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Heparin-induced thrombocytopenia

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Heparin-induced thrombocytopenia
Steven Coutre, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Mon Oct 17 00:00:00 GMT 2011 (More)

INTRODUCTION — Thrombocytopenia is a well-recognized complication of heparin therapy, usually occurring within 5 to 10 days after heparin treatment has started [1].


  • The more serious form (heparin-induced thrombocytopenia, type II; HIT-II) is an immune-mediated disorder characterized by the formation of antibodies against the heparin-platelet factor 4 complex. This disorder has also been called heparin-associated immune thrombocytopenia, heparin-associated thrombocytopenia and thrombosis (HITT), and white clot syndrome [1,2]. White clot syndrome refers to platelet-rich arterial thrombosis (rather than fibrin-rich venous thrombosis), which occurs with high frequency in patients who develop this disorder [2].
  • A second form of thrombocytopenia, of no clinical consequence (type I heparin-induced thrombocytopenia), is typically characterized by a lesser fall in platelet count that occurs within the first two days after heparin initiation and often returns to normal with continued heparin administration (table 1) [1]. The mechanism of the thrombocytopenia is nonimmune and appears to be due to a direct effect of heparin on platelet activation [3,4].


For the remainder of this review, the term HIT will refer only to the immune form (ie, type II). The clinical manifestations, diagnosis, prevention, and treatment of HIT will be reviewed here [1,5-9]. The clinical use of heparin and low molecular weight heparin is discussed separately. (See “Therapeutic use of heparin and low molecular weight heparin”.)

INCIDENCE AND RISK FACTORS — A critical assessment of immune-mediated HIT suggests a frequency of 0.2 to 5.0 percent in patients exposed to heparin for more than four days [10-15], with an overall incidence of 2.6 percent noted in a meta-analysis [10]. The incidence is closer to 0.2 percent for those treated with unfractionated heparin (UFH) for less than four days [16,17].

Of importance, two prospective observational studies showed a surprisingly high incidence of thrombocytopenia in patients treated with either unfractionated or low molecular weight heparin for ≥4 days, with 15 percent of patients showing a >50 percent reduction in baseline platelet counts in one study [18] and 42 percent in the other [19].

There are three factors in addition to longer duration of therapy that are most strongly associated with the development of HIT [15,17,20,21]:


  • Use of unfractionated heparin (UFH) rather than low molecular weight heparin (LMWH)
  • Surgical rather than medical patients
  • Female rather than male patients


The following observations illustrate these relationships:


  • In an analysis of data from seven prospective studies, the risk of HIT was higher following the use of UFH than LMWH (RR 5.3; 95% CI 2.8-9.9), higher in surgical than medical patients (RR 3.2; 95% CI 2.0-5.4), and higher in females than males (RR 2.4; 95% CI 1.4-4.1) [15]. The highest risk for HIT was seen in female surgical patients receiving UFH (RR 17; 95% CI 4.2-72).
  • The difference in risk between UFH and LMWH was illustrated in a meta-analysis of randomized and prospective nonrandomized studies, mostly in patients undergoing orthopedic surgery [10]. The risk of HIT was 2.6 percent with UFH and 0.2 percent with LMWH. One trial, for example, randomly assigned 665 patients to therapy with either UFH or LMWH for prophylaxis after hip surgery [11]. Immune-mediated thrombocytopenia developed in 2.7 percent of patients treated with UFH but none of those receiving LMWH. The incidence of heparin-dependent IgG antibodies was also higher in the patients receiving UFH (7.8 versus 2.2 percent). Similar results have been reported in patients with neurologic disorders treated with these two forms of heparin [22].
  • Antibodies are more likely to form in patients undergoing cardiac surgery (reported incidence of antibodies as high as 15 to 20 percent [23,24]) than in orthopedic patients [16,23,25]. However, among those in whom antibodies do form, orthopedic patients are more likely to develop HIT than those undergoing cardiac surgery (table 2) [23].
  • The risk of HIT after LMWH may be increased in those with prior exposure to heparin therapy. This was suggested in a prospective cohort study in 1754 consecutive medical patients treated with LMWH in which the overall incidence of HIT was 0.8 percent [26]. HIT was significantly more frequent in those with prior exposure to UFH or LMWH (1.7 versus 0.3 percent, OR 4.9; 95% CI 1.5-16).
  • In a study using the database of the National Hospital Discharge Survey, HIT was found to be rare among patients <40 years of age as well as in women following delivery [20].


Although most patients developing HIT have received IV or SQ heparin therapy for a thrombotic event or for prophylaxis, the amount of heparin required to cause HIT can be quite small. Occasional patients have developed this disorder after exposure to as little as 250 units from a heparin flush or after the use of heparin-coated catheters [27-29].


Antibody formation — The administration of heparin or other sulfated oligosaccharides for four or more days can trigger an antibody response. These IgG, IgM, and IgA antibodies are provoked not by heparin alone, but by the highly immunogenic complex of heparin and platelet factor 4 (PF4), a heparin-neutralizing protein contained in the alpha granules of platelets, which is released from the platelet upon its activation [30-33]. A region separate from the heparin-binding domain of PF4 is required to form the epitope recognized by many HIT antibodies [34]. Binding of these antibodies to PF4 absorbed onto polystyrene in the absence of heparin suggests that the involved epitope may be due to a conformational change within PF4 brought on by surface immobilization on polystyrene, a suitable linear polyanion, or, in vivo, by the action of heparin, heparan, or chondroitin sulfate [31,35,36].

However, naturally-occurring anti-PF4/heparin antibodies are present in 3 to 8 percent of the normal population. It has thus been suggested that preimmunization by antigens mimicking PF4/heparin complexes, such as PF4 complexes with negatively-charged polysaccharides on the surface of bacteria, such as may be present in patients with periodontal disease, may be responsible for the rapid appearance of these antibodies following treatment with heparin [37,38].

The heparin-PF4 complex, once formed, binds to an activated platelet surface and is recognized by the Fab region of the HIT antibody, forming a heparin-PF4-antibody complex on the platelet surface [30,39]. The Fc portion of this bound IgG further activates the same or adjacent platelets through the Fc gamma RIIA receptors on the platelet surface, leading to additional platelet activation with further release of PF4, creating a positive feedback loop [40].

Activated platelets with the heparin-PF4-antibody complex attached to their surface undergo aggregation and are removed prematurely from the circulation leading to thrombocytopenia (HIT) and the generation of procoagulant platelet-derived microparticles, frequently resulting in thrombin generation and thrombosis (HITT) (figure 1) [41]. The antibody complex may also activate microvascular endothelial cells, resulting in augmented release of Interleukin-6, von Willebrand factor, and other adhesion molecules [42]. It is not clear whether these antibodies can be associated with thrombosis in the absence of relative or absolute thrombocytopenia [43].

Although there are several mechanisms associated with drug-induced thrombocytopenia, HIT is distinct among them in being associated with platelet activation. (See “Drug-induced thrombocytopenia”.) This may explain why HIT is uniquely associated with thrombosis rather than bleeding.

Preliminary studies, which will require confirmation, suggest that the heparin-PF4-antibody complex may promote thrombosis by a number of other mechanisms [44]:


  • By inducing the production of tissue factor by monocytes [45]
  • By inhibiting activated protein C generation [46]


A transgenic mouse model of HIT is now available, which may shed more light on the pathogenesis of this disorder [47]. Highly immunogenic complexes of heparin with other positively charged proteins (eg, protamine, lysozyme) have been detected in animal model systems and in human subjects following cardiopulmonary bypass surgery, although their clinical significance is unclear at this time [48].

Disease variability — Why some of these antibodies cause clinical HIT, occasionally after heparin has been stopped, while others do not, is poorly understood. Potential explanations for these observations include the following [31,49]:


  • The antigenicity of PF4-heparin complexes is related to the concentration of PF4 on the platelet surface. Binding of HIT IgG occurs only over a narrow molar ratio of reactants, being optimal at 1 molecule of the PF4 tetramer to 1 molecule of unfractionated heparin.
  • Large antigenic complexes between PF4 and glycosaminoglycans (GAG) may also form on the surface of platelets independent of heparin. These antigenic GAG/PF4 complexes can contribute to initial antibody formation in the absence of heparin and such HIT antibodies may also be augmented in the presence of heparin.
  • Patients with high total and surface PF4 may therefore be at the highest risk for development of clinical HIT when exposed to heparin [50], or after heparin has been discontinued.


Since the binding of HIT antibodies to these PF4/heparin complexes occurs only over a narrow molar ratio of reactants, high concentrations of heparin, such as those used in cardiopulmonary bypass, disrupt antigen formation by depleting surface-bound PF4. This prevents thrombocytopenia induced by the HIT antibody, potentially explaining the low incidence of clinical HIT despite the high incidence of antibodies in this population [49]. A discussion of testing in the presence of both low and high concentrations of heparin is below. (See ‘Diagnostic testing’ below.)

Genetic and patient-specific interactions — Variability in the clinical manifestations and complications of HIT might also arise from interactions between the various systems involved in the pathogenesis of HIT (eg, antigen and antibody variables) and clinical variables in the patient. Thus, evidence has been presented for involvement of the following patient-specific factors in the genesis and/or severity of HIT:


  • Prothrombotic state of the patient [51,52]
  • Polymorphisms of platelet glycoproteins [53]
  • Polymorphisms of the receptor for the Fc portion of IgG which deal with HIT antibody clearance [54,55]
  • Severity of trauma and need for major surgery [21]



Onset and degree of thrombocytopenia — Immune-mediated HIT is associated with a fall in the platelet count of >50 percent that typically occurs 5 to 10 days after the initiation of heparin therapy (algorithm 1) [1,56]. Onset after two weeks is unusual, an observation that correlates with serologic studies showing that heparin-dependent antibodies usually develop between days five to eight after exposure to heparin, but rarely later [11,57]. Earlier onset of HIT may be seen if the patient had been treated with heparin in the previous one to three months and still has circulating HIT antibodies (see ‘Early onset HIT’ below) [58].

Thrombocytopenia and/or a fall in the platelet count greater than 50 percent, due to immune-mediated HIT is rarely severe, with platelet counts typically >20,000/microL and a median platelet count nadir of about 60,000/microL [59,60]. As a result, spontaneous bleeding is unusual. This is in contrast to other immune-mediated thrombocytopenias (eg, idiopathic thrombocytopenic purpura, post-transfusion purpura) where patients often present with platelet counts <10,000/microL and clinical bleeding (figure 2) [61]. (See “Approach to the adult patient with thrombocytopenia”.)

Delayed onset HIT — Delayed-onset HIT, in which thrombocytopenia and thrombosis occur after heparin has been withdrawn, has been increasingly described [62,63]. In one study, HIT was described in 12 patients an average of 9 days (range: 5 to 19 days) after heparin was withdrawn [62]. These patients had high titer platelet-activating antibodies that exhibited increased heparin-dependent as well as heparin-INDEPENDENT platelet activation, perhaps explaining why this complication arose after all heparin should have been cleared from the body.

One possible explanation of this phenomenon is that the unusually high antibody levels react with platelet-associated PF4 bound to non-heparin glycosaminoglycans (eg, chondroitin sulfate), rather than to heparin [31,64]. (See ‘Disease variability’ above.)

The incidence of this phenomenon is not known, although in a retrospective study from three hospitals, there were an estimated 260 patients with HIT and 14 cases of delayed-onset HIT, occurring at a median time of 14 days (range: 9 to 40 days) after onset of treatment with heparin [63]. The following criteria were used to diagnose delayed-onset HIT:


  • Exposure to heparin and discharge from the hospital after a reasonably benign course, during which time HIT went unrecognized.
  • Re-presentation with objectively proven venous and/or arterial thrombosis, with thrombocytopenia developing after reexposure to heparin.
  • Positive serologic tests for heparin-induced antibodies.


On readmission, 11 of the 14 cases were treated with unfractionated or LMW heparin, resulting in a prompt decrease in platelet counts, often with overt clinical deterioration. Three of the 11 patients reexposed to heparin died. After HIT was recognized as the cause of the thromboembolic episodes, heparin was stopped and/or patients received alternative anticoagulants (lepirudin, danaparoid, or argatroban), with ultimate recovery in the remaining patients.

Early onset HIT — Early onset of HIT (median time of platelet fall 10.5 hours after the start of heparin administration), may be seen in about 30 percent of patients with persistent antibodies due to heparin therapy within the previous one to three months [56,65,66].

Cardiac surgery patients — A major decrease in the platelet count of approximately 40 to 50 percent occurs universally during the first 72 hours following cardiac surgery, due at least in part to prolonged contact of platelets with the artificial surface of the extracorporeal circuit [67-69]. These patients usually receive large amounts of unfractionated heparin, a setting in which the incidence of HIT antibodies is as high as 25 to 70 percent by immunoassay and 4 to 20 percent by platelet activation assay [23,24,70,71]. Since several other potential causes of thrombocytopenia are often present, it is difficult to determine whether or not HIT is present in these patients.

While this question has not been satisfactorily settled, the presence of a secondary fall in the platelet count ≥50 percent that begins between the fifth and tenth postoperative day appears to be highly predictive of HIT [68,69,72,73].

Thrombosis — The major clinical problem associated with HIT is thrombosis, both venous and arterial. The precise mechanism of this hypercoagulable state is unknown, although the release of procoagulants from activated platelets has been postulated as a primary event. Other theories include the generation of platelet microparticles, fragments of the platelet membrane which are released and can serve as catalysts for clotting [74]. Since HIT antibodies also bind to heparan sulfate on the surface of endothelial cells [30], thrombosis may result from endothelial cell activation and/or increased tissue factor and thrombin generation due to endothelial cell injury [41,42,75].

The frequency with which thrombosis occurs can be illustrated by the following observations:


  • In a randomized trial of UFH versus LMW heparin in 665 patients following hip surgery, 8 of 9 patients with HIT developed a thrombotic event (seven venous and one arterial) [11]. The frequency of thrombosis was much higher than in those who did not develop HIT (89 versus 18 percent).
  • A retrospective review of 127 patients with serologically confirmed HIT found that venous and arterial thrombosis occurred in 78 and 18 patients (61 and 14 percent), respectively [76]. Approximately one-half of patients with HIT were recognized only after they had a complicating thrombotic event. Of the patients initially recognized with isolated thrombocytopenia, the subsequent 30-day risk of thrombosis was 53 percent.


Among patients receiving heparin for thromboprophylaxis or treatment, the initial sign of HIT usually is the development of thrombocytopenia. If such a patient develops an initial or recurrent thrombotic event, the presence of thrombocytopenia suggests that it is due to HIT rather than failure of anticoagulation [77]. (See “Overview of the causes of venous thrombosis”, section on ‘Heparin-induced thrombocytopenia’.)

The major manifestations of venous thrombosis are deep vein thrombosis (DVT) and pulmonary embolism. In the study cited above, pulmonary embolism was the most common life-threatening event, occurring in 25 percent of patients [76].

Other manifestations of venous thrombosis include venous limb gangrene (distal ischemic necrosis following deep vein thrombosis) and cerebral sinus thrombosis. In one report, eight patients with deep vein thrombosis developed venous limb gangrene and full-thickness skin necrosis after heparin was stopped in response to a diagnosis of HIT and initiation of warfarin [78]. The histologic appearance of the lesion was different from that seen with warfarin-induced necrosis and the patients were not deficient in the natural anticoagulants protein C, protein S or antithrombin [79]. However, the patients with venous limb gangrene had a much higher INR than the 58 patients who did not develop gangrene (median INR 5.8 versus 3.1), suggesting a contribution from acquired protein C deficiency [78]. (See “Protein C deficiency”, section on ‘Warfarin-induced skin necrosis’.)

Upper extremity DVT has also been described in HIT, but is less common than lower extremity DVT [80]. In a retrospective study of 260 patients with antibody-positive HIT, 14 episodes of upper extremity DVT were observed (5.4 percent); all occurred in patients with central venous catheters (CVC) and at the CVC site. (See “Catheter-induced upper extremity venous thrombosis”.)

Arterial thrombosis, although less common, can lead to a variety of clinical manifestations including stroke [81], myocardial infarction, acute limb ischemia from peripheral arterial occlusion, or organ infarction (mesentery, kidney). Since the arterial circulation is a high flow, high shear rate environment, thrombi tend to be platelet-rich. These clots are “white” due to the presence of platelet aggregates, hence the name “white clot syndrome” [2].

Skin necrosis — Skin necrosis at the site of heparin injections is a well-described complication of treatment with unfractionated or LMW heparin, and should immediately suggest the presence of HIT [82-87]. Affected patients have heparin-dependent antibodies but may not develop thrombocytopenia [84-86].

Affected areas are usually fat-rich, such as the abdomen, as in warfarin-induced necrosis; however, the distal extremities and the nose can also be involved. The appearance of erythema is followed by purpura and hemorrhage leading to necrosis. Although the lesions appear similar to warfarin-induced skin necrosis, deficiencies of the natural anticoagulants are not present.

Other complications — Other unusual complications of HIT include adrenal hemorrhage secondary to adrenal vein thrombosis, and transient global amnesia [88,89].


Suspecting HIT — The first step in establishing a diagnosis of HIT is suspecting the presence of this syndrome. Any one of the following scenarios should raise the possibility of HIT in a patient begun on heparin therapy within the preceding 5 to 10 days, or in a patient receiving prolonged treatment with low molecular weight heparin [1,90-92]:


  • Onset of otherwise unexplained thrombocytopenia
  • Venous or arterial thrombosis associated with thrombocytopenia
  • A platelet count which has fallen 50 percent or more from a prior value, even if absolute thrombocytopenia is not present
  • Necrotic skin lesions at heparin injection sites
  • Acute systemic (anaphylactoid) reactions (eg, fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest) occurring after IV heparin bolus administration.


The diagnosis of HIT is initially made on clinical grounds, because the assays with the highest sensitivity and specificity may not be readily available and have a slow turnaround time.

The most specific diagnostic tests for HIT include serotonin release assays, heparin-induced platelet aggregation assays, and solid phase immunoassays [1,93]. Patients with HIT also have elevated platelet- associated IgG levels, but this is a nonspecific finding [94]. (See “Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults”.)

Serotonin release assay — The 14C-serotonin release assay remains the gold standard among the diagnostic tests for HIT [95]. Platelets from normal donors are radiolabeled with 14C-serotonin. The platelets are then washed and patient serum is added along with either high or low heparin concentrations. A positive test is the release of 14C-serotonin when therapeutic (0.1 U/mL) concentrations of heparin are used, rather than high (100 U/mL) concentrations. This concentration dependence reflects the fact that the binding of HIT IgG occurs only over a narrow molar ratio of reactants. (See ‘Pathophysiology’ above.)

The serotonin release assay has been clinically validated in a prospective randomized trial [11], and has a sensitivity and specificity of >95 percent when performed by experienced laboratories [7,96]. A positive serotonin release assay was strongly associated with thrombocytopenia beginning five or more days after heparin exposure (odds ratio 78). The disadvantages of this test are high cost due to the use of radioactive material and the technical demands of the assay.

An assay in which the released serotonin is quantitated via a commercially available ELISA has been described, with a sensitivity and specificity of 100 and 97 percent, respectively [97]. However, this assay is not generally available.

Heparin-induced platelet aggregation — In the platelet aggregation assay, either washed normal donor platelets or platelet-rich plasma (PRP) is added to serum or platelet-poor plasma from a patient with suspected HIT and platelet aggregation is measured. Aggregation should be measured with no added heparin as one control as well as with low (0.1 to 0.3 U/mL) heparin concentrations and high (10 to 100 U/mL) heparin concentrations. A positive test would include low background aggregation with no added heparin, aggregation with the addition of a low concentration of heparin, and absent aggregation with high heparin concentrations.

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The platelet aggregation test is quite specific (>90 percent) but suffers from lack of sensitivity [98]. Some authors claim the use of washed normal donor platelets rather than PRP increases the sensitivity to approximately 80 percent [99].

Solid phase immunoassay — The solid phase ELISA immunoassay is different from the first two tests, since it is not a functional assay. Heparin-PF4 complexes or polyanion-PF4 complexes are coated on a microtiter plate and patient serum is added. If heparin-dependent antibodies are present in the serum sample, they will bind the complex, which can be identified by adding a second antibody.

This is a very sensitive assay (91 to >97 percent); a negative test strongly suggests the absence of HIT, while the clinical utility of a positive test remains to be determined, since many patients with a positive ELISA test (ie, an optical density at 405 nm greater than a predetermined cut-off value) do not have platelet-activating antibodies and do not develop clinical HIT (presence of antiphospholipid antibodies, systemic lupus erythematosus, pseudothrombocytopenia) [100-108]. Accordingly, this test has a low specificity of 74 to 86 percent.

Accordingly, the test has a high negative predictive value (>95 percent) but its positive predictive value is only moderate, varying from 50 to 93 percent, depending upon, among other factors, the population being studied and the timing of the platelet fall [1,102,103,109]. The specificity of the test may be improved by one or more of the following:


  • Assaying only for heparin-PF4-IgG antibodies, since, in a number of studies, assays for the presence of antibodies of the IgM and IgA class were not as specific for diagnosing clinical HIT [104,110-114].
  • Addition of a high-dose heparin confirmatory procedure. Inhibition of a positive ELISA result by 50 percent or more in the presence of excess heparin (100 units/mL) has been considered confirmatory of heparin-dependent antibodies [115], although this step has not been consistently reliable in cardiac surgery patients [116,117].
  • Consideration of the magnitude of the optical density result. (See ‘Defining test positivity’ below.)


Results in dialysis patients — The incidence of a positive solid phase immunoassay for HIT antibodies in dialysis patients has varied considerably (eg, zero to 18 percent); the significance of such antibodies is unclear. This issue was studied in a group of 740 renal failure patients receiving either hemodialysis or peritoneal dialysis and followed for a median duration of 3.6 years. The following observations were made [118]:


  • A positive ELISA test (optical density >0.4 OD units) was seen in 76 patients (10.3 percent). When heparin neutralization was employed, tests were considered positive in 66 of the 76 cases (8.9 percent).
  • Thrombocytopenia was noted in only nine patients (1.2 percent), all of whom also had a positive ELISA test, compatible with a clinical diagnosis of HIT. One of these nine patients had a venous thromboembolic event (0.1 percent).
  • Immunoassay positivity in the absence of thrombocytopenia did not predict for development of thrombocytopenia or for arterial or venous thromboembolic events, vascular access occlusion, or mortality.


Because immunoassay positivity in these patients in the absence of thrombocytopenia did not predict for development of significant clinical endpoints, it was concluded that dialysis patients should not be monitored for the presence of HIT antibodies in the absence of thrombocytopenia.

Defining test positivity — The strength of a positive immunoassay (ie, its optical density (OD) at 405 nm) provides useful information regarding the likelihood of HIT, with an optical density >1.0 more likely to be associated with platelet-activating antibodies [1,104,106,113,119,120].

This issue was directly approached in one study by determining the risk of a strongly-positive serotonin release assay (SRA, ≥50 percent serotonin release) for five different categories of OD reactivity using both a commercial and an in-house solid phase immunoassay. Results included [106]:


  • OD <0.40 — SRA positive in 0.0 to 0.1 percent
  • OD 0.40 to <1.00 — SRA positive in 1 to 5 percent
  • OD 1.00 to <1.40 — SRA positive in 18 to 30 percent
  • OD 1.40 to <2.00 — SRA positive in 19 to 46 percent
  • OD >2.00 — SRA positive in 89 to 100 percent


Based on their results, the authors concluded [106]:


  • A weak-positive test result (ie, an OD in the range of 0.40 to <1.00) was strong evidence AGAINST the diagnosis of HIT, with a probability of HIT of ≤5 percent.
  • The probability that a positive test result indicated the presence of platelet-activating HIT antibodies did not reach a threshold of >50 percent, meaning that the diagnosis of HIT was more likely than not, until the OD reached a value of ≥1.40. This threshold may be considerably higher in cardiothoracic bypass patients receiving unfractionated heparin.
  • For a very strongly positive immunoassay result (ie, OD >2.00), the probability of detecting platelet-activating antibodies was approximately 90 percent.


Accordingly, it has been suggested that the optical density of the test result, whether or not there was inhibition by high-dose heparin, and the cut-off for a positive result should all be reported by the laboratory, rather than stating that the test is either positive or negative [6,7,106,115,121]. As an example, in a study where HIT was diagnosed solely on clinical grounds, the probability of clinical HIT for a patient with an optical density on an ELISA test of 1.0 was approximately 20 percent if the high-dose heparin confirmatory test was negative and approximately 80 percent if it was positive (figure 3) [115].

Practical diagnostic issues — The ELISA test is best used along with one of the functional assays rather than as a single test, since up to 10 to 20 percent of sample results may be discordant between the ELISA assay and the functional assays [1,99,122-125]. In complex clinical settings and/or when the ELISA test is marginally positive, a functional assay can help to confirm or refute the diagnosis of HIT (figure 3).

From a practical standpoint, one is often faced with the report of a positive ELISA assay without additional details. In the absence of a confirmatory functional assay, the diagnosis of HIT should be determined by a clinical assessment (see ‘Pretest probability of HIT (the 4 T’s)’ below). Thus:


  • If the clinical presentation is consistent with HIT and there are no alternate explanations for the thrombocytopenia, a positive ELISA assay should be considered as supportive of the diagnosis of HIT.
  • There is the potential to over-diagnose HIT if any “positive” ELISA assay (ie, independent of the strength of the positive test) is considered “diagnostic” of HIT irrespective of the clinical scenario and the pretest probability (see below) [126].

    If, in the course of time, the pretest probability of the patient increases from a prior value, it is reasonable to repeat a previously negative ELISA test. A positive ELISA test under such circumstances is more likely to be associated with clinical HIT [127].


Pretest probability of HIT (the 4 T’s) — A difficulty in establishing the diagnosis of HIT is that medical and surgical patients may have multiple causes for thrombocytopenia other than the use of heparin. Furthermore, patients who do not have HIT may, on the basis of a false-positive test result, be inappropriately switched from heparin to much more expensive medications (eg, argatroban, lepirudin) that also increase the risk of bleeding.

In an attempt to address this problem, a pretest clinical score (called “the 4 T’s”) has been developed and prospectively validated in two centers [128].



  • Platelet count fall >50 percent and nadir >20,000: 2 points
  • Platelet count fall 30 to 50 percent or nadir 10 to 19,000: 1 points
  • Platelet count fall <30 percent or nadir <10,000: zero points


Timing of platelet count fall


  • Clear onset between days 5 and 10 or platelet count fall at ≤1 day if prior heparin exposure within the last 30 days: 2 points
  • Consistent with fall at 5 to 10 days but unclear (eg, missing platelet counts), onset after day 10, or fall ≤1 day with prior heparin exposure within 30 to 100 days: 1 point
  • Platelet count fall at <4 days without recent exposure: 0 points


Thrombosis or other sequelae


  • Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus: 2 points
  • Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis which has not been proven: 1 point
  • None: zero points


Other causes for thrombocytopenia present


  • None apparent: 2 points
  • Possible: 1 point
  • Definite: zero points


Test interpretation — A score is determined for each of the four above categories, resulting in a total score from zero to 8. Pretest probabilities for HIT are, as follows:


  • Zero to 3: Low probability
  • 4 to 5: Intermediate probability
  • 6 to 8: High probability


Among 111 patients with a low pretest probability of HIT using this scoring system, only one had clinically significant HIT antibodies (0.9 percent). In contrast, the overall rate of clinically significant HIT antibodies was 11.4 and 34 percent in those with intermediate and high scores, respectively.

A significant concern with these findings is that there was substantial variability in the rate of clinically significant HIT antibodies at the two centers in patients with intermediate (29 versus 8 percent) or high scores (100 versus 21 percent). A number of methodologic and center-specific factors may have contributed to these differences [128].

These initial results were confirmed at two other centers, in which the incidences of a positive rapid ELISA immunoassay for HIT antibodies were 1.6 and 4 percent and that of a positive serotonin release assay or HIPA assay was zero percent for a total of 458 patients with suspected HIT and a low probability on the 4 T’s test [113,129].

Accordingly, laboratory testing for HIT might reasonably be limited to patients with an intermediate or high pretest probability, since those with a low pretest probability are at very low risk of having clinically significant HIT antibodies (ie, <5 percent) [7,113,129].

Other pre-test probability models — Two other pre-test probability models have been proposed. Neither has been prospectively evaluated on a multicenter basis.


  • Lillo- Le Louet model. This model is intended for use exclusively in the postcardiopulmonary bypass setting [72]. (See ‘Cardiac surgery patients’ above.)
  • HIT Expert Probability Score. This model is based on broad expert opinion [130].


PREVENTION — Low-molecular-weight (LMW) heparin, the heparin analogue fondaparinux, and heparinoids, such as danaparoid, are associated with a much lower incidence of HIT than unfractionated heparin [20,90]. In a prospective study of postoperative orthopedic patients, the administration of a LMW heparin was associated with a lower incidence of heparin-dependent IgG antibodies (2.2 versus 7.8 percent with unfractionated heparin) and no cases of HIT (zero versus 2.7 percent) [11]. Similar observations were made in a multicenter study of two different LMW heparins in 499 patients who had undergone hip replacement; only one developed thrombocytopenia [131].

Danaparoid, an agent no longer available in the United States, has been used extensively to treat patients with HIT (see below) [132]. There is an approximately 10 percent crossreactivity with standard HIT-IgG in vitro and 5 percent crossreactivity in vivo [133]. The clinical relevance of this finding is unclear, since clinical sequelae resulting from danaparoid use are uncommon.

In general, the best way to prevent HIT is the judicious use of unfractionated heparin (eg, for a shorter period of time when used) or the substitution of LMW heparin, where appropriate (see ‘Incidence and risk factors’ above) [20]. Limiting heparin duration to less than five days and starting warfarin early to minimize the length of heparin use in patients requiring long-term anticoagulation are two often overlooked strategies.

Warfarin should not be given to patients who have HIT until the thrombocytopenia resolves following the use of agents such as argatroban or hirudin (see ‘Warfarin’ below), and LMW heparin should not be substituted for unfractionated heparin after HIT develops.


Initial intervention — The first intervention in a patient with HIT should be immediate cessation of all exposure to heparin, including heparin-bonded catheters and heparin flushes (eg, for arterial lines or heparin locks) (algorithm 1) [1,7]. LMW heparin should also be avoided since it may crossreact with the heparin-induced antibodies [1,134].

On making a diagnosis of HIT, heparin “allergy” should be included in the patient’s record, and a sign should be posted at the bedside (or attached to all intravenous delivery devices) that the patient has HIT and should not receive any form of heparin, including heparin flushes [135].

However, heparin cessation alone is often not sufficient, since these patients remain at risk for subsequent thrombosis [134,136]. In a retrospective series of 62 patients with isolated thrombocytopenia caused by heparin, the subsequent 30-day risk of thrombosis was 53 percent [76]. Another study evaluated 113 patients with HIT, in whom heparin was stopped early (mean 0.7 days) or late (mean 5 days) after the onset of thrombocytopenia [137]. The overall incidence of thrombosis was 45 and 34 percent in the early and late groups, respectively, with 61 and 40 percent of the thrombotic events occurring more than 24 hours after cessation of heparin.

There are a number of recommended alternative anticoagulants to heparin in a patient with HIT: a direct thrombin inhibitor such as lepirudin (recombinant hirudin), bivalirudin, or argatroban; fondaparinux; or danaparoid (not available in the United States) (algorithm 1 and table 3) [1,138-140].

In a nonrandomized comparison study, the efficacies of therapeutic (rather than prophylactic) doses of danaparoid and lepirudin in preventing death, amputation, or new thromboembolic complications did not differ significantly, although the risk of bleeding appeared to be higher in patients treated with lepirudin [134,141].

To date there have been no prospective randomized studies comparing the relative efficacy and toxicity of the available agents. However, because of their different modes of excretion and inactivation, patients with HIT and renal insufficiency are usually treated at our institution with argatroban, while those with hepatic impairment are usually treated with lepirudin.

Lepirudin — Lepirudin (Refludan®) is a recombinant hirudin, which has been approved by the FDA for treatment of HIT complicated by thrombosis. This agent has also been shown to be effective in preventing new thromboses in patients with isolated HIT and no clinically evident thromboembolic complications [136].

The efficacy of lepirudin was demonstrated in a prospective series of 82 patients with confirmed HIT: 56 with thrombosis; 18 without thrombosis; and 8 undergoing cardiopulmonary bypass surgery. The administration of lepirudin (0.1 to 0.4 mg/kg bolus followed by 0.1 to 0.15 mg/kg per hour infusion) was associated with a rapid and sustained increase in platelet count in 89 percent of patients, indicating the absence of cross-reactivity with heparin-induced antibodies [142]. In this and a later study, the incidence of the combined endpoints (death, amputation, new thromboembolic events, major bleeding) was significantly lower than in historical controls (25 to 30 versus 52 percent at day 35) [142,143].

Adequate anticoagulant levels were documented by prolongation of the activated partial thromboplastin time (aPTT). A meta-analysis of two available lepirudin trials indicated that an aPTT ratio between 1.5 and 2.5 was optimal [144]. Ratios below 1.5 had minimal effects on study endpoints (see above) and bleeding, while ratios above 2.5 (when compared with ratios of 1.5 to 2.5) did not further reduce study endpoints, but doubled the rate of bleeding.

The incidence of anaphylaxis in patients with HIT treated with lepirudin has been estimated to be only 0.015 percent on first exposure and 0.16 percent in reexposed patients, despite the high incidence of detectable anti-hirudin antibodies [145,146].

Revised dosing — A combined analysis of three prospective studies using lepirudin in patients with HIT noted a significantly higher rate of major bleeding in lepirudin-treated patients compared with historical controls (17.6 versus 5.8 percent) [143]. In one of these studies, the mean maintenance dose of lepirudin was 0.11 mg/kg/hour, lower than the recommended starting dose of 0.15 mg/kg/hour. Based on this observation, it was recommended that the bolus dose be omitted in all patients and the starting dose be reduced to 0.1 mg/kg/hour.

However, in a retrospective observational study in 181 patients with confirmed HIT treated with lepirudin, 20.4 percent experienced a major bleeding event despite the use of a mean dose (0.06 ± 0.04 mg/kg/hour) significantly lower than that recommended by the manufacturer [147] and by the combined analysis noted above [143]. On multivariate analysis, a mean lepirudin dose greater than 0.07 mg/kg/hour was a significant risk factor for major bleeding (odds ratio 11; 95% CI 2.5-49) while doses between 0.04 and 0.07 mg/kg/hour did not compromise its anti-thrombotic efficacy (odds ratio 0.62; 95% CI 0.20-1.9).

Accordingly, a starting dose of lepirudin in the range of 0.05 to 0.075 mg/kg per hour (no bolus), along with careful initial aPTT monitoring at four-hour intervals, has been advised in order to improve safety without compromising efficacy [147,148]. The 2008 ACCP Guidelines differ slightly: starting dose no higher than 0.1 mg/kg per hour (creatinine <1 mg/dL or <90 microM/L); the initial IV bolus should either be omitted, or, in case of perceived life- or limb-threatening thrombosis, be given at a reduced dose of 0.2 mg/kg [1].

Dosing in renal insufficiency — Caution should be used in patients with renal insufficiency, since the drug is cleared by the kidney and its anticoagulant effect is not easily reversed. As an example, major bleeding was noted in one-third of patients receiving lepirudin if the serum creatinine was greater than 1 mg/dL (90 micromol/L) [143]. Accordingly, dosage of this agent needs to be decreased in patients with renal insufficiency and the aPTT closely monitored due to the potential for drug accumulation.

The following initial doses have been considered appropriate for such patients [1]:


  • Creatinine 1 to 1.6 mg/dL (90 to 140 microM/L) — starting dose 0.05 mg/kg per hour
  • Creatinine 1.6 to 4.5 mg/dL (140 to 400 microM/L) — starting dose 0.01 mg/kg per hour
  • Creatinine >4.5 mg/dL (>400 microM/L) — starting dose 0.005 mg/kg per hour


Slightly different recommendations for lepirudin dosing in patients with renal insufficiency were made in a second study involving 53 patients studied retrospectively and 15 studied prospectively. Recommended starting infusion doses (no bolus) were [149]:


  • Estimated creatinine clearance (Est CrCl) >60 mL/min — starting dose 0.08 mg/kg per hour
  • Est CrCl 30 to 60 mL/min — starting dose 0.04 mg/kg per hour
  • Est CrCl <30 mL/min — starting dose 0.01 to 0.02 mg/kg per hour


Bivalirudin — Bivalirudin (Angiomax), a hemodialyzable direct thrombin inhibitor and hirudin analog (previously called hirulog) has been successfully employed in patients with HIT [1,150,151], with reduced doses safely employed in patients with combined hepatic and renal failure [152].

Bivalirudin has been approved by the FDA for patients with, or at risk of, HIT who are undergoing percutaneous coronary intervention, but not for HIT in other settings. (See “Anticoagulants other than heparin and warfarin”, section on ‘Bivalirudin’.)

The recommended initial dose of bivalirudin for HIT is approximately 0.15 mg/kg per hour, adjusted to achieve an aPTT 1.5 to 2.5 times baseline. Doses of 0.14 mg/kg per hour in patients with hepatic dysfunction and 0.03 to 0.05 mg/kg per hour in patients with renal or combined hepatic and renal dysfunction have been successfully employed [152].

Anti-hirudin antibody formation — In a prospective study of 196 patients taking hirudin for HIT for a mean duration of 10 days, anti-hirudin IgG antibodies were detected in 44 percent [153]. Longer treatment duration with lepirudin (18.6 versus 11.8 days) was the only clinical variable associated with antibody formation. Deaths were significantly less common in antibody-positive patients (1.2 versus 14 percent); other end-points such as limb amputations, new thromboembolic complications, time course of platelet count normalization, and major bleeding complications did not differ between antibody-negative and antibody-positive patients.

In 45 percent of the anti-hirudin antibody positive patients (12 percent of all hirudin-treated patients), the dose of hirudin had to be reduced (mean dose reduction 45 percent, range: 17 to 90 percent) in order to keep the aPTT in the targeted therapeutic range. It was therefore suggested that daily monitoring of the aPTT be performed in all patients receiving prolonged treatment with this agent (ie, more than five days), in order to avoid bleeding complications due to this phenomenon.

Argatroban — Argatroban is a direct thrombin inhibitor [154]. It is a small molecule that in contrast to hirudin, interacts with the active site of thrombin but does not make contact with exosites I or II. It has a short in vivo plasma half-life of 24 minutes [154]; its effect is monitored by the aPTT, although dose-dependent increases also occur in the prothrombin time [155]. Steady-state anticoagulation is reached one to three hours after intravenous administration; after discontinuation, the aPTT returns to normal within two hours [156]. (See “Anticoagulants other than heparin and warfarin”, section on ‘Argatroban’.)

Three reports of multi-institutional phase III prospective trials of argatroban in HIT, as compared with historical controls, have been published [157-159]. These studies showed superior efficacy of argatroban in reducing subsequent thrombotic events and death due to thrombosis, with no difference in bleeding rates.

As a result of these studies, the drug was approved by the FDA for both prophylaxis and treatment of thrombosis in heparin-induced thrombocytopenia. This agent has also been successfully employed in patients with a history of HIT needing acute anticoagulation [160]. The drug is eliminated via a hepatobiliary route; dose adjustment is required in the presence of hepatic dysfunction but is not required in the presence of renal impairment [161].

Large case series are not available concerning the utility of this agent in patients with HIT. One report from a university hospital noted clinical outcomes in 27 patients with HIT; 63, 48, and 41 percent had renal failure, hepatic failure, or both, respectively [162]. The median dose over the course of therapy was 0.5 microg/kg/min (range: 0.01 to 2.0). The following endpoints were noted:


  • Death — Six patients (22 percent). These occurred mainly in patients with preexisting multi-organ failure.
  • Any bleeding — Six (22 percent)
  • New thrombosis — Four (15 percent)
  • Bleeding requiring transfusion — One (4 percent)
  • Amputation required — None


In patients with normal hepatic function, the standard starting dose is 2 microg/kg per minute by continuous intravenous infusion, adjusted to maintain the aPTT at 1.5 to 3 times baseline. Since argatroban is mostly metabolized by the liver and excreted in bile, a conservative lower starting dose (eg, 0.5 to 1.2 microg/kg per minute) is appropriate in patients with hepatic dysfunction (eg, total serum bilirubin >1.5 mg/dL; >25.5 micromol/L) as well as in those with combined hepatic/renal dysfunction, heart failure, severe anasarca, or who are postcardiac surgery [1,163]. In such patients it is prudent to check the aPTT at four-hour intervals after drug initiation or dose change to ensure that the desired level of anticoagulation is present.

A small study in 24 patients has suggested that an even lower starting dose of argatroban (0.2 microg/kg per minute) may be appropriate in critically ill patients with multiple organ dysfunction syndrome and HIT [164].

Transition to warfarin — Transition from argatroban to warfarin is discussed below. Since both warfarin and argatroban elevate the PT/INR, institutional guidelines should be reviewed to determine the appropriate INR target when both agents are used in order to achieve an INR in the range of 2.0 to 3.0 when argatroban is discontinued. This target will differ according to the reagents used to determine the PT/INR in each particular institution. (See ‘Warfarin’ below.)

Fondaparinux — While published experience with this agent in HIT is limited, the pentasaccharide fondaparinux has a theoretical role in treatment and/or prevention of HIT, since the drug does not appear to interact with platelets or platelet factor 4. In one retrospective review of results from the Matisse trial, the use of fondaparinux as initial treatment for acute VTE in 10 patients with pre-existing platelet-activating HIT antibodies did not incite the development of HIT in any patient [165]. In contrast, the use of unfractionated or LMW heparin as initial treatment for acute VTE in four patients with pre-existing platelet-activating HIT antibodies resulted in the development of HIT in all four.

Although not formally approved for this indication by the FDA, there are an increasing number of anecdotal reports of patients with HIT being successfully managed with fondaparinux in lieu of a direct thrombin inhibitor, although the level of evidence supporting this is of low quality [166,167]. The 2008 ACCP Guidelines give a stronger recommendation for the use of danaparoid, lepirudin, or argatroban in HIT than for fondaparinux [1].

The long half-life of this agent, its renal elimination, and the lack of an antidote are important considerations when considering the use of this agent [135]. (See “Therapeutic use of fondaparinux”, section on ‘Heparin induced thrombocytopenia’.)

Danaparoid — Danaparoid (Orgaran®) is a heparinoid which includes predominantly dermatan sulfate and low-sulfated heparan sulfate. It had been approved by the Food and Drug Administration (FDA) in the United States for prophylaxis in patients undergoing hip-replacement surgery. However, as a result of shortage in drug substance, the manufacturer (Organon) has decided to discontinue providing this medication in the United States, although it is available in several other countries.

There is extensive experience using this agent in patients with HIT [132,168]. It has also been given to patients with HIT or a history of HIT who require cardiopulmonary bypass surgery [169-171]. Other than its effect as an alternative anticoagulant in patients with HIT, danaparoid, in therapeutic concentrations, has been shown to interfere with platelet factor 4-heparin complex formation [172].

There is a 10 percent crossreactivity between danaparoid and the antibody responsible for HIT in vitro, but the clinical significance of this is uncertain given the apparent therapeutic benefit in such patients [132]. However, in one study, persistence of, or recurrence of, thrombocytopenia without thrombosis was noted in 6.5 percent of patients with classical HIT who were switched from heparin to danaparoid [173].

The recommended use of danaparoid in HIT is a therapeutic dose (rather than a prophylactic dose), with an initial IV bolus of 2250 U, modified up or down according to body weight, followed by an IV infusion at the rate of 400 U/hour for four hours, 300 U/hour for the next four hours, and 200 U/hour thereafter. Doses are adjusted to achieve anti-Xa levels of 0.5 to 0.8 anti-Xa U/mL [1].

The disadvantages of using danaparoid are the need to measure anti-factor Xa levels to monitor its anticoagulant effect, its long half-life (25 ± 100 h) [138], renal elimination, and the absence of a reversing agent [174].

Warfarin — Warfarin should be initiated in a patient with HIT only when both of the following have been accomplished [1,78,137]:


  • The patient has been stably anticoagulated with a thrombin-specific inhibitor, and
  • The platelet count has increased to at least 150,000/microL


There should be a minimum of five days of overlapping therapy before the thrombin inhibitor is discontinued. The INITIAL use of warfarin alone for a patient diagnosed with HIT should be avoided since warfarin therapy may increase the risk of venous limb gangrene in patients with deep vein thrombosis through its rapid lowering of protein C levels [78,175].

When the above two goals have been reached and warfarin therapy is started, high initial doses (eg, ≥10 mg/day) should be avoided to minimize the transient hypercoagulable state induced by the rapid decline in protein C levels [1,176]. Accordingly, warfarin should be started at low maintenance doses of ≤5 mg/day (or phenprocoumon ≤6 mg/day) [1]. (See “Therapeutic use of warfarin”, section on ‘Initial dose’ and “Therapeutic use of warfarin”, section on ‘Maintenance therapy’.)

The target range for anticoagulation with warfarin should be an INR in the range of 2.0 to 3.0. The length of treatment with warfarin has not been defined in any prospective study, but in view of the high risk of thrombosis within 30 days of the diagnosis of HIT [76], warfarin anticoagulation should probably be continued for at least two to three months, and for at least three to six months if a thrombotic event has occurred [58,177].

Other agents — Other approaches (eg, arvin, thrombolysis, plasmapheresis, dextran, intravenous immunoglobulin) are not effective for the initial treatment of HIT and should not be used in place of danaparoid, lepirudin or argatroban, bivalirudin, or fondaparinux. A preliminary report of three patients suggests that a glycoprotein IIb/IIIa inhibitor in combination with a direct thrombin inhibitor may be effective when a thrombin inhibitor alone fails to relieve acute thrombosis [178].

Platelet transfusions — Platelet transfusions are generally considered as being relatively contraindicated for the prevention of bleeding in patients with HIT, largely due to the possibility that they might precipitate thrombotic events (ie, “add fuel to the fire”).

In two reports of a total of 41 patients with HIT, platelet transfusions resulted in appropriate 24-hour post-transfusion platelet count increments in the majority, with cessation of bleeding in two-thirds of the bleeding patients [179,180]. No thrombotic complications were noted in either report. A review of the literature revealed no case of a complication clearly attributable to platelet transfusion [179].

These authors, as well as the 2008 ACCP Guidelines, concluded that platelet transfusions can be considered in patients with HIT and overt bleeding or who are deemed to be at high bleeding risk, particularly if heparin has been stopped for at least several hours [1].

USE OF HEPARIN AFTER AN EPISODE OF HIT — Patients with a history of HIT who require cardiopulmonary bypass (CPB) have been successfully anticoagulated with a brief course of treatment with unfractionated heparin without complications. This approach is based on the theory that a secondary immune response after reexposure to heparin should not occur until at least three days after exposure. Thus, a brief exposure to heparin during CPB should not immediately elicit HIT antibodies. Furthermore, since the heparin would be rapidly cleared after the procedure, even if antibodies appeared, they would not be thrombogenic in the absence of heparin.

This approach was applied in 10 patients with a history of HIT who required CPB [181]. At the time of surgery all patients were negative for HIT antibodies according to a PF4 solid phase assay. There were no complications of surgery, no prolonged thrombocytopenia, and no increase in the serum concentration of HIT antibodies during a 10-day post-operative period.

Thus, when managing such patients, the use of unfractionated heparin could be considered using the following guidelines [1,65,181,182]:


  • Prove, using a sensitive assay for platelet factor 4/heparin antibodies, that HIT antibodies are no longer detectable. These antibodies usually disappear at a median time of 50 to 90 days following the last exposure to heparin, but a safer interval is >100 days [183]. (See ‘Early onset HIT’ above.)
  • Restrict the use of unfractionated heparin to the operative procedure itself. Low molecular weight heparin is not recommended, due to its longer half-life compared with unfractionated heparin as well as the inability to fully reverse its effect with protamine. (See “Therapeutic use of heparin and low molecular weight heparin”.)
  • Use alternative anticoagulants pre- and post-operatively if needed (eg, lepirudin, warfarin). Bivalirudin has been approved by the FDA for patients with, or at risk of, HIT who are undergoing percutaneous coronary intervention. However, there are concerns about how best to monitor use of this agent and that its use may be associated with a high incidence of bleeding in patients undergoing CPB [184]. (See ‘Bivalirudin’ above.)


This issue is more complex if CPB is urgently required in a patient with a past history of HIT in whom the platelet count has recovered but IgG antibodies to the platelet factor 4/heparin complex are still present (ie, “subacute HIT”). In a report of three patients with subacute HIT requiring urgent heart transplantation, reexposure to unfractionated heparin was uneventful when it was shown that they tested negative by a sensitive functional assay using washed platelets (eg, heparin-induced platelet aggregation) [185]. Heparin was discontinued and a direct thrombin inhibitor (argatroban or lepirudin) was used a few hours post-operatively in all three cases to prevent recurrence of thrombosis due to the re-exposure to heparin.

When CPB is urgently required, HIT antibodies are present, a sensitive functional assay is not available, and heparin is chosen as the anticoagulant, the use of intraoperative plasma exchange has been undertaken, in order to reduce the titer of the HIT antibodies [186,187]. Additional experience will be required before a recommendation can be made for such treatment [188].


Diagnosis — The presence of any one of the following should raise the possibility of immune heparin-induced thrombocytopenia (HIT) in a patient begun on heparin therapy within the preceding five to ten days, in a patient receiving prolonged treatment with low molecular weight heparin, or in a patient developing acute thrombocytopenia after being re-exposed to heparin. (See ‘Suspecting HIT’ above and ‘Clinical manifestations’ above.)


  • Otherwise unexplained thrombocytopenia
  • Venous or arterial thrombosis associated with thrombocytopenia
  • A platelet count which has fallen 50 percent or more from a prior value, even if absolute thrombocytopenia is not present
  • Necrotic skin lesions at heparin injection sites
  • Acute systemic (anaphylactoid) reactions occurring after IV heparin bolus administration.


Pretest probability — Once HIT has been suspected, the pretest probability of HIT should be judged. (See ‘Pretest probability of HIT (the 4 T’s)’ above.)


  • Low probability (0 to 3 points) — Causes for thrombocytopenia other than heparin should be re-evaluated in those with a low pretest probability. Laboratory testing for HIT is not generally appropriate in this group.
  • Intermediate or high probability (4 to 8 points) — Patients with intermediate or high pretest probability for HIT should have all forms of heparin and low molecular weight heparin immediately stopped and laboratory testing for HIT urgently obtained.


Because the results of functional assays for HIT may be delayed for as long as one week, they are useful only for final confirmation of the diagnosis. The diagnosis of HIT should be considered established in a patient with intermediate or high pretest probability and a positive solid phase ELISA test for HIT. (See ‘Defining test positivity’ above.)

Treatment — For patients with an intermediate or high pretest probability of HIT, in whom a solid phase immunoassay has been found to be positive, we recommend the immediate use of an alternative nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid, fondaparinux, bivalirudin) (Grade 1B). Any of these agents can be used in patients whose renal and hepatic functions are both normal (algorithm 1 and table 3). (See ‘Treatment’ above and ‘Initial intervention’ above.)


  • We suggest that patients with abnormal hepatic function and normal renal function be treated with lepirudin, danaparoid, or fondaparinux, while those with abnormal renal function and normal hepatic function receive argatroban at standard doses or lepirudin at reduced doses (Grade 2C).
  • For patients in whom both renal and hepatic function are abnormal we suggest treatment with argatroban or bivalirudin at reduced doses (Grade 2C).
  • We suggest that patients with HIT be anticoagulated for at least two to three months in the absence of a thrombotic event and three to six months if such an event has occurred (Grade 2C). Warfarin can be started once the patient has been stabilized with a nonheparin anticoagulant and the platelet count has recovered to ≥150,000/microL.


To accomplish this, low initial doses of warfarin, rather than high “loading” doses, should be started. The nonheparin anticoagulant should be continued for at least five days along with warfarin, until the platelet count has stabilized and the INR has reached the intended target range. (See ‘Warfarin’ above.)


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