Complications Of Heparin-induced Thrombocytopenia Research Articles

Heparin-induced thrombocytopenia: a rare presentation with skin necrosis.

Heparin-induced thrombocytopenia is the most clinically relevant non-hemorrhagic complication of heparin and is characterized by the presence of anti-platelet factor 4 (PF4)/heparinimmunoglobulin G (IgG) antibodies. The circulating PF4/heparinIgG immune complex binds to platelets via their FcyIIa receptors, activating them and promoting their aggregation, with consequent platelet consumption, thrombocytopenia, and thrombotic phenomena. Despite thrombocytopenia, this condition is not typically associated with bleeding complications. Instead, thrombosis is the most serious complication of heparin-induced thrombocytopenia, contributing to increased morbidity and mortality. Thrombotic events can be venous and arterial, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and thrombotic stroke. Skin necrosis at the site of heparin injections is a rare but well-described manifestation of heparin-induced thrombocytopenia. We report a case of heparin-induced thrombocytopenia presented as skin necrosis, highlighting the importance of recognizing this potentially fatal condition and the need for an immediate cessation of all sources of heparin and its replacement by other anticoagulants.

Platelet Factor 4 Binds to Released Von Willebrand Factor Strands from Injured Endothelium and Forms a Prothrombotic HIT Antigenic Complex

Heparin-induced thrombocytopenia (HIT) is driven by the binding of pathogenic HIT antibodies to platelet factor 4 (PF4) complexed to heparin. We, and others, have shown that PF4 bound to a variety of other polyanionic molecules, like surface glycosaminoglycans, also form HIT antigenic complexes. This is likely due to the formation of high molecular weight aggregates by the PF4. While studying the pathogenesis of HIT in a microfluidic system lined with human umbilical endothelial cells (HUVEC), we noted that PF4 did not bind diffusely to the HUVECs after a hematoporphyrin-induced photochemical injury as one would expect if binding were to the injured surface GAGs, but rather in a linear pattern described previously for von Willebrand Factor (vWF) under flow. We confirmed this by concurrent staining using PF4 and vWF-specific labeled antibodies. We also demonstrated that the HIT-like monoclonal antibody KKO, as well as IgG isolated from patients with likely HIT as determined by clinical assessment and ELISA positivity and positive serotonin release assay, bound to these PF4-vWF complexes. The HIT-like complexes were not uniformly distributed along the vWF, but occurred in a periodic fashion along thicker vWF strands. This suggested that the complexes were composed of multiple molecules of PF4 and vWF forming cross-chained high molecular weight aggregates that induce or enhance binding of HIT antibodies as previously reported for PF4/heparin in solution. We then wanted to identify the potential for therapeutics to intervene with PF4-vWF-KKO complex formation or stability. We tested this by introducing heparin; 2-0,3-0 desulfated heparin (ODSH); ADAMTS13 or n-acetylcysteine into channels post-complex formation. All interventions at therapeutically relevant concentrations were able to significantly remove or disrupt complex formation. When whole human blood + PF4 + KKO were flowed through channels lined with injured endothelium, large platelet aggregates developed within 10 mins along the extended strands of vWF. Significantly fewer platelet aggregates formed in the absence of PF4 or with KKO alone or PF4 plus an isotype control TRA. After 1 hour of flow, aggregates in the PF4 + KKO channels had grown significantly, but had largely disappeared in the other settings. Furthermore, by adding the FcgammaRIIA blocking antibody, IV.3, platelet binding could be reduced to background levels. These studies identify large vWF polymeric strands as a binding site for PF4 and a HIT antigen target. The Fc portions of the bound HIT antibody then contribute to platelet binding to the vWF. We are presently examining whether PF4-vWF-KKO aggregates contribute to thrombotic complications in HIT and defining the vWF domain(s) involved as these targets offer a potential novel intervention target in HIT. [Display omitted] DisclosuresCines:Amgen: Consultancy; Ionic: Consultancy; Juno: Consultancy; Astellas: Consultancy; T2 Biosystems: Research Funding; Rigel: Consultancy; Syntimmune: Research Funding.

Cost Reduction with Enoxaparin Vs. Heparin for Prophylactic and Therapeutic Use: A Retrospective Analysis in a Community Hospital Setting

BackgroundMost hospitals still use Unfractionated Heparin as the primary agent for Venous Thromboembolism (VTE) prophylaxis and therapy in the inpatient setting due to ease of use and insignificant cost. However, the incidence of Heparin-Induced Thrombocytopenia (HIT) has led to questions about other options for prophylaxis and therapeutic use in the hospital, with more recent data showing that Enoxaparin is safer in terms of incidence of HIT. This study examines the cost-effectiveness of Enoxaparin compared to Heparin for prophylactic and therapeutic usage in a community hospital.MethodsWe conducted a retrospective chart review of patients that had HIT panels ordered at the Inspira Health Network, Vineland campus (an approximately 262 bed community hospital located in southern New Jersey that services a population of approximately 61,050) from the period of April 1, 2015 through December 31, 2016. The starting date represents the time from which Enoxaparin became the primary alternative anticoagulant available at this hospital. Records of the total usage and cost of Heparin and Enoxaparin for the specified time period were collected from the hospital pharmacy database for evaluation, as were records of Heparin-Induced Thrombocytopenia (HIT) panels. The information was analyzed to establish whether or not a significant proportion of HIT panels was ordered for patients on Heparin versus Enoxaparin. Annual cost-savings for the hospital were extrapolated by using the comparative incidences of HIT panels and associated costs, including increased inpatient length of stay, hematology consultation, use of an alternative anticoagulant, and complications of Heparin-Induced Thrombocytopenia and Thrombosis (HITT). These variables were multiplied by the incidence rate for each specified drug and usage in order to determine the daily cost for each drug.ResultsThe overall use of Enoxaparin did not result in a significant decrease in the ordering of HIT panels in the hospital, with a relative rate ratio of 0.948 (95% Confidence Interval: 0.336, 2.21). However, when the data was stratified to reflect prophylactic and therapeutic usages of Enoxaparin and Heparin, there was a marked difference in the use of therapeutic Intravenous (IV) Heparin as opposed to therapeutic Enoxaparin. The rate ratio of HIT panel ordering when using therapeutic Enoxaparin instead of IV Heparin was 0.118 (0.006, 0.625). These numbers were used to extrapolate the total daily cost of Enoxaparin and IV Heparin; therapeutic Enoxaparin cost $30.62, while IV Heparin cost $161.94. IV Heparin use was associated with a higher incidence rate of HIT panel orders, and subsequently a higher daily cost due to the likelihood of increased length of stay, use of alternative anticoagulation, request for expert consultation, and complication of HITT.ConclusionEnoxaparin is associated with a significant cost-saving when used for therapy for patients with venous thromboembolism, when compared to IV Heparin. DisclosuresNo relevant conflicts of interest to declare.

Bivalirudin and ECLS

Bivalirudin and ECLS

Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population-based study

Heparin-induced thrombocytopenia can be a life-threatening and limb-threatening complication of heparin therapy. Incidence and complication rates of this condition have been extrapolated from studies with modest sample sizes, and despite the availability of therapeutic interventions the outcomes of heparin-induced thrombocytopenia are not well understood. We aimed to estimate disease burden, complication rates, and costs of heparin-induced thrombocytopenia in the USA. In this population-based study we analysed data from 2009 to 2013 from the Nationwide (National) Inpatient Sample (NIS), a large, all-payer inpatient health-care database in the USA. To validate the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for heparin-induced thrombocytopenia (289.84), we defined the sensitivity and specificity of this code using patient data from 2013 from a local hospital (Froedtert Memorial Lutheran Hospital, Milwaukee, WI, USA). The primary outcomes assessed were the incidence of hospital discharges with codes for heparin-induced thrombocytopenia and of discharges for heparin-induced thrombocytopenia associated with cardiopulmonary bypass, haemodialysis, hip or knee arthroplasty, trauma or injury (or both), and gingival or periodontal disease (or both). We also assessed the incidence of thrombosis, bleeding, limb or digit amputation, mortality, length of hospital stay, and associated hospital charges. Between 2009 and 2013, 97 566 discharges from the NIS assigned the ICD-9-CM code for heparin-induced thrombocytopenia, and 149 911 247 discharges coded for non-heparin-induced thrombocytopenia, were analysed. Overall, heparin-induced thrombocytopenia was identified in 97 566 (0·065%; SE 0·0012) of 150 008 813 discharges, corresponding to approximately one in 1500 hospital admissions. Patients undergoing cardiopulmonary bypass had the highest rates of heparin-induced thrombocytopenia (7702 [0·63%; SE 0·03] of 1 230 362), followed by those undergoing haemodialysis (23 012 [0·47%; 0·01] of 4 908 100), those with gingival or periodontal disease, or both (106 [0·12%; 0·03] of 88 621), and those with trauma or injury, or both (541 [0·09%; 0·01] of 602 944); patients with hip (845 [0·04%; 0·004] of 1 943 353) and knee (676 [0·02%; 0·002] of 3 022 602) arthroplasty had the lowest rates of heparin-induced thrombocytopenia. Thrombosis (29 079 [29·8%; SE 0·4] of 97 566) and bleeding (6044 [6·2%; 0·2] of 97 566) were common complications in heparin-induced thrombocytopenia, and 1446 (23·9%; 1·2) of 6044 patients with heparin-induced thrombocytopenia who had haemorrhage died. 742 (0·76%; SE 0·06) of 97 566 patients with heparin-induced thrombocytopenia discharges underwent amputations compared with 173 043 (0·12%; 0·001) of 149 911 247 with non-heparin-induced thrombocytopenia discharges (adjusted odds ratio 5·095 [95% CI 4·309-6·023]; p<0·0001). Overall, in-hospital mortality was 9842 (10·1%; SE 0·2) of 97 508 in discharge summaries coded for heparin-induced thrombocytopenia compared with 3 206 700 (2·1%; 0·01) of 149 811 891 in discharges for non-heparin-induced thrombocytopenia (adjusted odds ratio 4·075 [95% CI 3·846-4·317]; p<0·0001). The median length of stay among live discharges was 8·9 days (IQR 4·6-17·1) and total hospital charges were US$83 072 (IQR 37 240-188 419) for heparin-induced thrombocytopenia discharges compared with 2·6 days (1·4-4·8) and $21 360 (11 426-41 917) for non-heparin-induced thrombocytopenia discharges (p<0·0001 for both). 333 discharges from a local hospital were analysed to assess the diagnostic sensitivity and specificity of the heparin-induced thrombocytopenia ICD-9-CM code; sensitivity was 90·9% (95% CI 57·1-99·5) and specificity was 94·4% (91·1-96·6). Complication rates for heparin-induced thrombocytopenia remain high and more effective preventive and treatment interventions are needed. None.

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia.

Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications. Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P=.026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P=.046) were independently associated with the occurrence of thromboembolic events. Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.

HIT: Endotheliale Antigenansammlung führt zu thrombotischen Komplikationen

Hayes V et al. Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest 2017; 127: 1090 – 1098

Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder initiated by antibodies against complexes between human platelet factor 4 (hPF4) and heparin. A better understanding of the events that initiate the prothrombotic state may improve approaches to antithrombotic management. Here, we visualized thrombus formation in an in vivo murine model and an endothelialized microfluidic system that simulate the pathogenesis of HIT. hPF4 released from platelets predominantly bound to peri-injury endothelium and formed HIT antigenic complexes that were dissociated by heparin. In mice expressing both hPF4+ and human platelet IgG Fc receptor IIA (FcγRIIA), infusion of the HIT-like monoclonal antibody KKO increased fibrin and platelet deposition at sites of injury, followed immediately by antigen formation on proximate endothelial cells. After a few minutes, HIT antigen was detected within the thrombus itself at the interface between the platelet core and the surrounding shell. We observed similar results in the humanized, endothelialized microfluidic system. hPF4 and KKO selectively bound to photochemically injured endothelium at sites where surface glycocalyx was reduced. These studies support the concept that the perithrombus endothelium is the predominant site of HIT antigen assembly. This suggests that disrupting antigen formation along the endothelium or protecting the endothelium may provide a therapeutic opportunity to prevent thrombotic complications of HIT, while sparing systemic hemostatic pathways.

Use of "Big Data" to Define Disease Burden, Complication Rates and Healthcare Costs in Patients with Heparin Induced Thrombocytopenia (HIT)

Background: HIT is a life-threatening complication that occurs in a subset of heparin-treated patients. To our knowledge, a large population-based estimate of HIT disease burden, complication rates and economic cost has not been reported previously. Based on small studies, wide variations in the incidence of HIT has been observed in some patient populations. For example, among patients undergoing knee and hip arthroplasties, rates of HIT were reported to be less than 0.5% in some studies, but others, including a recent study suggest a much higher risk (Blood. 2016 25;127(8):1036-43). Similarly, rates of HIT reported in patients undergoing hemodialysis are highly variable, with some reporting an incidence as high as 3.9% (AJKD 1996; 28(1):82-5). To better address these discrepant findings and to benchmark disease burden and complication rates, we performed an analysis of the Nationwide Inpatient Sample (NIS).Methods: The NIS is a large inpatient healthcare database in the US. Unweighted, it contains data from >7 million hospital stays each year and weighted, it estimates >35 million hospitalizations. Full-year HIT data was available for 2009-2013, and this study period was queried to identify patients >18 years of age with a discharge diagnosis of HIT. Survey weighted domain analysis was conducted to estimate the incidence of HIT. HIT rates were also estimated in patients who underwent specific procedures (coronary artery bypass grafting [CABG, a known "high" risk setting for HIT development], hip and knee replacement, and dialysis. Incidence of thrombosis, bleeding, in-hospital mortality, and length and cost of hospitalization were also calculated. Outcomes in HIT patients were compared to those without HIT using ANOVA and Chi-squared test for continuous and categorical variables, respectively.Results: The annual HIT burden averaged ~22,000 annually over the study period with no change over that time frame (Fig 1A, p=0.1). The incidence of HIT was highest in patients undergoing CABG at 0.51%, followed closely by dialysis at 0.43% (Fig 1B). HIT rates were low in knee and hip arthroplasty at 0.02% each, even lower than the 0.07% overall rate of HIT for all patients (Fig 1B). The incidence of thrombosis was high in HIT (Fig 1B) with venous thrombosis being the most common type (17.9%), followed by pulmonary embolism (8.3%) and arterial thrombosis (2.3%) (Fig 1C), consistent with the relative incidence reported in the published literature. Rates of major bleeding in HIT is estimated to be 10-20% with direct thrombin inhibitor therapy. Our analysis yielded much lower major bleeding rates of 2.5% and 0.7% for gastrointestinal and intracranial bleeding, respectively (Fig 1D). In-hospital mortality in HIT was 9.5%, almost five times higher than in patients without HIT (Fig 1E). Notably, the length of hospitalization and cost of care were approximately 3x higher in patients with HIT compared to those without (Fig 1E & 1F).Conclusions: Surprisingly, HIT disease burden was large and unchanged during the study period averaging >20,000 cases annually. A recent study suggests that an "avoid unfractionated heparin" protocol can significantly decrease the incidence of HIT (Blood. 2016; 127(16):1954-9). Large scale interventions of this type may be needed to tackle this common disorder. Our data also suggests that rate of HIT in knee and hip arthroplasty are low, while in patients undergoing dialysis it is more common than generally believed. We found that thrombosis, a serious complication of HIT is a very common finding, but major bleeding rates were low. HIT also resulted in a disproportionate utilization of resources with costs per patient of ~ $150,000. There are important limitations with use of data from the NIS, where missing/miscoded information are concerns. Additionally, the NIS has no information on drug use. For example, HIT incidence in CABG includes all patients who underwent the procedure whether or not heparin exposure occurred (both off- and on-pump). In addition, rates of thrombosis may be overestimates as heparin may have been used to treat thrombosis in some patients and caused HIT with isolated thrombocytopenia. Despite these shortcomings, in addition to disease benchmarking, this information may aid healthcare providers and public health professionals plan and implement broad preventative and therapeutic interventions to tackle this dangerous yet common disease. [Display omitted] DisclosuresPadmanabhan:Bloodcenter of Wisconsin: Patents & Royalties: A patent application has been filed on a Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591; Fenwal (Fresenius Kabi): Research Funding; Terumo BCT: Consultancy, Honoraria; Mallinckrodt Pharmaceuticals: Consultancy, Honoraria; LEK Consulting: Consultancy, Honoraria; Schlesinger & Associates: Consultancy, Honoraria.

Abstract 567: A Successful Use of Tissue Plasminogen Activator and Argatroban for Acute Therapy of a Submassive Pulmonary Embolism Caused by Heparin-Induced Thrombocytopenia

The field of anticoagulation has become a highly relevant and expanding division of medicine. Clinicians must maintain an adequate knowledge of the indications, risks, and benefits of each particular anticoagulant before utilizing them in patient care. Despite great advancements in anticoagulate therapies, areas of uncertainty exist when applying combined use of anticoagulants. This vignette illustrates a unique circumstance of initial therapy combining argatroban with tissue plasminogen activator (tPA) and subsequent transition to warfarin in the management of submassive pulmonary embolism (PE) caused by heparin-induced thrombocytopenia (HIT). There are currently no other published cases or guidelines that have demonstrated this treatment strategy. We present the case of a 56-year-old African American female who was started on argatroban therapy for submassive bilateral PE secondary to HIT. She required tPA after becoming progressively unstable. The argatroban drip was continued without any hemorrhagic complications. This combination of therapy led to her stabilization, and she was ultimately safely transitioned to warfarin therapy for long term maintenance anticoagulation. Argatroban is effective in the prevention and treatment of life-threatening complications of HIT. Very little research has been conducted in patients receiving tPA followed by anticoagulation therapy. This case highlights the successful therapy with combined use of tPA and argatroban followed by warfarin transition in the treatment of submassive PE caused by HIT. We find that tPA was safe and effective when the initial argatroban failed to stabilize our patient. The continued use of argatroban infusion after tPA did not cause any hemorrhagic complications. Furthermore, the overlap use of warfarin with argatroban until an INR greater than 4 was achieved for maintenance therapy did not contribute to any hemorrhagic complications. We conclude that the combination of tPA and argatroban is effective in the acute management of hemodynamically unstable PE caused by HIT without significant hemorrhagic complications.

Zerebrovaskuläre Komplikationen der Heparininduzierten Thrombozytopenie Typ II (HIT-II)

Immunologically mediated heparin-induced thrombocytopenia (HIT) is a thrombotic disease caused by antibodies occurring after heparin exposure. Thrombocytopenia occurs within a few days after heparin exposure, about half of HIT-patients develop venous or arterial thrombotic complications. Neurological complications of HIT are mainly ischaemic stroke and sinus vein thrombosis. To ensure the primary clinical diagnosis functional and immunological assays for antibody detection are available. The probability for the occurrence of HIT depends on the nature of heparin employed (LMWH vs. UFH) and individual patient characteristics such as gender and primary disease (medical vs. surgical patients). In the case of suspected HIT heparin administration should be discontinued immediately and replaced by an alternative anticoagulation to prevent the expansion or development of further thrombotic complications. Herein we report a case of a patient suffering from HIT-associated embolic cerebral ischaemic stroke.

Heparin-induced thrombocytopenia: The role of platelets genetic polymorphisms

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy, characterized by thrombocytopenia and an increased risk for thrombotic complications secondary to the formation of IgG antibodies (Ab), recognizing a complex of heparin (H) and PF4.Using the 4T clinical score for HIT and the presence of heparin-associated Ab assayed by enzyme-linked immunosorbent assay and heparin-induced platelet aggregation, we define the phenotype of three groups of patients: 51 H/PF4/Ab patients with antibodies and without thrombocytopenia; 50 patients with thrombocytopenia (HIT) and 53 patients with thrombosis (HITT). In these patients we studied four polymorphisms: FcγRIIA-H131R, GpIIb/IIIa-HP-1, PECAM1-L125V (in linkage-disequilibrium with S563N and R670G), and FcγRIIIA-F158V, to understand if these variations may influence the different phenotypes of the patients. There were no difference in genotype or allele frequencies between controls and the three groups of patients. Afterward, we created a genotype score for multiple risk alleles for thrombosis considering as risk genotype FcγRIIA R/R131, HPA-1a/b, and PECAM1-V/V125. These polymorphisms were overrepresented in HITT patients, ascertained by a permutation test (10 000 replicates) p = 0.0198 for the two-single-nucleotide polymorphism (SNP) model and p = 0.0119 for the three-SNP model. The calculated odds ratio for thrombosis was 4.01[CI: 2.30–6.96] in the case of the presence of two at risk genotypes and 8.002 [CI: 4.59–13.93] if all the three at risk genotypes were present. In conclusion these polymorphisms could contribute to the risk of thrombotic complications in HIT.

Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia

AbstractPatients with heparin-induced thrombocytopenia (HIT) remain at risk for recurrent thromboembolic complications despite improvements in management. HIT is caused by antibodies that preferentially recognize ultralarge complexes (ULCs) of heparin and platelet factor 4 (PF4) tetramers. We demonstrated previously that a variant PF4K50E forms dimers but does not tetramerize or form ULCs. Here, we identified small molecules predicted to bind PF4 near the dimer-dimer interface and that interfere with PF4 tetramerization. Screening a library of small molecules in silico for binding at this site, we identified 4 compounds that inhibited tetramerization at micromolar concentrations, designated PF4 antagonists (PF4As). PF4As also inhibited formation of pathogenic ULCs, and 3 of these PF4As promoted the breakdown of preformed ULCs. To characterize the ability of PF4As to inhibit cellular activation, we developed a robust and reproducible assay that measures cellular activation by HIT antibodies via FcγRIIA using DT40 cells. PF4As inhibit FcγRIIA-dependent activation of DT40 cells by HIT antibodies as well as platelet activation, as measured by serotonin release. PF4As provide new tools to probe the pathophysiology of HIT. They also may provide insight into the development of novel, disease-specific therapeutics for the treatment of thromboembolic complications in HIT.

Heparin-induced thrombocytopenia

In the last 7 decades heparin has remained the most commonly used anticoagulant. Its use is increasing, mainly due to the increase in the number of vascular interventions and aging population. The most feared complication of heparin use is heparin-induced thrombocytopenia (HIT). HIT is a clinicopathologic hypercoagulable, procoagulant prothrombotic condition in patients on heparin therapy, and decrease in platelet count by 50% or to less than 100,000, from 5 to 14 days of therapy. This prothrombotic hypercoagulable state in HIT patient is due to the combined effect of various factors, such as platelet activation, mainly the formation of PF4/heparin/IgG complex, stimulation of the intrinsic factor, and loss of anticoagulant effect of heparin. Diagnosis of HIT is done by clinical condition, heparin use, and timing of thrombocytopenia, and it is confirmed by either serotonin release assay or ELISA assay. Complications of HIT are venous/arterial thrombosis, skin gangrene, and acute platelet activation syndrome. Stopping heparin is the basic initial treatment, and Direct Thrombin Inhibitors (DTI) are medication of choice in these patients. A few routine but essential procedures performed by using heparin are hemodialysis, Percutaneous Coronary Intervention, and Cardiopulmonary Bypass; but it cannot be used if a patient develops HIT. HIT patients with unstable angina, thromboembolism, or indwelling devices, such as valve replacement or intraaortic balloon pump, will require alternative anticoagulation therapy. HIT can be prevented significantly by keeping heparin therapy shorter, avoiding bovine heparin, using low-molecular weight heparin, and stopping heparin use for flush and heparin lock.

Characterization of Receptors Involved in Heparin Antibody Complex Mediated Induction of Tissue Factor Expression in Monocytes.

Abstract 224▪▪This icon denotes an abstract that is clinically relevant. Introduction:Heparin-induced thrombocytopenia (HIT) is a major cause of drug-induced thrombocytopenia and occurs in 1–5% of individuals exposed to heparin. Paradoxically, 30–50% of individuals with HIT develop thrombosis. The mechanism of thrombosis in HIT is poorly understood. We recently reported that HIT antibody complexes induce tissue factor (TF) expression in monocytes and result in the release of TF-positive microparticles (MPs). The mechanism by which HIT antibody complexes induce monocyte TF has not been established. The objective of this study is to characterize the receptors involved in HIT antibody complex mediated induction of TF expression in monocytes. As HIT antibody complex mediated activation of platelets is dependent on the FcgRIIA receptor, we evaluated the role of the FcgRII receptor in the induction of monocyte TF by HIT antibody complexes. We also evaluated the role of toll like receptor-4 (TLR4) and the platelet factor 4 (PF4) chemokine receptor CXCR3 in this process. Methods:The combination of heparin, PF4 and the murine monoclonal PF4/heparin-specific antibody KKO has been shown to cause activation of platelets and monocytes, and mimic HIT in vitro. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were pre-incubated for 30 min at 37°C with an inhibitory antibody to the FcgRII receptor (IV.3); anti-CXCR2, 3, or 4 antibodies; anti-TLR4 antibody; or mouse-IgG (mIgG) control. Following pre-incubation with antibodies for 30 minutes, heparin (1U/mL), PF4 (10μg/mL), and KKO (100μg/mL) – together referred to as the HIT antibody complex – were added. Heat-aggregated mIgG and LPS were used as positive controls for the FcgRII and TLR4 receptors, respectively. Following a 6-hour incubation, PBMCs were pelleted by centrifugation and MPs were isolated from the supernatant. The procoagulant activity (PCA) of PBMCs and MPs was measured using clotting assays performed in the presence of the anti-TF antibody HTF-1 or control antibody. TF dependent PCA was calculated by reference to a standard curve generated using relipidated recombinant TF. Results:Incubation of PBMCs with heat aggregated mIgG for 6 hours resulted in significant induction of cellular TF (345 +/− 36 pg/106 cells) which was blocked by 30 min pre-incubation with the antibody IV.3 (146 +/− 17 pg/106 cells, N=3, p<.003). However, pre-incubation with IV.3 had no significant effect on TF induction (140 +/− 5 pg/106 cells) associated with the HIT antibody complex when compared to control mIgG (110 +/− 18 pg/106 cells, N=3, p<0.11). PBMCs incubated with HIT antibody complexes in the presence of a TLR-4 antibody showed less TF activity (52 +/− 4 pg/106 cells) compared to control mIgG (80 +/− 10 pg/106 cells N=3, p<0.025). A similar, partial inhibition of TF activity was also observed in PBMCs incubated with LPS in the presence of an anti-TLR4 antibody (121 +/− 3 pg/106) compared with a control antibody (89 +/− 2 pg/106, N=3, p<.0013). Experiments with a more effective inhibitor of TLR4 are in progress. PBMCs incubated with the HIT antibody complexes in the presence of an anti-CXCR3 antibody showed less TF activity (36 +/− 7 pg/mL) compared to control mIgG (118 +/− 15 pg/106 cells, N=3, p<0.004). Antibodies against CXCR2 and CXCR4 did not have any significant effect on TF induction. Measurement of MP TF activity mirrored the results described above. Using flow cytometry and an anti-CXCR3 antibody labeled with FITC, we found that 5% (± 0.5%) of monocytes expressed CXCR3 (N=3), which is consistent with the reported literature. Conclusions:These data suggest that induction of TF in monocytes by HIT antibody complexes is not mediated by the FcgRII receptor. This is contrary to the mechanism of platelet activation by these antibody complexes, which is an FcgRIIa dependent process. We found that TLR4 plays a role in HIT antibody complex mediated induction of TF in monocytes and blocking TLR4 led to a 30% decrease in TF activity. On the other hand, CXCR3 appeared to play a more significant role with blockade of CXCR3 leading to a 70% decrease in TF activity. Further characterization of the role of these receptors in HIT antibody complex mediated induction of TF expression in monocytes is required. We speculate that the extent of CXCR3 and TLR4 expression in monocytes may influence the susceptibility to developing thrombotic complications in HIT. Disclosures:No relevant conflicts of interest to declare.

Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban

We retrospectively evaluated dosing patterns and 37-day outcomes in argatroban-treated African American (n = 52), Asian (n = 13), and Hispanic (n = 14) patients with heparin-induced thrombocytopenia (HIT). The Asians required a lesser median dose (1.0 microg/kg/min) than the other groups (1.9 microg/kg/min, each) to achieve comparable activated partial thromboplastin times (medians: 61-69 s). Durations of therapy were similar (medians: 4.0-5.5 days). New thrombosis occurred in 11 (21%) African Americans, 1 (8%) Asian, and 1 (7%) Hispanic; of these 13 patients, 9 (69%) had baseline HIT-related thrombosis. Amputation occurred in 6 (12%) African Americans and 3 (21%) Hispanics; of these nine patients, 6 (67%) had diabetes. One (2%) African American and 1 (7%) Hispanic died from thrombosis. The composite of death due to thrombosis, amputation due to ischemic complications of HIT, or new thrombosis occurred in 14 (27%) African Americans, 1 (8%) Asian, and 4 (29%) Hispanics. Two (4%) African Americans and none others (0%) had major bleeding. These findings suggest that despite argatroban anticoagulation, African Americans and Hispanics may have worse outcomes in HIT than Asians. In minority patients with adverse HIT outcomes, baseline HIT-related thrombosis or diabetes is often present.

Dosing Patterns and Outcomes in African American, Asian, and Hispanic Patients with Heparin-Induced Thrombocytopenia Treated with Argatroban.

Nonwhites, as compared with whites, have increased risk for thromboembolic complications in heparin-induced thrombocytopenia (HIT) (Lewis et al, Chest 2006). To better characterize the risk in nonwhite patients, we retrospectively evaluated dosing patterns and clinical outcomes in African American, Asian, and Hispanic patients administered argatroban therapy for clinically diagnosed HIT. Patients were from previously reported, multicenter, prospective studies of argatroban therapy (2 mcg/kg/min, adjusted to achieve aPTTs 1.5–3 times baseline) in HIT (defined as an otherwise unexplained platelet count <100 x109/L, or 50% reduction in platelet count, following heparin therapy). For African American (n=52), Asian (n=13), and Hispanic (n=14) patient groups, baseline characteristics, therapeutic argatroban dose and duration, aPTTs during therapy, and clinical outcomes (death, including death due to thrombosis; amputation, including amputation secondary to ischemic complications of HIT; new thrombosis; and major bleeding within a 37-day period) were summarized and compared. Among groups, no differences were detected in demographic or baseline features, excepting weight (median values: 62, 77 and 85 kg, respectively, for Asians, African Americans, and Hispanics). Median baseline platelet counts were 45–71 x109/L, and approximately 50% of patients in each group had HIT-related thrombosis before argatroban was initiated. Each group received a similar duration of argatroban therapy (4.0–5.5 days), yet Asians needed a lesser dose (1.0 mcg/kg/ min, versus 1.9 mcg/kg/min in other groups) to achieve comparable aPTTs (61–69 s). New thrombosis occurred most often in African Americans (21%, versus 7–8% in other groups) and when baseline HIT-related thrombosis was present (9/13 events, 69%). Amputation occurred most often in Hispanics (21%, versus 0–12% in other groups) and when diabetes was present (6/9 events, 67%). Mortality was 21–31%, and mortality due to thrombosis was 0–7%. Asians had the lowest frequency of any thrombotic-related outcome (composite of death due to thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis: 8%, versus 27–29% in other groups). Two patients, each African American, experienced major bleeding (gastrointestinal), for an overall major bleeding rate of 2.5% and by-group rates of 0–4%. Although limited by small group sizes, our study is among the first to characterize outcomes in minority patients administered nonheparin therapy for HIT. Our findings suggest that, despite achieving comparable levels of anticoagulation with argatroban, African Americans and Hispanics are higher risk patients than Asians for poor outcomes in HIT and also that in minority patients with adverse outcomes, baseline HIT-related thrombosis or diabetes is often present.

Heparin-induced thrombocytopenia (HIT) causing pulmonary emboli during coronary intervention

Thrombotic complications of heparin-induced thrombocytopenia (HIT) can be devastating if not recognized and treated promptly. We describe an unusual case of rapid-onset HIT resulting in massive-bilateral pulmonary emboli in a 70 year-old man who developed chest pain during elective percutaneous coronary intervention (PCI). The diagnosis was made the following day after persistent chest pain and laboratory work demonstrating a new thrombocytopenia, a mildly elevated troponin, and positive DIC panel led to confirmatory imaging tests. HIT-related thrombosis should be considered in the differential diagnosis of chest pain in patients undergoing PCI.

Arterial and Venous Complications of Heparin-Induced Thrombocytopenia in Burn Patients

Arterial and Venous Complications of Heparin-Induced Thrombocytopenia in Burn Patients

Argatroban Therapy for Heparin-Induced Thrombocytopenia in Acutely Ill Patients

Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated adverse reaction to heparin therapy. To evaluate clinical outcomes and effects of argatroban therapy in acutely ill HIT patients. Retrospective analysis. Hospital in-patient. Acutely ill patients with clinically diagnosed HIT from previous multicenter, historically controlled studies of argatroban therapy in HIT. Argatroban, adjusted to maintain activated partial thromboplastin times 1.5 to 3 times baseline, or historical control therapy (ie, no direct thrombin inhibition). We identified 488 patients who received argatroban (N = 390; mean dose of 1.9 microg/kg/min for a mean 6 days) or historical control therapy (N = 98) for HIT. The primary all-cause composite endpoint of death, amputation, or new thrombosis within 37 days occurred in 133 (34.1%) argatroban-treated patients and 38 (38.8%) controls (P = .41). Argatroban, versus control, significantly reduced the primary thrombosis-related composite endpoint of death because of thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis (17.7% vs 30.6%, P = .007). Significant reductions also occurred in new thrombosis and death because of thrombosis. Major bleeding was similar between groups (7.7% vs 8.2%; P = .84). Adverse outcomes were more likely to occur in patients who were initially diagnosed with HIT and thrombosis, had undergone cardiac surgery, were not white, or had more severe thrombocytopenia. In acutely ill HIT patients, argatroban, versus historical control, provides effective antithrombotic therapy without increasing major bleeding. Patients with more severe thrombocytopenia or HIT-related thrombosis on HIT diagnosis have a poorer prognosis, emphasizing the importance of prompt recognition/ treatment of HIT in acutely ill patients.