Heparin-induced thrombocytopenia-associated thrombosis: from arterial to venous to venous limb gangrene.

Heparin-induced thrombocytopenia (HIT) is an acquired immune-mediated hypercoagulability state that is strongly associated with thrombosis. During the 1970s and 1980s, the prevailing concept was that HIT was associated only with arterial thrombosis, through its unique pathogenesis via heparin-dependent, platelet-activating IgG antibodies. However, in 1990, when I began to encounter HIT in my clinical practice, I found that most such patients developed symptomatic venous thrombosis. This historical sketch summarizes some of the research that challenged the dogma of HIT being a mainly arterial prothrombotic disorder. Two studies - one a substudy of a randomized trial of post-orthopedic surgery thromboprophylaxis, and the second a retrospective five-hospital analysis of consecutive patients with positive test results for HIT antibodies - showed a marked predominance of venous over arterial thrombosis complicating HIT (~ 4 : 1). By the end of the 1990s, an even more dramatic manifestation of HIT-associated venous thrombosis was recognized: venous limb gangrene. Here, ischemic limb necrosis occurs despite palpable arterial pulses, as a result of both macrovascular and microvascular venous thrombosis. The surprising explanation was natural anticoagulant impairment (severe depletion of protein C, a vitamin K-dependent anticoagulant) resulting from treatment of HIT-associated deep vein thrombosis with warfarin (vitamin K antagonist). These insights from HIT research helped to elucidate the pathogenesis of ischemic limb losses in other intense non-HIT hypercoagulability states, including warfarin-associated venous limb gangrene complicating cancer-associated hypercoagulability, and symmetrical peripheral gangrene complicating disseminated intravascular coagulation of critical illness, in which proximate 'shock liver' helps to explain the profound failure of natural anticoagulant systems (protein C; antithrombin) in predisposing to peripheral limb microthrombosis in circulatory shock.

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin-induced thrombocytopenia.

Essentials The immunogenesis of Heparin-induced thrombocytopenia (HIT) is not well understood. Immunization to platelet factor 4 (PF4)-heparin occurs early in life, before any heparin exposure. PF4 and PF4-heparin complexes induce the proliferation of CD14+ cells. Reduced levels of regulatory cytokines contribute to immune dysregulation in HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4-heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF4-heparin complexes in patients with HIT. Patients/Methods Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass (CPB) (n = 17) and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4-heparin complexes. Cellular proliferation was assessed by [3 H]thymidine uptake and 5-ethynyl-2'-deoxyuridine detection. Results and Conclusions PBMCs proliferated in the presence of PF4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14+ cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin-10 and transforming growth factor-ß1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF4-heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT.

Acute haemolysis, DIC and renal failure after transfusion of uncross-matched blood during trauma resuscitation: illustrative case and literature review.

AIMS/OBJECTIVES: The aims of this study were to report a patient with acute haemolytic transfusion reaction (HTR) after transfusing uncross-matched red blood cell (RBC) units and to identify the frequency of this complication. BACKGROUND: Uncross-matched RBC units are commonly transfused in emergencies, but the frequency of acute HTR is unknown. METHODS: We describe a male stabbing victim who received three units of uncross-matched RBC units complicated by acute intravascular HTR, disseminated intravascular coagulation (DIC) and renal failure. We identified 14 studies evaluating the frequency of acute HTR post-emergency transfusion of uncross-matched RBC units. RESULTS: Acute HTR was shown by haemoglobinuria, free-plasma haemoglobin and methemalbumin, with anti-K and anti-Fya eluted from recipient red cells; acute DIC featured severe hypofibrinogenemia, thrombocytopenia, elevated fibrin D-dimer and multiple bilateral renal infarcts. Two of the three transfused units reacted with pre-existing RBC alloantibodies [anti-K (titre, 128), anti-Fya (titre, 512)], explained by transfusion 25 years earlier. Our literature review found the frequency of acute HTR following emergency transfusion of uncross-matched RBC units to be 2/3998 [0·06% (95% CI, 0·01-0·21%)]. CONCLUSIONS: Although emergency transfusion of uncross-matched blood is commonly practiced at trauma centres worldwide, with low risk of acute HTR (<1/1000), our well-documented patient case demonstrates the potential for acute HTR with severe complications.

Autoimmune heparin-induced thrombocytopenia.

Autoimmune heparin-induced thrombocytopenia (aHIT) indicates the presence in patients of anti-platelet factor 4 (PF4)-polyanion antibodies that are able to activate platelets strongly even in the absence of heparin (heparin-independent platelet activation). Nevertheless, as seen with serum obtained from patients with otherwise typical heparin-induced thrombocytopenia (HIT), serum-induced platelet activation is inhibited at high heparin concentrations (10-100 IU mL-1 heparin). Furthermore, upon serial dilution, aHIT serum will usually show heparin-dependent platelet activation. Clinical syndromes associated with aHIT include: delayed-onset HIT, persisting HIT, spontaneous HIT syndrome, fondaparinux-associated HIT, heparin 'flush'-induced HIT, and severe HIT (platelet count of < 20 × 109  L-1 ) with associated disseminated intravascular coagulation (DIC). Recent studies have implicated anti-PF4 antibodies that are able to bridge two PF4 tetramers even in the absence of heparin, probably facilitated by non-heparin platelet-associated polyanions (chondroitin sulfate and polyphosphates); nascent PF4-aHIT-IgG complexes recruit additional heparin-dependent HIT antibodies, leading to the formation of large multimolecular immune complexes and marked platelet activation. aHIT can persist for several weeks, and serial fibrin, D-dimer, and fibrinogen levels, rather than the platelet count, may be helpful for monitoring treatment response. Although standard anticoagulant therapy for HIT ought to be effective, published experience indicates frequent failure of activated partial thromboplastin time (APTT)-adjusted anticoagulants (argatroban, bivalirudin), probably because of underdosing in the setting of HIT-associated DIC, known as 'APTT confounding'. Thus, non-APTT-adjusted therapies with drugs such as danaparoid and fondaparinux, or even direct oral anticoagulants, such as rivaroxaban or apixaban, are suggested therapies, especially for long-term management of persisting HIT. In addition, emerging data indicate that high-dose intravenous immunoglobulin can interrupt HIT antibody-induced platelet activation, leading to rapid platelet count recovery.

Clinical effectiveness of a Bayesian algorithm for the diagnosis and management of heparin-induced thrombocytopenia.

Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated 'four Ts' (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93-1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95-99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48-0.98), specificity 0.99 (95% CI, 0.97-1.00), PPV 0.90 (95% CI, 0.56-0.99) and NPV 0.99 (95% CI, 0.96-1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients.

Diagnostic accuracy of IgG-specific versus polyspecific enzyme-linked immunoassays in heparin-induced thrombocytopenia: a systematic review and meta-analysis.

Essentials Immunoassay specificity varies in heparin-induced thrombocytopenia (HIT) testing. This meta-analysis examined 9 studies that tested samples by both IgG and polyspecific methods. IgG-specific assays confer superior diagnostic accuracy compared with polyspecific assays. These results further support recommendations in favor of IgG-specific testing. SUMMARY: Background There are conflicting data on whether the IgG-specific or polyspecific antiplatelet factor 4/heparin (PF4/H) enzyme-linked immunosorbent assay (ELISA) is preferred for the laboratory diagnosis of heparin-induced thrombocytopenia (HIT). Objectives To directly compare diagnostic accuracy of IgG-specific versus polyspecific ELISA in HIT. Patients/Methods A systematic search yielded nine studies comprising 1948 patients with suspected HIT tested by both IgG-specific and polyspecific ELISAs and a reference standard against which the diagnostic accuracy of the ELISAs could be measured. Study quality was assessed by QUADAS-2 criteria. Results There was identical sensitivity for IgG-specific and polyspecific ELISAs (0.97; 95% confidence interval (CI), 0.95-0.99) and superior specificity of IgG-specific compared with polyspecific ELISA (0.87 [0.85-0.88] vs. 0.82 [0.80-0.84], respectively). Performance was similar in subgroups using the serotonin release assay and a single commercial ELISA manufacturer. The negative predictive values of IgG-specific and polyspecific ELISA were similarly high (0.99, [0.99-1.00], but the positive predictive value was superior with IgG-specific compared with polyspecific ELISA (0.56 [0.52-0.61] vs. 0.32 [0.28-0.35], respectively). The positive likelihood ratio (LR) was higher in IgG-specific than polyspecific ELISA, although negative LRs were similar. There was high risk of quality concerns in domains of index test and reference standard. Conclusions The superior diagnostic accuracy of IgG-specific ELISA reinforces the ISTH-SSC recommendation for standardization of laboratory testing for HIT. Likelihood ratios of individual assays may be used in combination with clinical scoring systems as part of an integrated diagnostic algorithm for HIT.

Protamine (heparin)-induced thrombocytopenia: a review of the serological and clinical features associated with anti-protamine/heparin antibodies.

Protamine is widely used in medicine as a rapidly-acting antidote to heparin, particularly for reversing heparin anticoagulation after cardiac surgery. Protamine is also used as a stabilizing additive to certain preparations of insulin. Recent reports demonstrate that protamine and heparin form multimolecular complexes that result in high rates of immunization in post-cardiac surgery patients, particularly of immunoglobulin G (IgG) class antibodies; a subset of these anti-protamine/heparin IgG antibodies activates platelets through their FcγIIA (IgG) receptors. Although the clinical consequences of anti-protamine/heparin antibodies that are newly generated after cardiac surgery are unknown, there is evidence that platelet-activating anti-protamine/heparin antibodies already present at the time of cardiac surgery might occasionally explain more severe thrombocytopenia with delayed platelet count recovery, as well as thromboembolic complications, in the post-cardiac surgery setting. Triggers for such antibodies remain poorly-defined, but could include preoperative administration of heparin to diabetic patients receiving protamine-insulin as well as recent previous cardiac surgery. Anti-protamine/heparin antibodies have several features in common with anti-platelet factor 4 (PF4) PF4/heparin antibodies implicated in heparin-induced thrombocytopenia (HIT), including immunization by heparin-containing multimolecular complexes, predominant IgG class, pathological platelet-activating properties, relatively rapid IgG formation without IgM precedence, and antibody transience. Despite these similarities, the risk of anti-protamine/heparin antibody-mediated complications seems to affect the early post-cardiac surgery period, whereas HIT usually occurs at least 5 days following cardiac surgery. Clinicians need to become aware of this recently recognized immunohematological disorder, and research is needed to identify triggers of immunization, improve detection of pathological antibodies and identify patients at risk of this complication.

Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study.

UNLABELLED: Essentials Heparin-induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat. We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT. One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery. Rivaroxaban may be an effective and safe treatment option for HIT. SUMMARY: Background Rivaroxaban is a direct oral anti-Xa inhibitor that has the potential to greatly simplify treatment of heparin-induced thrombocytopenia (HIT). Objectives To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single-arm, prospective cohort study of patients with suspected or confirmed HIT. Patients/Methods Twenty-two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30. Results and Conclusions The primary outcome measure, incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism at 30 days, occurred in one HIT-positive participant (4.5%; 95% confidence interval [CI], 0-23.5%) and one HIT-positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT-positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.

Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is 'shock liver' the unrecognized provocateur of ischemic limb necrosis?

For unknown reasons, a small minority of critically ill patients with septic or cardiogenic shock, multiorgan failure, and disseminated intravascular coagulation develop symmetrical acral (distal extremity) limb loss due to microvascular thrombosis ('limb gangrene with pulses'). Case reports have described preceding 'shock liver' in some critically ill patients who developed such a picture of ischemic limb necrosis. This suggests that profoundly disturbed procoagulant-anticoagulant balance featuring uncontrolled generation of thrombin-resulting from failure of the protein C and antithrombin natural anticoagulant systems due to insufficient hepatic synthesis of these crucial proteins-could explain the microvascular thrombosis and associated limb loss. We hypothesize that shock liver is the key predisposing risk factor underlying ischemic limb necrosis in the majority of patients who develop this complication in the setting of acute disseminated intravascular coagulation complicating septic or cardiogenic shock. As shock liver precedes onset of limb ischemia by several days, therapeutic intervention may be possible.

Distinguishing between anti-platelet factor 4/heparin antibodies that can and cannot cause heparin-induced thrombocytopenia.

BACKGROUND: Many patients exposed to heparin develop antibodies against platelet factor 4 (PF4) and heparin, yet only those antibodies that activate platelets cause heparin-induced thrombocytopenia (HIT). Patients who produce anti-PF4/heparin antibodies without developing HIT either have antibodies that do not cause platelet activation or produce pathogenic antibodies at levels that are insufficient to cause HIT. Understanding the differences between anti-PF4/heparin antibodies with and without HIT will improve test methods and reduce overdiagnosis. AIMS: To investigate the presence of low levels of platelet-activating antibodies in patients investigated for HIT who had anti-PF4/heparin antibodies but failed to cause platelet activation in the (14) C-serotonin release assay (SRA). MATERIALS/METHODS: We developed a platelet activation assay similar to the SRA using exogenous PF4 without added heparin (PF4-SRA). This assay was able to detect low levels of platelet-activating antibodies. We used this PF4-SRA to test for platelet-activating antibodies in patients investigated for HIT. RESULTS: The PF4-SRA detected platelet-activating antibodies in seven (100%) of seven SRA-positive sera even after the samples were diluted until they were no longer positive in the standard SRA. Platelet-activating antibodies were detected in 14 (36%) of 39 patients who had anti-PF4/heparin antibodies but tested negative in the SRA and did not have clinical HIT. The clinical diagnosis of HIT was confirmed by chart review and concordant with the SRA results. CONCLUSIONS: A subset of heparin-treated patients produce subthreshold levels of platelet-activating anti-PF4/heparin antibodies that do not cause HIT. An increase in the titer of these pathogenic antibodies, along with permissive clinical conditions, could lead to HIT.

FcγRIIa proteolysis as a diagnostic biomarker for heparin-induced thrombocytopenia.

BACKGROUND: A significant challenge in the management of heparin-induced thrombocytopenia (HIT) patients is making a timely and accurate diagnosis. The readily available enzyme immunoassays (EIAs) have low specificities. In contrast, platelet activation assays have higher specificities, but they are technically demanding and not widely available. In addition, ~ 10% of samples referred for HIT testing are initially classified as indeterminate by the serotonin release assay (SRA), which further delays accurate diagnosis. HIT is characterized by platelet activation, which leads to FcγRIIa proteolysis. This raises the possibility that identification of the proteolytic fragment of FcγRIIa could serve as a surrogate marker for HIT. OBJECTIVES: To determine the specificity of platelet FcγRIIa proteolysis induced by sera from patients with HIT, and to correlate the results with those of the SRA. METHODS/PATIENTS: Sera from HIT patients and control patients with other thrombocytopenic/prothrombotic disorders were tested for their ability to proteolyse FcγRIIa. The results were correlated with anti-platelet factor 4 (PF4)/heparin antibodies (EIA), and heparin-dependent platelet activation (SRA). RESULTS: Only HIT patient samples (20/20) caused heparin-dependent FcγRIIa proteolysis, similar to what was shown by the SRA. None of the samples from the other patient groups or hospital controls caused FcγRIIa proteolysis. Among nine additional samples that tested indeterminate in the SRA, FcγRIIa proteolysis resolved five samples that had a positive anti-PF4/heparin EIA result; three had no FcγRIIa proteolysis, and two were shown to have heparin-dependent FcγRIIa proteolysis CONCLUSIONS: This study suggests that heparin-dependent FcγRIIa proteolysis is at least as specific as the SRA for the diagnosis of HIT.

A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia.

BACKGROUND: Drug-induced immune thrombocytopenia (DITP) can be confirmed by the demonstration of drug-dependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and test methods are not standardized. OBJECTIVE: To identify drugs with the strongest evidence for causing DITP based on clinical and laboratory criteria. PATIENTS/METHODS: We developed a grading system to evaluate the quality of DITP laboratory testing. The 'DITP criteria' were: (i) Drug (or metabolite) was required for the reaction in vitro; (ii) Immunoglobulin binding was demonstrated; (iii) Two or more laboratories obtained positive results; and (iv) Platelets were the target of immunoglobulin binding. Laboratory diagnosis of DITP was considered definite when all criteria were met and probable when positive results were reported by only one laboratory. Two authors applied the DITP criteria to published reports of each drug identified by systematic review. Discrepancies were independently adjudicated. RESULTS: Of 153 drugs that were clinically implicated in thrombocytopenic reactions, 72 (47%) were associated with positive laboratory testing. Of those, 16 drugs met criteria for a definite laboratory diagnosis of DITP and thus had the highest probability of causing DITP. Definite drugs were: quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin and suramin; the glycoprotein IIbIIIa inhibitors abciximab, tirofiban and eptifibatide; and heparin. CONCLUSIONS: We identified drugs with the strongest evidence for an association with immune thrombocytopenia. This list may be helpful for ranking potential causes of thrombocytopenia in a given patient.

Anti-PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis.

BACKGROUND: Anti-PF4/heparin antibodies are frequently generated after coronary artery bypass grafting (CABG) surgery, with platelet-activating IgG implicated in heparin-induced thrombocytopenia (HIT). It is controversial whether non-platelet-activating antibodies are associated with thrombosis. OBJECTIVES: To determine in post-CABG patients whether thromboprophylaxis using fondaparinux vs. unfractionated heparin (UFH) reduces the frequency of anti-PF4/heparin antibodies, and whether anti-PF4/heparin antibodies are associated with early graft occlusion. METHODS/PATIENTS: In a pre-planned secondary analysis of a randomized control trial (RCT) comparing fondaparinux vs. UFH thromboprophylaxis post-CABG, we determined the frequency of anti-PF4/heparin antibody formation by solid-phase enzyme-immunoassay (EIA) and of platelet-activating antibodies by serotonin-release assay (SRA); the SRA and fluid-phase EIA were used to assess fondaparinux cross-reactivity. We also examined whether anti-PF4/heparin antibodies were associated with early arterial or venous graft occlusion (6-week CT angiography). RESULTS: We found no significant difference in the frequency of antibody formation between patients who received fondaparinux vs. UFH (65.3% vs. 46.0%; P = 0.069), and no significant fondaparinux cross-reactivity. Venous graft occlusion(s) occurred in 6/26 patients who formed 'strong' IgG antibodies (≥ 1.0 optical density [OD] units and ≥ 2× baseline) vs. 3/66 who did not (P = 0.0139). In both unadjusted and adjusted analyses, strong postoperative (but not pre-operative) anti-PF4/heparin IgG responses were associated with a markedly increased risk of early venous (but not arterial) graft occlusion (adjusted OR, 9.25 [95% CI, 1.73, 49.43]; P = 0.0093); notably, none of the three SRA-positive patients developed a venous graft occlusion. CONCLUSIONS: Fondaparinux vs. UFH thromboprophylaxis postCABG does not reduce anti-PF4/heparin antibody formation. Non-platelet-activating anti-PF4/heparin IgG antibodies generated post operatively are associated with early venous graft occlusion.

Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series.

BACKGROUND: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin-induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet-activating anti-platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparin-dependent, platelet-activating antibodies. OBJECTIVES: To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin-release assay (SRA), a sensitive and specific test for platelet-activating HIT antibodies. METHODS/PATIENTS: We reviewed consecutive eligible patients with SRA-positive HIT (mean peak serotonin release, 91% [normal, < 20%]; mean IgG-specific PF4/heparin enzyme immunoassay result, 2.53 optical density units [normal, < 0.45 units]) in one medical center over a 30-month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 × 10(9) L(-1)). Where available, plasma samples were used to measure thrombin-antithrombin (TAT) complex levels. RESULTS: Sixteen patients with SRA-positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty-six per cent of patients had HIT-associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progressive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. CONCLUSION: Fondaparinux shows promise for the treatment of patients with SRA-positive acute HIT.

HIT paradigms and paradoxes.

The current major problem with HIT is its overdiagnosis. This concept follows from the HIT central paradigm: HIT is caused by a subset of antibodies against platelet factor 4 (PF4)/heparin complexes that have strong platelet-activating properties. Prospective studies show that only a minority of sera containing such antibodies exhibit platelet-activating properties. Ironically, the earliest tests for HIT--platelet activation assays--remain today the most diagnostically useful, particularly the washed platelet assays. But the wider application of PF4-dependent immunoassays, and their much greater sensitivity for the larger subset of non-platelet-activating (and non-HIT-inducing) antibodies, has resulted in HIT overdiagnosis in many centres. Studies of anti-PF4/heparin immunization in diverse clinical situations have provided insights into the factors that influence the HIT immune response. Besides the conundrum of anticoagulant-induced thrombosis (including its potentiation of coumarin-induced microthrombosis), HIT evinces numerous other paradoxes: (i) it is a platelet-activating disorder with venous thrombosis as its predominant clinical manifestation; (ii) 'delayed-onset' (or 'autoimmune') HIT can lead to dramatic worsening of HIT-associated thrombosis despite cessation of heparin; (iii) partial thromboplastin time (PTT) monitoring of direct thrombin inhibitor treatment - and confounding of PTT monitoring by HIT-associated consumptive coagulopathy - infers that the worst subset of HIT patients may fail this therapeutic approach; (iv) the highly sulfated pentasaccharide anticoagulant, fondaparinux, can (rarely) cause HIT yet appears to be an effective treatment for this disorder; and (v) the transience of the HIT immune response means that many patients with previous HIT can safely receive future heparin.