Heparin-Induced Thrombocytopenia: 9 Questions Physicians Often Ask

ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a potentially life- and/or limb-threatening complication of heparin or low molecular weight heparin. In this article, the importance of early diagnosis, appropriate inpatient, and outpatient management of HIT will be reviewed. Special attention will be given to outpatient management in the subacute phase of HIT immediately upon hospital discharge as well as chronic long-term management.

Key words: heparin, heparin-induced thrombocytopenia, heparin-associated thrombocytopenia, low molecular weight heparin, deep vein thrombosis, pulmonary embolism, warfarin, anticoagulation, anticoagulants, lepirudin, argatroban, danaparoid, fondaparinux

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are frequently used in the inpatient as well as the outpatient setting. The most common adverse event associated with these agents is bleeding; however, UFH and LMWH can also be associated with heparin-induced thrombocytopenia (HIT), which can lead to significant arterial and venous thrombosis and mortality.

HIT is a clinicopathological diagnosis in which early identification and appropriate treatment in the acute as well as the long-term setting can be lifesaving. In this article, we address 9 questions that physicians often ask about HIT.

1. What is heparin-induced thrombocytopenia?

HIT is a highly prothrombotic, potentially devastating complication of heparin, which may cause paradoxical thrombosis within venous and arterial circulation.¹ It often causes pulmonary embolism (PE) or deep venous thrombosis (DVT); however, it can lead to stroke, myocardial infarction, adrenal infarction, acute limb ischemia, venous limb gangrene, and heparin-induced skin necrosis.^1-4 Although HIT was first recognized more than 50 years ago by Weismann and Tobin, it is still underrecognized and often its catastrophic implications are not well acknowledged.⁵

Pathogenesis of HIT. It is an immune-mediated drug reaction. With heparin exposure, immunoglobulin G (IgG) antibodies are formed that recognize platelet factor (PF) 4/heparin complexes. These IgG/PF4/heparin complexes then bind to Fc IIa (IgG) receptors on platelets, leading to platelet activation and release of pro-coagulants such as microparticles from the platelets resulting in thrombosis.⁶

Incidence of HIT. The incidence of HIT is highly variable depending on the type and quantity of the heparin agent used and on the patient’s medical and surgical status.¹ HIT can be seen in up to 5% of postoperative patients receiving therapeutic or prophylactic doses of UFH. However, the incidence drops down to 0.6% in nonsurgical patients treated with prophylactic or therapeutic doses of LMWH and is as low as less than 0.1% in nonsurgical patients treated only with heparin flushes.¹

Clinical features of HIT. Thrombocytopenia (platelet count of less than 150,000/µL) is the most common clinical feature; however, up to 10% of patients with HIT will not have thrombocytopenia by definition. Some of these patients will have a proportional fall in their platelet count of 30% to 50% even if the nadir count stays above 150,000/µL, and up to 30% of patients may initially present with thrombosis rather than thrombocytopenia.^1,7 Thrombosis is another important clinical feature that occurs in up to 60% of patients either on the same day when thrombocytopenia develops or even preceding thrombocytopenia.⁷

Rarer manifestations of HIT are venous limb gangrene (seen in 5% to 10% of patients with DVT treated acutely with warfarin), acute limb ischemia, arterial thrombosis, adrenal hemorrhage from adrenal vein thrombosis, heparin- and warfarin-induced skin necrosis, and acute systemic reactions.^1,2,4-6

Onset of drop in platelet count. There are 3 distant patterns of drop in platelet count⁸:

•Typical-onset.

•Rapid-onset.

•Delayed-onset.

The typical-onset drop in platelet count occurs within 5 to 10 days after heparin initiation and is seen in 70% of patients with HIT. In the rapid-onset type, there is an abrupt decline in platelet count (usually in less than 24 hours), which occurs in patients with preexisting circulating HIT antibodies due to recent heparin exposure (within the previous 100 days). Delayed-onset HIT is seen in fewer than 5% of patients and is associated with a drop in platelet count after 10 days of heparin therapy.^1,7

2. How hypercoagulable is HIT?

HIT is one of the most well-known prothrombotic conditions. More than 50% of patients with HIT without thrombosis on diagnosis will develop thrombosis in the next 30 days.⁹ Venous thrombosis is more commonly seen with up to 40% of patients developing PE.⁷ Arterial thrombosis is seen in up to 10% of patients and is more likely to be seen in post-cardiac surgery patients (ratio of 1:8.5).^1,7 It is estimated that 5% to 10% of patients with HIT die of thrombotic complications.¹

3. What is the difference between HIT and heparin-associated thrombocytopenia?

HIT, also called HIT type II, is an immunological process associated with severe thrombotic complications, whereas heparin-associated thrombocytopenia (HAT), or HIT type I, is a non-immunological condition associated with heparin-related thrombocytopenia. Unlike HIT type II, HAT usually features a mild decrease in platelet count (less than 30%) and occurs within first 4 days of heparin initiation; the platelet count tends to improve within 3 days of platelet count decrease even with continued exposure to heparin. HAT develops mainly in patients who are receiving intravenous UFH, and it is not associated with thrombotic complications.¹⁰

4. When should I suspect and evaluate for HIT?

Suspect HIT in every patient who receives heparin and experiences a drop in platelet count of more than 30% (even if the platelet count is higher than 150,000/µL), or new thrombosis or extension of preexisting thrombosis, or when it is difficult to reach therapeutic levels of activated partial thromboplastin time (aPTT) even with high doses of heparin. In addition, platelet counts should be monitored in patients who are receiving heparin for prophylaxis or treatment of thromboembolism. This should also include patients receiving heparin flushes for intravenous lines or even when heparin is administered for dialysis, since HIT can occur with any dose of heparin.

Pretest probability. When HIT is suspected, the first step is to calculate the pretest probability for HIT based on the “4T score” clinical decision-making model developed by Warkentin, regardless of whether the patient is hospitalized or seen in the clinic.^1,10,11 In this pretest assessment, the score is calculated on 4 variables and based on the score, patients are determined as having low, intermediate, or high pretest probability for HIT (Box). A score of 0 to 8 points is generated; for the score of 0 to 3 points, the pretest probability for HIT is low. A score of 4 to 5 indicates intermediate pretest probability, while a score of 6 to 8 indicates a high pretest probability. In patients with intermediate or high pretest probability, heparin should be discontinued immediately without waiting for laboratory confirmation and alternative anticoagulants should be used.^1,11

Only 0% to 3% of patients with a low pretest probability for HIT have clinical HIT.^11,12 However, even many patients (24% to 61%) with an intermediate or high pretest 4T score do not have HIT.^1,11,12 HIT is commonly referred to as a clinicopathologic syndrome requiring both clinical and laboratory evidence to confirm diagnosis.^1,10 After establishing the pretest probability, laboratory confirmation is required.¹

Laboratory testing. There are 2 types of laboratory assays: antigenic and functional assays.¹³ Functional assays detect heparin-dependent platelet activation and antigenic assays measure the IgG antibodies to the heparin/PF4 complex.¹³ Among the antigenic assays, the enzyme-linked immunosorbent assays that test for antibodies that are reactive against PF4/heparin or PF4/polyvinyl sulfonate are most commonly used and are very sensitive for HIT, but not specific and hence can potentially identify false-positives. However, these are most frequently used because they are standardized and easily available. The HIT antibody tests are very sensitive but not as specific. In comparison, the serotonin release assay (SRA) and heparin-induced platelet activation assay are functional assays, which have very high sensitivity and specificity for HIT because they only detect antibodies that are capable of activating platelets.¹³ However, the major disadvantage of these assays is that they are available at only a few select centers, require human platelets from known reactive donors, and in case of SRA require working with radiation.¹⁰ Because these gold standard functional assay results are usually not available for about a week, making the initial diagnosis by clinical evaluation with pretest assessment and appropriate interpretation of antigenic assay results is vital.

5. How is HIT treated?

As discussed, the first step is to assess the pretest probability for HIT by calculating the 4T score. If your patient has a moderate or high pretest probability, then he or she is at high risk for HIT and heparin administration should be stopped immediately. Remember, the patient with HIT is hypercoagulable and is at high risk for producing a thrombus. Anticoagulation with non-heparin anticoagulants should be initiated immediately without waiting for laboratory confirmation. Currently, anticoagulants recommended by the American College of Chest Physicians (ACCP) are argatroban, lepirudin, and danaparoid (danaparoid is not available in United States).¹ Lepirudin and argatroban are both FDA approved for use in patients with HIT or suspected HIT.¹⁰

Lepirudin. This recombinant form of hirudin has a short half-life (80 minutes) and is given intravenously or subcutaneously. It can be monitored by aPTT and is primarily metabolized by the kidneys.¹⁰ Up to 60% of patients develop anti-hirudin antibodies and therefore are rarely at risk for anaphylaxis and even death.^10,14

Argatroban. It also has a short half-life (39 to 51 minutes), is given intravenously, and is metabolized through the liver; thus, dose adjustments are recommended in patients with moderate liver disease. Unlike lepirudin, it does not form antibodies. It is known to artifactually prolong the international normalized ratio (INR) and can cause difficulties with INR interpretation when transitioning to warfarin therapy. The manufacturer recommends continuing with co-therapy until the INR is higher than 4 before argatroban is discontinued, and that the INR be checked 4 to 6 hours after discontinuation to ensure that it remains within the therapeutic range.¹⁰

Which agent to use? There are no head-to-head trials that compare lepirudin with argatroban. Both agents do not have antidotes. Because of their differing dose adjustment requirements, it is generally recommended to use argatroban for patients with renal insufficiency and lepirudin for patients with liver dysfunction.¹⁰

6. How is HIT treated in special circumstances?

Pregnancy. The ACCP guidelines recommend using danaparoid in pregnant patients. However, since danaparoid is not available in United States, lepirudin or fondaparinux is recommended.¹

Bridging in a patient with prior known history of HIT. In patients with a history of HIT who have no active antibodies detected in serum, anticoagulation for bridging to warfarin can be pursued with fondaparinux. However, if antibodies are still present, then lepirudin or argatroban should be used. Check the PF4 antibody profile before starting fondaparinux or warfarin and use argatroban or lepirudin until the PF4 antibody results are available.

Cardiovascular surgery and interventions. After cardiac surgery, there are usually multiple reasons to develop thrombocytopenia, such as cardiopulmonary bypass, intra-aortic balloon pump, medications, and sepsis. Platelet counts commonly drop by up to 40% after cardiac surgery and continue to decline for the first 2 days after surgery. The following patterns should raise concern for HIT following cardiac surgery: a fall in platelet count that begins 4 days after surgery or thrombocytopenia that persists for 4 days after surgery.¹⁵ Argatroban and lepirudin can be used in these patients.

Bivalirudin and argatroban have been extensively studied for use in patients undergoing vascular interventions. Management of patients with HIT who require cardiac surgery can be complicated because heparin re-exposure is usually needed in these patients.

In patients with HIT or subacute HIT and with persistent heparin/PF4 antibodies who require urgent cardiac surgery, the current ACCP guidelines recommend using bivalirudin as the anticoagulant over heparin and other agents.¹ In cases of non-urgent cardiac surgery, the ACCP recommends delaying the surgery (usually for more than 3 months) and retesting for heparin/PF4 antibodies. If no antibodies are present after that delay, then a minimal amount of heparin can be used intraoperatively only; and postoperatively, bivalirudin or argatroban should be used if anticoagulation is needed for any indications, including recurrent HIT.¹ If antibodies persist after the delay, then the ACCP recommends further delaying the surgery or proceeding with bivalirudin as the anticoagulant intraoperatively too.

7. Is platelet transfusion necessary in acute HIT?

Spontaneous bleeding is uncommon in HIT even with profound thrombocytopenia. Historically, platelet transfusion given to a patient with HIT was described as “adding fuel to the fire” by further causing thrombosis.¹ This was based on 2 case series. The first series had 2 patients who received platelets and 1 who was still on heparin developed arterial thrombosis. In the second series, 1 patient was given platelets and did not develop thrombosis but had an inadequate rise in platelet count.^16,17 Interestingly, there was a recent single center case series of SRA-proven HIT in 37 patients who received platelet transfusions and did not develop any new thrombosis or die as a result of these transfusions.¹⁸ Based on current data, the ACCP recommends platelet transfusions in patients with HIT and thrombocytopenia only when there is bleeding and need for an invasive procedure with a high risk of bleeding.¹

8. Can fondaparinux cause HIT?

There are less than a handful of case reports of fondaparinux-induced HIT in the literature, many of which lack confirmatory diagnosis with functional assays and/or have exposure to UFH or LWMH close to the time of development of HIT.^19-24 Interestingly, fondaparinux develops a heparin/PF4 complex antibody similar to enoxaparin. However, clinically evident fondaparinux-associated HIT is extremely rare.^25,26 Fondaparinux was recently reported to be used safely in a study of 16 patients with acute HIT.²⁷ However given lack of significant evidence, the ACCP recommends using fondaparinux only in patients with a history of HIT without active heparin/PF4 complex antibodies and in pregnant patients when lepirudin or danaparoid is not available or cannot be used.¹ Although this adverse effect is rare, fondaparinux may cause HIT; therefore, primary care physicians should evaluate patients for HIT if they develop concerning features such as thrombocytopenia or thrombosis with recent fondaparinux use.

9. What is the duration of anticoagulation therapy in patients with HIT?

Given the extremely prothrombotic nature of HIT, especially in the initial 30 days after diagnosis, anticoagulation is vital.⁹ The ACCP recommends 30 days of anticoagulation for patients with isolated HIT (HIT without thrombosis) and at least 3 months of anticoagulation for patients with HIT and a HIT-related thrombosis.¹

We have already discussed options for initial anticoagulants; however, most of these patients are treated with warfarin for long-term anticoagulation. Warfarin should not be started until the platelet count has significantly recovered, which is usually 150,000/µL or higher. It should be initiated at small doses (maximum, 5 mg of warfarin) and bridged with initial choice anticoagulant for at least 5 days of overlap and until the INR is in the therapeutic range for at least 2 consecutive days.¹ Starting warfarin with low platelet counts, using high doses of warfarin, or inadequate bridging with a parenteral anticoagulant can result in severe complications, such as worsening thrombosis, venous limb gangrene, or warfarin skin necrosis.

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