Rapid-onset heparin-induced thrombocytopenia without previous heparin exposure

Heparin-induced thrombocytopenia (HIT) is one of the most common immune-mediated drug reactions. Immunoglobulin G-type antibodies against platelet factor 4(PF4)/heparin complexes are known to play a key role in the pathogenesis of HIT. Rapid-onset HIT is caused by the presence of circulating HIT antibodies at the time of heparin readministration. These antibodies are generally resulted from a recent immunizing exposure to heparin. Here we report a case of rapid-onset HIT developed after a septicemia without previous heparin exposure. The diagnosis of HIT as well as the presence of platelet activating and heparin-dependent antibodies was confirmed by ELISA and flow cytometric functional assays. Our case report reinforces that rapid-onset HIT cannot be excluded only based on the absence of previous heparin exposure. In addition, it may support the new theory of pre-immunization by PF4-coated bacteria in the pathomechanism of HIT. We also call the attention that venous limb gangrene can be rarely associated with HIT and thrombosis even in the absence of coumarin therapy. Furthermore, transient presence of anti-phospholipid antibodies can cause a differential diagnostic problem in the cases of HIT.     

Simultaneous binding of heparin and platelet factor-4 to platelets: Further insights into the mechanism of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is mediated by antibody against complexes of platelet factor-4 (PF4) and heparin. Although it has been assumed that these complexes bind to platelets and provide a target for the antibody, this has never been demonstrated. Furthermore, there is evidence suggesting that heparin-PF4 complexes do not bind to platelets. We have analyzed the effect of each ligand on the platelet binding of the other. We particularly focused on the result when heparin and PF4 are in equimolar concentration because we had previously shown that this was the condition under which HIT-IgG increased on the platelet surface. We found that when the molar concentration of PF4 approximates or exceeds that of heparin, the ligands bind simultaneously to the cells and HIT-IgG binds also. However, when heparin is in molar excess, both PF4 binding and HIT-IgG binding are diminished. Our data are consistent with the hypothesis that heparin-PF4 complexes bind via their heparin component to heparin binding sites on the platelet membrane rather than by their PF4 component to PF4 sites. The conditions promoting the binding of the complexes also lead to binding of HIT-IgG. Am. J. Hematol. 58:24–30, 1998. © 1998 Wiley-Liss, Inc.     

The complicated relationships of heparin-induced thrombocytopenia and platelet factor 4 antibodies with COVID-19

COVID-19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of platelet factor 4/heparin antibodies being present in COVID-19-infected patients. This has thus been identified in some publications as representing a high incidence of heparin-induced thrombocytopenia (HIT), whereas in others, findings have been tempered by general lack of functional reactivity using confirmation assays of serotonin release assay (SRA) or heparin-induced platelet aggregation (HIPA). Moreover, in at least two publications, data are provided suggesting that antibodies can arise in heparin naïve patients or that platelet activation may not be heparin-dependent. From this literature, we would conclude that platelet factor 4/heparin antibodies can be observed in COVID-19-infected patients, and they may occur at higher incidence than in historical non-COVID-19-infected cohorts. However, the situation is complex, since not all platelet factor 4/heparin antibodies may lead to platelet activation, and not all identified antibodies are heparin-dependent, such that they do not necessarily reflect “true” HIT. Most recently, a “HIT-like” syndrome has reported in patients who have been vaccinated against COVID-19. Accordingly, much more is yet to be learnt about the insidious disease that COVID-19 represents, including autoimmune outcomes in affected patients.     

Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a common adverse effect of unfractionated heparin (UFH) therapy. In contrast, only a few patients have been reported with HIT following low-molecular-weight heparin (LMWH) therapy (LMW-HIT). To define the clinical and biological characteristics of LMW-HIT, 180 patients treated for suspected HIT at 15 French centres were investigated. Clinical history was recorded and HIT was confirmed in 59 patients with positive serotonin release assay results: 57 of them had high levels of antibodies (Abs) to heparin-platelet factor 4 complexes (H/PF4) and two had Abs to interleukin 8. Eleven patients were treated exclusively with LMWH (LMW-HIT) and 48 with UFH either alone (UF-HIT, n = 34) or combined with LMWH (UF/LMW-HIT, n = 14). The LMW-HIT and UF-HIT groups were similar with respect to sex, age, platelet count before heparin therapy, frequency of bleeding and occurrence of disseminated intravascular coagulation. The interval to onset of HIT was longer in LMW-HIT patients compared with UF-HIT patients (P = 0.03). Severe thrombocytopenia (platelets < 15 x 10(9)/l) was more frequent in the LMW-HIT group (P = 0.04). Thrombosis occurred in three of 11 LMW-HIT patients, i.e. as frequently as in UF-HIT patients. LMW-HIT is potentially severe and may be observed after longer heparin treatment compared with UF-HIT. It is highly recommended, therefore, that platelet counts be monitored carefully whenever LMWH is administered.     

Further characterization of antibody and antigen in heparin-induced thrombocytopenia

Patients with immune heparin-induced thrombocytopenia (HIT) possess antibodies that bind to a complex of platelet factor 4 (PF4) and heparin. We observed that HIT antibodies will also bind to PF4 alone adsorbed on polystyrene ELISA wells but not to soluble PF4 in the absence of heparin. Having developed a technique to affinity-purify anti-PF4-heparin HIT IgG, we are able to provide the first estimates of the avidity of HIT IgG. HIT IgG displayed relatively high functional affinity for both PF4-heparin (Kd = 7-30 nM) and polystyrene adsorbed PF4 alone (Kd = 20-70 nM). Furthermore, agarose beads coated with PF4 alone were almost as effective as beads coated with PF4 plus heparin in depleting HIT plasmas of anti-PF4-heparin antibodies. We conclude that the HIT antibodies which bind to polystyrene adsorbed PF4 without heparin are largely the same IgG molecules that bind PF4-heparin and therefore most HIT antibodies bind epitope(s) on PF4 and not epitope(s) formed by part of a PF4 molecule and part of a heparin molecule. Binding of PF4 to heparin (optimal) or polystyrene/agarose (suboptimal) promotes recognition of this epitope.     

Platelet GPIIb/IIIa antagonist, XV459, in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a serious, immune-related complication of heparin therapy. One of the most severe manifestations of HIT is the development of thromboembolic events, which is based on platelet activation and aggregation caused by HIT-associated antibodies. Therapeutic options for patients with HIT are limited despite advancement toward the development of alternative (nonheparin) anticoagulants, such as direct thrombin inhibitors and indirect anti-factor Xa agents. Platelet GPIIb/IIIa receptor antagonists have been shown to be the final common pathway for platelet aggregation regardless of the use of activator or anticoagulant. In this study, the ability of a novel platelet GPIIb/IIIa antagonist, a free acid form of roxifiban (XV459), to block platelet activation/aggregation in response to highly characterized heparin-PF4 antibody-positive plasma/heparin was examined using light transmittance aggregometry, serotonin release, and (125)I-fibrinogen binding assays to human platelets. XV459 at 20 nM maximally inhibited (P < 0.001) the platelet-activation/aggregation responses as mediated by the HIT antibody-positive plasma (in the presence of therapeutic heparin concentrations). Compared with controls, both HIT antibodies/heparin and TEAC (a mixture of thrombin [0.1 IU/ml], epinephrine [1 microg/ml], arachidonate [0.1 mM], and collagen [10 microml]) resulted in significantly higher levels of fibrinogen binding to human platelets (5-7-fold increase; P < 0.001). Concentration-dependent profiles of XV459 on the mean percent inhibition of (125)I-fibrinogen binding in the presence of HIT antibodies and TEAC were achieved ( approximately 50% inhibition at 10 nM XV459). The platelet GPIIb/IIIa receptor antagonist (XV459) might be of potential benefit in the management of thrombotic thrombocytopenia produced by heparin and/or related glycosaminoglycans.     

肝素诱导性血小板减少症亚心诊疗要点

肝素诱导性血小板减少症是由IgG抗体介导的促血栓形成性免疫性疾病。临床表现为肝素治疗后数天至数月发生血小板减少计数（与肝素治疗前相比）减低与伴或不伴新发血栓,呈现高凝与血栓矛盾状态。发病隐蔽,死亡率高。这为临床诊疗带来极大挑战。本文根据武汉亚洲心脏病医院185例疑似HIT患者的诊疗数据结合最新欧美HIT管理指南汇集成以下疑似HIT诊疗思路,降低HIT患者不良事件发生率。     

Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes

Immune heparin-induced thrombocytopenia (HIT) is a life-threatening adverse effect of heparin. It can result from any type of heparin exposure and by any route of administration; however only a few cases are reported after exposures to small quantities of heparin from catheter flushes. The major clinical problem associated with HIT is thrombosis. Early detection and institution of alternative, non-heparin anticoagulation are important. We report a patient with HIT associated with use of therapeutic-dose unfractionated heparin in whom immune sensitization to heparin was triggered by two 500-unit exposure to UFH associated with intravascular catheter flushing for antineoplastic chemotherapy in a patient with colon adenocarcinoma.     

Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation

Antibodies to heparin platelet factor 4 (H-PF4) complexes were purified from the plasma of three patients with heparin-induced thrombocytopenia (HIT) using affinity chromatography. From each plasma, the largest amount of antibodies was eluted with 2 M NaCl at pH 7.5 (peak 1) and the remainder was obtained using 0.1 M glycine/0. 5 M NaCl at pH 2.5 (peak 2). In an enzyme-linked immunosorbent assay (ELISA), we then showed that each patient had developed antibodies to PF4 displaying different characteristics. In patient 1, peak 1 IgG reacted almost exclusively with H-PF4 complexes, whereas peak 2 IgG had similar reactivity with PF4 whether or not heparin was present. Patient 2 expressed a mixture of IgA, IgM and IgG and both fractions bound to PF4 alone or to H-PF4 complexes. Finally, IgG in patient 3 only bound to H-PF4 and was unreactive with PF4 alone. Using [14C]-serotonin release assays, the antibodies developed in the three patients and exhibiting the strongest ability to activate platelets with heparin were those having the highest affinity to H-PF4. These results strongly support the hypothesis that HIT antibodies to PF4 are heterogeneous regarding their affinity and specificity for target antigens and this may greatly influence their ability to activate platelets and their pathogenicity.     

Mechanisms of thrombocytopenia in varicella

51Cr-labeled platelet and 125I-labeled fibrinogen kinetic studies in four thrombocytopenic children with varicella infection revealed marked platelet destruction (platelet survival times 0.1, 0.4, 1.0, and 2.4 days) and relatively normal fibrinogen disappearance. The platelet count was directly related to the platelet survival time. Marrow megakaryocyte mass was increased twofold to fourfold. IgG or IgM antiplatelet antibody was present on autologous platelets in the three patients tested. These data suggest that thrombocytopenia in some patients with varicella is the consequence of immune mediated platelet destruction.     

Danaparoid for cardiopulmonary bypass in patients with previous heparin-induced thrombocytopenia

Anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia requires the use of other anticoagulants. We report a case in whom this was achieved using the heparinoid danaparoid (Orgaran). Based on our experience and a review of the literature, we provide guidelines for managing these rare patients. A danaparoid dose substantially lower than that recommended by the manufacturer may minimize bleeding complications.     

The unique immunological features of heparin‐induced thrombocytopenia

Heparin‐induced thrombocytopenia (HIT) is a serious drug reaction that leads to a decrease in platelet count and a high risk of thrombosis. HIT patients produce pathogenic immunoglobulin G (IgG) antibodies that bind to complexes of platelet factor‐4 (PF4) and heparin. HIT immune complexes crosslink Fc‐receptors resulting in platelet and monocyte activation. These events lead to the release of procoagulant chemokines and tissue factor, which together create an intensely prothrombotic state. HIT represents an atypical immune response because it has features of both T cell‐dependent and T cell‐independent mechanisms. The disorder is characterized by newly formed anti‐PF4/heparin IgG antibodies, which are characteristic of a T cell‐dependent mechanism; however, re‐exposure to heparin, months after HIT, does not lead to a memory response, which is consistent with a T cell‐independent mechanism. In this review, we discuss the immunobiological events that can explain these features, including the role for T cell‐dependent and T cell‐independent mechanisms in HIT antibody generation, the immunogenic characteristics of the PF4/heparin antigen, and the concept of a temporary loss in immune regulation contributing to the onset of HIT. We also present a novel immunobiological model to explain the atypical immune response that is characteristic of HIT.     

Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia

We report two patients with deep-vein thrombosis complicating immune heparin-induced thrombocytopenia who developed venous limb gangrene during overlapping therapy with a direct thrombin inhibitor (lepirudin or argatroban) and warfarin. In both patients, therapy with the direct thrombin inhibitor was interrupted during persisting severe athrombocytopenia while warfarin administration continued. Both patients exhibited the typical feature of a supratherapeutic international normalized ratio (INRs, 5.9 and 7.3) that has been linked previously with warfarin-associated venous limb gangrene. These data suggest that warfarin anticoagulation be postponed in patients with acute heparin-induced thrombocytopenia until substantial recovery of the platelet count has occurred.     

Differences in specificity of heparin-dependent antibodies developed in heparin-induced thrombocytopenia and consequences on cross-reactivity with danaparoid sodium

Heparin-induced thrombocytopenia (HIT) is frequently associated with antibodies (Abs) to heparin–PF4 complexes (H-PF4). In order to investigate whether there are variations in specificity of Abs, we studied 63 samples from patients with suspected HIT. Two groups of samples were separated after comparing their reactivity against H-PF4 or recombinant PF4 (r-PF4) using ELISA. In group Ab1 ( n  = 46), Abs only or mainly bound to H-PF4 complexes and thus most of the epitopes recognized probably involved both heparin and PF4. In group Ab2 ( n  = 17), Abs exhibited similar reactivity to r-PF4 and H-PF4, and the antigens recognized were possibly neoepitopes mainly expressed by modified PF4 and by H-PF4 complexes. Platelet activation tests were positive with 56 samples containing high titres of Abs to H-PF4. Most samples ( n  = 59) contained IgG antibodies, often associated with IgA antibodies which were more frequently found in group Ab2, and/or IgM. With unfractionated heparin treatment, HIT was associated with Ab1 or Ab2 antibodies, whereas only Ab1 antibodies were detected after low-molecular-weight heparin (LMWH). Furthermore, cross-reactivity with danaparoid sodium was present only in group Ab1 and mainly involved LMWH-treated patients.     

Spontaneous heparin-induced thrombocytopenia syndrome without any proximate heparin exposure,infection, or inflammatory condition: Atypical clinical features with heparin-dependent platelet activating antibodies

Recent studies suggest that a thromboembolic disorder resembling heparin-induced thrombocytopenia (HIT), so-called spontaneous HIT syndrome, can occur in patients without any history of heparin exposure. It is likely due to anti-platelet factor 4 (PF4)/polyanion antibodies induced by other polyanions, such as bacterial surfaces and nucleic acids. We describe an atypical case of spontaneous HIT syndrome. A 70-year-old man suddenly presented with acute cerebral sinus thrombosis (CST). Soon after the initiation of unfractionated heparin (UFH) for the treatment of CST, his platelet count fell precipitously and he developed deep vein thrombosis, a clinical picture consistent with rapid-onset HIT but without any proximate episodes of heparin exposure, infection, trauma, surgery, or other acute illness. Antigen assays and a washed platelet activation assay indicated that the patient already possessed anti-PF4/heparin IgG antibodies with heparin-dependent platelet activation properties on admission. Cessation of UFH and initiation of argatroban resulted in prompt recovery of his platelet count without further thromboembolic events. We identified two similar cases in the literature. However, these patients do not meet the recently proposed criteria for spontaneous HIT syndrome. Even in atypical cases, however, inappropriate or delayed diagnosis of HIT appears to be associated with worse outcomes. We propose that these atypical cases should be included in the category of spontaneous HIT syndrome.     

Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia

BACKGROUND: Heparin has rarely been reported to cause acute cardiorespiratory reactions or collapse. Some reports relate this to underlying heparin-induced thrombocytopenia. OBJECTIVE: To confirm and increase awareness of acute life-threatening cardiopulmonary events when patients with heparin-induced thrombocytopenia are re-exposed to heparin. DESIGN: Retrospective observational case series. PATIENTS/SETTING: Four cardiovascular surgery patients were identified in two adjacent large urban hospitals over a 2-yr-period who experienced eight episodes of cardiorespiratory collapse immediately following heparin administration. All had underlying heparin-induced thrombocytopenia. RESULTS: Intravenous boluses of unfractionated heparin were given to four patients with known or previously unrecognized heparin-induced thrombocytopenia. Two patients experienced severe respiratory distress within 15 min for which they required endotracheal intubation. Two other patients experienced cardiac arrest or a lethal arrhythmia within minutes of receiving intravenous heparin. Serologic tests for heparin-induced antibodies were positive in all patients. In three cases, the platelet count was normal or near normal but fell dramatically (71%) immediately following the heparin bolus. Three cases had prior diagnoses of heparin-induced thrombocytopenia, but health care workers administered heparin either unaware of the diagnosis or ignorant of its significance. No patients died, but all required some form of cardiopulmonary resuscitation and subsequent intensive care. CONCLUSIONS: Heparin administration to patients with heparin-induced antibodies can result in life-threatening pulmonary or cardiac events. Appreciation of this phenomenon can unmask cases of heparin-induced thrombocytopenia and strengthens the mandate to avoid any heparin exposure in affected patients. Recognition is crucial to avoiding disastrous outcomes.     

Heparin-induced thrombocytopenia associated with interleukin-8-dependent platelet activation in a patient with antiphospholipid syndrome

Platelet factor 4 heparin enzyme immunoassay, platelet aggregation test, and serotonin release assay are commonly used to diagnose and confirm heparin-induced thrombocytopenia. We describe a case of recurrent thrombocytopenia appearing in a few hours after each heparin administration and who tested negative for the three assays. Further analysis revealed anti-interleukin (IL)-8 antibodies and IL-8-dependent platelet activation facilitated by heparin, which may explain this unusual case of heparin-induced thrombocytopenia.     

The clinical diagnosis of heparin-induced thrombocytopenia in patients receiving continuous renal replacement therapy

Background Thrombocytopenia is common in critically ill patients who receive continuous renal replacement therapy. Often, these patients receive heparin therapy and the diagnosis of heparin induced thrombocytopenia (HIT) is considered as a potential etiology. No data regarding the clinical diagnosis of HIT is available for patients receiving continuous renal replacement therapy. Patients and methods We performed a retrospective study of 29 consecutive patients who received CRRT in a medical-surgical intensive care unit (ICU) and determined trends in platelet counts following CRRT and the frequency of meeting platelet based clinical criteria for consideration of a HIT diagnosis. Results For patient exposures to CRRT concurrent with heparin, 54% met at least one clinical threshold for consideration of the diagnosis of HIT. In 31% of exposures, both a platelet count <100,000/mm³ and a >50% decrease from baseline were seen. In contrast, the majority (73–85%) of patients receiving CRRT had a low pre-test probability of HIT using the “4T’s” scoring system. Mean platelet counts while on CRRT concurrent with heparin were significantly lower than when patients received heparin alone (P < 0.02). Conclusions The clinical diagnosis of HIT in ICU patients initiating CRRT is challenging given the decrease in platelet counts seen following CRRT initiation in the majority of patients. A prospective study in this population is needed to optimize patient outcomes.