Likelihood Of Heparin-induced Thrombocytopenia Research Articles

Incidence of Heparin-Induced Thrombocytopenia in Non-Surgical Patients

Introduction: Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin exposure. HIT occurs when Platelet Factor 4 (PF4) forms a complex with heparin, resulting in the formation of autoantibodies. HIT occurs more frequently in surgical patients compared with non-surgical patients due to the inflammatory release of PF4 and perioperative heparin exposure. Previously, unfractionated heparin (UFH) has been compared to low molecular weight heparin (LMWH) solely among surgical patients which has been correlated with a higher incidence of HIT relative to LMWH. However, there is little data regarding UFH versus LMWH in non-surgical patients. The purpose of this study was to determine whether there was a significant difference in the incidence of HIT between these two forms of anticoagulation in non-surgical patients. We also sought to delineate differences in incidence of HIT with respect to BMI, gender, and age. Methods: This is a retrospective study that included all patients admitted to 14 hospitals within Hospital Corporation of America's (HCA) North Florida Division between January 2016 and September 2022. Data was retrieved and analyzed by HCA statisticians. Patient selection was based not only on whether they had been diagnosed with HIT, but various other factors including age, weight, gender and type of anticoagulation (LMWH vs UFH). Patients who had undergone surgery or even been hospitalized within the six months had been excluded. Other excluded conditions include disseminated intravascular coagulation (DIC), hemolytic-uremic syndrome (HUS), immune thrombocytopenic purpura (ITP), drug induced systemic lupus erythematosus (DILE), and systemic lupus erythematosus (SLE). Results: A total of 2,061 patients were included. Unfractionated heparin group was significantly associated with the likelihood of the patient being diagnosed with HIT (χ 2 = 184.06, p < 0.0001). The odds ratio is 0.237, indicating that patients who received unfractionated heparin were 4.219 (1/0.237) times as likely to develop HIT as patients who received LMWH. When controlling for age, sex, and BMI, age was significantly associated with the likelihood of the patient being diagnosed with HIT (χ 2 = 8.423, p < 0.01). The odds ratio was 1.010, indicating that with each additional year of age, patients were 1.010 times as likely to develop HIT. BMI was also significantly associated with likelihood of HIT (χ2 = 4.892, P < 0.03), indicating that obesity was identified as a potential factor associated with the development of HIT. Female were less likely to develop HIT when compared to men overall (χ2 = 7.238, P < 0.05). Conclusions: HIT is a rare but important cause of morbidity and mortality in patients exposed to heparin containing products. This study explored the profile of HIT incidence in non-surgical patients receiving UFH versus LMWH and in young versus older age groups. Here we provide evidence that a long-standing understanding regarding the incidence of HIT in surgical patients holds true in strictly non-surgical patients. Additionally, we have acquired evidence that age may very well play a role in HIT.

Heparin-induced thrombocytopenia associated with low-molecular-weight heparin: clinical feature analysis of cases and pharmacovigilance assessment of the FAERS database.

Background: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are commonly used anticoagulants for the management of arterial and venous thromboses. However, it is crucial to be aware that LMWH can, in rare cases, lead to a dangerous complication known as heparin-induced thrombocytopenia (HIT). The objective of this study was to evaluate the pharmacovigilance and clinical features of HIT associated with LMWH, as well as identify treatment strategies and risk factors to facilitate prompt management. Methods: We extracted adverse event report data from the FDA Adverse Event Reporting System (FAERS) database for pharmacovigilance assessment. Case reports on LMWH-induced thrombocytopenia dated up to 20 March 2023 were collected for retrospective analysis. Results: Significantly elevated reporting rates of HIT were shown in adverse event (AE) data of LMWHs in the FAERS database, while tinzaparin had a higher proportional reporting ratio (PRR) and reporting odds ratio (ROR) than other LMWHs, indicating a greater likelihood of HIT. Case report analysis indicated that a total of 43 patients showed evidence of LMWH-induced thrombocytopenia with a median onset time of 8days. Almost half of the events were caused by enoxaparin. LMWHs were mainly prescribed for the treatment of embolism and thromboprophylaxis of joint operation. Patients with a history of diabetes or surgery appeared to be more susceptible to HIT. Clinical symptoms were mostly presented as thrombus, skin lesion, and dyspnea. Almost 90% of the patients experienced a platelet reduction of more than 50% and had a Warkentin 4T score of more than 6, indicating a high likelihood of HIT. In all patients, LMWHs that were determined to be the cause were promptly withdrawn. Following the discontinuation of LMWHs, almost all patients were given alternative anticoagulants and eventually achieved recovery. Conclusion: LMWH-induced thrombocytopenia is rare but serious, with increased risk in patients with diabetes or a surgical history. Prompt recognition and management are crucial for the safe use of LMWHs.

Heparin-induced thrombocytopenia: An illustrated review

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect from unfractionated or low-molecular-weight heparin that results in thrombocytopenia and potentially catastrophic thrombosis. HIT occurs due to the development of platelet-activating antibodies against multimolecular complexes of platelet factor 4 and heparin. Given the frequency of thrombocytopenia and heparin use among hospitalized patients, calculation of the 4Ts Score is recommended to identify patients at increased likelihood of HIT and direct further evaluation. In patients with an intermediate or high probability 4Ts Score, an immunoassay and functional assay are recommended to confirm or refute the diagnosis of HIT. Heparin avoidance and initiation of nonheparin anticoagulation are the mainstays of acute HIT management. In this illustrated review, we provide visual summaries of the diagnosis and management of HIT, highlighting connections between pathophysiology and clinical care as well as summarizing efforts in quality improvement in the field. We further emphasize common pitfalls and pearls in diagnosis and management to encourage evidence-based care. We include graphical representation of the unique challenges of HIT with cardiopulmonary bypass and also delineate autoimmune HIT and its subtypes.

Comparison of Screening Scores for Heparin- Induced Thrombocytopenia After Cardiopulmonary Bypass

To compare screening scores for heparin-induced thrombocytopenia (HIT) after cardiopulmonary bypass (CPB). Retrospective cohort study. Cardiothoracic surgery units within a large tertiary healthcare facility from September 2010 to January 2020. All adult patients tested for heparin-induced platelet antibody (HIPA) within 2 weeks after surgery requiring CPB. Using data available to providers at the time HIPA were checked, the 4T's Score, a modified 4T's Score, and a score proposed by Lillo-Le Louet (LLL) etal. were calculated. A retrospective chart review was performed for each patient to determine actual presence of HIT, and screening scores were compared for accuracy. Criteria for inclusion were met in 266 patients. Of these, 34 (12.8%) were high likelihood of HIT, 16 (6.0%), additional patients were clinically ambiguous, and 216 (81.2%) were high likelihood of alternative cause for thrombocytopenia. HIPA tests done before postoperative day 5 were not associated with any high-likelihood cases of HIT regardless of preoperative heparin exposure. Although traditional 4T's ≥4, modified 4T's ≥3, and LLL ≥2 had statistically similar sensitivity for predicting HIT, the modified 4T's and LLL had superior specificity (p < 0.001). Appropriate screening for HIT curbed inappropriate HIPA testing, and reduced the need for empirical treatment while awaiting confirmatory test results. Traditional 4T's was statistically inferior to both the LLL score and a modified version of the 4T's to screen for HIT within 2 weeks of CPB.

Integration of a Heparin-Induced Thrombocytopenia Order-Set (HITOS): A Retrospective Study

Introduction: Heparin-induced thrombocytopenia (HIT) may occur after exposure to heparin containing products. When HIT is suspected, early recognition and diagnosis is crucial due to the risk for developing a life-threatening thrombotic event that can lead to substantial morbidity and even death.However, making the diagnosis of HIT is challenging due to a high false positive rate associated with most widely used screening tests for HIT. Therefore, clinical assessment of the likelihood of HIT is essential to help guide the decision to order a HIT laboratory test and to make changes in anticoagulation management. In 2014, we integrated a new custom HIT Order-Set (HITOS) with the EPIC electronic medical record (EMR) system. HITOS requires a clinician seeking to order a HIT laboratory test to input data to calculate a 4Ts pretest likelihood score for HIT. Recommendations are then automatically provided for proceeding or not with the HIT test and for anticoagulant management. Specifically, for patients with a low likelihood of HIT, HITOS recommends continuing heparin without HIT testing. For patients with an intermediate or high likelihood, HITOS recommends discontinuing heparin in favor of an alternative anticoagulant and proceeding with HIT testing. Our study goals were to evaluate the effect of HITOS on patterns of HIT test ordering and on anticoagulation management in patients with suspected HIT.Methods: We performed a retrospective review of all inpatient charts in which an order for the laboratory test for HIT (heparin-PF4 antibody enzyme immunoassay) was recorded at Dartmouth Hitchcock Medical Center from December 2012 to December 2016. HITOS was launched in December 2014. Subjects were excluded from the study if their charts contained incomplete data, external laboratory results, previous documentation of a HIT diagnosis or duplicate testing . Data were extracted from the EMR for each study subject and included demographic information, clinical data, HIT test results and details of anticoagulation management before and after HIT laboratory testing. In the pre-HITOS group, the 4Ts score was applied retrospectively to assess the likelihood of HIT and was calculated independently by two study members. A score of ≤ 3 defined low likelihood for HIT; 4-5 points, intermediate; 6-8 points, high. The 4Ts score was obtained from the EMR in the post-HITOS group. Before and after HITOS comparisons were analyzed using the chi-square test for independence with a = 0.05.Results: A total of 465 EMR were reviewed; 401 subjects were included in the final analysis. The pre and post-HITOS groups included 213 and 189 subjects, respectively, with a similar median age (66 years, range 21 to 94 and 65 years, range 23 to 94). Pre-HITOS, a HIT test was ordered in 54% of low, 39% of intermediate and 7% of high likelihood cases. Post-HITOS, a HIT test was ordered in 30%, 57% and 14% of the respective cases (p <0.001 for each pre/post comparison). When there was at least an intermediate clinical likelihood for HIT, appropriate discontinuation of heparin at time of HIT testing occurred more frequently in the post-HITOS group (74% vs 66 %, respectively; p <0.001), and more patients in the post-HITOS group were accorded a clinical diagnosis of HIT than in the pre-HITOS group (11.1% vs 5.6%, respectively; p <0.05) group.Conclusions: Implementation of HITOS was associated with a decrease in HIT laboratory test ordering if the clinical likelihood for HIT was low and was associated with a higher rate of appropriate heparin discontinuation when the clinical likelihood of HIT was intermediate or high. Our results suggest that integration of HITOS may help refine the diagnostic process in patients with suspected HIT, though additional study will be required to evaluate the cost-effectiveness and effects on morbidity and mortality of this approach. DisclosuresNo relevant conflicts of interest to declare.

A multicentre assessment of contemporary laboratory assays for heparin induced thrombocytopenia

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy. In some patients, HIT causes platelet activation and thrombosis (sometimes abbreviated HITT), which leads to adverse clinical sequalae ('pathological HIT'). The likelihood of HIT is initially assessed clinically, typically using a scoring system, of which the 4T score is that most utilised. Subsequent laboratory testing to confirm or exclude HIT facilitates exclusion or diagnosis and management. The current investigation comprises a multicentre (n=9) assessment of contemporary laboratory testing for HIT, as performed over the past 1-3 years in each site and comprising testing of over 1200 samples. The primary laboratory test used by study participants (n=8) comprised a chemiluminescence procedure (HIT-IgG(PF4-H)) performed on an AcuStar instrument. Additional immunological testing performed by study sites included lateral flow (STiC, Stago), enzyme linked immunosorbent assay (ELISA), Asserachrom (HPIA IgG), PaGIA (BioRad), plus functional assays, primarily serotonin release assay (SRA) or platelet aggregation methods. The chemiluminescence procedure yielded a highly sensitive screening method for identifying functional HIT, given high area under the curve (AUC, generally ≥0.9) in a receiver operator characteristic (ROC) analysis against SRA as gold standard. ELISA testing resulted in lower ROC AUC scores (<0.8) and higher levels of false positives. Although there is clear association with the likelihood of HIT, the 4T score had less utility than literature suggests, and was comparable to a previous study reported by some of the authors.

Heparin-induced Thrombocytopenia: Pathophysiology, Diagnosis and Management.

Heparin-induced thrombocytopenia (HIT), even rare, is a life-threatening, immune-mediated complication of heparin exposure. It is considered the most severe non-bleeding adverse reaction of heparin treatment and one of the most important adverse drug reactions. The pathophysiological basis of HIT results from the formation of an immunocomplex consisting of an auto-antibody against platelet factor 4 (PF4) - heparin complex, which binds to the surface of platelets and monocytes, provoking their activation by cross-linking FcgIIA receptors. Platelets and monocyte activation, leads to the generation of catastrophic arterial and venous thrombosis, with a mortality rate of 20%, without early recognition. The definitive diagnosis of HIT i.e., clinical and laboratory evidence, can not be done at the onset of symptoms because laboratory results may not be available for several days. Thus, the initial approach is to predict the likelihood of HIT, because in highly suspected patients immediate heparin cessation and initiation of alternative anticoagulation treatment are crucial for the prevention of the devastating thrombotic sequelae. Herein, we describe the pathophysiology, the clinical manifestations, the diagnostic approach, and the management of patients with HIT.

The Risk of Major Bleeding in Patients with Suspected Heparin-Induced Thrombocytopenia (HIT)

Introduction: Without prompt treatment, heparin-induced thrombocytopenia (HIT) is associated with a daily rate of life- and limb-threatening thrombosis of 6.1%. Current recommendations are to empirically treat a patient with an intermediate or high pre-test likelihood of HIT with a non-heparin (alternative) anticoagulant while awaiting HIT laboratory test results. The real-world bleeding rates of empiric treatment with an alternative anticoagulant in patients with suspected HIT have not been well-described. We assessed the rates of major bleeding in a prospective cohort of patients with suspected HIT. Because HIT is generally considered a prothrombotic and not a prohemorrhagic disorder, we hypothesized that major bleeding would be less common in alternative anticoagulant-treated patients with HIT than in treated patients who were ultimately determined not to have HIT.Methods: From June 2012 to January 2015, we enrolled 310 patients with suspected HIT at the Hospital of the University of Pennsylvania and an affiliated community hospital. All patients underwent HIT laboratory testing with a poly-specific PF4/heparin ELISA and in-house serotonin release assay. Patients were adjudicated to be HIT-positive or HIT-negative by an independent adjudication panel of HIT experts based on clinical course and results of HIT laboratory testing. We retrospectively reviewed the electronic health record to assess for the presence of a major bleeding event from the time of suspicion of HIT until hospital discharge or death. Major bleeding events were defined by International Society on Thrombosis and Haemostasis (ISTH) criteria (fall in hemoglobin ≥2 g/dL, transfusion of ≥2 units of packed red blood cells, fatal bleed, bleed occurring in a critical organ and/or requiring a repeat surgical intervention). Secondary outcomes of progressive or new thrombosis following suspicion of HIT testing, in-hospital and 30-day mortality were also assessed. Patients were considered to be treated for suspicion for HIT if they received an alternative anticoagulant following a HIT laboratory test order. The demographics and clinical features of patients defined by adjudicated HIT status were compared using the Wilcoxon test and chi-square tests for continuous and for categorical variables, respectively. The proportion of bleeding and thrombotic events were compared between groups using a chi-square test. All analyses were performed using Stata v14.2.Results:The demographics of our cohort by adjudicated HIT status are displayed in Table 1. 44 patients in the cohort were adjudicated to be HIT-positive and 266 were adjudicated HIT-negative. 42/44 (95.5%) HIT-positive patients and 116 of 266 (43.6%) HIT-negative patients received an alternative anticoagulant.Of those who were empirically treated with an alternative anticoagulant, the median duration of treatment was 3 days (IQR 2-5.5) in HIT-negative patients, compared with 11.5 days (IQR 6-16) in the HIT-positive group (p=0.001). The majority of treated patients received argatroban (88.0% of HIT-positive patients and 76.7% of HIT-negative patients). In those patients who received an alternative anticoagulant, a major bleeding event occurred in 40.9% of HIT positive patients and 44.8% HIT negative patients (p=0.45).The majority of major bleeding events met ISTH criteria based on hemoglobin fall or blood transfusion (Table 2). New or progressive thrombosis following suspicion for HIT was more common in HIT-positive patients (35.7%) than in patients who were HIT-negative and treated (15.5%) or not treated (11.3%) (p=0.001) (Table3).Conclusions:Contrary to our hypothesis, HIT was not protective against bleeding. A similar proportion of HIT-positive patients had ISTH major bleeding compared with HIT-negative patients treated with an alternative anticoagulant. The current paradigm for empiric treatment of patients with suspected HIT may need to be reconsidered in light of our findings of greater than expected bleeding associated with treatment. Limitations of our study include relatively small size, recruitment from a single health system, and predominant use of a single alternative anticoagulant (argatroban). Further studies are needed to determine whether our results apply to other centers and other alternative anticoagulants. [Display omitted] DisclosuresPishko:Novo Nordisk: Research Funding. Cuker:Synergy: Consultancy; Genzyme: Consultancy; Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding.

Incidence of heparin-induced thrombocytopenia in lower-extremity free flap reconstruction correlates with the overall surgical population

Lower-extremity free flap reconstruction is a growing trend in the management of lower extremity wounds. Heparin-induced thrombocytopenia (HIT) is a significant risk to free flap reconstruction. The purpose of this study was to investigate the incidence of HIT in patients receiving lower-extremity free flap surgery. We conducted a retrospective, single center, IRB approved cohort study in which we reviewed all patients who received lower-extremity free flap surgeries between 2011 and 2016. The 4T and HIT Expert Probability (HEP) scores were calculated to assess the likelihood of HIT. One hundred patient charts revealed three patients with HIT. One patient was excluded due to a prior diagnosis of HIT. HIT incidence in patients receiving lower-extremity free flaps was between 1% and 3%, which is consistent with the national average. 4T scores indicated that two of three HIT-positive patients had a high probability of HIT (approximately 64%), and one of three HIT-positive patients had an intermediate probability (approximately 14%). HEP scoring indicated that all the three (100%) patients had HIT. These data suggest that the incidence of HIT in patients receiving lower-extremity free flaps correlates with the incidence of HIT nationally. The use of available scoring methods and other algorithms, combined with patient history helps to assess the immediate perioperative risks of HIT in the absence of rapid immunologic confirmatory tests. This knowledge can allow for successful free flap salvage or for performance of free flaps in patients with a history of HIT.

HIT or miss? A comprehensive contemporary investigation of laboratory tests for heparin induced thrombocytopenia

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy, which in a proportion of patients causes platelet activation and thrombosis. Initial clinical assessment of the likelihood of HIT is facilitated by laboratory testing to confirm or exclude HIT. This prospective investigation was performed over an 18-month period, and has involved testing of over 300 test samples from over 100 consecutive patients. Clinical assessment by 4T score was supplemented by laboratory tests that comprised both immunological [lateral flow ('STiC'), chemiluminescence (AcuStar; HIT-IgG(PF4-H)), ELISA (Asserachrom HPIA IgG)] and functional assays [SRA, platelet aggregation using whole blood ('Multiplate') and platelet rich plasma ('LTA')]. We observed both false positive and false negative test findings with most assays. Overall, the whole blood aggregation method provided a reasonable alternative to SRA for identifying functional HIT. STiC, AcuStar and ELISA procedures were fairly comparable in terms of screening for HIT, although STiC and AcuStar both yielded false negatives, albeit also resulting in fewer false positives than ELISA. The 4T score had less utility in our patient cohort than we were expecting, although there was an association with the likelihood of HIT. Nevertheless, we accept that our observations are based on limited test numbers. In conclusion, no single approach (clinical or laboratory) was associated with optimal sensitivity or specificity of HIT exclusion or identification, and thus, a combination of clinical evaluation and laboratory testing will best ensure the accuracy of diagnosis.

Pediatric Heparin-Induced Thrombocytopenia: Prevalence, Thrombotic Risk, and Application of the 4Ts Scoring System

To characterize heparin-induced thrombocytopenia (HIT) at a single pediatric center including the prevalence and the accuracy of the 4Ts scoring system as a predictor of HIT. In this retrospective cohort study, we identified 155 consecutive patients <21 years old with sufficient data for 4Ts scoring. The 4Ts scoring system is a validated pretest tool in adults that predicts the likelihood of HIT using clinical features. Hospital-wide exposure to unfractionated and low molecular weight heparin was determined by querying the hospital pharmacy database. The majority of patients with suspected HIT (61.2%) were on surgical services. Prediction of HIT risk using initial 4Ts scoring found 3 (2%) had high risk 4Ts scores, 114 (73%) had intermediate risk 4Ts scores, and the remaining 38 (25%) had low risk 4Ts scores. HIT was confirmed in 0/38 patients with low risk 4Ts scores, 2/114 patients with intermediate-risk 4Ts scores, and all 3 patients with high-risk 4Ts scores presented with HIT with thrombosis. Of 12 positive HIT screening tests, results were falsely positive in 66.6% of patients with intermediate risk 4Ts scores and 100% of patients with low risk 4Ts scores. The prevalence of HIT was 0.058% and HIT with thrombosis was 0.046% in pediatric patients on unfractionated heparin. The prevalence of HIT appears significantly lower in pediatric patients compared with adults. Application of the 4Ts system as a pretest tool may reduce laboratory evaluation for HIT in heparin-exposed children with low risk 4Ts scores, decreasing unnecessary further testing, intervention, and cost.

Intricacies Of Treating Heparin Induced Thrombocytopenia With Preexisting Antiphospholipid Syndrome and Renal Insufficiency

Treatment of heparin induced thrombocytopenia (HIT) requires the use of alternatives anticoagulants, such as a direct thrombin inhibitor – argatroban. Use of argatroban relies on frequent laboratory monitoring of the activated partial thromboplastin time (aPTT) to maintain an adequate level of anticoagulation. This requirement poses a challenge in patients with prolonged baseline aPTT, such as in antiphospholipid syndrome. While other assays are being explored they require an extended turn around time because of their limited availability. We present a case of a 63 year old male with a history of antiphospholipid syndrome, end stage renal disease on hemodialysis, hepatitis C, and on long term anticoagulation with warfarin for cerebral vein thrombosis. His hospital course required transition to unfractionated heparin and subsequently developed thrombocytopenia. A heparin-platelet factor 4 ELISA antibody assay was performed for an intermediate clinical likelihood of HIT and returned positive. Although not confirmed with the gold standard serotonin release assay (SRA), clinical suspicion for HIT obligated treatment with an alternative anticoagulant. Conventional dosing and administration of argatroban however could not be performed because of the patient’s prolonged baseline aPTT. Other agents such as fondaparinux were also not possible in the setting of renal insufficiency. Short of other treatment techniques accepted in this unique set of circumstances we practiced a fixed dose argatroban (0.5 mcg/kg/min for Child’s class B cirrhosis). The patient tolerated the empiric dosing well until discontinued because of a negative SRA. This case demonstrates the limitations of current treatment recommendations of HIT and need for further investigation in similar patients. Disclosures: No relevant conflicts of interest to declare.

Combination Of 4T's Score and Rapid Gel Centrifugation Assay Excludes HIT In a Prospective Cohort Study

The diagnosis of heparin-Induced thrombocytopenia (HIT) is based on the presence of a compatible clinical picture combined with laboratory evidence of heparin-dependent, platelet-activating IgG antibodies. The 4T's Score is a clinical prediction rule that determines the likelihood that a patient has HIT before laboratory testing is performed. A rapid assay (H/PF4-PaGIA, Diamed, Switzerland) uses gel centrifugation to measure binding of antibodies to antigen-coated polystyrene beads (15 min turnover time). The purpose of this study is to evaluate the clinical utility of a diagnostic strategy which combines the 4T's Score with a H/PF4-PaGIA result to guide management of patients with suspected HIT while awaiting results of the serotonin-release assay (SRA). MethodsProspective cohort study of 538 consecutive adult patients with suspected HIT at 4 Canadian hospitals. Physicians completed a standardized 4T's Score sheet and the H/PF4-PaGIA was performed using fresh plasma in a central lab by technologists blinded to the 4T's Score (frozen plasma was used for 85 patients due to disruptions in worldwide availability of the assay.) The SRA and an in-house IgG anti-PF4/H enzyme-immunoassay (EIA) were performed on all patients by blinded technologists. Serologically-confirmed HIT (“HIT positive”) was defined as >50% serotonin release (mean) at three reaction conditions (0.1 U/mL heparin; 0.3 U/mL heparin; enoxaparin, 0.1 U/ml), as well as inhibition (<20% release or >50% inhibition) at 100 U/mL heparin and in the presence of Fc receptor-blocking monoclonal antibody, and a positive EIA. Thrombotic events, major bleeding events, and mortality were captured at day 30.Recommendations for management of patients while awaiting the SRA: patients with a Low 4T's Score (irrespective of H/PF4-PaGIA result) and patients with an Intermediate 4T's Score and negative H/PF4-PaGIA were to receive low-dose danaparoid or fondaparinux. Therapeutic-dose non-heparin anticoagulation was recommended for all patients with an Intermediate 4T's Score and positive H/PF4-PaGIA and for all patients with a High 4T's Score irrespective of H/PF4-PaGIA result.The primary outcome measure was the frequency of management failures defined as a patient with serologically-confirmed HIT who had one of the following combinations of diagnostic testing (a) Low 4T's Score and negative H/PF4-PaGIA; (b) Low 4T's Score and positive H/PF4-PaGIA or (c) Intermediate 4T's Score and negative H/PF4-PaGIA. Results527 patients with mean age 66.5 yr (sd 15.4) were analyzed; 11 patients with missing diagnostic testing results were excluded. Clinical outcomes of the management of patients according to the diagnostic strategy will be reported separately. Results of diagnostic accuracy of the 4T's Score and H/PF4-PaGIA compared to the SRA are provided below.HIT Negative (i.e., SRA-)HIT Positive (i.e., SRA+)TotalH/PF4-PaGIA -H/PF4 PaGIA +H/PF4 PaGIA indeterminateH/PF4 PaGIA -H/PF4 PaGIA +4T's ScoreLow27833226321Intermediate137161010164High243001542Total439523231527The prevalence of serologically-confirmed HIT in the study population was 6.5%. Two patients with indeterminate SRAs but IgG>1.0 were reported as HIT Positive.A negative H/PF4-PaGIA result reduced the probability of HIT based on the 4T's Score from 2.5% to 0.7% (95% CI: 0.1-2.6%) in the Low group, from 6.1% to 0% (95% CI: 0-2.7%) in the Intermediate group and from 35.7% to 0% (95% CI: 0-14.3%) in the High group. A positive H/PF4-PaGIA result increased the probability of HIT based on the 4T's Score to 15.4% (Low 4T's), 38.5% (intermediate 4T's) and 83.3% (High 4T's).The proportion of management failures was 1.5% (95% CI : 0.7%-3.0%). Of the 8 patients who were identified as management failures, 2 (Low 4T's) had a negative H/PF4-PaGIA. Out of 33 HIT Positive patients, 8 (24.2%) would have been missed based on a Low 4T's Score alone and 2 (6.1%) based on negative H/PF4-PaGIA alone. The combination of a Low or Intermediate 4T's Score and a negative H/PF4-PaGIA result had a negative predictive value for HIT of 99.5% (95% CI: 98.3-99.9). ConclusionsThe proportion of management failures was low (1.5%) and within acceptable limits (95% CI : 0.7%-3.0%). Combining the 4T's Score with the result of H/PF4-PaGIA excludes the diagnosis of HIT in the majority of patients with a Low or Intermediate probability for HIT and raises the likelihood of HIT in patients with a High probability. Disclosures:Linkins:BioRad DiaMed: PaGIA assays purchased at cost for study Other. Bates:BioRad Diamed: provided assays for study at cost Other. Lee:BioRad Diamed: provided assays for study at cost Other. Warkentin:GSK: Research Funding; WL Gore: Consultancy; Immucor GTI Diagnostics: Research Funding; Paringenix: Consultancy; Pfizer Canada: Honoraria; BioRad Diamed: provided assays for study at cost, provided assays for study at cost Other.

Correlation of PF4 ELISA Results and Clinical Likelihood of HIT: Can We Improve on Specificity?.

The diagnosis of heparin-induced thrombocytopenia (HIT) is made clinically with the support from the laboratory. While the Serotonin Release Assay (SRA) is considered by some to be the “gold standard” diagnostic test for HIT, this complex assay is not widely available. The PF4 ELISA is readily available, but is positive in many patients (pts) who do not have HIT. Measures suggested to improve the specificity of the PF4 ELISA include detecting only IgG antibodies and regarding only high potency antibodies as confirmatory evidence for HIT. We sought to correlate the clinical findings in 77 pts whose samples were tested in the PF4 ELISA with the serologic results (OD in PF4 ELISA for IgGAM, G, A and M and SRA) to determine if strength of reaction or antibody class is related to the clinical likelihood of HIT or to the results of the SRA. In addition, because occasional sera are positive in PF4 ELISA, but fail to inhibit by at least 50% when excess heparin is added (“reactive” samples), we examined whether this confirmatory (heparin inhibition) step provides additional specificity to the test result. We reviewed clinical information on the pts and assigned each a clinical “4T” score (Lo et al, J Thromb Haemost, 2006) estimating the likelihood of HIT. The IgGAM PF4 ELISA results were categorized as negative (OD < .4), reactive (OD >.4 with < 50% inhibition), weakly positive (OD.4 – 1.0) and strongly positive (OD > 1.0). The analysis showed that the pts with strongly positive results had 4T scores and SRA activity that were significantly higher than those of the other groups (Mean score 5.16 and SRA 61% Vs 2.5 – 3.7 and 8 – 10%, TTEST p=.02 – .00001). The weakly positive group had somewhat higher scores than the negatives and reactives (3.75 Vs 2.5 and 2.6, p = .02 and .04) but did not differ from either of these groups in SRA activity (8.0% Vs 10% and 8%, p = .4). The reactive and negative groups had similar scores and SRA activity despite 6/20 of the reactive samples having ODs >1.0. The fraction of samples with either high clinical scores (≥ 6) or high SRA activity (≥ 75%) did not differ among the negative, reactive, or wk positive groups, but was significantly higher in the strongly positive group (CHITEST, p =.0005) (Tab). Fewer samples were classified as weakly positive or reactive when the IgG only PF4 ELISA was used with no reduction in the number of strong positives (Tab ). Of note, one sample that was strongly positive in the IgGAM assay (OD 1.2) and negative in the IgG only test had a strong IgM antibody (OD 1.1). This pt had a clinical score of 6 and likely had true HIT. A second sample that was weakly positive in both the IgGAM and IgG only assays was strongly positive in the IgA only test (OD 1.4). This pt also had a clinical score of 6. 6 additional samples were weakly or strongly positive in the IgGAM assay without IgG antibody and had IgM with or without IgA antibodies. The clinical scores were 0.5, 2, 2.5, 4, 4.5 and 5, suggesting that clinical HIT was unlikely in 3 and possible in the remaining 3.IgGAM CategoryNo. of PtsNo. with Clin Score ≥ 6No. with SRA > 75%IgG Only CategoryNo. of PtsNo. with Clin Score ≥ 6No. with SRA > 75%Negative Reactive2411Negative44212011Reactive700Weak Pos1420Weak Pos710Strong Pos1999Strong Pos191011These findings confirm previous reports showing that a strongly positive PF4 ELISA test result (using either the IgGAM or the IgG-only assay) correlates well with a positive SRA and with the likelihood of having HIT. However, pts with reactive PF4 ELISA results generally have a negative SRA and a low 4T score and are an exception to this rule. The heparin inhibition step identifies reactive samples found in 1–2% of all pts referred for PF4 ELISA testing and improves the correlation between test results and the likelihood of having HIT. Finally, while the IgG only PF4 ELISA reduces the number of weakly positive or reactive results and preserves nearly all of the clinically relevant strong positives, we have identified at least 2 definite and 3 possible examples of relevant non-IgG HIT antibodies, 4 of which would have been missed using an IgG only test. Since pts have been described who had apparent HIT with thromboembolic complications whose antibodies were solely IgM, testing for IgG antibodies only could have adverse consequences for these exceptional individuals.

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.

Does the Platelet Factor 4 (PF4) ELISA Correlate with the Clinical Diagnosis of Type II Heparin-Induced Thrombocytopenia?.

Type II heparin-induced thrombocytopenia (HIT) is an antibody-mediated complication of heparin therapy that is associated with a consumptive thrombocytopenia and a high risk of thromboembolism. It is now known that antibodies associated with type II HIT recognize sites on PF4 when complexed with heparin. Due to technical challenges associated with the serotonin release assay, most clinicians rely on the PF4 ELISA to establish a laboratory diagnosis of HIT. However, it is unclear whether the ELISA has predictive value in identifying those patients who have clinically apparent disease and whether ELISA optical density (OD) measurements correlate with the development of thrombosis. We retrospectively reviewed the medical records of 103 sequential patients who tested positive for HIT by a commercial PF4 ELISA from 2000–2002. While blinded to ELISA OD values, we recorded patient age and gender, admission diagnosis, hospital course, type of heparin administered, route of administration, baseline and nadir platelet counts, timing of thrombocytopenia, HIT therapy, clinical thrombotic events within 30 days, and other potential causes of thrombocytopenia to determine the clinical likelihood of HIT. The association between OD values and both the clinical likelihood of HIT and objectively confirmed thrombotic events was analyzed using the Pearson Chi-square test. Median patient age was 62 yrs and 52% of patients were female. Those with cardiac disease, cancer, and venous thromboembolism constituted 44%, 19% and 9% of the study population, respectively. Median platelet count nadir was 40K/mL (range, 2K–90K), and average onset of thrombocytopenia was 6.5 days. Median ELISA OD value was 0.77 (0.40–3.81). The clinical likelihood of HIT was noted in 24/103(23%) patients, and 22(21%) suffered a thrombotic event. An ELISA OD &gt;1.0 was significantly associated with the clinical likelihood of HIT (p=0.03), though OD values ranged from 0.41 to 3.81 among these patients. Neither an OD threshold of 1.0 or 1.5 was associated with thromboembolism (p=0.2 and p=0.1, respectively). In contrast, the clinical likelihood of HIT was significantly associated with subsequent thrombosis (p=0.002). ELISA results were not significantly associated with the extent or onset of thrombocytopenia, type of heparin or route administered, patient age or gender, admission diagnosis, or hospital course. In conclusion, PF4 ELISA OD values are significantly associated with the clinical likelihood of HIT but are not predictive of HIT on an individual patient basis. Clinical judgment but not ELISA OD values is associated with subsequent thromboembolism. In summary, the clinical likelihood of HIT, and not ELISA results, remains the best parameter by which to modify anticoagulation therapy in patients being assessed for HIT. Figure Figure

Prospective Evaluation of 4T's Score and Rapid Particle Gel Immuno-Assay Specific to H/PF4 Complexes To Exclude Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin treatment because of the risk of venous and arterial thromboses. HIT is often difficult to diagnose in practice since most patients have several potential causes of thrombocytopenia. A scoring system named 4T's and based on four criteria (i.e. Thrombocytopenia, Timing of platelet count fall, Thrombosis or other sequelae, oTher cause of thrombocytopenia) has recently been proposed to estimate the probability of HIT before laboratory testing (T Warkentin, BJH 2003), and a particle gel immunoassay (H/PF4-PaGIA, Diamed, Switzerland) has also been developed to provide a rapid detection of HIT antibodies in less than one hour after blood sampling. The aim of this study was to compare the performance of both methods to exclude HIT in emergency conditions. One hundred twenty consecutive patients suspected of having HIT were included in 4 different centers over 9 months. Medical records were independently analyzed by two physicians, and the probability of HIT was evaluated using the 4T's score blind to the results of the PaGIA. In addition to PaGIA performed on the day of suspicion, serotonin release assay (previously identified as higly specific for HIT) and PVS/PF4 ELISA (GTI, Brookfiled, WI) were also performed, and HIT was confirmed when both assays were positive. The risk of HIT was evaluated by the 4T's score as low (LR), intermediate (IR) and high (HR) in 35% (n = 42), 63% (n = 73) and 4% (n = 5) of patients, respectively (Table). Since SRA (that detects pathogenic HIT IgG antibodies) was negative in all LR patients, the negative predictive value (NPV) of the 4T's score, which allowed the diagnosis of HIT to be eliminated in 35% of cases, was 100%. PaGIA was negative in 99 cases, including 16 patients for whom PVS/PF4 ELISA was positive (median 0.519, range 0.410 – 2.4). The diagnosis of HIT was excluded in all of these patients by the clinical evolution and since SRA was consistently negative. The NPV of PaGIA was thus 100% and this test was able to eliminate HIT in 82% of patients. The diagnosis of HIT was confirmed in 12 patients (SRA positive), including 5 evaluated as HR and 7 as IR by the 4T's score, and PaGIA was positive in all these cases (sensitivity 100%). However, the positive predictive value (PPV) of PaGIA was lower (51%) since positive results were also obtained in 9 cases for whom the diagnosis of HIT was eliminated. In conclusion, the 4T's scoring system appears to be a reliable first step to evaluate the likelihood of HIT, and to avoid unecessary biological assays in patients evaluated as LR. In addition, PaGIA can be applied to eliminate HIT with a high NPV, and could be particularly useful in patients classified as IR by the 4T's score. Finally, platelet activation tests such as SRA are always mandatory to confirm HIT in every patient having developed antibodies specific to polyanion-modified PF4.PaGIAPVS/PF4 ELISASRA4T's scoren−/+−/+−/+Low Risk (LR)4237/533/942/0Intermediate Risk (IR)7362/1152/2166/7High Risk (HR)50/50/50/5Total12099/2185/35108/12

Clinical Features and Outcomes in Patients with Heparin-Induced Thrombocytopenia (HIT): Report of the CAMC HIT Registry.

In 2001, our tertiary-care academic medical center implemented a HIT Task Force to develop quality improvement (QI) initiatives for HIT (Blood . 102:2766a, 2003). From these initiatives, a CAMC IRB-approved HIT Registry was developed. We present, from inpatient (IP) Registry data, a retrospective analysis of the clinical features/outcomes of patients (pts) reported/identified with clinical HIT from Jan 1999 to June 2003. IP medical records for case selection were identified from archival pharmacy records, the laboratory records of HIT antibody (Ab) assays, and case-reporting. Demographic features, co-morbid conditions, HIT-cohorts, HIT frequency in open heart surgery (OHS) pts, platelet counts (baseline; time HIT 1st suspected, nadir), thromboembolic complications (TEC), HIT Ab testing (H-PF4 ELISA;HIPA), agents utilized for HIT treatment, mean hospital length of stay (LOS), individual/composite outcomes of new TEC, amputations, and all-cause or HIT-specific mortality are presented. Clinical HIT was identified or recorded in 285 pts: 1999: 35, ‘00: 66, ‘01:63, ‘02:67, 1–6.30.03: 54. The median age was 68 yrs (range, 26–90). M/F (%): 47/53. Co-morbidities included coronary artery disease (68%), hyperlipidemia (49%), diabetes mellitus (40%), renal failure (4.6%), active malignancy (2.5%). The median/mean time from initiating heparin (H) to HIT recognition was 8.7/5.0 days. Median platelet counts (mm3) at baseline/time HIT was 1st suspected/HIT nadir were 208,000/72,000/53,000. A H-PF4 or HIPA assay was (+) in 80% (228). HIT cohorts included OHS (187; 66%), medical admission (69; 24%), & non-cardiac surgery (29; 10%) pts. HIT was identified following IP discharge (D/C) in 19% (35/187) of OHS and 10% (3/29) of non-cardiac surgery pts. The OHS HIT frequency among total OHS pts was: 1.8% (187/10,529). TEC at HIT presentation was 43% (123) and included (> 1 event/pt may have occurred): DVT (101), PE (17), graft occlusion (17), MI (10), venous gangrene (4), TIA (4). A new TEC occurred in 14% (41). Anticoagulant therapy for HIT was administered in 88% of Registry pts: r-hirudin (56%), Argatroban (26%) and danaparoid (6%). The mean duration of direct thrombin inhibitor (DTI) therapy/warfarin overlap with a DTI was 8.9 days /4.5 days. Warfarin was administered at D/C in 78% (176/225) pts. The HIT-admission mean LOS was 21days. The all-cause/HIT-specific mortality was 21% (60)/14% (39). Major bleeding /amputation occurred in 9.0%/2.4%. The composite outcome of new TEC, amputation and all-cause death was 26% (75/285). This report is among the largest reported hospital experiences. HIT was identified most frequently after OHS. Delayed HIT after hospital D/C occurred in 13%. Outcomes comparable to prior reports include time to HIT development, clinical HIT Ab detection, OHS HIT frequency, baseline/new TEC, alternative anticoagulant use, all-cause mortality and the composite outcome. QI initiatives arising from this analysis emphasize initiating DTI therapy when HIT 1st suspected and warfarin when platelets are sufficiently recovered; incorporating a prospective tool for scoring the likelihood of HIT; detailed analyses of the delayed-onset HIT cohort and assessing the financial impact of HIT in hospitalized pts.