Heparin-induced Thrombocytopenia Antibody Test Research Articles

Incidence of Heparin Induced Thrombocytopenia in the Transplant Population: A Large Retrospective Cohort, Single Transplant Centre Experience

AbstractAbstract 3320 Objective:Heparin induced thrombocytopenia (HIT), a prothrombotic complication of heparin therapy, can lead to serious thromboembolic events and cause significant morbidity and mortality. Its occurrence has never been studies in transplant patients, where use of heparin products is very common. We aim to study its prevalence in the transplant population at our institute. Methods:This is a retrospective cohort, single center study which looked into the clinical and laboratory database of all the patients that has undergone any kind of transplant at our institution over a period of 25 years (January 1985 - December 2010). In patients with clinical suspicious of HIT, a pre-test probability was calculated using the 4T scoring system. Results of the laboratory test like the ELISA HIT antibody (HIT ab) test and the functional serotonin release assay test (SRA) along with clinical manifestation of skin necrosis or thromboembolic events were reviewed. Results:Medical records of 2800 patients that has undergone transplant from January 1985- December 2010 were reviewed. HIT antibody assay was performed in 262 patients in which HIT was suspected. Of these, only 48 (18%) patients (mean age 57 ± 11 years, 71% women) had HIT ab positive, 9 were pre transplant recipient and remaining 39 were post transplant recipients. Baseline characteristics of the transplant population are illustrated in Table.1. Confirmatory test, SRA was performed in 8 HIT antibody positive patients, of whom only 4 were positive. The mean 4T score in HIT suspected patients was 3.7 ±1.3, while the score in HIT ab positive patients was 4.2 ± 1.2. Thrombotic complications were seen in 11(0.4%) patients, with the highest incidence rate of 1% in heart transplant recipients. No transplant patient had skin manifestations. Direct Thrombin inhibitor (DTI) was used only in 5 patients who had thrombotic events. No other complication or mortality was reported in any of the HIT ab positive transplant patients. Conclusion:To our knowledge, this is the first study of its kind that has shown very low incidence of HIT in transplant population. In conclusion, transplant patients can safely undergo any type of organ transplant, without having any peri or post operative complications or immediate mortality related to HIT.Table 1Baseline characteristics of the transplant population.Type of transplant (n)HIT ab positive (%)SRA positive4T scoreThrombotic complicationDTIBone Marrow transplant (450)1 (0.2)061-DVT0Heart transplant (410)22 (5)263-DVT/1-PE2Liver transplant (718)11 (1)153-DVT1Lung transplant (210)6 (3)151-CVT/1-DVT1Kidney transplant (1012)8 (0.8)041-PVT1DVT: Deep vein thrombosis; PE: Pulmonary Embolism; CVT: Cerebral vein thrombosis.PVT: Portal vein thrombosis. Disclosures:No relevant conflicts of interest to declare.

Argatroban Dose Reductions for Suspected Heparin-Induced Thrombocytopenia Complicated by Child-Pugh Class C Liver Disease

To report our experience of reduced-dose argatroban in a patient with suspected heparin-induced thrombocytopenia (HIT) and Child-Pugh class C liver disease and review the relevant literature to summarize current recommendations on argatroban use in patients with severe liver disease. A 58-year-old male with Child-Pugh class C liver disease (Model for End-Stage Liver Disease [MELD] score = 31, total bilirubin 4.5 mg/dL) and hemodialysis-dependent renal failure was hospitalized with acute deep vein thrombosis (DVT). Three days after heparin initiation for DVT, he developed thrombocytopenia. Given his heparin exposure (both for treatment of DVT and ongoing hemodialysis), HIT was suspected and all heparinoids were immediately discontinued. Argatroban was initiated for the treatment of HIT while laboratory testing for HIT antibodies and the serotonin release assay were completed. Because of the patient's advanced liver disease, the starting dose of argatroban was reduced to 0.2 μg/kg/min, with frequent monitoring of the activated partial thromboplastin time (aPTT) (goal 60-85 seconds). Despite this dose reduction, the aPTT was supratherapeutic. Following further dose reductions, a final argatroban maintenance dose of 0.05 μg/kg/min was necessary for the attainment of goal aPTTs. Reducing the starting dose of argatroban to 0.5 μg/kg/min is recommended in patients with liver disease. Nevertheless, this recommended dose is largely based on data from patients with more moderate liver disease (eg, Child-Pugh class A or B), and dosing in more advanced liver disease remains largely unexplored. Patients with more advanced liver disease may require additional dose reductions to avoid supratherapeutic concentrations of anticoagulation agents and to minimize bleeding risk. This report illustrates the importance of careful selection of argatroban dosing and appropriate aPTT monitoring in patients with severe liver disease. Excessive anticoagulation may precipitate major bleeding complications, placing patients with this complicated disease at undue risk.

Evaluation of appropriate serologic testing for suspected heparin-induced thrombocytopenia

The predictive value of clinical "4-T's" scoring in patient selection for serologic testing to confirm suspected heparin-induced thrombocytopenia (HIT) was evaluated. In a chart review-based study at a large hospital, all adult inpatients who underwent enzyme-linked immunosorbent assay (ELISA) testing for HIT-antibody detection during a two-year period were identified. Scoring of the 4 T's (degree of thrombocytopenia, timing of symptom onset, presence of thrombosis or other sequelae, and other potential causes) was retrospectively performed on a random sample of cases (n = 70) by three pharmacist investigators. Based on the 4-T's scores, the probability of HIT confirmation via ELISA testing was classified as low, intermediate, or high; by comparing those classifications with documented ELISA results, the positive predictive value of 4-T's scoring was calculated. Interrater variability in 4-T's scoring was also assessed. 4-T's scoring of the 70 randomly selected cases indicated low, intermediate, and high probabilities of HIT confirmation via ELISA testing in 52, 17, and 1 case, respectively. Negative ELISA results were documented in the records of 37 patients in the low-probability group; the 4-T's scoring system was calculated to have an adjusted negative predictive value of 77.3%. The calculation of Gwet's agreement coefficient indicated substantial agreement in 4-T's scoring by the three raters. The study results suggest that among patients whose 4-T's scores indicate a low probability of HIT, the results of subsequent ELISA testing for HIT antibodies are likely to be negative in about 8 of 10 cases.

Treatment Outcomes of Heparin-Induced Thrombocytopenia in Subarachnoid Hemorrhage Patients: A 4-Year, Retrospective Single-Center Review

The treatment and outcomes of heparin-induced thrombocytopenia (HIT) are not well described in neurosurgery patients. This study reviewed the treatment for HIT in subarachnoid hemorrhage (SAH) patients, and compared outcomes in patients with isolated HIT (iHIT) and HIT with thrombotic syndrome (HITTS). Adult patients with SAH discharged from the University of Illinois Hospital & Health Sciences System from 2006 to 2009 were included if they had at least one positive HIT antibody test. Patients were categorized with either iHIT or HITTS based on documented evidence of thrombosis. The primary outcome was the incidence of new thromboses prior to discharge. Secondary outcomes included the incidence of major bleeding, new thromboses up to 3months after discharge, or hospice/death. Patients having any secondary outcome were defined as having a "poor treatment-related effect". A total of 176 patients were screened and 30 patients met inclusion criteria. Eighteen patients (60%) were categorized with iHIT and 12 (40%) with HITTS. Twelve patients (67%) with iHIT received prophylaxis with fondaparinux and nine patients (75%) with HITTS were treated with argatroban. There were no differences in the primary (11 vs. 25%, p=0.364) or secondary outcomes in the iHIT group versus the HITTS group. Patients with iHIT had a 5.5% incidence of "poor treatment-related effects" compared to a 33.3% incidence in patients with HITTS (p=0.024). SAH patients with iHIT and HITTS did not differ in the incidence of new thromboses, incidence of hemorrhage, or hospice/death. Patients with iHIT had fewer "poor treatment-related effects" than HITTS patients.

Improving the specificity of the PF4 ELISA in diagnosing heparin‐induced thrombocytopenia

Heparin induced thrombocytopenia (HIT) is a serious complication of heparin therapy. The PF4 ELISA is a serologic assay that provides laboratory support for the clinical diagnosis of HIT, but it is often positive in patients who do not have the syndrome. We examined whether the specificity of the PF4 ELISA can be improved by 1) taking antibody potency into consideration, 2) by measuring only IgG antibodies, and 3) by utilizing a high concentration heparin inhibition step. We reviewed clinical information on 116 patients whose samples were referred for HIT antibody testing and assigned each a clinical score related to the likelihood of the patient having HIT. The scores were then correlated with serologic findings. Patients with strongly positive PF4ELISA results (OD ≥ 1.0) using both versions of the assay (IgG/A/M and IgG only) had clinical scores and SRA activity that were significantly higher than those having reactive or negative results. When the IgG-only PF4 ELISA was used, only the strongly positive result group had significantly higher clinical scores and SRA release, and fewer samples were classified as weakly positive or reactive, suggesting that detection of IgG only in the PF4 ELISA improves the assay's specificity. The heparin inhibition step identified "reactive" samples that were associated with clinical scores and SRA release indistinguishable from the "negative" result groups, confirming that this step further improves specificity of the test. This study supports utilizing these 3 modifications of the PF4 ELISA to improve specificity in supporting the clinical diagnosis 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.

Heparin Induced Thrombocytopenia in Pediatric Patients: Utility of Laboratory Testing

Abstract 1171▪▪This icon denotes a clinically relevant abstract Background:Heparin-induced thrombocytopenia (HIT) is characterized by the development of platelet-activating antibodies in response to heparin exposure, resulting in thrombocytopenia and a paradoxical risk for thrombotic complications. The diagnosis of HIT rests on clinical findings with supporting laboratory evaluation. The major features of HIT (thrombocytopenia and thrombosis after heparin exposure) are often seen in critically-ill children, but this is usually due to causes other than HIT. Clinical scoring systems (such as the 4T scoring system) to assess the pre-test probability of HIT are used widely in adults, but have yet to be fully validated in children. However, without prompt diagnosis and discontinuation of heparin, HIT can result in life and limb threatening thrombosis; on the other hand, overdiagnosis of HIT can lead to unnecessary exposure to alternative anticoagulants. Tests for HIT antibodies include ELISA immunoassays (EIA) for anti-PF4/heparin antibodies, which are widely available. The ELISA has high sensitivity but poor specificity with a high false positive rate. Functional tests, such as the 14C serotonin release assay (SRA), have high sensitivity and specificity, but are not routinely performed at most hospitals. In adults, higher antibody titers by ELISA are associated with SRA positivity and clinical manifestations of HIT. While the predictive value of these laboratory tests have been studied extensively for the diagnosis of HIT in adults, relatively little is known about their performance in the evaluation of pediatric patients. The aim of this study is to assess the utility of the ELISA and SRA tests, and clinical scoring systems to diagnosis HIT pediatric patients. Methods/Results: We identified 194 patients < 22 years of age who were referred for HIT testing between March 2001 and February 2010 at Johns Hopkins Hospital. 263 samples were evaluated by ELISA and/or SRA. ELISA was performed on 221 samples. Using the adult cut off value of 0.4 OD, 197 were negative, and 25 were positive (11%). SRA was performed on 39 samples and 3 were positive (8%). We found that positive SRA assays were found only in patients with ELISA OD values > 1.0. Two out of these three patients with SRA positivity had clinical HIT as diagnosed by treating physicians. The 4T Score (Warkentin, Br J Haem, 2003) and the HIT Expert Probability (Cuker, J Thromb Haemost, 2010) are pre-test scoring models that stratifies patients to high, intermediate, and low probability of HIT but have not been evaluated in pediatrics. A retrospective evaluation of utility of these scoring systems is currently underway. Conclusion: The utility of HIT antibody testing has not been formally evaluated in children. Only a subset of patients with positive ELISA tests will show SRA positivity. Higher titers of anti-PF4/heparin antibodies are associated with SRA positivity in pediatric patients, similar to adults. Further studies to validate predictive scoring systems in pediatic patients for the diagnosis of HIT is warranted. Disclosures:Streiff:BristolMyers Squibb: Research Funding; sanofi-aventis: Consultancy; Daiichi-Sankyo: Consultancy; Eisai:; sanofi-aventis: Honoraria.

The impact of the heparin-induced thrombocytopenia (HIT) computerized alert on provider behaviors and patient outcomes

The aim of this study was to measure the effect of an electronic heparin-induced thrombocytopenia (HIT) alert on provider ordering behaviors and on patient outcomes. A pop-up alert was created for providers when an individual's platelet values had decreased by 50% or to <100,000/mm(3) in the setting of recent heparin exposure. The authors retrospectively compared inpatients admitted between January 24, 2008 and August 24, 2008 to a control group admitted 1 year prior to the HIT alert. The primary outcome was a change in HIT antibody testing. Secondary outcomes included an assessment of incidence of HIT antibody positivity, percentage of patients started on a direct thrombin inhibitor (DTI), length of stay and overall mortality. There were 1006 and 1081 patients in the control and intervention groups, respectively. There was a 33% relative increase in HIT antibody test orders (p=0.01), and 33% more of these tests were ordered the first day after the criteria were met when a pop-up alert was given (p=0.03). Heparin was discontinued in 25% more patients in the alerted group (p=0.01), and more direct thrombin inhibitors were ordered for them (p=0.03). The number who tested HIT antibody-positive did not differ, however, between the two groups (p=0.99). The length of stay and mortality were similar in both groups. The HIT alert significantly impacted provider behaviors. However, the alert did not result in more cases of HIT being detected or an improvement in overall mortality. Our findings do not support implementation of a computerized HIT alert.

Severe thrombosis and acute thrombocytopenia in a cancer patient

A 62-year-old Caucasian female who had recently been diagnosed with multiple myeloma with a sacral plasmacytoma received induction treatment with bortezomib, cyclophosphamide, and dexamethasone. She had a significant response to therapy and had just begun the process of mobilization and collection of peripheral blood progenitor cells for autologous stem cell transplantation when she presented to the emergency center (EC) with pain and swelling of the left upper extremity. Her blood pressure on presentation was 114/69 mmHg with a heart rate of 98 beats per minute. Serum sodium was 136 mEq/L, potassium 4.3 mEq/L, chloride 98 mEq/L, carbon dioxide 24 mEq/L, blood urea nitrogen 9 mg/dL, serum creatinine 0.6 mg/dL, glucose 119 mg/dL, calcium 8.6 mg/dL, albumin 3.9 mg/dL, phosphorus 2.5 mg/dL, and magnesium 2.1 mg/dL. Liver function tests were within normal limits, with the exception of lactate dehydrogenase that was elevated at 728 IU/L. Prothrombin time (PT) was 16.5 sec (normal 12.7―15 sec), international normalized ratio (INR) 1.24, and activated PTT (aPTT) was 38.3 sec (normal 24.7―35.9 sec). D-dimer was >20 μg/mL (normal 0―0.4 μg/dL) and fibrinogen was 424 mg/dL. A complete blood count (CBC) showed a white blood cell (WBC) count of 11,400/μL, hemoglobin of 11.6 g/dL, and platelet count of 14,000/μL. Review of the peripheral smear revealed the presence of anisocytosis and ovalocytes, and the absence of fragmented red blood cells (schistocytes). The platelet count had dropped from 316,000/μL to 14,000/μL in a 7-day period (see Fig. 1). Home medications included zolpidem, lorazepam, duloxetine, famotidine, fentanyl, hydromorphone, and ondansetron. Doppler ultrasound study showed a completely occlusive thrombus within the left internal jugular vein extending to the subclavian, axillary, brachial, and basilic veins. The patient had recently had a left subclavian central venous catheter (CVC) placed 11 days prior to presenting to the EC. The CVC was removed, but no anticoagulation was started secondary to severe thrombocytopenia.

Perioperative thrombocytopenia in cardiac surgical patients — incidence of heparin-induced thrombocytopenia, morbidities and mortality

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy. At our institution, postoperative cardiac surgical patients are screened for HIT antibodies, when platelet counts persist to be less than 50% of the baseline level or less than 50000 nl(-1). In the present study, we compared the outcomes in HIT-antibody-positive and HIT-antibody-negative patients. Patients who underwent a cardiac surgical procedure between 1999 and 2007 and in whom a clinical suspicion of HIT prompted a test for heparin-dependent platelet-activating antibodies, that is, the heparin-induced platelet activation (HIPA) test, were retrieved from the database. Patients were divided in group 1 (antibodies present) and group 2 (no antibodies present). In 153 of more than 10000 patients (1.5%), a HIPA test was performed, Of those, 21 patients tested positive (group 1) and 132 tested negative (group 2). Central venous and pulmonary thrombo-embolism was more frequent in group 1 (10% vs 2%, p=0.04). Intestinal, microvascular thrombo-embolism was more frequent in group 2 (15% as opposed to 0%, p=0.03). By multivariate analysis, only patient age (p=0.04, confidence interval (CI): 1.04 (1.00-1.08)), female sex (p=0.03 CI 3.45 (1.51-7.86)) and perioperative sepsis (p<0.001 CI 6.88 (2.96-16.02)) were associated with mortality. Patients in whom a low platelet count prompted testing for HIT antibodies, had a high mortality (59%), independent of whether heparin-dependent antibodies were present, indicating that a persistently lowered platelet count is a bad prognostic sign after cardiac surgery. Interestingly, the HIPA-positive patients had more central venous and pulmonary embolisms. Patient age, female sex and perioperative sepsis were risk factors for perioperative mortality.

Urgent Cardiac Surgery in a Patient with a Remote History of Heparin-Induced Thrombocytopenia: Use of the Anti-PF4/Heparin ELISA Confirmatory Test

The use of established heparin protocols when heparin-induced thrombocytopenia (HIT) antibodies are negative is currently recommended for the management of patients with previous HIT who require cardiac surgery. Routine preoperative testing for HIT antibodies using an anti-PF4/heparin enzyme-linked immunosorbent assay (ELISA) introduces the problem of detecting nonpathogenic HIT antibodies, which can lead to a false diagnosis of the presence of platelet-activating antibodies. Our case report demonstrates the clinical utility of a newer confirmatory procedure performed using high dose heparin. We use this procedure in situations in which pretest probability is low (remote HIT) and the anti-PF4/heparin ELISA test results are weak to moderately positive (absorbance 0.4-1.0).

What is the potential for overdiagnosis of heparin‐induced thrombocytopenia?

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4//heparin (PF4/H) complexes. According to the "iceberg model," only a subset of anti-PF4/heparin antibodies of IgG class evincing strong platelet-activating properties cause clinical HIT. Since many centers rely predominantly on an anti-PF4/polyanion enzyme-immunoassay (EIA) to diagnose HIT, we estimated the potential for overdiagnosis when only this single test is available. We examined a database of 100 patients in whom the probability of HIT had been estimated using a clinical scoring system (4Ts), and where patients underwent systematic testing for HIT antibodies using three assays: the platelet serotonin release assay (SRA), an "in-house" EIA that detects IgG anti-PF4/heparin antibodies (EIA-IgG), and a commercial EIA that detects anti-PF4/polyanion antibodies of all three immunoglobulin classes (EIA-GTI). Whereas 16 of 100 patients fulfilled a "classic" definition of HIT (intermediate/high probability plus strong platelet-activating anti-PF4/heparin IgG antibodies), an additional 16 patients fulfilled a "liberal" definition in which any investigated patient (irrespective of the pretest probability) who had a positive EIA-GTI was considered to have HIT. The clinical features of these 16 additional patients--including generally weak antibodies and low risk for thrombosis--suggest underlying non-HIT explanations for thrombocytopenia. Patients with a positive SRA generally corresponded to those with intermediate or high pretest probability of HIT who also had strong EIA-GTI reactivity (>1.20 OD units). We conclude there is the potential to overdiagnose HIT by approximately 100% if any positive EIA is considered to "confirm" the diagnosis of HIT irrespective of the clinical scenario.

Utility of consecutive repeat HIT ELISA testing for heparin‐induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. Limited data are available regarding repeat HIT antibody testing after an initial negative test. We conducted a retrospective study to determine the utility of repeat testing. Heparin antibodies were detected using the GTI-PF4 enzyme-linked immunoabsorbent assay, ELISA (GTI Diagnostics, Waukesha, WI). Patients (n = 137) were assigned to one of three groups based upon the initial negative test optical density (OD) range of low = 0-0.132, medium = 0.133-0.267, and high = 0.268-0.399. A pretest clinical score was retrospectively determined using the "4T's" (Thrombocytopenia, Timing of platelet fall, Thrombosis, and the absence of oTher causes of thrombocytopenia). A subsequent positive ELISA was found in 16% (22/137) of patients who underwent repeat testing. Most of these patients had a low pretest clinical score (62%). Four patients had an interval change in the pretest score between the initial negative and subsequent positive tests. Only these four patients developed HIT with thrombosis (HITT). Eighty percent of patients with a high initial negative test OD value had a positive ELISA on repeat testing; however, the initial negative test OD value could not predict whether a patient developed HITT. In contrast, an increase in the pretest clinical probability between initial and repeat testing better predicted HITT. Consecutive repeat ELISA testing for heparin antibodies may be warranted in patients with an increase in their pretest clinical score after an initial negative test as an adjunct to confirm the diagnosis of HIT.

Heparin-Induced Thrombocytopenia

Unfractionated heparin is widely used for numerous clinical situations. A well-known adverse effect of heparin exposure is thrombocytopenia. Heparin-induced thrombocytopenia is a clinicopathologic syndrome that can be associated with severe complications and significant mortality. The pathophysiology of heparin-induced thrombocytopenia includes an immune-mediated reaction to heparin that activates platelets and results in an acquired hypercoagulability. Diagnosis of heparin-induced thrombocytopenia should incorporate clinical signs and symptoms and laboratory testing for heparin-induced thrombocytopenia antibodies. Therapy should include discontinuation of heparin, initiation of a direct thrombin inhibitor, and eventually therapy with warfarin (only after the platelet count is at least 100 x 10(9)/L).

Severe heparin-induced thrombocytopenia: when the obvious is not obvious, a case report

Thrombocytopenia commonly occurs in hospitalized patients, particularly critically ill patients. We present an exemplifying case of severe heparin-induced thrombocytopenia (HIT) in an effort to solidify its high priority in the differential diagnosis of thrombocytopenia. A 75-year-old female underwent cardiac surgery with intraaortic balloon pump (IABP) placement. A platelet count drop to 25 × 10(9)/L by the third postoperative day was attributed to the IABP, which was removed. Her thrombocytopenia remained refractory to multiple platelet transfusions over several days. Right hand cyanosis then developed, attributed to a right radial arterial catheter, which was removed. All toes and fingers then showed severe ischemic changes. Ten days after the initial platelet count drop, a critical care specialist new to the treating team suspected HIT. Heparin exposure was stopped and argatroban was initiated. A HIT antibody test was subsequently strongly positive. The patients thrombocytopenia gradually resolved. No additional thromboses occurred during a 27-day intensive care unit stay. This case underscores the need for vigilance in suspecting HIT in patients with thrombocytopenia and recent heparin exposure. To avoid catastrophic outcomes in such patients, heparin should be stopped and alternative anticoagulation should be initiated, at least until HIT is excluded.

Testing for Heparin-Induced Thrombocytopenia Antibodies

Heparin-induced thrombocytopenia (HIT) has a distinct clinical profile and unique pathogenesis. It is caused by platelet-activating IgG antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) bound to heparin or certain other polyanions. Although an immune response to PF4/heparin associated with heparin treatment is very common, clinical HIT occurs only among the minority of patients whose antibodies are capable of strongly activating platelets. This explains why certain platelet activation assays and anti-PF4/polyanion immunoassays have high sensitivity for HIT and why diagnostic specificity is highest for those assays that preferentially detect pathogenic antibodies, such as the washed platelet activation assays or immunoassays that detect only IgG antibodies. Negative results obtained in a solid-phase PF4/polyanion immunoassay generally exclude HIT (high negative predictive value), especially in a setting of a low pretest probability. In addition, because the magnitude of a positive test result correlates with greater likelihood of HIT, a Bayesian diagnostic approach that combines pretest probability and the magnitude of a positive test result is recommended. Recent studies suggest that presence of anti-PF4/polyanion antibodies in certain clinical settings confers an adverse prognosis, even without clinically evident HIT. Whether such antibodies impart "forme fruste" HIT or are simply a surrogate marker for a non-HIT adverse risk factor such as inflammation is unresolved.

Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction caused by heparin. As thrombocytopenia is common in hospitalized patients receiving heparin, it would be useful to have a clinical scoring system that could differentiate patients with HIT from those with other reasons for thrombocytopenia. To compare prospectively the diagnostic utility of a clinical score for HIT in two different clinical settings. The pretest clinical scoring system, the '4 T's', was used to classify 100 consecutive patients referred for possible HIT in one hospital (Hamilton General Hospital, HGH) into high, intermediate, and low probability groups. This system was also used to classify likewise 236 patients by clinicians in Germany referring blood for diagnostic testing for HIT in Greifswald (GW). The clinical scores were correlated with the results of laboratory testing for HIT antibodies using the serologic criteria for HIT with high diagnostic specificity. In both centers, patients with low scores were unlikely to test positive for HIT antibodies [HGH: 1/64 (1.6%), GW: 0/55 (0%)]. Patients with intermediate [HGH: 8/28 (28.6%), GW: 11/139 (7.9%)] or high scores [HGH: 8/8 (100%), GW: 9/42 (21.4%)] were more likely to test positive for clinically significant HIT antibodies. The positive predictive value of an intermediate or high clinical score for clinically significant HIT antibodies was higher at one center (HGH). A low pretest clinical score for HIT seems to be suitable for ruling out HIT in most situations (high-negative predictive value). The implications of an intermediate or high score vary in different clinical settings.

Prevalence of Heparin Antibodies in ICU Patients (The HAICU Study).

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated prothrombotic disorder characterized by absolute or relative thrombocytopenia occurring after exposure to heparin. Although thrombocytopenia in HIT patients usually resolves after discontinuing heparin, the risk for thrombosis persists up to 3 months.PURPOSE: The HAICU study was conducted to determine the prevalence of heparin-induced antibodies and HIT on admission to the intensive care unit (ICU) and their development within a week of hospitalization.METHODS: Platelet counts and heparin-platelet factor 4 antibodies (GTI ELISA) were measured on admission and again on day 7 ± 2 or discharge on a convenience sample of ICU patients. Patients with new onset thrombocytopenia (unexplained platelet count <100 x109/L or a 50% decrease in count) or a positive ELISA had confirmatory testing for HIT antibodies using a serotonin release assay. HIT was prospectively defined as positive HIT antibodies by both assays or as HIT antibodies with new onset, unexplained thrombocytopenia.RESULTS: Over 6 months, 118 patients were enrolled from three ICUs. Subjects had an average ICU LOS of 9 +/− 11 days, hospital LOS of 20 +/− 11 days and Apache II Physiology Score of 14 +/− 7; 59% were male. HIT, as defined above, occurred in 3 (3%) patients on admission. After 7.2 ± 2 days, HIT occurred in an additional 9 patients. Overall, 12 of 118 (10%) ICU patients had HIT at or within a week of admission (Table 1). 5 had documented prior exposure to heparin within 100 days of ICU admission, and 4 received heparin during the period when HIT assays were performed. Cases were distributed throughout the ICU's, yet relatively more often in the neurotrauma and shock-trauma units than the medical unit.CONCLUSION: Heparin-induced antibodies and HIT are common in the ICU, occurring in 3% of patients on admission and 10% in the first week. Physicians need to be aware of heparin exposure and the possibility of HIT in this population.Patients Positive for Heparin Antibodies by Type of ICU and Time PointUnitNo. of PatientsPercent (%)Day of ICU AdmissionDay 7 +/− 2TOTALPercent Positive per ICU (%)NTICU5647.515611STICU393323513MICU2319.50114TOTAL118100391210

New Approaches to the Diagnosis of Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome that is most reliably diagnosed when a patient with a clinical scenario that is consistent with heparin-induced immunization is shown to have antiplatelet factor 4/heparin, platelet-activating IgG antibodies. A Bayesian diagnostic approach is discussed, wherein the physician estimates the pretest probability of HIT (eg, the timing and severity of thrombocytopenia in relation to heparin treatment and associated thrombosis) and determines the posttest probability using the results of HIT antibody testing. By this approach, the magnitude of a positive test result determines its likelihood ratio in influencing the posttest probability of HIT.