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What are the two types of HIT?

HIT type I (HIT I)

  • mild, transient drop in platelet count that typically occurs within the first two days of heparin exposure.
  • The platelet count typically returns to normal with continued heparin administration.
  • The mechanism appears to be a direct effect of heparin on platelets, causing non-immune platelet aggregation. The typical platelet count nadir is approximately 100,000/microL.
  • This form of HIT is not considered clinically significant, is not associated with thrombosis, and patients can be managed expectantly without discontinuation of heparin.

HIT type II (HIT II)

  • clinically significant syndrome due to antibodies to platelet factor 4 (PF4) complexed to heparin, referred to as "HIT antibodies" or "PF4/heparin antibodies"
  • These antibodies can cause thrombosis along with thrombocytopenia; hence, this syndrome has also been called heparin-induced thrombocytopenia and thrombosis (HITT).
  • The risk of thrombosis, including life-threatening limb gangrene, persists until both heparin is eliminated and a non-heparin anticoagulant is initiated.


Source = Clinical presentation and diagnosis of heparin-induced thrombocytopenia - UpToDate


Phases of HIT/subclinical HIT?

  • Subclinical (also subacute) HIT refers to the state where a patient has recovered from an episode of HIT (ie, their platelet count has returned to normal or the patient's baseline) but has persistent HIT antibodies.
    • Subclinical HIT should be distinguished from the presence of naturally occurring or clinically silent anti-PF4 antibodies (eg, with no associated thrombocytopenia, thrombosis, or other clinical manifestations
  • Remote HIT refers to platelet count recovery and negative heparin-PF4 antibodies.
    • Individuals with subacute or remote HIT are at high risk of HIT recurrence if re-exposed to heparin.

Source: Clinical presentation and diagnosis of heparin-induced thrombocytopenia - UpToDate


What is autoimmune HIT?


What is the pathophysiology of HIT?

Formation of HIT antibodies — HIT has an unusual immunobiology compared with other drug-induced antibodies, which includes the following features

  • IgG antibodies are formed rapidly (within days). There is no primary IgM response for clinically significant platelet factor 4 (PF4)/heparin antibodies
  • IgG antibodies disappear over time; however, this does not imply that heparin can be used upon disappearance of the antibodies.
  • Immune memory does not always occur (ie, rechallenge does not always cause an anamnestic response), although individuals with recent heparin exposure may develop clinical findings of HIT in a shorter timeframe than those without recent heparin exposure.
  • HIT antibodies are directed against PF4 complexed with heparin.
    • It is thought that the binding of heparin (or other polyanions) induces a conformational change in the PF4 protein that creates a neoantigen, and HIT antibodies bind to this PF4 neoantigen.
    • As a result of this heparin dependency, these antibodies usually only cause clinical symptoms when heparin is present. Formation of HIT antibodies typically requires exposure to heparins for four or more days.

Platelet factor 4 (PF4) - The PF4 protein is stored in platelet alpha granules.

  • It is small cytokine belonging to the CXC chemokine family.
  • Platelet activation causes release of PF4, which forms a tetramer that binds to and neutralizes heparin and related endogenous proteoglycan molecules (eg, heparan sulfate, chondroitin sulfate) on endothelial surfaces. Heparin-PF4 complexes also form on the platelet surface.
  • HIT antibodies may bind to heparin-PF4 complexes on the platelet surface (via heparin binding to cell surface proteins) or to PF4 attached to platelet surface glycosaminoglycans (heparin-like molecules)


The mechanisms of thrombocytopenia in HIT

  1. Removal of IgG-coated platelets by macrophages of the reticuloendothelial system (eg, spleen, liver, bone marrow), via binding to the FcγRIIA, similar to other types of drug-induced immune thrombocytopenia; consumption of platelets at sites of thrombosis
  2. Platelet destruction due to the development of a consumptive coagulopathy. A second cause of thrombocytopenia is consumption of platelets within thrombi.


Mechanisms of thrombosis

  1. Platelet activation and endothelial cell injury — Unlike most other forms of drug-induced immune thrombocytopenia, HIT is also associated with arterial and venous thrombosis. The mechanism is likely multifactorial, but the primary mechanism is thought to be due to activation of platelets and injury to endothelial cells via activation of the cell surface FcγRIIA on platelets and endothelial cells, respectively.
  2. Neutrophil activation and NETosis — Neutrophil extracellular traps (NETs) are structures created when neutrophils extrude their DNA as uncoiled strands of chromatin that incorporate cellular contents such as histones, myeloperoxidase, and elastase. NETs play a central role in host defense against infection. NETosis aso plays a key role in thrombosis in individuals with HIT

Source: Clinical presentation and diagnosis of heparin-induced thrombocytopenia - UpToDate



HIT risk factors

  • Surgery
  • UFH (vs LMWH)
  • Heparin dose
  • Females
  • Older age


Clinical manifestation of HIT?

  1. HIT occurs typically 5 - 10 days after initiation of heparin; earlier if prior eposure to heparin in  1 - 3 months and circulating HIT antibodies
  2. Thrombocytopenia 
    • Plts < 150 in 85-90% of patients; mean nadir ~ 60
    • Plts <20 = rare
  3. Bleeding (uncommon)
  4. Thrombosis - up to 50% if not treated with non-heparin anticoagulant;
    • venous (20 - 50%) > arterial thrombi (3 - 10%)
    • asymptomatic DVT screening with LE dopplers
  5. Thrombotic sequelae 
    • Skin necrosis
    • limb gangrene
    • organ infarction or ischemia
  6. Anaphylaxis has been described

Source: Clinical presentation and diagnosis of heparin-induced thrombocytopenia - UpToDate


What are the 4 Ts score parameters for HIT?

4 Ts score

  • Recommended by American Society of Hematology to assess pretest probability)
    • However, definitive laboratory data (ie, immunoassay and/or functional assay for HIT antibodies) may not be available for several days. Thus, we make a presumptive diagnosis of HIT based on clinical findings and laboratory data that are immediately available (eg, platelet count, same-day HIT testing), and we confirm or refute the diagnosis once we have the definitive results of HIT antibody testing.

  • Thrombocytopenia
  • Timing of onset after heparin exposure
  • Thrombosis or other clinical sequelae
  • oTher cuases for thrombocytopenia present


Source: Clinical presentation and diagnosis of heparin-induced thrombocytopenia - UpToDate


Two major laboratory tests for HIT?

  1. Immunoassays – Immunoassays detect the presence of a PF4-heparin antibody but not its ability to bind and activate platelets (see 'Immunoassay (eg, ELISA)' below). The results are reported in optical density (OD) units. These assays are widely available, fast, and straightforward to interpret, but they have a higher incidence of false positive results than functional assays; they may also detect antibodies that are not clinically significant. While the assays can be performed rapidly, rapid turnaround of results cannot be assumed, as some laboratories batch assays and only perform them on certain days of the week. Clinicians should speak with the laboratory if there is increased urgency in obtaining results. Clinicians should also be aware that there is variability among different immunoassays. The ranges of sensitivities, specificities, and predictive values of various commercially available immunoassays and rapid immunoassays were described in two systematic reviews and meta-analyses that included data from over 15,000 patients
  2. Functional assays – Functional assays assess the ability of a PF4-heparin antibody to bind and activate platelets, and thus to cause the clinical HIT syndrome (see 'Functional assays' below). The results are reported as positive or negative. Functional assays are more resource-intensive and require more expertise to perform and interpret, but they are considered more specific for confirming a diagnosis of HIT and may be especially helpful if the immunoassay gives an indeterminate result. Most institutions do not have an in-house functional assay, but these assays are commonly available as a send-out test. Thus, the turnaround time is usually longer than that of an ELISA (eg, days).
    • Functional assays test the ability of HIT antibodies from patient serum to activate test platelets, which more strongly correlates with the presence of HIT than the results of an immunoassay. We reserve functional assays for those with indeterminate immunoassays or those for whom the clinical picture and immunoassay results are discordant (eg, patient with very high probability 4 Ts score and negative immunoassay). In centers where a functional assay is available rapidly, it may be appropriate to proceed directly to a functional assay rather than start with an immunoassay.
    • Serotonin release assay (SRA)
    • Heparin-induced platelet activation (HIPA)


Source: Clinical presentation and diagnosis of heparin-induced thrombocytopenia - UpToDate



DDx of thrombocytopenia

  • Falsely low platelemt counts (pseudotrombocytoepnia)
  • Primary immune thrombocytoepnia (ITP)
  • Drug-induced immune trombocytopenia (DITP)
    • Heparin, quinine, sufonamides, acetominophen, NSAIDs, ampicillin, piperacillin, vancomycin, Gylcoprotein IIb/IIIa inhibitors, cimetidine
  • Infection
    • HIV, HCT, EBV, H.pylori, Sepsis with DIC, intracellular parasites
  • Hypersplenisms due to chronic liver disease
  • alcohol
  • Pregnancy
  • MDS
  • Cancer with DIC
  • Cancer with BM infiltration or suppression
  • PNH
  • Thrombotic microangiopathy (e.g. TTP, HUS, drug-induced)
  • Antiphospholipid syndrome
  • Aplastic anemia
  • Hereditary thrombocytopenias

Source: Approach to the adult with unexplained thrombocytopenia - UpToDate


What is the approach for unexplained thrombocytopenia?

  • Repeat CBC
  • peripheral smear 
    • will exclude pseudothrombocytopenia: if present, will need to have heparin or sodium citrate collecting tube instead of EDTA-dependent agglutinin that induces platelet clumping
    • assesses for other RBC and WBC abnormalities
  • HCV and HIV testing
  • LFTs
  • LDH
  • Coagulation studies
  • Folate, Vit B12
  • Renal function