Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin. Its central feature is thrombocytopenia caused by antibody-mediated platelet activation. HIT can be viewed as an acquired hypercoagulability disorder, with increased thrombin generation in vivo, and increased risk for arterial and, especially, venous thrombosis. The pathogenic HIT antibodies are directed against neoepitopes on a ‘self’ protein, platelet factor 4 (PF4), that are expressed when PF4 is bound to heparin or certain other polyanions. This review focuses on studies published since 1990, and summarizes the pathogenesis, laboratory testing, frequency and clinical picture of HIT. Two treatment situations are reviewed critically: management of thrombosis complicating HIT and treatment of ‘isolated HIT’ (HIT recognized because of thrombocytopenia alone). There is potential for medicolegal risk, particularly if inappropriate therapy contributes to patient harm.
Definition and terminology
Heparin-induced thrombocytopenia (HIT) can be defined as any clinical event best explained by platelet factor 4 (PF4)/heparin-reactive antibodies (‘HIT antibodies’) in a patient who is receiving, or who has recently received, heparin (or another polyanion implicated in this syndrome). Thrombocytopenia is the most common ‘event’ in HIT and occurs in at least 90% of patients, depending upon the definition of thrombocytopenia. A high proportion of patients with HIT develop thrombosis. Alternative (non-heparin) anticoagulant therapy reduces the risk of subsequent thrombosis.
HIT is a clinicopathological syndrome
The diagnosis of HIT should be based upon: (a) the occurrence of one or more HIT-associated clinical events, and (b) detection of HIT antibodies in patient serum or plasma (Warkentin et al, 1998; Warkentin, 2002a) (Table I). By thus viewing HIT as a clinicopathological disorder, it follows that a patient who develops HIT antibodies during heparin treatment but who neither manifests thrombocytopenia nor other adverse events does not have HIT, but rather HIT antibody seroconversion alone. It also follows that a patient who may appear on clinical grounds to have HIT, but in whom sensitive tests for HIT antibodies are negative, also does not have HIT. Indeed, the high negative predictive value of current assays has led to recognition of various HIT-mimicking disorders (‘pseudo-HIT’) (Warkentin, 2001a).
|Thrombocytopenia† with or without any of the following||A. Platelet activation assay using washed platelets|
|A. Venous thrombosis||Serotonin release assay|
|Deep vein thrombosis||Heparin-induced platelet activation test|
|Coumarin-induced venous limb gangrene‡||Microparticles (flow cytometry) using citrated platelet-rich plasma|
|Pulmonary embolism||B. Platelet aggregation assay using citrated platelet-rich plasma|
|Cerebral venous (dural sinus) thrombosis||C. Antigen assay|
|Adrenal haemorrhagic infarction§||PF4/heparin-enzyme immunoassay (EIA)††|
|B.Arterial thrombosis||PF4/polyvinyl sulphonate-EIA††|
|Lower-limb artery thrombosis||‘In-house’ PF4-dependent-EIA that detects HIT-IgG‡‡|
|Cerebrovascular accident||Fluid-phase EIA|
|Myocardial infarction||Particle gel immunoassay|
|C. Skin lesions (at heparin injection sites)¶|
|D.Acute systemic reaction post intravenous heparin bolus**|
|E. Hypofibrinogenaemia secondary to decompensated DIC|
|Terminology used in this review||Related terminology in the literature|
|Heparin-induced thrombocytopenia (HIT)*||Heparin-induced thrombocytopenia type II†|
|Isolated HIT||Heparin-induced thrombocytopenia (HIT) (syndrome) (HITS)|
|HIT-associated thrombosis||Heparin-induced thrombocytopenia–thrombosis (HITT) (syndrome) (HITTS)|
|White clot syndrome‡|
|Latent HIT§||Subacute HIT|
|Non-immune heparin-associated thrombocytopenia (HAT)||Heparin-induced thrombocytopenia type I†|
Figure 1 summarizes the pathogenesis of HIT. The central concept is heparin-induced generation of pathogenic antibodies of immunoglobulin (Ig)G class that recognize multimolecular complexes of PF4 and heparin (Amiral et al, 1992) on platelet surfaces, leading to platelet activation in vivo and associated thrombin generation. There is evidence that endothelial cells and monocytes can also be activated by HIT antibodies.
Heparin and platelet factor 4
Heparin is a glycosaminoglycan (GAG), i.e. it consists of linear polymers of repeating disaccharide subunits (Fig 2) that vary in chain length and grade of sulphation. Binding of PF4 to heparin is independent of its antithrombin-catalysing pentasaccharide region.
PF4 is a 70-amino acid (7780 Da), platelet-specific member of the C-X-C subfamily of chemokines (Fig 3). Four PF4 molecules self-associate to form compact tetramers of globular structure (∼31 000 Da). PF4 is rich in the basic amino acids, lysine and arginine (32 and 12 residues per tetramer respectively), which form a ‘ring of positive charge’, providing the interface between the PF4 tetramer and heparin (Fig 3). PF4 is stored in platelet α-granules, where it is bound to the GAG, chondroitin sulphate. Under normal conditions, only trace levels of PF4 (∼3 ng/ml) are found in human plasma. However, heparin infusion increases PF4 levels about 15- to 30-fold for several hours, by displacing PF4 from endothelial cell surfaces.
HIT antigen neoepitopes
The immune response against PF4/heparin complexes is polyspecific, i.e. antibodies are directed against multiple neoepitope sites (Suh et al, 1998; Ziporen et al, 1998; Newman & Chong, 1999; Li et al, 2002). Suh et al (1998) showed that heparin must be in a flexible, relatively unconstrained state to react with PF4 and so create the neoepitopes. Recently, Li et al (2002) identified two neoepitopes recognized by many HIT antibodies (Fig 2).
Amiral et al (2000) studied purified HIT antibodies from three patients, and showed that greater platelet-activating ability of HIT-IgG antibodies correlated with higher affinity either for PF4/heparin complexes or (in one patient) against PF4 alone. These studies are consistent with clinical studies showing that only a minority of PF4/heparin-reactive IgG are platelet activating, but that HIT typically occurs only in patients with relatively high titres of platelet-activating IgG (Suh et al, 1997; Warkentin et al, 2000). The reported affinity of HIT-IgG for PF4/heparin complexes is intermediate between that of relatively low- and high-affinity antigens (β2-glycoprotein I and tetanus toxoid respectively), although the potential for both Fab arms of HIT-IgG to recognize neoepitopes on the multimolecular PF4/heparin complexes could significantly increase affinity (Newman & Chong, 1999).
Non-specific nature of polyanion
Despite heparin's key role in initiating HIT, its ability to produce neoepitopes on PF4 is surprisingly non-specific. Indeed, two non-heparin polyanions, pentosan polysulphate (used to treat interstitial cystitis) (Fig 2) and polysulphated chondroitin sulphate (antiarthritis agent), can lead to formation of anti-PF4/heparin antibodies, thrombocytopenia and thrombosis (Greinacher et al, 1992; Goad et al, 1994).
Further, the polyanion, polyvinyl sulphonate (Fig 2), which has neither sulphate nor saccharide, also promotes neoepitope formation on PF4 (Visentin et al, 2001). Characteristic features of polyanions that support neoepitope formation include regular spacing of negative charge at 0·5 nm intervals and a minimum polymer length sufficient to span at least 40% of the circumference of the PF4 tetramer along its ring of positive charge. PF4/polyvinyl sulphonate complexes are used to detect HIT antibodies in a commercially available assay.
Binding of PF4/heparin complexes to platelet surfaces
Heparin/PF4 complexes bind to platelets by the negative charge of the highly sulphated heparin chains (Greinacher et al, 1993; Horne & Hutchison, 1998). Maximal binding of PF4/heparin complexes, and thus optimal platelet activation by HIT-IgG, occurs when PF4 and heparin are present in an optimal stoichiometric relationship, ranging from approximately equimolar to a PF4/heparin ratio of about 2:1 (Visentin et al, 1994; Horne & Hutchison, 1998). Although low-sulphated oligosaccharides, such as danaparoid and de-N-sulphated heparin, do not support very well the binding of PF4 and HIT antibodies to the platelet surface, in very high concentrations, these molecules prevent activation of platelets by HIT-IgG (Greinacher et al, 1993). This suggests that even low-sulphated oligosaccharides interact with PF4 to some extent, and in large concentrations displace PF4 from the platelet surface to the fluid phase.
Platelet activation leads to PF4 release from α-granules and may increase risk of HIT, either by greater immunization risk or by promoting platelet-activating effects of HIT-IgG (Horne & Hutchison, 1998). Once platelet activation by HIT-IgG begins, the syndrome is self-exacerbating (positive feedback), because PF4 released from platelets can form additional immune complexes (Greinacher, 1995; Newman & Chong, 2000).
HIT as an autoimmune disease
Some HIT-IgG recognize PF4 bound to solid phase in the absence of heparin (Greinacher et al, 1994a; Newman & Chong, 1999; Amiral et al, 2000), and activate platelets in vitro without added heparin (Amiral et al, 2000; Warkentin & Kelton, 2001a). Indeed, HIT neoepitopes are on PF4 (Fig 3) and so HIT can be considered a drug-induced ‘autoimmune’ disorder. The ability of HIT-IgG to activate platelets in the absence of heparin could explain the onset of thrombocytopenia and thrombosis several days after stopping heparin, so-called ‘delayed-onset HIT’ (Warkentin & Kelton, 2001a).
The sequence of events by which HIT-IgG activate platelets was recently investigated by Newman and Chong (2000) using purified HIT-IgG and platelet aggregometry. Addition of heparin to citrated platelet-rich plasma led to the release of small amounts of PF4 that bound to platelet surfaces. Subsequently, increasing amounts of HIT-IgG bound to platelets over time, in parallel with progressive platelet aggregation. Although Fc receptor-blocking monoclonal antibody prevented platelet activation by HIT-IgG, it did not stop binding of HIT-IgG to platelets. Further, platelet activation by HIT-IgG occurred even though heparin remained in considerable molar excess to PF4, i.e. the PF4:heparin ratio was lower than expected for antibody binding in an enzyme immunoassay (EIA). This suggests that the platelet surface microenvironment achieves the necessary stoichiometric relationship as PF4 is increasingly released during progressive platelet activation. This is consistent with a model of in-situ formation on platelet surfaces of the PF4/heparin/IgG immune complexes, rather than forming first in plasma.
Occupancy of platelet FcγIIa receptors by PF4/heparin/IgG immune complexes leads to receptor clustering and phosphorylation. Subsequent signalling events include tyrosine kinase activity (e.g. p72syk) that phosphorylates phospholipase Cγ2 (PLCγ2), producing diacylglycerol and inositol triphosphate (for review see Denomme, 2001). PLCγ2 phosphorylation requires adequate levels of phosphatidylinositol-trisphosphate, which requires activation of platelet adenosine diphosphate (ADP) receptors. This explains the importance of using the ADP scavenger, apyrase, during platelet washing in certain assays for detecting HIT antibodies: apyrase avoids ADP-induced platelet desensitization during washing, thus retaining high sensitivity of the platelets to activation by HIT-IgG via the potentiating effects of ADP (Polgár et al, 1998).
A consequence of platelet activation by HIT-IgG is the formation of procoagulant, platelet-derived microparticles (Warkentin et al, 1994a; Lee et al, 1996; Hughes et al, 2000). Warkentin and Sheppard (1999) have shown that HIT-IgG and other platelet IgG agonists (heat-aggregated IgG, platelet-activating monoclonal IgG) cause an even greater platelet procoagulant response than physiological platelet agonists such as collagen and thrombin. Evidence that platelet activation occurs in vivo in patients with HIT includes elevated P-selectin on circulating platelets (Chong et al, 1994) and increased numbers of platelet-derived microparticles (Warkentin et al, 1994a).
Thrombin is irreversibly inhibited by covalent binding to its major physiological inhibitor, antithrombin. The resulting thrombin–antithrombin (TAT) complexes have a short half-life (20 min) and thus can be measured in plasma to quantify recent thrombin generation in vivo. Two studies noted greatly elevated TAT complexes in HIT patients, with median values of greater than 40 ng/ml (normal < 4 ng/ml) (Warkentin et al, 1997; Greinacher et al, 2000). These values were also much higher than seen in patients with post-operative deep vein thrombosis unrelated to HIT. Increased in-vivo thrombin generation is a general feature of hypercoagulability disorders such as congenital protein C or antithrombin deficiency that evince increased risk for venous thrombosis.
Immunoglobulin classes and subclasses
Although PF4/heparin-reactive antibodies of IgM and IgA class are also frequently generated in patients with HIT, it remains controversial whether these antibody classes cause HIT in the absence of HIT-IgG antibodies. In prospective studies of HIT antibody formation post surgery, we found platelet-activating IgG antibodies in all 15 patients identified with HIT (Warkentin et al, 2000). In contrast, Amiral et al (1996a) reported finding only IgM and/or IgA antibodies in 12 of 38 patients with apparent HIT, three with pulmonary embolism. However, as pulmonary embolism can mimic clinical HIT (‘pseudo-HIT’), it remains unproven, in my opinion, that HIT can be caused by IgA or IgM antibodies. An alternative explanation could be platelet-activating IgG antibodies against other chemokines (Amiral et al, 1996b).
Any of the four HIT-IgG subclasses can be identified in HIT sera, some more commonly than others (IgG1 > IgG3 > IgG2 > IgG4), with more than one subclass often seen in individual patients (Denomme et al, 1997; Suh et al, 1997). To date, no difference in clinical profile of HIT in relation to particular IgG subclasses or the added presence of IgM or IgA class antibodies has been reported.
Fc receptor polymorphism and HIT
The class of Fcγ receptors found on platelets (FcγIIa) has low affinity for IgG (for review see Denomme, 2001). Thus, these receptors probably bind HIT-IgG only after PF4/heparin/IgG complexes have formed on platelet surfaces, as circulating immune complexes would be preferentially cleared by high-affinity leucocyte Fcγ receptors. Because FcγIIa receptors bear a his131/arg131 polymorphism that influences platelet activation by human IgG2 (his131 >> arg131), speculation arose that this polymorphism might influence risk for HIT. However, no consistent at-risk profile has emerged. The largest study (Carlsson et al, 1998) noted over-representation of the arg131 receptor among patients with HIT-associated thrombosis, leading the authors to suggest that less efficient clearance of immune complexes by the reticuloendothelial system might predispose to greater in-vivo platelet activation and risk of thrombosis.
Endothelial and monocyte activation
Heparan sulphate is a GAG found on endothelial cell surfaces that is less sulphated than heparin. Nevertheless, HIT antibodies of both IgG and IgM class recognize PF4 bound to heparan sulphate on endothelium, leading to speculation that high levels of PF4 during acute HIT could focus immunoinjury to the endothelium (Visentin et al, 1994). Kwaan and Sakurai (1999) observed hyperplastic endothelial cells, together with immunoglobulin deposition within platelet thrombi and proliferative endothelial cells in ischaemic tissues obtained from patients with HIT.
Two reports suggested that HIT-IgG can activate monocytes in the presence of PF4 (Arepally & Mayer, 2001; Pouplard et al, 2001). Moreover, these activated monocytes expressed tissue factor and generated procoagulant activity. Heparin is not required for PF4 binding to monocytes, which is mediated by surface proteoglycans such as chondroitin sulphate.
Immunization by heparin
Exactly how heparin triggers immunization remains uncertain. Bacsi et al (1999, 2001) found that PF4/heparin complexes stimulate T cells isolated from patients with HIT. However, little evidence exists for immune memory in HIT. First, HIT antibodies often become undetectable within weeks after an episode of HIT (Warkentin & Kelton 2001b). Second, HIT antibodies are usually not restimulated when such a patient with previous HIT is re-exposed to heparin (Pötzsch et al, 2000) and, if antibodies are regenerated, they are not formed more quickly than 5 d following re-exposure (Warkentin & Kelton 2001b; Lubenow et al, 2002a).
Various animal models have been described for HIT (for review see Warkentin, 2002b). Only one model, reported by Reilly et al (2001), recapitulates several key clinical and laboratory features of HIT. These investigators developed a novel murine model employing double-transgenic FcγRIIA/hPF4 mice, i.e. mice with platelets bearing human FcγRIIa and human PF4 (mice lack platelet Fcγ receptors, and murine PF4 is not recognized by HIT antibodies). When these mice were treated with a HIT-mimicking murine monoclonal antibody (named KKO) that recognizes hPF4/heparin and then given heparin, the mice developed severe thrombocytopenia and fibrin-rich thrombi in multiple organs, including the pulmonary vasculature.
Laboratory testing for hit antibodies
Only a minority of patients who form HIT antibodies develop thrombocytopenia or other sequelae of HIT (Amiral et al, 1995, 1996c; Warkentin et al, 1995). Thus, assays that are more sensitive at detecting HIT antibodies are less specific for clinical HIT, even if they have high specificity for detecting antibodies. Tests for HIT antibodies can be classified as platelet activation assays and PF4-dependent antigen assays (Table I).
Platelet activation assays
Historically, standard platelet aggregation assays were first used to detect platelet-activating HIT antibodies (for review see Warkentin, 2001b). However, greater sensitivity, specificity and test throughput is achieved using ‘washed’ platelets.
Platelet aggregometry. A standard platelet aggregometer can detect aggregation of platelets (prepared as citrated platelet-rich plasma) in the presence of patient plasma and heparin (Chong et al, 1993; Warkentin & Greinacher, 2001). However, this method is relatively insensitive for clinical HIT (sensitivity 35–85%) (Greinacher et al, 1994b; Warkentin & Greinacher, 2001). Inability to perform multiple assays limits specificity, as relatively few reaction conditions and controls can be tested. False-positive reactions can result from acute-phase reactants such as fibrinogen that cause a patient plasma-dependent increase in platelet aggregation in the absence of HIT antibodies (Warkentin & Greinacher, 2001).
Platelet activation using washed platelets. Platelets that are washed and resuspended in divalent cation-containing buffer have increased sensitivity and specificity for detecting platelet-activating HIT antibodies, compared with conventional aggregometry. Donor selection is important, as platelet responsiveness to HIT-IgG varies among normal donors (Warkentin et al, 1992). A variety of platelet activation endpoints can be used, including release of radioactive serotonin (Warkentin et al, 1992), visual assessment of platelet aggregation (Greinacher et al, 1991), or generation of platelet-derived microparticles detected by flow cytometry (Lee et al, 1996). The assays are performed in microtitre wells, so hundreds of reactions can be assessed simultaneously. This permits study of many reaction conditions, e.g. platelet activation at various heparin concentrations, in the presence of platelet Fc receptor-blocking monoclonal antibody and so forth, which optimizes specificity. HIT antibodies produce a characteristic reaction profile: maximal activation at 0·1–0·3 IU/ml heparin that exceeds the buffer control, minimal activation at 100 U/ml heparin, and inhibition by Fc receptor-blocking monoclonal antibody. Unfortunately, washed platelet activation assays are technically demanding, and performance varies widely among laboratories (Eichler et al, 1999). Another limitation is that about 2–3% of patient samples contain immune complexes or platelet-activating human leucocyte antigen (HLA) alloantibodies and so yield indeterminate results, i.e. platelet activation occurs at all heparin concentrations tested.
Solid-phase EIA. Two EIAs are commercially available that detect antibodies of the three major immunoglobulin classes (IgG, IgM, IgA) against PF4 bound either to heparin (Asserachrom, Stago, France) (Amiral et al, 1992) or polyvinyl sulphonate (GTI, Brookfield, WI, USA) (Visentin et al, 2001). The former assay utilizes recombinant PF4, whereas the latter obtains PF4 from outdated platelets. Research laboratories that perform ‘in-house’ PF4/heparin-EIAs have the option to detect antibodies of just the IgG class, which increases specificity for clinical HIT by avoiding detection of non-pathogenic IgA and IgM antibodies (Lindhoff-Last et al, 2001). Recently, a rapid antigen assay has been developed (Meyer et al, 1999) that appears to have operating characteristics (sensitivity–specificity trade-offs) intermediate between the commercial EIAs and a washed platelet activation assay (Eichler et al, 2002a).
Fluid-phase EIA. Newman et al (1998) developed a fluid-phase antigen assay that avoids the problems of protein (antigen) denaturation inherent in solid-phase assays. This assay may give a lower rate of false-positive reactions and, unlike solid-phase EIA's, is useful for assessing in-vitro crossreactivity of HIT-IgG against low-molecular-weight heparin (LMWH) and heparinoids.
In general, testing is performed when HIT is clinically suspected. In this context, washed platelet activation assays and antigen assays have similar high sensitivity for diagnosis of HIT. Indeed, negative testing by two sensitive and complementary assays (e.g. PF4-dependent EIA and washed platelet activation assay) essentially rules out HIT (Warkentin, 2001a, 2002a). Test sensitivity is significantly less using standard platelet aggregometry (Greinacher et al, 1994b). Diagnostic specificity is greater with the washed platelet activation assays compared with EIAs, as the latter are more likely to detect clinically insignificant antibodies (Warkentin et al, 2000).
The clinician's estimate of the probability of HIT (‘pretest probability’), together with the type of assay used and its quantitative result (generating a ‘likelihood ratio’), determines the ‘post-test probability’ of HIT (Bayesian model) (Warkentin & Heddle, 2003). For example, a strong-positive washed platelet activation assay is associated with a much higher likelihood ratio for HIT than a weak-positive EIA (about 20–50 vs 2–3). Thus, for a patient with a pretest probability of HIT of about 50%, the associated post-test probabilities range from about 65% to > 95% respectively. Very-strong-positive assay results are characteristic of delayed-onset HIT (Warkentin & Kelton, 2001a).
Figure 4A illustrates a generic ‘iceberg’ showing the relationship between antigen assays, washed platelet activation assays, thrombocytopenia and HIT-associated thrombosis (Lee & Warkentin, 2001). This model is consistent with the following observations: (i) only a subset of PF4/heparin-reactive antibodies have platelet-activating properties (Amiral et al, 2000; Warkentin et al, 2000); (ii) washed platelet activation assays have greater diagnostic specificity for clinical HIT than antigen assays; and (iii) thrombosis is not associated with HIT antibody formation that does not result in a significant platelet count fall (Warkentin et al, 1995).
|Type of heparin||Bovine lung UFH > porcine intestinal mucosal UFH > LMWH; additionally, there may be variability between batches|
|Patient population*||Post surgery > medical > obstetrical|
|Duration of heparin||Platelet count fall typically begins between days 5–10, with thrombocytopenia usually reached by d 7–14; thus, each day of heparin use beyond d 5, and to d 14, increases risk of HIT|
|Dose of heparin||Change from prophylactic-dose to therapeutic-dose heparin can cause abrupt platelet count fall in patient with HIT antibodies|
|Sex||Female > male|
|Definition of thrombocytopenia used||Proportional platelet count fall (> 50%) is more sensitive for detecting HIT than an absolute platelet count threshold (e.g, 100 or 150–109/l)|
A meta-analysis of four randomized trials performed in the 1980s showed that unfractionated heparin (UFH) from bovine lung was more likely to cause HIT than heparin derived from porcine intestinal mucosa (Lee & Warkentin, 2001). More recently, a randomized trial by Francis et al (2003a) found that beef lung UFH was also more likely to be associated with HIT antibody formation after heart surgery. Greater polysaccharide chain length and degree of sulphation of bovine lung heparin could explain its higher immunogenicity.
HIT is more common with UFH than LMWH. In post-operative orthopaedic surgery, in patients receiving heparin prophylaxis, UFH is about threefold more likely to be associated with formation of HIT-IgG antibodies and also about threefold more likely to cause thrombocytopenia when HIT-IgG are formed, i.e. overall, UFH is about 8–10 times more likely to cause HIT (Warkentin et al, 1995, 2000, 2003; Warkentin & Sigouin, 2002). In a non-randomized comparison of UFH and LMWH given after cardiac surgery, Pouplard et al (1999) also observed HIT more often with UFH. HIT antibodies were formed more often in medical patients receiving UFH compared with LMWH (Lindhoff-Last et al, 2002).
HIT is less common in medical and obstetrical patients than in surgical patients (Lee & Warkentin, 2001). Fausett et al (2001) reported that none of 244 pregnant women developed HIT during use of UFH, even though HIT occurred in 10 of 244 (4%) non-pregnant patients who received UFH (P = 0·0014). This was especially striking given that the pregnant patients received heparin for longer (61·7 vs 10·5 d; P = 0·0001). Lepercq et al (2001) observed no HIT among 624 pregnancies managed with LMWH.
Severin and Sutor (2001) reviewed the literature that described HIT in 27 children. Patients were either neonates/infants or (pre)adolescents, with no cases observed in children between 3 and 7 years of age. This bimodal age distribution probably reflects the high-risk periods for children to receive heparin. In my opinion, neonatal HIT is not established, as antigen and washed platelet activation assays have not been used in this population.
Warkentin and Sigouin (2002) found that women are more likely to develop HIT: odds ratio 3·3 (95% confidence interval 1·1–10·2). Although women were no more likely to form HIT antibodies, they were more likely to develop HIT when antibodies were formed, possibly because they formed higher levels of HIT-IgG.
Although it is widely assumed that previous heparin therapy increases the subsequent risk of HIT, no evidence supports this contention (Girolami et al, 2003). Indeed, patients with a prior history of HIT can safely receive heparin following the disappearance of HIT antibodies (vide infra). The only unequivocal link between previous heparin use and risk of HIT is the syndrome of ‘rapid-onset HIT’, in which a recent immunizing exposure to heparin explains an abrupt platelet count fall, if heparin is given prior to disappearance of the antibodies (Warkentin & Kelton, 2001b; Lubenow et al, 2002a).
Thrombocytopenia is the central feature of HIT: the median platelet count nadir is about 55 × 109/l (Fig 5). In at least 85–90% of patients, the platelet count falls below 150 × 109/l (Warkentin, 2001c). In the remaining patients, HIT is recognized either because of a substantial fall in the platelet count (e.g. 50% or more) or because of clinical events, such as thrombosis or skin lesions at heparin injection sites, that draw attention to HIT despite less substantial platelet count declines (Hach-Wunderle et al, 1994; Warkentin, 1996a).
Figure 6 illustrates three temporal profiles of HIT: typical-onset, rapid-onset and delayed-onset HIT (Warkentin & Kelton, 2001a,b; Rice et al, 2002). In about two-thirds of patients, typical-onset HIT is recognized because of a platelet count fall that begins 5–10 d after starting a course of heparin, although thrombocytopenic levels may not be reached until d 7–14.
In about 30% of patients, HIT is recognized because of an abrupt drop in platelet count upon the administration of heparin (‘rapid-onset HIT’). These patients have typically received heparin within the past 100 d, and so the thrombocytopenia is explained by heparin being given to a patient who already has clinically significant levels of HIT antibodies. Sometimes, the previous heparin exposure may have been minor or even unrecorded in the medical record, e.g. intraoperative heparin ‘flushes’ (Ling & Warkentin, 1998).
Rarely, HIT begins several days after the patient last received heparin (‘delayed-onset HIT’). Even a single 5000 unit heparin injection has been reported to cause thrombocytopenia and thrombosis beginning about 1 week later (Warkentin & Bernstein, 2003).
Thrombosis and other sequelae
HIT is strongly associated with thrombosis (Table I): the odds ratio varies from 12 to 40, depending upon the definition of thrombocytopenia (Warkentin, 2001c; Girolami et al, 2003). About half of all patients with HIT are recognized only after developing HIT-associated thrombosis (Warkentin & Kelton, 1996).
Venous thrombosis complicates HIT more often than arterial thrombosis (Warkentin & Kelton, 1996; Wallis et al, 1999). Indeed, pulmonary embolism is more common than all the arterial thrombotic events combined. Arterial thrombosis most often involves large lower-limb arteries, with thrombotic stroke and myocardial infarction seen less often. Rare but well-described thrombotic sequelae include cerebral venous thrombosis (presenting as severe headache and progressive neurological deficits) and adrenal vein thrombosis (presenting as unilateral or bilateral adrenal haemorrhagic infarction). Localizing factors, such as atherosclerosis or vascular injury from catheters, influence the site of thrombosis (Hong et al, 2003). Factor V Leiden did not contribute to an increased risk of thrombosis among HIT patients (Lee et al, 1998).
Heparin-induced skin lesions. Skin lesions at heparin injection sites, ranging from erythematous plaques to skin necrosis, are a feature of the HIT syndrome. For unknown reasons, only one-third of patients develop thrombocytopenia, even though HIT antibodies are readily detected (Warkentin, 1996a). Sometimes, thrombocytopenia and thrombosis begin a few days after heparin has been stopped because of skin lesions.
Acute systemic reactions following an intravenous bolus heparin. About one-quarter of patients who receive an intravenous heparin bolus at a time when they have circulating HIT antibodies develop symptoms or signs such as fever, chills, respiratory distress, hypertension or even transient global amnesia (Table I) (Warkentin et al, 1994b; Popov et al, 1997; Warkentin, 2001c). Sometimes, cardiac or respiratory arrest results. These reactions begin 5–30 min following the intravenous heparin bolus and are accompanied by an abrupt fall in the platelet count.
Decompensated disseminated intravascular coagulation (DIC). Although increased thrombin generation is a general feature of HIT, decompensated DIC, defined as reduced fibrinogen or an otherwise unexplained increase in the international normalized ratio (INR), occurs in only 5–15% of patients (Warkentin, 2001c). DIC may be more common in delayed-onset HIT, as IgG-induced platelet activation occurs in the absence of heparin anticoagulation (Warkentin & Kelton, 2001a). Prolongation of the partial thromboplastin time by DIC complicates monitoring of direct thrombin inhibitors.
When should HIT be suspected? The four T's
Table IV lists four features to help estimate the pretest probability of HIT (Warkentin & Heddle, 2003). Even without thrombosis, a high pretest probability is suggested when the timing of onset of thrombocytopenia is consistent with heparin-induced immunization in the absence of another explanation. Very severe thrombocytopenia (platelet count < 10 × 109/l) with bleeding suggests a non-HIT diagnosis such as post-transfusion purpura (Lubenow et al, 2000; Warkentin 2001a).
|Points (0, 1, or 2 for each of 4 categories: maximum possible score = 8)|
|Thrombocytopenia||> 50% fall or platelet nadir 20–100 × 109/l||30–50% fall or platelet nadir 10–19 × 109/l||fall < 30%or platelet nadir < 10 × 109/l|
|Timing* of platelet count fall or other sequelae||Clear onset between d 5–10; or less than 1 d (if heparin exposure within past 100 d)||Consistent with immunization but not clear (e.g. missing platelet counts) or onset of thrombocytopenia after d 10||Platelet count fall too early (without recent heparin exposure)|
|Thrombosis or other sequelae (e.g. skin lesions)||New thrombosis; skin necrosis; post heparin bolus acute systemic reaction||Progressive or recurrent thrombosis; erythematous skin lesions; suspected thrombosis not yet proven||None|
|Other cause for thrombocytopenia not evident||No other cause for platelet count fall is evident||Possible other cause is evident||Definite other cause is present|
|Pretest probability score: 6–8 = High; 4–5 = Intermediate; 0–3 = Low|
Certain disorders strongly resemble HIT on clinical grounds. These include: cancer-associated DIC with thrombosis, and pulmonary embolism with DIC-associated thrombocytopenia, among others (Warkentin, 2001a). The high negative predictive value of sensitive assays for HIT antibodies permits HIT to be ruled out in these pseudo-HIT disorders (Warkentin, 2001a).
Thrombosis complicating HIT requires treatment with an alternative, rapidly acting anticoagulant. As HIT is frequently complicated by thrombosis even after stopping heparin, there is increasing emphasis on substituting heparin with an alternative anticoagulant even when HIT is suspected because of thrombocytopenia alone (Greinacher & Warkentin, 2001; Hirsh et al, 2001).
Table V lists treatment paradoxes of HIT (Warkentin, 2001d). Treatments previously assumed to be effective (e.g. replacing heparin with warfarin) are ineffective (Warkentin & Kelton, 1996) and potentially even deleterious (warfarin-induced venous limb gangrene) (Warkentin et al, 1997, 1999). Prophylactic platelet transfusions are relatively contraindicated in HIT. LMWH is contraindicated to treat HIT (high risk of in-vivo crossreactivity) despite its lower frequency of causing this syndrome (Ranze et al, 2000). Therapeutic doses of anticoagulant are generally recommended for managing HIT, even when prevention of thrombosis is sought. A recently recognized paradox is that re-exposure to heparin is an appropriate way to manage anticoagulation during cardiac surgery in patients with previous HIT whose antibodies have disappeared (Pötzsch et al, 2000; Warkentin & Kelton, 2001b). These various treatment paradoxes could contribute to medicolegal risk if seemingly logical – but contraindicated – therapies are employed (McIntyre & Warkentin, 2001).
|Coumarins (e.g. warfarin) increase risk of microvascular thrombosis in acute HIT (venous limb gangrene; skin necrosis)||Coumarins are contraindicated in acute HIT; delay coumarin overlap with alternate anticoagulant pending substantial resolution of thrombocytopenia.||Warkentin et al (1997, 1999); Hirsh et al (2001); Smythe et al (2002)|
|LMWH is contraindicated to treat HIT despite its lower frequency of causing HIT||High risk (about 50%) of in vivo crossreactivity if LMWH is used to treat HIT caused by UFH||Ranze et al (2000); Greinacher & Warkentin (2001)|
|Prophylactic platelet transfusions are relatively contraindicated in HIT||Spontaneous bleeding is uncommon in HIT, and platelet transfusion theoretically may contribute to thrombotic risk||Greinacher & Warkentin (2001)|
|High risk of thrombosis persists even after heparin is stopped||Treatment of ‘isolated HIT’ with alternative anticoagulant is recommended||Warkentin & Kelton (1996); Hirsh et al (2001); see also Table VIII|
|Therapeutic (rather than prophylactic) dose anticoagulation is appropriate even when treating isolated HIT||High treatment failure rate when (EU-approved) prophylactic-dose danaparoid regimen used to treat isolated HIT||Farner et al (2001); Lewis et al (2001); Warkentin (2001d)|
Alternative anticoagulants to heparin
Three anticoagulants have been studied for treatment of HIT-associated thrombosis. These are the heparinoid, danaparoid sodium, and two direct thrombin inhibitors, lepirudin and argatroban (Table VI). They have not been directly compared in prospective studies, although a retrospective comparison of danaparoid and lepirudin found similar efficacy for treatment of HIT-associated thrombosis, with greater bleeding risk with lepirudin (Farner et al, 2001). The decision to choose a particular agent should be based upon availability/approval, pharmacokinetic considerations (especially in renal or hepatic impairment) and prior physician experience or preference.
|Anticoagulant||Dosing (therapeutic range)||Pharmacokinetics (t½)||Comment|
|Agents approved for treatment of HIT|
|Danaparoid sodium (Orgaran)||Bolus: 2250 U*; infusion, 400 U/h × 4 h, then 300 U/h × 4 h, then 200 U/h, with monitoring by antifactor Xa levels (0·5–0·8 anti-Xa units/ml†)||Renal metabolism (25 h [antifactor Xa activity], 2–4 h [antifactor IIa activity])||Approved for treatment and prevention of HIT-associated thrombosis in the EU, Canada, New Zealand, Australia; withdrawn from US market, April 2002; potential for in vivo crossreactivity (rare) which is not predictable by in-vitro testing; thus, crossreactivity testing is not recommended prior to use|
|Lepirudin (Refludan)||Bolus: 0·4 mg/kg‡; infusion, 0·15 mg/kg/h (target aPTT range, 1·5–2·5 × baseline‡§)||Renal excretion (80 min)||Approved in USA, Canada and EU for treatment of HIT-associated thrombosis; t1/2 rises considerably in renal failure; high rate of antihirudin antibodies (40–60%) that are usually not clinically significant; anaphylaxis reported post lepirudin bolus (rare), especially with repeat treatment course|
|Argatroban (Novastan in some non-USA jurisdictions)||2 µg/kg/min, without initial bolus (target aPTT range, 1·5–3·0 × baseline§)||Hepato-biliary excretion (40–50 min)||Approved in the USA and Canada for both prevention and treatment of HIT-associated thrombosis (identical therapeutic-dose regimens used for both indications); argatroban increases the INR: thus, higher therapeutic range required during overlapping argatroban/warfarin (Sheth et al 2001)|
|Investigational agents for treatment of HIT|
|Bivalirudin (Angiomax)||0.15–0.20 mg/kg/h, without initial bolus (target aPTT range, 1·5–2·5 x baseline§¶)||Enzymic > renal (25 min)||Approved in the U.SA for anticoagulation during percutaneous coronary interventions (non-HIT); anecdotal experience in HIT; low t½ and enzymic metabolism are theoretical advantages over lepirudin for cardiac surgery in HIT (under current investigation)|
|Fondaparinux (Arixtra)||Uncertain||Renal 17–20 h||Approved for DVT prophylaxis following orthopaedic surgery; theoretically, lack of in vitro crossreactivity with HIT antibodies suggests it may be efficacious in HIT (not yet studied for this indication)|
Despite treatment of HIT-associated thrombosis with one of these three anticoagulants, there remains a 5–20% frequency of new thrombosis (Table VII). The frequency of an unfavourable outcome is even greater (20–40%) if the endpoint additionally includes all-cause mortality and limb amputation. This discrepancy suggests that severe limb ischaemia/necrosis and other unfavourable patient characteristics are often present when therapy with an alternative anticoagulant is initiated. Thus, some patients die or sustain amputation even when new thrombosis is effectively prevented by anticoagulation.
|Anticoagulant||n*||New thrombosis event-rate (control group)||Composite endpoint‡ event-rate (control group)||Major bleeds||Comment||Study|
|Danaparoid||25||12·0% (52·9%)†||20·0% (52·9%)||0·0%||Randomized, open-label trial comparing danaparoid with dextran-70; new thrombosis endpoint included outcomes judged ‘ineffective or slightly effective’; composite endpoint (danaparoid) included 4 deaths and one other patient with progressive thrombosis (limb amputation status not available)||Chong et al (2001)|
|53||9·4% (7·9%)||20%¶ (20%¶)||2·5%||Similar outcomes between therapeutic-dose danaparoid (retrospective cohort) and lepirudin (prospective cohort ‘control’); bleeding rate included patients treated with low-dose danaparoid||Farner et al (2001)|
|122||6·6% (–)||25·7% (–)||–||Retrospective cohort study (compassionate release program); no control group; new thrombosis represented ‘failure’ in 8/122 evaluable patients treated for thrombosis; composite endpoint represented all-cause mortality on entire study population (other endpoint data not available)||Magnani (1993)|
|35||5·7% (24·5%)†||–||–||Retrospective cohort study; control group received ancrod (defibrinogenating snake venom no longer recommended for HIT)||Warkentin (1996c)|
|Lepirudin||113||10·1% (27·2%)†||21·3% (47·8%)†||18·8% (7·1%)†||Meta-analysis of two prospective, historically controlled trials; all patients tested positive for HIT antibodies||Greinacher et al (2000)|
|98||6·1% (–)||21·5% (–)||20·4%||HAT3 trial (prospective study pending regulatory assessment); all patients positive for HIT antibodies||Eichler et al (2002b)|
|496||5·2% (–)||#22·0%§ (–)||5·4%||Post-marketing study; 77% positive for HIT antibodies by washed platelet activation assay; thrombotic death rate = 1·8%||Lubenow et al (2002b)|
|Argatroban||144||19·4% (34·8%)†||43·8 (56·5%)†||11·1%||Prospective cohort study (historical controls); 65% of patients shown to have HIT antibodies||Lewis et al (2001)|
|229||13·1% (34·8%)†||41·5% (56·5%)†||6·1%||Prospective cohort study (historical controls); HIT antibody testing not required for study entry (number testing positive not given)||Lewis et al (2003)|
Danaparoid sodium (Orgaran©) is a mixture of anticoagulant glycosaminoglycans, predominantly heparan sulphate (84%) and dermatan sulphate (12%). It is renally metabolized (Table VI), and requires modest dose reduction (about one-third) with significant renal dysfunction. Danaparoid was superior to dextran-70 (antiplatelet agent) in a randomized, open-label clinical trial (Table VII) (Chong et al, 2001). Danaparoid does not prolong the INR, and has a long half-life, which makes it ideal for treating venous thromboembolism complicating HIT, where gradual transition to oral anticoagulation is important. Therapeutic-dose danaparoid is recommended whether treating HIT-associated thrombosis or isolated HIT (Farner et al, 2001; Warkentin, 2001d). Danaparoid given by subcutaneous injection has 100% bioavailability; thus, the 24-h intravenous dose can be divided into two or three daily injections.
Lepirudin (Refludan®, 6980 Da) is a recombinant hirudin approved to treat thrombosis complicating HIT. It forms irreversible 1:1 complexes with thrombin. Its half-life is about 80 min, which increases dramatically in renal insufficiency (Table VI). As no antidote exists, use in patients with unstable renal function or renal failure is relatively contraindicated. The usual dose is 0·4 mg/kg (intravenous bolus) followed by an initial infusion rate of 0·15 mg/kg/h, adjusted for a target activated partial thromboplastin time (aPTT) of 1·5–2·5 × baseline. However, except when severe thrombosis is present, it may be preferable to omit the initial bolus and to use a lower target aPTT range (1·5–2·0 × baseline) (A. Greinacher, personal communication): this regimen has similar efficacy, less risk of drug accumulation and bleeding, and theoretically has less risk of anaphylaxis (by avoiding bolus use). When available, the patient's baseline aPTT may be preferable to using the mean of the aPTT normal range for calculating the target therapeutic aPTT. If lepirudin is used during severe renal failure or haemodialysis, one approach is to give 0·005–0·01 mg/kg/h (i.e. one-tenth or less of the usual dose) without initial bolus, subsequently adjusted by aPTT (Fischer, 2001).
Greinacher et al (1999a,b) performed the pivotal historically controlled prospective cohort studies evaluating lepirudin for treatment of HIT-associated thrombosis, which also were reported as a meta-analysis (Greinacher et al, 2000) (Table VII). Subsequent phase IV and post-marketing studies suggest clinical outcomes have improved further with greater use (Eichler et al, 2002b; Lubenow et al, 2002b). As a foreign protein derived from leeches, the use of lepirudin frequently causes antihirudin antibodies that lead to drug accumulation in a minority of patients (Eichler et al, 2000), presumably from impaired renal clearance of anticoagulant-active lepirudin-IgG complexes. It is likely that antihirudin antibodies explain anaphylaxis post lepirudin bolus infusion, which has been observed in ten patients (A. Greinacher, pers. comm.).
Argatroban® (Novastan® outside the USA) is a small-molecule (527 Da) direct thrombin inhibitor associated with a lower thrombotic event rate in historically controlled prospective cohort studies of both thrombosis complicating HIT and isolated HIT (Lewis et al, 2001, 2003). The identical dosage (starting infusion rate of 2 µg/kg/min without initial bolus) was used in both indications. The half-life is shorter than lepirudin (40–50 vs 80 min). Also, unlike lepirudin, argatroban undergoes hepatobiliary excretion. Thus, the dose must be reduced in liver failure. Argatroban is approved for treatment of isolated HIT and thrombosis complicating HIT in the USA and Canada. Argatroban prolongs the INR, and a higher-than-usual target INR during warfarin co-therapy (which depends upon the thromboplastin reagent used to measure the INR) should be used (Sheth et al, 2001).
The hirudin analogue bivalirudin (Angiomax®, formerly Hirulog) is approved for anticoagulation during percutaneous transluminary coronary angioplasty (PTCA). There is anecdotal experience of using this agent for HIT (Francis et al, 2003b). Argatroban is approved in the USA for anticoagulation during PTCA in patients with acute or prior HIT (Lewis et al, 2002).
Fondaparinux (Arixtra®) is an antithrombin-dependent pentasaccharide approved for antithrombotic prophylaxis after orthopaedic surgery. This agent does not crossreact with HIT antibodies (Amiral et al, 1997), and theoretically should be effective for HIT, provided its exclusive antifactor Xa action can control thrombin generation in HIT.
Coumarin-associated venous limb gangrene and skin necrosis syndromes
Warfarin (coumarin class of vitamin K antagonist) can lead to microvascular thrombosis when used to treat HIT-associated deep vein thrombosis, resulting in acral necrosis known as coumarin-induced venous limb gangrene (Warkentin et al, 1997). Patients typically have a supratherapeutic INR, which constitutes a surrogate marker for severe protein C deficiency via parallel severe reduction in factor VII (Warkentin, 2001e). Less often, warfarin causes necrosis of non-acral skin in HIT (‘classic’ skin necrosis) (Warkentin et al, 1999). Patients who develop coumarin-induced venous limb gangrene in HIT usually do not have congenital abnormalities in the protein C anticoagulant pathway, suggesting that HIT itself is a risk factor for procoagulant complications of coumarin (Warkentin, 1996b). Venous limb gangrene has been reported during overlapping therapy of warfarin with either lepirudin or argatroban, and has occurred when the direct thrombin inhibitor was prematurely stopped during persistent thrombocytopenia (Smythe et al, 2002; Srinivasan et al, 2003). Thus, warfarin should be delayed pending substantial resolution of thrombocytopenia in patients with HIT (Hirsh et al, 2001). This also reduces risk for underdosing with lepirudin or argatroban because of aPTT prolongation from warfarin.
Sometimes, thromboembolectomy to remove platelet-rich ‘white clots’ is needed to restore limb blood flow. Intraoperative anticoagulation with danaparoid or lepirudin has been reported in these settings. Adjunctive use of antiplatelet agents can be considered in HIT patients with arteriopathy. High-dose intravenous gammaglobulin inhibits platelet activation by HIT-IgG in vitro (Greinacher et al, 1994c) and may hasten platelet count recovery in severe HIT. In my opinion, vena cava filters are rarely appropriate for HIT (risk to worsen thrombosis).
Natural history of isolated HIT
Several studies have indicated a high risk of thrombosis in patients with isolated HIT despite cessation of heparin with or without substitution by warfarin (Table VIII). In the three largest studies, the risk of thrombosis ranged from 23·0% to 51·6%, and the combined endpoint (all-cause mortality, new thrombosis, limb amputation) ranged from 38·8% to 61·3%. Thrombotic death occurred in 4·3% and 4·8% of patients in two studies. A high rate (50%) of subclinical deep vein thrombosis has been reported when patients with isolated HIT underwent routine compression ultrasonography.
|Study design (follow-up)||n||Any thrombosis %*||Comment||Author|
|Retrospective (not stated)||3||66·6%||First report suggesting high risk of thrombosis in isolated HIT; 4 patients presenting with HIT-associated thrombosis excluded||Boon et al (1994)|
|Prospective (to hospital discharge)||4||75·0%||Nine patients identified with HIT: 5 patients presented with HIT-associated thrombosis; of the remaining 4 patients with isolated HIT, symptomatic DVT occurred in 3 (75%) despite cessation of heparin||Warkentin et al (1995)|
|Retrospective (30 d)||62||51·6%†||Patient cohort‡ identified by positive platelet serotonin release assay; 65 patients presenting with HIT-associated thrombosis excluded; composite endpoint of all-cause death, limb amputation, and new thrombosis was 61·3%; thrombotic death rate, 4·8%; Patients: post trauma/orthopaedic/general surgery (40%), post cardiac surgery (8%), medical (45%), other (7%)||Warkentin & Kelton (1996); Warkentin (2002d)|
|Retrospective (–)||16||50·0%||Patient cohort had no thrombosis preceding HIT; all patients had positive platelet aggregation test for HIT antibodies; patients underwent routine duplex venography, with asymptomatic DVT identified in 8 (50·0%)||Tardy et al (1999)|
|Retrospective (to hospital discharge)||113||38·1% (23·1§)||Patient cohort identified by positive platelet aggregation test; 27·4% all-cause mortality (thrombotic death rate not given); Patients: post trauma/orthopaedic/general surgery (21%), post cardiac surgery (59%), medical patients (12%), other (8%)||Wallis et al (1999)|
|Prospective [1·7 d (mean)]||113||10·4% (first 1·7 d; see comment)||Patient cohort awaiting entry into prospective lepirudin trials: 6·1% per day composite endpoint event-rate × 1·7 d (mean) time to starting lepirudin indicates early 10·4% rate of all-cause death, thrombosis, or limb amputation||Greinacher et al (2000)|
|Retrospective (42 d)||35||20·0%||83% of patients received low-dose danaparoid; composite endpoint (all-cause mortality, amputation, new thrombosis) was 31·4% (categorical analysis) and 53% (time-to-event analysis)||Farner et al (2001)|
|Retrospective cohort (37 d)||139||23·0%||Historical control group for argatroban studies; thrombosis rate for HIT may have been underestimated, as only 81% tested positive for HIT antibodies; composite endpoint (all-cause mortality, amputation, new thrombosis) was 38·8%; thrombotic death rate, 4·3%||Lewis et al (2001, 2003)|
HIT-associated thrombosis is not prevented even when heparin is stopped promptly because of early detection of HIT through platelet count monitoring (Wallis et al, 1999). Perhaps, persisting thrombin generation despite heparin cessation contributes to the ongoing thrombotic risk. If so, this implies that routine platelet count monitoring of heparin-treated patients might lead to improved outcomes only if stopping heparin is routinely accompanied by substituting an alternate anticoagulant (Warkentin, 2001d).
Treatment of isolated HIT
Argatroban is approved in the USA for the prevention of HIT-associated thrombosis. In a prospective cohort study of isolated HIT, new thrombosis was significantly reduced by argatroban compared with historical controls (6·9%vs 15·0%; P = 0·027), as was the combined event rate of new thrombosis, all-cause mortality and limb amputation (25·6%vs 38·8%; P = 0·014) (Lewis et al, 2001).
Although unapproved for this indication, lepirudin given in ‘prophylactic’ doses (0·1 mg/kg/h i.v. without initial bolus adjusted to aPTT 1·5–2·0 × baseline) for isolated HIT resulted in new thrombosis in only 2·7% of patients and with the combined end-point in just 9·0% of patients (Lubenow et al, 2002c). A similar low rate of thrombosis (2·1%) was also observed in a post-marketing study of 612 patients given lepirudin for isolated HIT (Lubenow et al, 2002b). Major bleeding was reported in 3·1% and 5·9–14·4% of patients treated with argatroban and lepirudin respectively (Lewis et al, 2001; Lubenow et al, 2002b,c). As discussed, danaparoid generally should be given in therapeutic doses when used for preventing thrombosis in patients with acute HIT (Farner et al, 2001; Warkentin 2001d).
Given the unfavourable natural history of isolated HIT, and the evidence for the benefit of using either argatroban, lepirudin, or (therapeutic-dose) danaparoid, treatment of isolated HIT is recommended (Greinacher & Warkentin 2001; Hirsh et al, 2001). An alternative approach is to incorporate screening for subclinical deep vein thrombosis by duplex ultrasonography in the treatment algorithm (Tardy et al, 1999).
Cardiac surgery in the patient with acute or previous HIT
For patients in whom HIT antibodies are no longer detectable, it is acceptable to give heparin at the usual doses to permit cardiopulmonary bypass (CPB) (Poetzsch & Madlener, 2001; Warkentin, 2002c). Post-operatively, alternative anticoagulants are given. HIT antibodies are usually not generated post-operatively, or do not appear for at least 5 days (Pötzsch et al, 2000; Warkentin & Kelton, 2001b).
For patients needing urgent heart surgery who have either acute HIT or latent HIT, two treatment approaches are described. First, alternative anticoagulants can be given during CPB, such as danaparoid (Magnani et al, 1997; Warkentin et al, 2001), lepirudin (Poetzsch & Madlener, 2001) or bivalirudin. Drawbacks with danaparoid include its long half-life, need for antifactor Xa monitoring and lack of an antidote; many patients develop severe bleeding (Magnani et al, 1997). Drawbacks of lepirudin include the need to monitor using the ecarin clotting time (Pötzsch et al, 1997), risk for severe drug accumulation during renal failure and lack of antidote. Bivalirudin has theoretical advantages over lepirudin for CPB, e.g. shorter half-life and predominant enzymic rather than renal clearance, and it is under study for this indication (Warkentin & Greinacher, 2003).
A second approach is to administer heparin together with an antiplatelet agent such as epoprostenol (prostacyclin analogue) (Aouifi et al, 2001) or tirofiban (glycoprotein IIb/IIIa antagonist) (Koster et al, 2001a,b). Both approaches have been used successfully, but experience is limited. Recently (November 2002), the manufacturer of tirofiban advised against this indication because of reported bleeding fatalities.
Preventing HIT and associated thrombotic complications
‘Safer’ heparin preparations should be given when appropriate. For example, porcine UFH is preferred over bovine UFH because of a lower risk of HIT (Lee & Warkentin, 2001; Francis et al, 2003a). HIT occurs 8–10 times less often with LMWH compared with UFH in post-operative orthopaedic patients, and is associated with a lower risk of HIT or HIT antibody formation in situations such as post cardiac surgery and treatment of venous thrombosis (Pouplard et al, 1999; Lindhoff-Last et al, 2002).
Early detection of HIT by platelet count monitoring has not been shown to reduce HIT-associated thrombosis, possibly because earlier strategies (of stopping heparin alone) often fail to prevent thrombosis. Recent emphasis on substituting heparin with an alternative anticoagulant when HIT is suspected has increased the importance of platelet count monitoring. The different risks of HIT in various clinical situations suggest that intensity of platelet count monitoring should reflect the risk of HIT in a given situation (Warkentin, 2002a).
The author thanks Professor Dr Andreas Greinacher for critically reviewing this manuscript, and to Jo-Ann I. Sheppard, Aurelio Santos, Jr, and James W. Smith for help in preparing the Figures. The author acknowledges the contribution of Professor Beng H. Chong (Chairman, Platelet Immunology Scientific and Standardization Committee, International Society on Thrombosis and Haemostasis) in initiating discussion towards developing a scoring system that takes into account clinical and laboratory criteria to diagnose HIT.