Heparin-induced thrombocytopenia (HIT) is a severe complication that can occur in patients exposed to any form or amount of heparin products. A fall in platelet counts and a hypercoagulable state characterize HIT. Patients who experience HIT may also develop thromboembolic complications that are associated with morbidity and mortality. This is a significant burden since heparin is widely used for treatment and prophylaxis of thromboembolism, for line flushes, and in heparin-coated catheters. This review will discuss the pathophysiology, diagnosis, and management of patients with HIT.
Type I HIT, also known as Heparin-associated thrombocytopenia (HAT), is a non-immune mediated reaction. Type I HIT is much more common than type II and can occur as early as day 1 of therapy. This is a mild reaction, it is not associated with any complications, and platelet counts will spontaneously normalize even if heparin is continued.
Type II HIT is an immune, antibody-mediated reaction. Because it takes time for the antibodies to form, this reaction usually occurs after 5 to 14 days of receiving heparin. However, if a patient has been exposed to heparin within the last 100 days, antibodies may remain in the system, causing this reaction to manifest as soon as day one of re-exposure to heparin. This is a very serious reaction that causes a hypercoagulable state and can lead to life-threatening complications. The rest of this review will focus on type II HIT and its management.
HIT can occur in up to 5% of patients exposed to heparin products. HIT causes an extremely hypercoagulable state, where up to 50% of patients develop thromboembolic complications, associated with a mortality rate of up to 30%. 
There are several medication-related as well as patient-related factors that can increase the risk of HIT. Because of the difference in structure and function, HIT is more likely to occur with unfractionated heparin (UFH) than with low molecular weight heparin (LMWH). Fondaparinux is a heparin-like drug that does not cause HIT nor does it react with heparin-induced antibodies. UFH is a heterogeneous product that consists of long saccharide chains of varying lengths and molecular weights; the average UFH molecule is 45 saccharide units long. LMWH is also a heterogeneous product; however, LMWH is, on average, 15 saccharide units long. Fondaparinux is a synthetic pentasaccharide, consisting of only the 5 sugars. The shorter the saccharide chain and the smaller the molecular weight, the less likely the drug is to bind to plasma proteins and cells. Therefore, there is a reduced risk of a HIT with LMWH compared to UFH, whereas fondaparinux does not cause HIT, and can be safely utilized in patients with a history of HIT and potentially in the treatment of acute HIT.
Although no amount of heparin is too small to cause this reaction, HIT is more likely to occur in patients exposed to higher doses of the drug; and the longer the duration of therapy, the higher the risk. Furthermore, females and elderly patients appear to be at an increased risk. The incidence of HIT is also higher among surgical patients, and this may be due to increased platelet activation and PF4 activity due to mechanical intervention and injury.
Under normal physiological conditions, PF4 is stored in alpha-granules of the platelets and is released upon platelet activation. PF4 is positively charged and can, therefore, bind to the negatively charged heparan (a heparin-like substance normally present on the endothelial cell surface); PF4 can also bind to exogenous heparin with much higher affinity than heparan.
PF4 binding to heparin may trigger the formation of IgG, IgA, or IgM antibodies specific to the heparin-PF4 complex. HIT can only occur if IgG, while attached to the heparin-PF4 complex, binds to the FC receptor on the platelet surface and leads to platelet activation. Activated platelets then release pro-thrombotic substances (such as thrombin) and PF4. As IgG activates more platelets, more PF4 is released forming more complexes with heparin, thus activating more platelets. This creates a severely hypercoagulable state and a continuous cycle that can only be broken when heparin is discontinued, and appropriate treatment is initiated.
The most characteristic clinical feature of HIT is thrombocytopenia. Platelet counts fall because macrophages consume the IgG-coated platelets and the reticuloendothelial system removes them. Simultaneously, as platelets become activated, they aggregate, and the platelet count drops as thrombus forms.
Because HIT causes a hypercoagulable state, venous and/or arterial thrombosis can occur. The most common complications are DVT, PE or skin necrosis. The latter is particularly a risk if warfarin is administered in the acute phase. The risk of these complications is highest within the first 10 days, but the pro-thrombotic state persists up to 30 days after stopping heparin. 
Signs and symptoms include sudden onset of pain, redness, and swelling of an arm or leg. Ecchymotic lesions may develop. Typically, a rash or sore develops where a heparin shot was given. Patients may experience weakness, numbness, or problems or painful extremity movement.
The most common symptom of HIT is enlargement or extension of a blood clot or the development of a new blood clot. This may take the form of clots either in arteries or veins. Venous thrombosis may occur in the arm or leg in the form of deep vein thrombosis and the lung in the form of a pulmonary embolism; the latter most often originates in the leg and migrates to the lung.
In those receiving heparin IV, a complex of symptoms may occur. These include chills, fever, hypertension, tachycardia, shortness of breath, and chest pain. Others may develop a skin rash consisting of red spots.
HIT should be suspected when there is an unexplained drop in platelet counts in a patient currently on heparin or recently exposed to heparin products. HIT typically presents as a steady drop in platelet counts (no fluctuations), while hemoglobin and hematocrit counts remain relatively stable. 
The first step in the diagnosis of HIT is the calculation of the 4T score. This is a scoring system used to determine the likelihood of a patient having HIT based on the presence or absence of certain parameters. The score may be calculated using the following table.
A 4T score of 0 to 3 points means HIT is unlikely, and heparin therapy may continue while the clinician looks for other causes of thrombocytopenia. A score of 4 to 5 corresponds to intermediate probability and a score of 6 to 8 means high probability. All forms of heparin, including line flushes, should be immediately discontinued and treatment with an alternative anticoagulant should be pursued in any patient who scores 4 or more. Also, the clinical diagnosis with the 4T score should be confirmed with the PF4 ELISA and the Serotonin Release Assay (SRA).
The PF4 ELISA is an immunoassay that detects the presence of antibodies. This test is highly sensitive and has a high negative predictive value; HIT can be ruled out if this test is negative. The PF4 ELISA has low specificity, leading to false positives. This is because the test detects not only IgG antibodies but also IgA and/or IgM, neither of which is involved in the pathogenesis of HIT. The lab will report a positive ELISA when the optical density (OD) is greater than 0.4. The higher the optical density, the more likely the patient is to have true HIT and the higher their chance of thrombosis. Evidence from retrospective studies suggests that less than 3% of patients with an OD of 0.4-1 will have a true positive result. The ASH guideline recommends getting a confirmatory SRA for any patient with a positive ELISA; however, if the patient is in a region where the SRA is not available, the diagnosis of HIT may be confirmed with positive ELISA when the OD is greater than 2 (which correlates with ~ 90% chance of having HIT).
Thus, if the PF4 ELISA is positive, the result should be confirmed with the SRA, the gold standard test for confirming HIT with high sensitivity and specificity. Unlike ELISA, which detects the presence of antibodies, the SRA is a functional test, which detects the activation of platelets in the presence of antibodies. A donor platelet that becomes activated in the presence of heparin and a sample of the patient's blood (containing IgG) will release serotonin. A positive SRA confirms the diagnosis of HIT, and negative SRA rules out HIT, even in the setting of a positive ELISA.
The treatment of HIT should start as soon as a 4T score of 4 or more is calculated. The first step in the treatment is the discontinuation of all forms of heparin including heparin flushes, heparin-coated catheters, and heparin in dialysate. Next, an alternative anticoagulant must be initiated to prevent or treat any HIT-induced thrombosis. In patients recently started on warfarin, warfarin should be held, and phytonadione (vitamin K) should be administered to replete protein C and S stores. The PF4 ELISA an SRA should be sent to confirm the diagnosis. 
According to the 2018 American Society of Hematology (ASH) Guideline, an alternative anticoagulant must be initiated at the therapeutic intensity in the vast majority of patients, including the following: Any patient with a high-probability 4T score (6-8), any patient with intermediate-probability 4T score (4-5) and another indication for therapeutic anticoagulation, or any patient with intermediate-probability 4T score (4-5) and no indication for therapeutic anticoagulation, but who is not at high bleeding risk. Alternatively, a prophylactic dose of an alternative anticoagulant may be initiated in a small subset of patients who are considered to be at high risk of bleeding, provided that they do not require therapeutic anticoagulation for a different indication, and they have an intermediate probability 4T score. If prophylactic anticoagulation is initiated in a patient meeting those criteria, and the immunoassay comes back positive, the patient should be switched to therapeutic anticoagulation while awaiting functional assay results.
As per the current practice guidelines, one of the following anticoagulants may be selected: argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant (DOAC). 
Argatroban and bivalirudin have a short duration of action and are a good option for critically ill patients, patients who are at increased risk of bleeding, or patients who might require an urgent procedure.  Argatroban is a direct thrombin inhibitor that does not interact with PF4 or heparin-induced antibodies. Argatroban has a short half-life of 39 - 51 minutes.  It is given as a continuous infusion without a bolus to achieve aPTT 1.5 – 3 x baseline value.  This drug is hepatically metabolized and requires a lower starting rate and more frequent aPTT monitoring in patients with hepatic dysfunction, heart failure and/or multi-organ failure.  Argatroban can profoundly increase INR; however, no therapeutic range for INR has been established for patients on argatroban. This is a false INR elevation due to the drug’s reaction with the thromboplastin reagent and therefore, does not relate to bleeding risk. Argatroban’s effect on the INR must be considered, and a specific protocol must be followed when bridging back to warfarin because of the additive effect of the two drugs on INR. 
Bivalirudin is another direct thrombin inhibitor that may safely be used in this patient population; however, this agent is usually reserved for use during cardiac catheterization procedures or cardiac surgery as an alternative to heparin. It is FDA approved for patients undergoing percutaneous coronary intervention with or without a HIT. It is more expensive than the argatroban.
Another anticoagulant that may be used in a HIT is fondaparinux. Although not FDA-approved for this indication, fondaparinux is considered safe and effective and is one of the recommended agents according to the ASH guideline. Fondaparinux is given as a once-daily subcutaneous injection. An important consideration is that this drug is renally cleared and contraindicated in CrCL <30 mL/min.
Before the 2018 ASH guideline, treatment options during acute HIT had focused on parenteral anticoagulants, either on-label with argatroban or off-label with fondaparinux. But, recently the evidence supporting efficacy and safety of DOACs is increasing with most of the published experience being with rivaroxaban. The current guideline lists DOACs as an acceptable treatment option. Dosing for these agents is extrapolated from dosing recommendations for VTE and the same contraindications to their use in VTE apply to their use in HIT.
Other conditions to be considered on the differential when diagnosing HIT include, but are not limited to: type I HIT (HAT), disseminated intravascular coagulation (DIC), liver disease, bleeding, hemodilution, Immune thrombocytopenia (ITP), myelosuppression, as well as other drug-induced causes.
The American Society of Hematology describes 5 phases of HIT:
The management of suspected and acute HIT is reviewed in detail above. Absolute contraindications during the acute period include the use of UFH, LMWH, warfarin and platelet transfusions. When warfarin is first initiated, the natural anticoagulants, protein C and S, whose synthesis is vitamin K-dependent, will be depleted first, while the vitamin-K dependent clotting factors remain in circulation, leading to a hypercoagulable state. If warfarin is administered at the onset of a HIT, protein C and S depletion can severely worsen coagulation and increase the risk of thromboembolic complications, particularly skin necrosis. If recently started, warfarin must be stopped and reversed with phytonadione to replete protein C and S stores.
Warfarin can be started once 2 criteria have been met. First, the platelet count has made a substantial resolution and reached a stable plateau, ideally a platelet count of at least 150, 000 cells/microliter or the patient's baseline, if the baseline was below 150, 000 cells/microliter. Second, the patient must be therapeutically anticoagulated with argatroban or fondaparinux before the initiation of warfarin and the two agents must overlap for at least 5 days before switching to monotherapy with warfarin.
Platelet transfusions are contraindicated during the acute phase, as transfused platelets can bind to IgG and become activated and release PF4, thus worsening the hypercoagulable state.
Subacute HIT A and subacute HIT B can be further broken down into 2 categories: isolated HIT and HITT (HIT with Thrombosis). In patients with HIT and no thrombosis, anticoagulation for 1 month should be considered as the risk of thromboembolic complications persists for up to 30 days after stopping heparin. In the case of HITT patients, who develop new thrombosis due to HIT, 3 months of anticoagulation is suggested, given that HIT is considered to be a reversible provoking risk factor. During this phase, the guideline now recommends DOACs over warfarin in patients without contraindications to DOACs.
Following an episode of HIT, IgG antibodies may remain in the system for up to 100 days (median of 85 days); if the patient receives any amount of UFH or LMWH during this period, platelet counts can drop in as little as 12 hours. If this 100-day period has passed, heparin products can be used with caution if necessary, at the lowest dose and for the least amount of time possible. Ideally, and if time permits, an SRA should be obtained, to ensure it is negative before using heparin. If unable to obtain the SRA, then the use of a direct thrombin inhibitor or fondaparinux should be considered. Bivalirudin would be the drug of choice in patients undergoing PCI or CABG.
Clinical features that distinguish HIT from other types of thrombocytopenia include the timing of onset and the presence of thrombosis. HIT is generally not associated with bleeding. The onset of HIT typically occurs 5-14 days after the start of heparin therapy and it may also occur after heparin cessation. In order to achieve the best outcomes, clinicians, nurses, and pharmacists should be aware of the signs and symptoms associated with HIT pathology and report any findings suggestive of this pathology to the team immediately. Only through an interdisciplinary approach to the diagnosis and treatment of HIT will the best outcomes be achieved. [Level 5]
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