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.     

Heparin-induced thrombocytopenia: analysis of risk factors in medical inpatients

Heparin-induced thrombocytopenia (HIT) is an unpredictable reaction to heparin characterized by thrombocytopenia and increased risk of life-threatening venous and/or arterial thrombosis. Data are lacking regarding additional risk factors that may be associated with the development of HIT. This study aimed to identify the risk factors that may be associated with HIT in medical inpatients receiving heparin. Twenty five thousand six hundred and fifty-three patients admitted to the medicine service who received heparin product were reviewed retrospectively. The diagnosis of HIT was confirmed if the platelet count dropped >50% from baseline and there was a positive laboratory HIT assay. Fifty-five cases of in-hospital HIT were observed. Multivariate analysis identified the administration of full anticoagulation dose with unfractionated heparin or exposure to heparin products for more than 5 d with an increased risk of HIT. Moreover, patients who were on haemodialysis, carried a diagnosis of autoimmune disease, gout or heart failure were also at increased risk. The results suggest that when using heparin products in these patient cohorts, increased surveillance for HIT is necessary.     

Non-transient “self-sustaining” heparin-induced thrombocytopenia: 4-year persistence of a platelet-activating PF4/heparin–antibody status without heparin exposure

Abstract

The more we come to understand the pathophysiology of heparin-induced thrombocytopenia (HIT) syndrome, the more we realize that HIT is a rather unusual immune response. One peculiar feature of HIT is the transient character of the antibodies. After cessation of exposure to heparins, the antibodies tend to disappear after 40–100 days. If re-immunization occurs, it generally takes at least 4 days to redevelop antibodies (if they are formed at all). We report about a patient who most likely developed platelet-activating IgG-specific platelet factor 4 (PF4)/heparin antibodies after knee surgery, experienced a transient ischemic attack years later [when HIT was diagnosed by using PF4/heparin ELISA] and presented a high number of these antibodies even 4 years after this first diagnosis of HIT without further re-exposure to heparin.     

Use of systemic bivalirudin with catheter‐directed thrombolysis in a patient with heparin‐induced thrombocytopenia: A case report

In patients with submassive pulmonary embolism, the use of catheter‐directed thrombolysis (CDT), using low‐dose alteplase is associated with improvement in overall hemodynamics. The data for use of CDT in patients with heparin‐induced thrombocytopenia are limited. We report a case of CDT in a patient with HIT using bivalirudin anticoagulation. Data of the use of bivalirudin and argatroban for systemic anticoagulation with CDT are limited.     

Heparin-induced thrombocytopenia: recent experience in a large teaching hospital

Background: Heparin‐induced thrombocytopenia (HIT) is a potentially serious adverse reaction caused by platelet‐activating antibodies. Aim: To describe experience with HIT. Methods: Twenty‐two patients identified by laboratory records of heparin‐associated antibodies with a 50% or greater decrease in platelet count were reviewed in our 600‐bed metropolitan teaching hospital from 1999 to April 2005. Results: There was an increase in the frequency of HIT diagnosed during the review period, which was associated with a rise in the number of requests for HIT antibodies. Thrombotic complications were identified in 14 of 22 patients with HIT. Mean age was 65 years, and 11 patients were men. Seven patients died and HIT was considered contributory in four. One patient required mid‐forearm amputation. Unfractionated heparin was used in all cases and five patients also received enoxaparin. Mean time to HIT screen, reflecting when the diagnosis was first suspected, was 14 days. Platelet nadir ranged from 6 × 10⁹/L to 88 × 10⁹/L, with a percentage drop in platelet count of 67–96%. Alternative anticoagulation (danaparoid) was not used in three patients, two of whom died. Conclusions: HIT is a potentially life‐threatening complication of heparin therapy, associated with a fall in platelet count and a high incidence of thromboembolic complications. It is most frequently seen using unfractionated heparin therapy. The increase in frequency of HIT diagnosed in our hospital appears to be associated with a greater awareness of the entity, although detection is often delayed. Platelet count should be monitored in patients on heparin and the presence of antiplatelet antibodies determined if HIT is suspected. Treatment involves both discontinuation of heparin and the use of an alternative anticoagulant such as danaparoid because of the persisting risk of thrombosis.     

Heparin‐induced thrombocytopenia complicating children after the Fontan procedure: Single‐center experience and review of the literature

Heparin‐induced thrombocytopenia (HIT) is a life‐threatening complication of heparin therapy. The risk for HIT correlates with the cumulative dosage of heparin exposure. In Fontan patients, recurrent systemic anticoagulation, traditionally with heparin, is used to alleviate the thrombotic complications that may occur postoperatively when the venous pressure rises and the systemic venous flow into the pulmonary arteries becomes sluggish, putting them at increased risk. As a pressure gradient‐dependent circulation, elevation in systemic venous pressure, most often by venous thrombosis, contributes to circuit failure. Therefore, when HIT complicates patients after the Fontan procedure, it is associated with a high thrombotic morbidity and mortality; thus, a high index of suspicion is mandatory, based on the clinical signs of HIT. It is crucial to intervene early with alternative anticoagulants when HIT is suspected as this step may improve outcome in these patients.     

Frequency of anti-heparin-platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis

Heparin-induced thrombocytopenia (HIT), characterized by the formation of antibodies to a complex of platelet factor 4 (PF4) and heparin, is a well-recognized risk factor for thromboembolic complications. The frequency of antibody development varies among patient populations. Hemodialysis patients have repeated heparin exposure and should be at risk of developing HIT. This might, contribute to the development of vascular access thrombosis. We prospectively evaluated 88 hemodialysis patients for the presence of anti-PF4/heparin antibodies. Eighteen patients (20%) had a prior history of 1 or more prior access thrombosis. One patient (1.14%), without a history of graft thrombosis, tested positive for anti-PF4/heparin antibodies. In our study, the presence of anti-PF4/heparin antibodies was rare and was not increased in patients with a history of vascular access thrombosis.     

Bilateral adrenal hemorrhage associated with heparin induced thrombocytopenia

Heparin induced thrombocytopenia (HIT) is associated with serious and sometimes devastating thrombotic events. We report a case of bilateral adrenal hemorrhage (BAH) associated with HIT after prophylactic use of low molecular weight heparin. The vague presenting symptoms of acute adrenal insufficiency offers a diagnostic challenge, which if delayed may be life threatening. A high index of suspicion for adrenal hemorrhage is required in patients receiving any form of heparin therapy presenting with new onset thrombocytopenia, abdominal pain, and fevers.     

Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a common immunological drug reaction. After exposure to heparin, some patients develop heparin dependent antibodies with no evidence of thrombosis, while others are at risk of thrombocytopenia, thrombosis, limb loss, and death. We conducted a retrospective chart review on all patients serologically positive for HIT by HPIA ELISA in a single tertiary-care hospital, to determine whether patients with malignancy had an increased risk of thrombotic complications. Medical records of 55 patients who tested positive for HIT and met clinical criteria for HIT were analyzed. All patients had been treated with unfractionated heparin. Malignancy was diagnosed in 11 patients, either at surgery or post-mortem examination. A higher rate of venous thrombosis and pulmonary embolism was observed in patients with HIT and malignant disease when compared to patients with no underlying malignancy (odds ratio 13.6, 95% CI 2.9-63.8).     

Heparin induced thrombocytopenia: position paper from the Italian Society on Thrombosis and Haemostasis (SISET)

Heparin induced thrombocytopenia (HIT) is a rare immune mediated adverse drug reaction occurring after exposure to heparin. It is a serious and potentially fatal condition, which may be associated with the development of arterial or venous thrombotic events. Although known for many years, HIT is still often misdiagnosed. Pre- test clinical probability, screening for anti-PF4/heparin antibodies and documentation of their platelet activating capacity are the cornerstones of diagnosis. However, both clinical algorithms and test modalities have limited predictive values and limited diffusion so that the diagnosis and management is challenging in the clinical practice. For this reason, there is an unmet need for novel rational non-anticoagulant therapies based on the pathogenesis of HIT.The present paper reports the position of the Italian Society on Haemostasis and Thrombosis (SISET) in order to increase awareness of HIT among clinicians and other health care professionals and to provide information on the most appropriate management.     

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.     

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.     

Heparin induced thrombocytopenia

This article describes the pathogenesis, diagnostics, treatment and prevention of heparin induced thrombocytopenia (HIT). Although HIT is considered to be a hematological diagnosis, every physician who treats patients with heparin can encounter it in daily practice. It is even more probable that surgeons of any specialisation will meet with HIT patients. A section of them elude diagnostic detection. There are two forms of HIT - HIT I and HIT II. HIT I is caused by a direct pro-aggregation effect of heparin. It has no clinic significance. HIT II is an antidote mediated adverse reaction to heparin. Antidotes will generate only after the exposure to heparin. They are targeted against the platelet factor 4 and they act only at the presence of heparin. They may lead to the aggregation of thrombocytes in the vascular system (there is a decrease in thrombocyte count). This event can be accompanied by a development of venous or arterial thrombosis that can have a rapid and even fatal course. This fact clarifies the importance of HIT II diagnostics. Diagnosis of HIT II is based on recognizing of the typical decrease in thrombocyte count usually 1 day after heparin administration is initiated. Clinical manifestations are more likely in patients with already damaged endothelium. If thrombocyte count decrease is not connected with clinical manifestations, it is the so called isolated HIT II and in patients who display the signs of thrombosis, it is HIT II associated with thrombosis. The goal of this article is apart from implementing the recommendations of the 7th conference of the American Respiratory Society in real life also the exploration of the diagnostic and therapeutic limits (availability) in the Czech Republic.     

Identification, Diagnosis and Treatment of Heparin-induced Thrombocytopenia and Thrombosis: A Registry of Prolonged Heparin Use and Thrombocytopenia among Hospitalized Patients with and without Cardiovascular Disease

Background: Heparin-induced thrombocytopenia (HIT) is estimated to occur in 1–5% of all patients receiving heparin, and 25–50% of such cases develop heparin-induced thrombocytopenia with thrombosis (HITT) A conservative estimate based only on cardiovascular patients suggests that in the United States approximately 100,000 patients develop thrombocytopenia, and 25–50,000 develop HITT annually. Both HIT and HITT are associated with high morbidity and mortality and represent substantial worldwide public health concerns.Registry Design: The objective of the Complication After Thrombocytopenia Caused by Heparin (CATCH) Registry is to identify the incidence of HIT and/or HITT in patients treated with systemic heparin (unfractionated or low molecular weight heparin) in contemporary practice. Additional objectives include to: (1) provide a comprehensive database of patients with suspected HIT or HITT, (2) monitor and define clinical events, including thrombocytopenia, thrombosis, and mortality among patients treated with prolonged (> 96 hours) heparin, (3) describe the incidence and outcomes of HIT and HITT in patients who are treated with heparin and who develop thrombocytopenia in the Coronary Care Unit setting, and (4) document and characterize current diagnostic and therapeutic strategies of suspected HIT. The unblinded registry will record approximately 5,000 patients at 60–80 US hospitals with either prolonged systemic heparin administration or thrombocytopenia and those with suspected HIT or HITT. Enrollment began in the first quarter 2003 and was completed at the end of 2004.Implications: The registry will provide valuable insights to the incidence and consequences of HIT and HITT that will enable improvements in diagnosis and treatment.The CATCH Registry is supported by a grant from Berlex Laboratories, Inc.     

The epitope specificity of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is caused by antibodies (HIT-Abs) that bind to a complex of heparin and platelet factor 4. We investigated the epitope specificity of the HIT-Abs, and found that the HIT-Abs recognized solid-phase immobilized complexes with an optimum ratio of four to eight molecules of PF4 per molecule of heparin. To try to define the epitopes within the PF4 molecule, intact and reduced (linearized) PF4 was tested against 29 different sera from patients with HIT. In addition, eight different peptides that spanned the PF4 molecule were studied for their ability to bind to the HIT-Abs either alone or in the presence of heparin. With the exception of a subpopulation of patient samples (5/29, 17%), we found that reduced PF4 and the peptides were uniformly nonreactive with the HIT-Abs in the presence of heparin. Reduced PF4 and PF4 carboxy-terminal peptides with a minimum size of 19 amino acids were recognized by a minority (5/29) of HIT-Abs samples but only when heparin was present. The specificity of this subgroup of samples from patients with HIT was highly restricted and the loss of one amino acid (peptide reduced in length from 19 to 18 amino acids) rendered the peptides non-reactive. The clinical characteristics of these patients were similar to the other HIT patients.
These studies demonstrate that the majority of HIT-Abs recognize a noncontiguous conformational epitope on the PF4 molecule that is produced when four to eight PF4 molecules are bound together by heparin.     

Gouty tophi in the bone marrow

Heparin induced thrombocytopenia (HIT) remains a rare, but significant, condition related to mortality and morbidity. The incidence has decreased with reduced use of unfractionated heparin, with the exception of cardiac surgery. Due to the high risk of thrombosis, a switch to a non‐heparin anticoagulant is required, until platelet counts normalize. Within the acute setting, argatroban, fondaparinux and direct acting oral anticoagulants (DOACS) are therapeutic options. In patients with HIT‐associated thrombosis or who require long‐term anticoagulation, warfarin remains the preference, but DOACs are attractive alternatives.     

Thrombocytopenia due to acute venous thromboembolism and its role in expanding the differential diagnosis of heparin-induced thrombocytopenia

Thrombocytopenia is an uncommon but serious consequence of heparin administration. Occasionally patients with massive acute venous thromboembolism (VTE) will develop thrombocytopenia. As heparin or some thrombin inhibitor is strongly indicated in acute VTE, it is important to distinguish this event from heparin-induced thrombocytopenia (HIT). Four patients are presented who developed thrombocytopenia so early in their course of VTE and/or therapy with heparin that HIT was considered unlikely. The mean nadir platelet count for these four patients was 60,000/microl occurring at a mean time of 18 hr after the initiation of heparin therapy. Because of strong indications to continue heparin for their acute VTE in the face of a very low likelihood that they did have HIT, heparin was continued with excellent results and resolution of the thrombocytopenia. The literature of this subject is reviewed. Thrombocytopenia following VTE is actually rather common, but it is usually milder than in these four cases. In some cases such as these four, the thrombocytopenia can be sudden and rather severe causing diagnostic confusion with HIT.     

A fatal complication after repair of post-infarction ventricular septal rupture: heparin-induced thrombocytopenia with thrombosis

Heparin-induced thrombocytopenia (HIT) is a rare but potentially devastating and life-threatening complication from using heparin. HIT not only causes thrombocytopenia, but it also carries an increased risk for fatal thrombotic complications. In this report, we describe the case of a patient in whom fatal HIT developed after successful surgical repair of a posterior post-infarction ventricular septal rupture with cardiopulmonary bypass.     

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.     

低分子肝素与普通肝素在冠脉介入治疗中应用的对比研究

目的 比较低分子肝素(LMWH)与普通肝素(UH)在经皮冠脉介入治疗(PCI)中的抗凝效果及安全性.方法 将适合PCI的冠心病患者分为三组:A组,LMWH组,即PCI手术前、手术中、手术后均应用LMWH;B组,UH组,即PCI手术前、手术中、手术后均应用UH;C组,交叉抗凝组,即PCI手术前用LMWH,手术中应用UH,手术后用LMWH.观察30 d内三组临床效果及出血等不良事件.结果 C组反复心绞痛发作患者较A组、B组增多,差异有统计学意义,而心脏性死亡、中风、急性及亚急性支架内血栓形成或急性再次血运重建等差异无统计学意义.C组少量出血患者较A组、B组增多,差异有统计学意义.严重出血,特别是需要输血的患者三组间差异无统计学意义.导管室使用LMWH的A组患者出现2例导管内血栓形成.结论 LMWH和UH都各有优缺点.LMWH无需监测活化凝血时间,无需静脉持续输注,而UH用药期间需要监测APTT,有时可引起血小板减少症(HIT).应用LMWH的个别患者会出现导管内血栓形成,交叉抗凝临床效果,如反复心绞痛发作较高,在出血不良事件方面也有增加趋势.