEDLINE]
  • Heparins
  • Risk of HIT is Less with Low Molecular Weight Heparins in Surgical Patient Populations (But Not in Medical Patient Populations)
    • HIT occurs in 2.6% % of unfractionated heparin-treated surgical patients [MEDLINE]
    • HIT occurs in 0.2% of low molecular weight heparin-treated surgical patients [MEDLINE]
    • Fondaparinux: HIT is less common with Fondaparinux (as a matter of fact, some cases of HIT have been treated with Fondaparinux)
    • Meta-analyses suggest that the relative risks of HIT with unfractionated vs low molecular weight heparins are comparable in medical patients (Chest, 2007) [MEDLINE]

Sex

  • Female Sex Carries a 2.37x-Fold Increased Risk of HIT (Blood, 2006) [MEDLINE]: unclear reasons
    • Female Predominance of HIT is Observed Only in Those Receiving Unfractionated Heparin (as Opposed to low Molecular Weight Heparin): with the highest risk observed in female surgical patients

Age

  • Unclear if Older Age is a Risk fFactor for HIT: studies are currently lacking
  • HIT is Very Rare in Children

Surgery

General Comments

  • Risk of HIT is Higher in Surgical Patients (Likely Related to Vascular Trauma), as Compared to Medical Patients (Blood, 2006) [MEDLINE]

Cardiopulmonary Bypass (CPB) (see Cardiopulmonary Bypass)

  • Cardiopulmonary Bypass Patients Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time
  • Incidence
    • HIT Occurs in 1% of Cardiopulmonary Bypass Cases (Blood, 2000) [MEDLINE]
  • Timing of Thrombocytopenia
    • Thrombocytopenia Which Occurs Between 5-10 Days Post-Cardiac Surgery is Highly Predictive for HIT (J Thromb Haemost, 2010) [MEDLINE]
      • In Contrast, Early-Onset and Persistent Thrombocytopenia is Usually Caused by Non-HIT Mechanisms (Coinciding with Heparin-Dependent Antibody Seroconversion)

Orthopedic Surgery

  • Orthopedic Surgery Patiens Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time
  • Incidence
    • HIT Occurs in 4.9% of Orthopedic Patients Treated with Unfractionated Heparin (Blood, 2000) [MEDLINE]
    • HIT Occurs in 0.9% of Orthopedic Patients Treated with Low Molecular Weight Heparin (Blood, 2000) [MEDLINE]

Vascular Surgery

  • Vascular Surgery Patients Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time

Cardiology/Interventional Cardiology Patients

  • Cardiology/Interventional Cardiology Patients Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time

Presence of Inherited Hypercoagulable States

  • Risk of HIT is Not Higher in Patients with Inherited Hypercoagulability (Such as Factor V Leiden and Prothrombin Gene Mutation)

Physiology

Formation of Heparin-Dependent IgG Antibodies to Platelet Factor 4 Complexed with Heparin

  • Latency of Antibody Formation: formation of heparin-induced antibodies is believed to take at least 4 days of exposure to heparin
    • However, there are rare cases where the antibodies can form in the absence of heparin exposure: in these cases, an inflammatory stimulus or exposure to non-heparin polyanions may be involved
    • While heparin-induced IgM and IgA antibodies can also develop, IgG is thought to be the only pathogenic antibody (since the platelet surface Fc receptor only recognizes IgG)
    • Interestingly, naturally-occurring antibodies against platelet factor 4 complexed to heparin exist in 3-8% of the general population without HIT: these may develop when platelet factor 4 binds to negatively-charged polysaccharides on bacteria, creating an antigen in platelet factor 4 that mimics platelet factor 4 complexed to heparin (and this may explain why some patients have rapid development of heparin-induced antibodies following heparin exposure)
  • Necessity of Presence of Heparin for Heparin-Induced Antibody Binding: it is believed that the binding of heparin (or other polyanions) induce a conformational change in platelet factor 4 protein, resulting in a neoantigen, to which the heparin-induced antibodies bind
    • Therefore, heparin-induced antibodies only cause clinical symptoms when heparin is present
  • Heparin-Induced Antibody Binding to Platelet Factor 4-Heparin Complexes on the Platelet Surface
    • Fc region of the antibody is captured by the Fc receptor on the surface of the same or adjacent platelets -> platelet activation -> further platelet factor released from platelet alpha granules

Clinical Variability Based Upon Molecular Parameters

  • Optimal 1:1 Molar Ratio of Platelet Factor 4 Tetramer/Heparin Molecules: results in the formation of more ultralarge complexes (and is more imunogenic) and is related to the severity of clinical sequelae
    • This may explain why patients treated with high doses of heparin (as are used during cardiopulmonary bypass) are less likely to develop HIT than those exposed to standard doses of heparin
  • Type of Heparin: heparins vary in their ability to produce the optimal 1:1 ratio of platelet factor 4 tetamer/heparin molecules (this ratio results in formation of more ultralarge complexes)
    • HIT occurs in 2.6% of unfractionated heparin-treated patients (ultralarge complexes form most efficiently with unfractionated heparin) [MEDLINE]
    • HIT occurs in 0.2% of low molecular weight heparin-treated patients (ultralarge complex formation is 10x less efficient with low molecular weight heparin, as compared to unfractionated heparin) [MEDLINE]
    • Fondaparinux (Arixtra) (see Fondaparinux): HIT is less common with fondaparinux (ultralarge complex formation is negligible with fondaparinux, as it has no affinity for platelet factor 4)
  • Patients with Larger Amounts of Circulating or Platelet Surface-Bound Platelet Factor 4: have a higher risk and severity of HIT
  • Titer of Heparin-Induced Antibody: high titer antibodies that react with platelet factor 4 bound to non-heparin glycosaminoglycans (such as chondroitin sulfate) may explain the occurrence of HIT in patients who have never been exposed to heparin or in those who develop delayed-onset HIT after heparin withdrawal

Mechanisms of Thrombocytopenia

  • Removal of IgG-Coated Platelets by Reticuloendothelial System Macrophages in Spleen/Liver/Bone Marrow: similar to other types of drug-induced thrombocytopenia
  • Platelet Consumption in Thrombi

Mechanisms of Arterial and Venous Thrombosis

  • Endothelial Cell Activation
  • Endothelial Cell Injury Due to Binding of HIT Antibodies to Endothelial Heparan Sulfate: leads to increased tissue factor and thrombin generation
  • Endothelial Cell Release of Adhesion Molecules: such as IL-6 and vWF
  • Heparin-Induced Antibody Activation of Monocytes
  • Heparin-Induced Antibody Alteration of Other Aspects of the Coagulation Cascade: such as deceased activated protein C generation, etc
  • Platelet Activation
  • Release of Platelet Microparticles (Fragments from Platelet Membrane): these catalyze clot formation
  • Release of Procoagulant Substances from Activated Platelets

Formation of Heparin-Induced Antibodies (Detectable by Laboratory Assays) Without Clinical Thrombocytopenia and HIT (Blood, 2000) [MEDLINE]

  • Heparin-Induced Antibodies May Occur with Heparin Exposure
    • Cardiopulmonary Bypass Patients Treated with Unfractionated Heparin (see Cardiopulmonary Bypass,)
      • Days of Treatment: 5.1 +/- 2.2 days
      • Frequency of Heparin-Induced Antibodies: 20% (by activation assay) or 50% (by antigen assay)
      • Frequency of Clinical HIT: 1% of cases
    • Orthopedic Patients Treated with Unfractionated Heparin
      • Days of Treatment: 9.2 +/- 2.2 days
      • Frequency of Heparin-Induced Antibodies: 9.3% (by activation assay) or 14.1% (by antigen assay)
      • Frequency of Clinical HIT: 4.9% of cases
    • Orthopedic Patients Treated with Low Molecular Weight Heparin
      • Days of Treatment: 9.5 +/- 3.0 days
      • Frequency of Heparin-Induced Antibodies: 3.2% (by activation assay) or 7.5% (by antigen assay)
      • Frequency of Clinical HIT: 0.9% of cases
  • Heparin-Induced Antibodies May Occur Without Heparin Exposure

Diagnosis

Immunoassays

General Comments

Solid-Phase ELISA

Functional Assays

General Comments

Serotonin Release Assay (SRA)

Heparin-Induced Platelet Aggregation (HIPA)


Clinical Subtypes of Heparin-Induced Thrombocytopenia (HIT)

Heparin-Induced Thrombocytopenia-Type I

Heparin-Induced Thrombocytopenia-Type II (aka Heparin-Induced Thrombocytopenia and Thrombosis, HITT)


Clinical Scoring Systems

4 T’s Scoring System (Am J Hematol, 2008) [MEDLINE]

Scoring System

Clinical Efficacy

Lillo-Le Louet Model

HIT Expert Probability (HEP) Score


Clinical Manifestations

Hematologic Manifestations

Thrombocytopenia (see Thrombocytopenia)

Other Manifestations

Thrombosis

Anaphylaxis (see Anaphylaxis)


Clinical: Spontaneous HIT (Autoimmune HIT)


Treatment

HIT Type I

Cessation and Avoidance of Heparins + Use of Non-Heparin Anticoagulation

HIT Type II (aka Heparin-Induced Thrombocytopenia and Thrombosis, HITT)

Cessation and Avoidance of Heparins For Life

Anticoagulation

Use of Platelet Transfusions in Heparin-Induced Thrombocytopenia

Resolution of Thrombocytopenia and Heparin-Induced Antibodies

Special Clinical Situations (per Chest 2012 Antithrombotic Therapy and Prevention of Thrombosis Guidelines (9th ed) [MEDLINE])

Need for Cardiac Surgery or Percutaneous Coronary Intervention

Other Clinical Scenarios

Pregnancy


References