Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction associated with thrombocytopenia and a high risk for thrombosis.
In contrast to other drug-induced thrombocytopenia, significant spontaneous bleeding is rare with HIT even when thrombocytopenia is severe. This makes the diagnosis of HIT very perplexing. Clinical picture alone will not provide enough clues for the diagnosis. A careful history about the use and allergic reactions to medications, diseases that necessitate heparin use, and date and duration of heparin use should be obtained from the patient. Ancillary procedures should supplement history and physical examination in making a diagnosis.
HIT can be classified into three subtypes:
Complete Blood Count
HIT commonly presents as a decrease in platelet count.
The thrombocytopenia is defined as:
The diagnosis of HIT can only be established by using enzyme-linked assays to detect antibodies against heparin-PF4 complexes or heparin-dependent platelet activation.
The current gold standard among the different enzyme-linked assays is the serotonin release assay (SRA). Other tests such as the polyspecific antigen assays (IgG/A/M) and the IgG-specific enzyme-immunoassay (EIA) are at par with SRA in terms of sensitivity (99%) in detecting HIT antibodies . What distinguishes SRA from other tests is its 95-99% diagnostic specificity compared to polyspecific IgG/A/M (50-75%) and IgG-EIA (55-90%) .
The SRA works by utilizing washed platelets loaded with serotonin to detect the presence of HIT antibodies in a patient’s serum. Heparin addition to the platelets should trigger platelet activation and subsequent serotonin release when HIT antibodies are present.
The management of HIT can be broken down into 4 steps:
Stop all heparin administration
The offending agent should be removed immediately to stop further release of HIT antibodies.
Switch to an alternative anticoagulant
The following are some choices of anticoagulant to be used:
DTIs bind directly to thrombin and do not require binding to plasma cofactors such as antithrombin. This characteristic makes it appealing to use in HIT. Lepirudin and Agatroban are DTIs that are clinically proven to safely treat HIT.
The recommended dose is 75mcg/kg/hr and the dosage should be titrated based on aPTT monitoring. The recommended aPTT level is 45-70 seconds. It is important to note that lepirudin is cleared by the kindneys. It should not be used by patients with renal insufficiency.
The recommended dose is 1 mcg/kg/hr that is titrated based on aPTT monitoring. The level of aPTT should be maintained at 45-70 seconds. It is important to remember that agatroban is metabolized in the liver. Patients with hepatic problems should not use this drug.
Fondaparinux is a synthetic analogue of the unique pentassachardie sequence in heparin. However, fondaparinaux binds only to antithrombin and not thrombin. It also does not bind to plasma proteins; therefore, it does not activate platelets and cause release of and bind to PF4. The recommended dosage for fondaparinux in treatment of HIT is 2.5mg OD given subcutaneously.
Do not give platelet transfusions
Thrombocytopenia is a result of the circulating HIT antibodies causing intravascular coagulation. Therefore, the underlying cause (heparin) should be removed rather than give an unnecessary transfusion. Platelet transfusion will only be rendered useless since the platelets will become activated and participate in coagulation as it reaches the circulation.
Do not give warfarin until the platelet count reaches the lower normal limit of 150 x 109/L
HIT causes thrombin generation that consumes protein C. Warfarin is a vitamin K antagonist that depletes the protein C (a vitamin K-dependent anticoagulant) further. The end result is skin necrosis if the protein C in the body becomes insufficient.
Warfarin should only be given once platelet count is normal. It should be overlapped for 5 days with the alternative anticoagulants to maintain the half-lives of all the clotting factors.
The major complications of HIT such as DVT and PE occur in 6-10 out of 100 cases . Early recognition and diagnosis is the key to avoiding unwanted complications.
The thrombocytopenia usually becomes corrected after 7 days in majority of patients. The circulating HIT antibodies will be cleared by the body after approximately 6-8 weeks unless there is re-exposure to heparin therapy.
The main etiology of HIT is a history of treatment with heparin, particularly unfractionated heparin (UFH).
The risk of HIT is dependent on the type of heparin used for treatment.
HIT is reported to occur in 0.2% to 5% of heparin-treated adults.
The typical detection of HIT occurs in between days 5 to 14 of heparin therapy.
It is very rare to see thrombocytopenia below the value of 100,000/L in patients with HIT. Baseline levels should be obtained prior to heparin treatment. A drop of 50% from the baseline should provide a high index of suspicion among patients with heparin use .
HIT is frequently seen in surgical patients with comparison to medical patients.
The type of surgery also plays a factor in HIT.
The incidence of HIT is very low (less than 1%) in both critically ill patients  and those undergoing chronic hemodialysis . HIT occurs in less than 0.1% of pregnant women .
Females are more likely to be affected with HIT than males .
A late complication of HIT is thrombosis. Thrombosis that is venous in origin is more common than arterial  with a ratio of 2:1 .
Heparin’s high-molecular weight is largely in part to its content of at least 18 saccharide units. These saccharide units enable heparin to bind to antiithrombin. However, the saccharide units are not exclusive to antithrombin alone. They also bind to platelets, which release PF4 upon activation, and plasma proteins such as PF4, which carries a great affinity for heparin. A heparin-PF4 complex, which is fortified by forming linear mulitimolecular clusters , can carry presenting antigens. An immune-mediated IgG antibody response ensues to neutralize the antigens by binding to the F domain of PF4. The antibody-antibody interaction promotes platelet aggregation and coagulation  by activating platelets which release thrombin-generating microparticles. Therefore, HIT’s thrombocytopenic manifestation is a result of intravascular platelet activation  caused by the immunologic response to the PF4-heparin antigen. The PF4-heparin complex antibodies also activate monocytes  and neutrophils. This leads to a prothrombotic platelet—monocyte—neutrophil linkage that further augments the formation of thrombosis in HIT.
HIT is an immunologic response to the administration of heparin. Careful switch to LMWH or other alternative anticoagulants must be discussed with the patient, especially high-risk patients, to ensure safety. These drugs may be more expensive than heparin but the cost-effectiveness of their administration in terms of safety is invaluable.
Heparin is a frequently used anticoagulant that works by activating antithrombin. A unique pentassacharide sequence found in heparin wraps around antithrombin to activate it. The activated antithrombin directly inhibits factor Xa and binds to thrombin. The newly formed antithrombin-thrombin complex renders thrombin inactive.
Unfortunately, heparin does not exclusively bind to thrombin and factor Xa. It also attaches to the endothelium which affects the half-life of the drug. It also binds to other plasma proteins such acute phase reactants and platelet factor 4 (PF4) . PF4 is released by activated platelets in the presence of thrombus and is highly attracted to heparin.
Binding of heparin to PF4 produces a PF4-heparin complex that is perceived as antigen. This triggers a cascade of IgG antibodies that are directed against the complex’s antigen. The interaction of the antigen with the antibody promotes activation of platelets and subsequent generation of platelet microparticles. These microparticles exhibit a prothrombotic effect by binding clotting factors and generating thrombin formation. The antibody-mediated process is known as Heparin-Induced Thrombocytopenia (HIT). Despite the thrombocytopenia, the major clinical complication of HIT is venous and/or arterial thrombosis  caused by the release of platelet microparticles.
It is important to note that HIT is a clinicopathologic syndrome . Clinical presentation alone will not provide sufficient evidence to diagnose HIT. The suspected HIT patient must be check for the presence of circulating IgG antibodies against the PF4-heparin antigen. The main limiting factor with ancillary diagnosis is that the antibodies present in HIT do not present in a typical primary (initially IgM followed by IgG) or secondary response fashion (persistence of IgG) . Therefore, timing is key to solve the HIT mystery. The IgG antibodies typically rise between days 4-10 after the first heparin dose . Therefore, prompt diagnostic procedures during these days should be done as soon as HIT is suspected to ensure accurate diagnosis and early intervention with alternative anticoagulants. A timely diagnosis will prevent life-threatening complications from arising.
Heparin-induced thrombocytopenia (HIT) is a sudden drop in platelet count after the use of heparin for treatment. This is mainly due to an immunologic or allergic response to some contents produced as heparin enters the blood. It occurs from 0.2-5% of patients receiving heparin and is very variable since each individual has a different response to heparin treatment.
Previous Heparin Treatment
It is best to consult your physician for monitoring if you are undergoing heparin treatment. This holds true especially for first timers to ensure safety since HIT can be very tricky to diagnose. A timely diagnosis is key to preventing unwanted complications of heparin such as deep vein thrombosis (DVT), pulmonary embolism(PE), myocardial infarction (MI), or stroke.
Treatment of HIT should be done under the supervision of a physician. Blood monitoring is done throughout the treatment to make sure that bleeding or complications do not take place.
The allergic response to heparin usually clears out totally after 6-8 weeks. The platelet count should return to normal after a week of stopping heparin treatment.