Direct Thrombin Inhibitor Therapy Research Articles

Autoimmune Heparin-Induced Thrombocytopenia.

Autoimmune thrombocytopenia (aHIT) is a severe subtype of heparin-induced thrombocytopenia (HIT) with atypical clinical features caused by highly pathological IgG antibodies ("aHIT antibodies") that activate platelets even in the absence of heparin. The clinical features of aHIT include: the onset or worsening of thrombocytopenia despite stopping heparin ("delayed-onset HIT"), thrombocytopenia persistence despite stopping heparin ("persisting" or "refractory HIT"), or triggered by small amounts of heparin (heparin "flush" HIT), most cases of fondaparinux-induced HIT, and patients with unusually severe HIT (e.g., multi-site or microvascular thrombosis, overt disseminated intravascular coagulation [DIC]). Special treatment approaches are required. For example, unlike classic HIT, heparin cessation does not result in de-escalation of antibody-induced hemostasis activation, and thus high-dose intravenous immunoglobulin (IVIG) may be indicated to interrupt aHIT-induced platelet activation; therapeutic plasma exchange may be required if high-dose IVIG is ineffective. Also, aHIT patients are at risk for treatment failure with (activated partial thromboplastin time [APTT]-adjusted) direct thrombin inhibitor (DTI) therapy (argatroban, bivalirudin), either because of APTT confounding (where aHIT-associated DIC and resulting APTT prolongation lead to systematic underdosing/interruption of DTI therapy) or because DTI inhibits thrombin-induced protein C activation. Most HIT laboratories do not test for aHIT antibodies, contributing to aHIT under-recognition.

Quality improvement approaches to heparin-induced thrombocytopenia: a scoping review

BackgroundHeparin-induced thrombocytopenia (HIT) is a relatively uncommon condition characterized by 2 exceedingly common phenomena in hospitalized patients: thrombocytopenia and heparin exposure. Consequently, HIT is frequently overdiagnosed and inappropriately treated. These issues are the focus of many quality improvement (QI) initiatives. ObjectivesIn this scoping review, we identified and characterized all published QI studies on improving the diagnosis and management of HIT. MethodsWe conducted a systematic literature search through April 2022 for studies reporting on QI interventions regarding the diagnosis, treatment, and/or prevention of HIT. ResultsThirty studies were included in the final review. Studies were separated into 5 groups based on the focus of the interventions: increasing HIT recognition, reducing HIT incidence, reducing HIT overdiagnosis, promoting safer HIT management, and creating HIT task forces. Nine studies focused on the implementation of 4Ts score calculator into electronic medical record orders for HIT testing, while only 1 evaluated the impact of reducing unfractionated heparin use in favor of low-molecular-weight heparin. Six studies focused on the implementation of direct thrombin inhibitor management protocols, while none evaluated the use of alternative anticoagulants in HIT management. ConclusionThe bulk of published HIT QI research focused on reducing overdiagnosis and promoting safer direct thrombin inhibitor therapy, while minimal attention has been devoted to HIT prevention and the use of evidence-based alternative HIT therapies.

A Rare Case of Acute Myocardial Infarction Due to Coronary Artery Dissection and Heparin-Induced Thrombocytopenia

Background: Although both coronary artery dissection and heparin-induced thrombocytopenia may provoke myocardial infarction, it is extremely rare for both conditions to develop simultaneously in a single patient. We report a case of a 69-year-old woman who sustained a head-on motor vehicle accident with associated chest trauma. Methodology: During a subsequent hospitalization, she was exposed to subcutaneous heparin and developed significant thrombocytopenia. Shortly after that, she was represented with acute myocardial infarction. Result: Coronary angiography revealed a spiral dissection with superimposed thrombosis within the right coronary artery, while laboratory testing confirmed the diagnosis of heparin-induced thrombocytopenia. She was treated with catheter-based thrombectomy and adjunctive direct thrombin inhibitor therapy, followed by three months of systemic anticoagulation with warfarin. Conclusion: To our knowledge, this represents the first published case of a native vessel myocardial infarction due to the combination of coronary artery dissection and heparin-induced thrombocytopenia.

HIT Diagnosis: A Proposed New Definition for Clinical Research

Introduction: Heparin-induced thrombocytopenia (HIT) is a rarely diagnosed but often suspected complication of heparin therapy. Initial diagnosis is generally made based upon a combination of pretest probability (such as the 4Ts score) and the results of readily available immunoassays. However, confirmation requires the result of a functional assay such as the serotonin release assay (SRA), which is currently considered to be the gold standard. Because the SRA is technically challenging, it is offered only in a few reference laboratories, resulting in a turnaround time of several days to a week. In addition, recent data suggest that the accuracy of the SRA may not be as high as previously thought. Thus, new laboratory assays that are both highly sensitive and specific for HIT antibodies are urgently needed. Here we propose a new set of criteria, independent of the SRA, that may be used to define HIT in the evaluation of novel assays.Methods: We conducted a retrospective cohort study of adult inpatients undergoing laboratory testing for suspicion of acute HIT at the University of Washington Medical center and/or Harborview Medical Center between May 2016 and July 2017. All patients underwent enzyme-linked immunosorbent assay (ELISA) testing for antiPF4/heparin antibodies (IgG-specific Zymutest EIA, Hyphen Biomed). According to institutional policy, those samples with optical density (OD) ≥ 0.300 were reflexively sent to a reference laboratory for SRA testing. Charts were examined by trained reviewers for calculation of the 4Ts score, results of ELISA and SRA testing (when available) and outcomes at 30 days including clinical diagnosis/management of HIT and mortality.Results: We identified 155 patients undergoing evaluation for HIT. Each patient was placed into one of three categories: ‘negative’, ‘indeterminate’, or ‘positive’, based upon a combination of 4Ts score and the optical density (OD) resulting from ELISA testing. Any patient with an OD ≤0.300 was considered to be ‘negative’ regardless of the 4Ts score. Patients with ODs ranging from 0.301-0.999 were defined as ‘negative’ unless the 4Ts score was high (6-8), in which case they were defined as ‘indeterminate’. Patients with an OD of 1.000-1.999 were defined as ‘positive’ if the 4Ts was high (6-8), indeterminate if the 4Ts was intermediate (4-5) and negative if the 4Ts was low (0-3). Patients with an OD ≥2.000 were defined as ‘positive’ unless the 4Ts score was low (0-3) in which case they were defined as ‘indeterminate’. The number of patients that fell into each category as well as the number of subjects with a clinically confirmed diagnosis of HIT are shown in Table 1.The median age of all subjects was 60 and was this was roughly similar across ‘negative’, ‘indeterminate’, and ‘positive’ categories (60, 62, and 66, respectively). Males represented 62% of all subjects and 71% of patients categorized as HIT positive. Seventy percent of all subjects received heparin for venous thromboembolism prophylaxis. Eighty-nine percent of ‘negative’ and 100% of ‘indeterminate’ subjects were exposed to unfractionated heparin (UFH). Six of 7 ‘positive’ patients were exposed to UFH and 1 to low molecular weight heparin (LMWH). All ‘positive’ patients were clinically managed for HIT by stopping all heparin products and/or beginning patients on direct thrombin inhibitor therapy, with 57% mortality within 30 days of ELISA testing. One (0.8%) ‘negative’ and 7 (32%) ‘indeterminate’ patients were clinically managed for HIT. Thirty-day mortality was 25% and 4.5% in ‘negative’ and ‘indeterminate’ groups respectively.Discussion: Our study proposes a framework for the use of clinical pretest probability scores and rapidly available HIT ELISA testing to define HIT in research studies. Such a strategy allows for assessment of accuracy of newly developed assays. The inclusion of an ‘indeterminate’ category adds statistical complexity but is necessary to avoid misclassification of patients who may or may not have true HIT. Mortality in HIT positive patients defined in this manner was high, although small numbers limit definitive conclusions and unfractionated heparin was implicated in most cases of HIT, as has been observed previously. [Display omitted] DisclosuresPadmanabhan:BloodCenter of Wisconsin: Patents & Royalties: A patent application has been filed related to the PF4-dependent P-selectin expression assay (Method of Detecting Platelet- Activating Antibodies That Cause Heparin-Induced Thrombocytopenia/Thrombosis; PCT/US14/62591).; Retham Technologies LLC: Equity Ownership.

Optimal Bridging Strategy Post-Ventricular Assist Device Implantation Remains Unclear.

To the Editor: It was with enthusiasm that we read the article by Bates et al. describing bivalirudin utilization in a heterogeneous ventricular assist device (VAD) population.1 We were concerned, however, regarding their argument for the potential of bivalirudin as an initial bridging agent post-device implantation. No patients in their cohort received bivalirudin in this setting without being transitioned from either warfarin or heparin for either suspected or confirmed thrombosis or heparin-induced thrombocytopenia. Furthermore, the median time from VAD insertion to initiation of bivalirudin in their study was 116 days. Although we recognize the potential benefits of direct thrombin inhibitor therapy in the scenarios described within their cohort, the evidence for use of bivalirudin during the immediate postimplantation period as a bridge to oral anticoagulation is not well-elucidated. We have published the largest series to date of bivalirudin bridged patients (35) to oral anticoagulation after VAD placement.2 In our analysis, three different strategies were compared: bivalirudin, heparin, and no bridging immediately after VAD implantation. Our results suggested that bivalirudin was no different compared with heparin or no anticoagulation in terms of both thrombotic complications and bleeding events within 30 days of VAD implantation when controlling for international normalized ratio (INR) goals. In addition, the cost of heparin therapy was more than 40 times less than bivalirudin, although with the generic introduction of bivalirudin since the publication of our research, this number has certainly diminished. Overall, neither the Bates et al. data nor ours is sufficient to appropriately answer the question of which strategy is optimal to utilize post-VAD implantation.1,2 In addition, as the authors suggest, device type may also influence the benefits or weaknesses of various anticoagulant therapies. With the dramatic reduction in the rate of suspected of confirmed pump thrombosis observed in MOMENTUM-3, it is unclear if benefits observed in patients with older generation devices will translate to benefits in patients with the HeartMate 3.3 A large randomized trial, although welcome, is unlikely to be undertaken leaving a gap in the literature, which has yet to be filled for over a decade. Statements, however, on the utility of an approach without conclusive data, such as the use of bivalirudin in the post-implant period, and with some evidence showing that it has no discernable benefit should be made cautiously, if at all.

Utilization and Outcomes of Children Treated with Direct Thrombin Inhibitors on Paracorporeal Ventricular Assist Device Support.

Thrombotic and bleeding complications have historically been major causes of morbidity and mortality in pediatric ventricular assist device (VAD) support. Standard anticoagulation with unfractionated heparin is fraught with problems related to its heterogeneous biochemical composition and unpredictable pharmacokinetics. We sought to describe the utilization and outcomes in children with paracorporeal VAD support who are treated with direct thrombin inhibitors (DTIs) antithrombosis therapy. Retrospective multicenter review of all pediatric patients (aged <19 years) treated with a DTI (bivalirudin or argatroban) on paracorporeal VAD support, examining bleeding and thrombotic adverse events. From May 2012 to 2018, 43 children (21 females) at 10 centers in North America, median age 9.5 months (0.1-215 months) weighing 8.6 kg (2.8-150 kg), were implanted with paracorporeal VADs and treated with a DTI. Diagnoses included cardiomyopathy 40% (n = 17), congenital heart disease 37% (n = 16; single ventricle n = 5), graft vasculopathy 9% (n = 4), and other 14% (n = 6). First device implanted included Berlin Heart EXCOR 49% (n = 21), paracorporeal continuous flow device 44% (n = 19), and combination of devices in 7% (n = 3). Adverse events on DTI therapy included; major bleeding in 16% (n = 7) (2.6 events per 1,000 patient days of support on DTI), and stroke 12% (n = 5) (1.7 events per 1,000 patient days of support on DTI). Overall survival to transplantation (n = 30) or explantation (n = 8) was 88%. This is the largest multicenter experience of DTI use for anticoagulation therapy in pediatric VAD support. Outcomes are encouraging with lower major bleeding and stroke event rate than that reported in literature using other anticoagulation agents in pediatric VAD support.

Evaluation of intravenous direct thrombin inhibitor monitoring tests: Correlation with plasma concentrations and clinical outcomes in hospitalized patients.

The parenterally administered direct thrombin inhibitors (DTIs) argatroban and bivalirudin are effective anticoagulants for acute heparin-induced thrombocytopenia (HIT) treatment. The activated partial thromboplastin time (aPTT) has classically been used as the monitoring test to assess degree of anticoagulation, however concerns exist with using aPTT to monitor DTI therapy. In this observational study plasma samples from DTI treated patients were analyzed by aPTT, dilute thrombin time (dTT) and ecarin chromogenic assay (ECA) to delineate results into concordant and discordant groups. Discordant samples were further analyzed via liquid chromatography with tandem mass spectrometry (LC MS/MS). In total 101 patients with 198 samples were evaluated. Discordance between tests were frequent (59% of DTI treated patients). Bivalirudin aPTT vs dTT discordance was observed in 45% (57/126) of samples. Amongst bivalirudin samples with test discordance dTT results were more likely to be concordant with LC MS/MS than the aPTT (77% vs 9%, p < 0.0001). Argatroban aPTT vs dTT discordance was observed in 43% (31/72) and aPTT vs ECA discordance was observed in 40% (29/72) of samples. Amongst argatroban samples with test discordance both the dTT and ECA tests were more likely to have concordant results with LC MS/MS than the aPTT (88% vs 9%, p < 0.0001 for both dTT and ECA tests). There were no differences between discordant and concordant patient groups in a composite outcome of bleeding/thrombosis rate (23% vs 27%, p = 0.689). Further investigation is warranted to elucidate the effect of suitable monitoring assays on patient outcomes in the setting of DTI therapy.

Platelet response to direct thrombin inhibitor or fondaparinux treatment in patients with suspected heparin-induced thrombocytopenia.

Making a definitive diagnosis of heparin-induced thrombocytopenia (HIT) can be problematic. A prompt platelet rise following treatment has been proposed as a "post-test" criterion for diagnosis. However, the platelet response following discontinuation of heparin and initiation of a recommended alternative anticoagulant remains largely undefined and unstudied. This study aimed to characterize platelet response to initial treatment in patients with a low, intermediate, or high likelihood of having HIT. This was a multicenter retrospective cohort study. Patients were over 18years in age, underwent serologic testing for HIT, and received alternative anticoagulation treatment for HIT. Classification of each patient's likelihood of having HIT was based on an empiric, pre-hoc combination of the 4T score and serology results. The primary outcome for this study was a platelet count response after initiation of direct thrombin inhibitor (DTI) or fondaparinux therapy within 48h. 124 patients were analyzed. The sensitivity and specificity of having an immediate platelet rise of at least 10,000/µL by day 2 after starting treatment among high-likelihood for HIT patients were 0.71 (95% CI 0.55-0.84) and 0.64 (95% CI 0.5-0.76), respectively. The negative predictive value of no platelet rise was 75.5% (95% CI 0.61-0.86). A prompt platelet count rise may be appropriate to consider along with other known criteria for the clinical diagnosis of HIT. The rise should be immediate following discontinuation of heparin and initiation of recommended treatment, with an upward rise within 48h.

Monitoring of Argatroban and Lepirudin: What is the Input of Laboratory Values in "Real Life"?

Monitoring of direct thrombin inhibitors (DTIs) in patients with heparin-induced thrombocytopenia (HIT) is primarily performed using the activated partial thromboplastin time (aPTT). This assay is poorly standardized, reagent dependent, and not DTI specific. We compared aPTT, thrombin time (TT), and prothrombin time (PT) to drug levels obtained by the ecarin chromogenic assay (ECA). We analyzed 495 samples of patients with confirmed or suspected HIT on treatment with either argatroban (n = 37) or lepirudin (n = 80). Mean DTI levels ± standard deviation (SD) were 0.41 ± 0.36 µg/mL for argatroban and 0.20 ± 0.21 µg/mL for lepirudin. Results of aPTT were highly variable: 67 ± 22 seconds for argatroban and 55 ± 20 seconds for lepirudin. Significant correlations ( P < .01) were found between ECA-based DTI level and TT (argatroban, r = .820 and lepirudin, r = .830), PT (argatroban, r = -.544), and aPTT (lepirudin, r = .572). However, there was no correlation of aPTT with argatroban or PT with lepirudin concentration. Multiple regression analyses revealed that the TT predicted 54% of argatroban and 42% of lepirudin levels, but no significant impact was seen for PT or aPTT. The aPTT-guided monitoring of DTI therapy leads to a high percentage of patients with inaccurate plasma levels, hence resulting to either undertreatment or overtreatment. Knowledge of baseline values prior to DTI therapy and inclusion of clinical settings are essential for dosing DTIs when using aPTT. However, due to several limitations of aPTT, monitoring according to exact plasma concentrations as obtained by specific tests such as ECA may be more appropriate.

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.

Differences in the clinical course of heparin induced thrombocytopenia before and after the availability of HIT IgG class testing

IntroductionTo determine whether the HIT IgG class platelet factor 4 (PF4) enzyme immunoabsorbant assay (EIA) influenced the duration of parenteral direct thrombin inhibitor (pDTI) therapy or bleeding risk in patients started on pDTI for a presumed diagnosis of HIT. Materials/Methods187 patients started on pDTI for presumed HIT were assessed in two time periods before (period 1, n=88 patients) and after the introduction of an IgG-specific assay (period 2, n=99 patients). ResultsPatients in period 2 were treated with pDTI therapy for a median of 5days less (p<0.0001) however the incidence of Grade III and IV bleeding episodes was not different. Bleeding was observed to occur early during the hospital course at a median of 2-3 days after initiation of the pDTI. The average pDTI drug acquisition cost was markedly decreased in period 2 when compared to period 1 (p<0.0001). ConclusionsImplementation of the IgG class HIT EIA resulted in a decrease in the number of days on a pDTI and a decrease in the average pDTI acquisition cost per patient without an observed change in serious bleeding events.

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Introduction: The Direct thrombin inhibitors (DTI) are the standard of care for the treatment of proven or suspected Heparin Induced Thrombocytopenia (HIT). The management of DTI therapy is complicated by a narrow therapeutic index, frequent monitoring and titration, and interclass pharmacokinetic variability. Our institution formulated and implemented a dosing and titration guideline for bivalirudin and argatroban. Methods: Fifty consecutive patients receiving a DTI for proven or suspected HIT were identified following the implementation of the guideline. This group was compared to a control group of 50 consecutive patients who were managed with DTI therapy prior to guideline implementation. The data were evaluated and compared between the two groups including baseline characteristics, metrics relevant to achieving goal aPTT, and adverse events. Results: Notable proportions of patients in both cohorts, pre and post guideline implementation, were in the cardiac surgery Intensive Care Unit (40% and 44%) and on bivalirudin (76% and 80%).The percentage of patients reaching therapeutic aPTT goals increased after implementation of the guideline (72% vs. 92%, p=0.016), as did patients reaching therapeutic aPTT goals on initial dose administered (16% vs. 44%, p<0.01). Number of dose changes required to reach therapeutic aPTT goal decreased after implementation (3.14 + 3.02 vs. 1.85 + 2.78, p <0.05).There was a trend toward reduced median hours to therapeutic aPTT: 17.13 (6.00-36.75) vs. 10 (3.50- 28.00), p = 0.06. No differences in bleeding, thrombosis or critical aPTT values were observed. Conclusions: The percentage of patients reaching therapeutic aPTT goals significantly improved after the implementation of a DTI dosing guideline with no significant changes in thromboembolic events.

Impact of an Immunoglobulin G–Specific Enzyme‐Linked Immunosorbent Assay on the Management of Heparin‐Induced Thrombocytopenia

To evaluate whether using an immunoglobulin G (IgG)-specific platelet factor 4 (PF4) test reduces the rate of positive PF4 results and has an impact on prescribing practices of nonheparin anticoagulants (direct thrombin inhibitors and fondaparinux) in patients assessed for heparin-induced thrombocytopenia (HIT). Single-center prospective cohort study with a historical control group. Large academic medical center. A total of 672 patients assessed for HIT. Patients were assessed for HIT by using either an IgG-specific PF4 enzyme-linked immunosorbent assay (ELISA; 336 patients) or a nonspecific PF4 ELISA (336 patients; historical control group). No significant difference was noted in the proportion of patients with a low, intermediate, or high risk of HIT based on the 4Ts pretest clinical scoring system. The PF4 ELISA was positive in 6.9% versus 11.3% of patients (p=0.04) in the IgG-specific and nonspecific cohorts, respectively. A smaller proportion of patients were prescribed a direct thrombin inhibitor in the IgG-specific cohort (19.4% vs 25.9%; p=0.04). No significant difference in fondaparinux use was noted between the cohorts. The duration of direct thrombin inhibitor therapy, bleeding events, hospital length of stay, and in-hospital mortality was similar in both cohorts. Use of an IgG-specific PF4 ELISA was associated with a lower rate of positive PF4 test results. Direct thrombin inhibitor prescribing was also significantly lower during the time period where the IgG-specific PF4 ELISA was used, with no significant differences noted in safety outcomes.

Heparin-induced thrombocytopenia: is it a graft-threatening complication?

Heparin-induced thrombocytopenia (HIT), a prothrombotic complication of heparin therapy, can lead to serious thromboembolic events and cause significant morbidity and mortality. We aim to study the prevalence of HIT in the transplant population at our institute. This is a retrospective, single-center study which looked into the transplant database over a 25-year period. In patients with clinical suspicion of HIT, the 4T score was used, and laboratory tests such as ELISA HIT antibody and functional serotonin release assay, along with clinical manifestation of thromboembolic events were reviewed. Medical records of 2800 patients who underwent transplantation from January 1985 to December 2010 were reviewed. HIT antibody assay was performed in 262 patients from this group in which HIT was suspected. Of these, only 48 patients were HIT antibody positive along with moderate to high 4T score. The mean 4T score was 6.75±1.4. Thrombotic complications were seen in 11 patients, with the highest in cardiac transplant recipients. Direct thrombin inhibitor (DTI) therapy was used in only eight patients who had thrombotic event. No other complications or mortality was reported in any of the HIT antibody-positive transplant patients. To our knowledge, this is the first study of its kind that has shown very low incidence of HIT in the transplant population except for in cardiac transplant recipients.

Incidence of Direct Thrombin Inhibitor Therapy for Presumed Heparin Induced Thrombocytopenia Before and After Implementation of Heparin Induced Thrombocytopenia IgG Subtype Antibody Test

AbstractAbstract 3336 Introduction:Heparin Induced thrombocytopenia (HIT) is a clinicopathological entity in which thrombocytopenia occurs in temporal relation to the initiation of heparin therapy. The diagnosis is made using clinical criteria and a scoring system (4T) can be applied to assess the probability of the diagnosis. A variety of sensitive tests are available but the most widely applied is an enzyme immunoassay (EIA), which detects and semi-quantifies antibodies of any class to the heparin-PF4 complex. The role of testing is largely supplementary, but recently focus has been placed on the epidemic of HIT overdiagnosis due to overreliance on laboratory tests irrespective of the clinical scenario. A newer EIA can measure the pathogenic IgG antibody only. This study examines the number of patients started on direct thrombin inhibitor (DTI) therapy for a presumptive diagnosis of HIT prior to the implementation of the IgG antibody and after its introduction at one large academic tertiary care center. Methods:All patients placed on the DTIs argatroban and lepirudin between October 2006-May 2009 in the pre IgG subtype antibody period and May 2009-February 2012 in the post IgG subtype period for a presumptive diagnosis of HIT were identified. Demographic data including age, sex, and primary service were recorded. All HIT antibody (Ab) immunoglobulin class EIA and IgG specific EIA optical density were recorded, as available. 4T criteria and rates of thrombosis were assessed retrospectively. Incidence of WHO Grade III (requiring transfusion) or IV (life threatening) bleeding was documented. Chi Square, Mann Whitney U, and Fisher's exact tests were used as appropriate for statistical analysis. Results:89 patients pre availability of the IgG EIA assay and 100 patients post availability of the IgG EIA assay met inclusion criteria and were evaluated. Groups were matched in terms of sex and 4T pretest probability distribution as well as rates of thrombosis. Patients post IgG EIA availability were older and had lower mean total HIT Ab optical densities. Post IgG EIA patients were treated with DTI therapy 5 days less, which was statistically significant. The incidence of Grade III and IV bleeding episodes, however, was statistically similar between groups. In the pre IgG EIA group, 7 bleeds (4 Grade III, 3 Grade IV) occurred in patients with low pretest probability for HIT based on 4T criteria. In the post IgG EIA group, 8 bleeds (5 Grade III, 3 Grade IV) occurred in patients with low pretest probability for HIT based on 4T criteria.Table 1Comparison between demographic and clinical outcome data derived from patients treated with DTI therapy for presumed HIT prior to IgG EIA availability and post IgG EIA availabilityPre IgG EIA (N=89)Post IgG EIA (N=100)P valueMedian Age (Range)60.5 (18–91)67 (25–98)0.03M:F46:4354:460.754T Pretest ProbabilityLow34460.28Intermediate44400.19High11140.74Median Total Antibody Optical Density0.620.490.02Median Days on Direct Thrombin Inhibitors (DTIs)83<0.0001Grade III/IV Episodes of Bleeding20220.92Grade III12170.50Grade IV850.28Episodes of Thrombosis16171 Conclusion:Implementation of the IgG HIT EIA resulted in a decrease in the number of days on a DTI without an observed change in serious bleeding events, indicating that such bleeding occurs early after initiation of DTI therapy. Further, patients pre and post availability of the IgG EIA were started on DTI therapy despite a low pretest clinical risk for HIT. The use of a test with a shorter turn-around time to exclude HIT or more rigorous enforcement of clinical guidelines will be required to minimize misdiagnosis and avoid therapy related morbidity. Disclosures:No relevant conflicts of interest to declare.

Safety and effectiveness outcomes of an inpatient collaborative drug therapy management service for direct thrombin inhibitors

The impact of a collaborative drug therapy management (CDTM) agreement enabling pharmacist-managed direct thrombin inhibitor (DTI) therapy was evaluated. A retrospective chart review was conducted to compare selected outcome measures between cohorts of adults who received argatroban or bivalirudin therapy for suspected heparin-induced thrombocytopenia (HIT) before (n = 25) and after (n = 25) the implementation of an institutional DTI protocol under which properly trained and credentialed pharmacists have a primary role in dosing and monitoring DTI infusions. The primary endpoints were the mean time to attainment of activated partial thromboplastin time (aPTT) values in a specified therapeutic range and the proportion of total inpatient treatment time during which aPTT values were in that range. Secondary endpoints included the incidence of major and minor bleeding and the incidence of medication errors. After implementation of the DTI protocol, therapeutic aPTT values were achieved more rapidly (a mean of 3.4 hours in the postimplementation cohort versus a mean of 7.7 hours in the preimplementation cohort, p = 0.009) and maintained more consistently. Rates of bleeding and overall mortality were similar in the two groups; the frequencies of documented medication errors were 12% and 40% in the postimplementation and preimplementation cohorts, respectively (p = 0.05). A pharmacist-driven DTI program resulted in improved effectiveness and safety outcomes, as demonstrated by improved attainment of target aPTT values and a decreased frequency of medication errors.

HITlights: A career perspective on heparin‐induced thrombocytopenia

Two decades of research into heparin-induced thrombocytopenia (HIT) permit a personal historical perspective on this fascinating syndrome. Previously, the frequency of HIT was unknown, although complicating thrombosis was believed to be rare and primarily arterial. The opportunity to apply a remarkable test for "HIT antibodies"--the (14) C-serotonin-release assay (SRA)--to serial plasma samples obtained during a clinical trial of heparin thromboprophylaxis, provided insights into the peculiar nature of HIT, such as, its prothrombotic nature--including its strong association with venous thrombosis (RR = 11.6 [95%CI, 6.4-20.8; P < 0.0001); its more frequent occurrence with unfractionated versus low-molecular-weight heparin; the "iceberg" model, which states that among the many patients who form anti-PF4/heparin antibodies during heparin therapy, only a minority whose antibodies evince strong platelet-activating properties develop HIT; and the characteristic HIT timeline, whereby serum/plasma antibodies are readily detectable at or prior to the HIT-associated platelet count fall. Applying the SRA also to patients encountered in clinical practice led to recognition of warfarin-induced venous limb gangrene (for which HIT is a major risk factor via its extreme hypercoagulability) and delayed-onset HIT (whereby thrombocytopenia begins or worsens following heparin discontinuation, due to the ability of HIT antibodies strongly to activate platelets even in the absence of heparin--so-called heparin-"independent" platelet activation). Recent concepts include the increasing recognition of HIT "overdiagnosis" (due to the low diagnostic specificity of the widely-applied PF4-dependent immunoassays), and the observation that HIT-associated consumptive coagulopathy is a risk factor for treatment failure with PTT-adjusted direct thrombin inhibitor therapy ("PTT confounding" secondary to HIT-associated coagulopathy).

Development and implementation of a comprehensive heparin-induced thrombocytopenia recognition and management protocol

A quality initiative to improve the management of heparin-induced thrombocytopenia (HIT) at an academic medical center, including the development of guidelines on the use of direct thrombin inhibitors (DTIs), is described. In keeping with the Joint Commission's National Patient Safety Goal (NPSG) for anticoagulant therapy (goal 03.05.01), a multidisciplinary working group conducted a needs assessment to identify areas for improvement in the center's HIT management practices, particularly the use of DTI therapy (an issue not specifically addressed by NPSG 03.05.01). The resulting action steps included (1) the implementation of a detailed protocol for the recognition and management of HIT, as well as guidelines on the use of the DTIs argatroban and lepirudin, (2) more efficient use and optimized documentation of initial and confirmatory tests in the electronic medical record (EMR), and (3) the education of pharmacists, nurses, and physicians on the use of the HIT protocol, with initial and ongoing case-based competency testing of pharmacy staff. Early postimplementation experience indicated that the protocol and associated activities have resulted in improved DTI prescribing and dosing, HIT documentation, and patient education practices while expanding pharmacists' involvement in ensuring optimal, cost-effective management of patients with HIT. In one institution, an HIT working group extended the scope of NPSG 03.05.01 to include the parenteral DTIs. The implementation of the HIT protocol has resulted in greater compliance with appropriate DTI dosing and improved EMR documentation of HIT.

Assessing the impact of a heparin-induced thrombocytopenia protocol on patient management, outcomes and cost

Establishing the diagnosis of heparin induced thrombocytopenia (HIT) is challenging as laboratory tests for HIT vary in specificity and availability. As HIT suspicion far exceeds confirmation of diagnosis, overtreatment is an emerging concern. This pilot study evaluated the impact of a HIT Recognition and Management Protocol on direct thrombin inhibitor (DTI) prescribing, outcomes, and cost. The primary endpoint was DTI cessation within 12 hours of receipt of negative HIT serology. An observational cohort study using a pre-post design was performed. Sixty-one patients were in the pre-period (before implementation) and 46 in the post-period (after implementation). DTI therapy was discontinued within 12 hours of negative serology in 19.4% of pre-period patients compared to 40% of post-period patients, p=.058. DTI therapy was discontinued within 24 hours of receipt of a negative PF4/heparin ELISA more often in the post-period; 7/23 (30.4%) pre-period patients versus 16/26 (61.5%) post-period patients, p <0.05. Protocol implementation resulted in a significant improvement in timely initiation of DTI therapy (within 12 hours of HIT antibody testing) in those with a moderate to high suspicion of HIT; 8/31 (25.8%) of pre-period patients versus 24/31 (77.4%) of post-period patients, p <0.0001. Thrombotic events occurred in significantly more patients in the pre-period as compared to the post-period; 21/61 (34.4%) versus 6/46 (13%), respectively, p = 0.01. Major bleeding was reduced by 6.6 % after protocol implementation. The projected annual cost savings from decreased inappropriate DTI use was over $450,000. Protocol implementation had a positive impact on DTI prescribing, outcomes and cost.

A Rare Case of Acute Myocardial Infarction due to Coronary Artery Dissection and Heparin-Induced Thrombocytopenia

Although both coronary artery dissection and heparin-induced thrombocytopenia may provoke myocardial infarction, it is extremely rare for both conditions to develop simultaneously in a single patient. We report a case of a 69-year-old woman who sustained a head-on motor vehicle accident with associated chest trauma. During a subsequent hospitalization, she was exposed to subcutaneous heparin and developed significant thrombocytopenia. Shortly thereafter, she re-presented with an acute myocardial infarction. Coronary angiography revealed a spiral dissection with superimposed thrombosis within the right coronary artery, while laboratory testing confirmed the diagnosis of heparin induced thrombocytopenia. She was treated with catheter-based thrombectomy and adjunctive direct thrombin inhibitor therapy, followed by three months of systemic anticoagulation with warfarin. To our knowledge, this represents the first published case of a native vessel myocardial infarction due to the combination of coronary artery dissection and heparin-induced thrombocytopenia.