Diagnosis Of HIT Research Articles

Use of Fibrinogen and D-Dimer to Predict Platelet Recovery in Heparin-Induced Thrombocytopenia

Introduction Heparin-induced thrombocytopenia (HIT) occurs in approximately 0.5-1.0% of patients treated with unfractionated heparin, though true incidence is hard to quantify due to difficulties in recognition and diagnosis. The mainstay of treatment is the initiation of non-heparin anticoagulants until platelet recovery and for one to three months thereafter. There is no available model to predict platelet recovery. A predictive model may help identify (1) patients who are improving even if not reflected in platelet count, particularly in refractory cases; and (2) those who may require adjunctive therapies for treatment. It has been previously proposed that in a distinct subset of HIT, termed “autoimmune HIT,” the fibrinogen and d-dimer may be helpful markers to assess treatment response. Anecdotally, in complex HIT cases at our institution, we have observed improvements in fibrinogen and d-dimer preceding the resolution of thrombocytopenia. In this study, our aim was to establish a correlation between the fibrinogen, d-dimer, and the platelet count. Fibrinogen and d-dimer assay accessibility make them alluring for widespread use, if informative. We hypothesized that the fibrinogen and d-dimer trends would correlate with improvements in platelets. Methods This study design was reviewed and approved by the Vanderbilt University Medical Center (VUMC) Institutional Review Board. All inpatients admitted to VUMC between August 2022 and March 2023 with a positive HIT immunoassay (ELISA) were identified. Venous blood aliquots in sodium citrate used for anticoagulation management were collected daily. Patients with confirmed HIT based on a positive serotonin release assay were included in the analysis. Samples were collected until resolution of HIT, discharge, and/or death. Fibrinogen and d-dimer were measured on stored samples and compared to the daily platelet counts for each patient. Statistical Analysis To determine how baseline platelet count, time, fibrinogen and d-dimer relate to longitudinal measurements of platelet counts (assessed between 1- and 22-days post-baseline) we used a generalized least squares model with an AR1 within-patient correlation pattern, determined using AIC and variograms assessing fit with the data. Results In total, samples from 10 patients with HIT were collected. Baseline characteristics are presented in Table 1. Longitudinal regression analysis presented in the ANOVA plot in Figure 1 suggested that d-dimer ( X2 3.72, p=0.71) and fibrinogen ( X2 9.29, p=0.16) had no statistically significant correlation with platelet recovery, and the only strong variable was time ( X2 30.46, p=0.0002), indicating non-flat trajectories. Baseline platelet count showed signal for positive effect ( X2 3.34, p=0.07). Other effects were assessed, but not significant. Discussion The results of our exploratory laboratory correlation study suggest that fibrinogen and d-dimer values were not reliably correlated with platelet counts in patients with HIT, despite anecdotal experience suggesting benefit in monitoring fibrinogen and d-dimer in difficult HIT cases. The best correlation and strongest association with the improvement in platelet counts was time. Our study has several limitations. First is our small patient sample size. In addition, 4 patients (40%) died due to unrelated complications, therefore limiting the number of data points available for interpretation. Lastly, mean and median fibrinogen values are within the normal range in our data set; d-dimer mean and median are only mildly abnormal. Future prospective studies should be considered to further explore the relationship between fibrinogen and d-dimer with platelet trajectory when markedly abnormal at time of HIT diagnosis, as we have observed in severe HIT cases.

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.

PB0348 Can 5B9, a Monoclonal Antibody to PF4/H, be Useful in Improving the Performance of the Asserachrom HPIA Test for the Diagnosis of HIT?

PB0348 Can 5B9, a Monoclonal Antibody to PF4/H, be Useful in Improving the Performance of the Asserachrom HPIA Test for the Diagnosis of HIT?

Heparin-induced thrombocytopenia post-cardiovascular interventional therapy: a case report

BackgroundHeparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction characterized by thrombocytopenia and thromboembolism. Herein, we present a case of HIT with subcutaneous hemorrhage after cardiovascular interventional therapy.Case presentationA 74-year-old man was admitted to the hospital for elective atrial fibrillation (AF) catheter ablation and left atrial appendage closure because of intermittent dizziness and palpitations. At presentation, the routine laboratory test results showed no abnormalities. He received subcutaneous enoxaparin for stroke prevention and unfractionated heparin for intraprocedural anticoagulation during coronary angiography and the AF procedure. On the second day after the AF procedure, the patient developed profound thrombocytopenia, moderate anemia, and mild subcutaneous hematoma. Blood tests and imaging examinations excluded acute hemolysis and other active bleeding. A 4Ts score of 5 and markedly positive platelet factor 4 IgG antibody established the diagnosis of HIT. Due to progressive subcutaneous hemorrhage in the thighs that could not be suppressed by pressure dressing, the patient received platelet transfusion and rivaroxaban for anticoagulation. The following days, the patient remained clinically stable from the hemorrhage, and his platelet count recovered. No thrombotic events occurred during hospitalization or follow-up.ConclusionThis case emphasizes the significance of suspecting HIT in patients with unexplained rapid thrombocytopenia after frequent heparin exposure. Decision-making regarding alternative anticoagulation and platelet transfusion in HIT with hemorrhage must be based on unique patient characteristics.

First-line treatment with oral anticoagulant predicts survival in acute cardiac patients with heparin-induced thrombocytopenia

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated disorder related to the use of unfractionated heparin and low-molecular-weight heparin. Although thrombocytopenic, HIT is a paradoxical prothrombotic state associated with increased risk of vascular thrombosis and death. Non-heparin anticoagulants, parenteral and oral, are recommended for the treatment of HIT. As heparin is commonly used and thrombocytopenia is frequent in critically ill cardiac patients, HIT constitute a relevant clinical issue in the intensive cardiac care unit. Despite this, the incidence of HIT as well as factors influencing clinical outcomes in acute cardiac patients with HIT are unknown and have not been investigated so far. Purpose The purpose of our study was to evaluate the incidence of HIT in the population of cardiac patients and to determine if any predictor of survival for acute cardiac patients with HIT can be found. Methods We retrospectively collected data of all patients with HIT who were hospitalized in our intensive cardiac care unit in 2016 - 2021. We had used functionalized latex immunoassay to confirm the diagnosis of HIT in all patients. The choice of the non-heparin anticoagulant, oral or parenteral, for the first-line treatment of HIT had been left to clinical judgment of the physician. We performed statistical analysis including clinical and laboratory variables to find the predictors of survival in critically ill cardiac patients with HIT. Results Among 22 483 patients hospitalized in 2016 - 2021 in our department of cardiology 12 were diagnosed with HIT (incidence 1 : 1874). 5 of them were treated with parenteral non-heparin whereas 7 with oral anticoagulant as first-line treatment. 4 patients with HIT died during the index hospitalization. All of them were treated with parenteral non-heparin anticoagulant. 7 of 8 survivors were treated with oral anticoagulant as primary drug. First-line treatment with oral anticoagulant was the predictor of survival (p=0,0152) in our study group. There was no other neither clinical nor laboratory factor influencing outcomes in critically ill cardiac patients with HIT (Table 1). Conclusion First-line treatment with oral anticoagulant was the only one predictor of survival in acute cardiac patients with HIT. Oral anticoagulants may be preferred for the treatment of HIT in this population.

Detection of Double Hit and Triple Hit Cytogenetics at Relapse Identifies a Very High Risk Subset of Relapsed/Refractory Multiple Myeloma Patients

INTRODUCTIONmSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. While cytogenetics at diagnosis helps in the decision-making process regarding initial therapy, their role in relapsed MM is not very well studied. We aimed to study the clinical profile and outcomes of patients with DH/THM detected at relapse in a real-world setting.METHODSThe case records of all relapsed multiple myeloma patients requiring active therapy between January 2018 and December 2020 were identified. All patients underwent bone marrow examination and repeat FISH cytogenetic analysis. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted.RESULTSA total of 17 patients were diagnosed with DH/THM at relapse during the study period. Median age of the cohort was 59 years with almost an equal number of male and female patients (M=9; F=8). Renal failure (serum creatinine >2.0mg/dl) was seen in 8 patients (47.1%), while bone lesions, anemia (Hemoglobin <10gm/dl) and hypercalcemia (serum calcium >12mg/dl) were seen in 12 (70.6%), 12 (70.6%) and 6 (35.3%) patients respectively. Five patients (29.4%) fulfilled the criteria for plasma cell leukemia.Twelve patients (70.6%) were in first relapse, while 3 patients were diagnosed at second relapse and 1 patient each at 3 rd and 5 th relapse respectively. All but 2 patients had received Bortezomib previously (N=15; 88.2%). Eleven patients (64.7%) had previous exposure to Lenalidomide and 8 patients (47.1%) had previous exposure to Thalidomide. Two patients had previously undergone autologous hematopoietic cell transplant. Median follow-up prior to diagnosing DH/THL was 28 months (Range- 5-89 months).All patients had gain of 1q with at least 3 copies, while 12 patients (70.6%) had 4 or more copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q which was seen in 10 patients (58.8%). This was followed by co-occurrence of TP53 deletion with gain of 1q in 5 patients (29.4%). Two patients (11.8%) had triple hit myeloma.Seven patients (41.2%) died within the first month of relapse and a further 3 patients died during the next month. Of the 10 patients who received at-least 1 cycle of therapy, 8 received triplet therapy with the combination of a proteasome inhibitor and an Immunomodulator, one patient received doublet with Lenalidomide and dexamethasone and one patient received Daratumumab based quadruplet therapy. Bortezomib based therapy was used in 5 patients and 4 patients received Carfilzomib based therapy. None of the patients underwent a 2 nd auto transplant. Two patients achieved VGPR or better with therapy. Of the 7 evaluable patients, 5 re-relapsed during follow up.The follow up of entire cohort ranged from 0 to 29 months. Sixteen patients (94.1%) died during follow up. The most common cause of death was progressive/active disease (9 patients, 56.3%) followed by a combination of active disease with sepsis (4 patients, 25%). Median OS was 1 month for the entire cohort.DISCUSSIONThe outcome of DH/THM at relapse is associated with an aggressive presentation and poor outcomes in the real-world setting. These patients are candidates for early aggressive or novel therapy or clinical trials. DisclosuresNo relevant conflicts of interest to declare.

Early Mortality and Aggressive Presentation Lead to Poor Outcomes in Patients with Newly Diagnosed Double Hit and Triple Hit Multiple Myeloma

INTRODUCTIONmSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. The outcome of these patients with the use of proteasome inhibitors and IMiDs with upfront Auto HSCT is not known in the real-world setting. We retrospectively studied the outcome of these patients in a resource constrained setting.METHODSThe case records of all newly diagnosed multiple myeloma patients who fulfilled the criteria for active myeloma between January 2018 and December 2020 were identified. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted.RESULTSA total of 55 patients with newly diagnosed DH/THM were treated at our center during the study period. Median age of the cohort was 60 years with almost an equal number of male and female patients (M= 26; F= 29). Renal failure (serum creatinine >2.0mg/dl) was present in 33 patients (60%) while bone lesions, anemia (Hemoglobin <10 gm/dl) and hypercalcemia (serum calcium >12mg/dl) were present in 44 (80%), 51 (92.7%) and 24 (43.6%) patients respectively. Six patients (10.9%) fulfilled the criteria for plasma cell leukemia.All but 2 patients had gain of 1q with at least 3 copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q, which was seen in 28 patients (50.9%). This was followed by co-occurrence of TP53 deletion with gain of chromosome 1q in 11 patients (20%). Nine patients (16.4%) had triple hit myeloma.Bortezomib was used in the initial therapy of 43 patients (78.2%) and IMiDs (lenalidomide, thalidomide and pomalidomide) were used in the initial therapy of 32 patients (58.2%). Most patients received triplet therapy (N=32; 58.2%) with the most common regimen being RVd. Nine patients (16.4%) died within the first month of diagnosis and another 7 died in next month [15 patients in 2 months (29.1%)]. The most common cause of death within 2 months was progressive disease (N=13; 81.3%). Twenty-two patients (40%) achieved VGPR or better with anti-myeloma therapy and 7 patients (12.7%) underwent autologous HCT. Of the 39 evaluable patients, 21 patients (53.8%) relapsed during follow up with a median EFS of 8 months. Of the 7 patients who underwent transplant, 5 patients have had a follow-up of more than 1 year, of whom 3 have relapsed. One patient with post-transplant relapse died with progressive disease and CMV colitis.Median follow up of the entire cohort was 11 months (Range- 0 to 35 months). After excluding patients who died within the first 2 months of diagnosis, the median follow up was 14 months (Range- 3 to 35 months). Thirty-three patients (60%) patients died during follow-up. The most common cause of death was active or progressive disease (25 patients, 78.1%). Median OS for the cohort was 13 months. On univariate analysis, survival was better for patients without renal injury at presentation (29 months vs 6 months; p=0.007) and patients with <5% circulating plasma cells (14 months vs 2 months; p=0.045). Patients who achieved VGPR had a better OS than patients who did not (Not reached vs 3 months; p=0.000) as did patients who underwent auto transplant (Not reached vs 10 months; p=0.023). OS did not significantly differ with TP53 deletion status, or number of copies of 1q (3 or greater than 3). In the multi-variate analysis, presence of renal failure (Hazard ratio- 2.663; p-0.017) and >5% circulating plasma cells (Hazard ratio- 3.082; p-0.020) were significantly associated with increased risk of mortality, while achievement of VGPR or better with therapy was associated with longer survival (Hazard ratio- 0.174; p-0.001).DISCUSSIONThe outcome of DH/THM remains poor in the real-world setting. The outcome was not affected by specific high-risk cytogenetic abnormalities or their combination in our study. Progressive disease within the first two months of diagnosis was the most common cause of death in more than 1/3 rd of the patients. Novel therapies and protocols are required to improve outcomes for this group of multiple myeloma patients. DisclosuresNo relevant conflicts of interest to declare.

Dabigatran as first-line treatment for heparin-induced thrombocytopenia in the intensive cardiac care setting

Abstract Introduction Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated disorder related to the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) which is associated with increased risk of vascular thrombosis. HIT constitute a relevant and not so uncommon clinical issue in the intensive cardiac care unit setting. Parenteral non-heparin anticoagulants are recommended for the treatment of HIT. The efficacy of dabigatran, direct oral anticoagulant, is poorly documented in this indication. In laboratory-confirmed HIT only few cases with short-term use and early conversion to and from another anticoagulant were reported. Purpose The purpose of our study was to evaluate the efficacy and safety of dabigatran as a first-line and the only one anticoagulant used in the treatment of HIT. Methods We prospectively enrolled 5 patients with the diagnosis of HIT who were hospitalized in our intensive cardiac care unit in 2017–2021. Heparin was stopped immediately on the suspicion of HIT and off-label dabigatran therapy was initiated the same day. There were no conversion to another non-heparin anticoagulant – dabigatran was used continuously from suspicion of HIT for at least 3 months. In all patients we used latex immunoassay to confirm the diagnosis of HIT. Lower-extremity compression ultrasonography was performed to exclude thrombosis. We distinguished HIT with thrombosis (HITT) and isolated HIT (HIT without thrombosis). The minimal follow-up period on dabigatran treatment was 3 months and the maximal 4 years. Results All the patients were male with the median age of 73 years (interquartile range, 52–78 years) and all were exposed to both, UFH and LMWH. The median platelet (PLT) count before exposition to heparin was 182000/μl (interquartile range, 171000/μl–321000/μl). Platelet count fall &amp;gt;50% was observed after a median time of 9 days (interquartile range, 7–11 days) after exposition to heparin and a median PLT count nadir was 87000 μl/l (interquartile range, 25000/μl–103000/μl). Two patients had intermediate and three high probability of HIT. HITT was diagnosed in one patient. The manifestation of HITT was upper-extremity arterial thrombosis and pulmonary embolism. Four patients were diagnosed with isolated HIT. PLT count recovery &amp;gt;15ehab724.2982/μl was observed after a median time of 3 days on dabigatran treatment (interquartile range, 2–7 days). In the patient with HITT, a complete resolution of upper-limb arterial thrombosis was observed. At the minimal observation period end point (3 months) all the patients survived without bleeding or new thrombotic event. Moreover, neither bleeding nor recurrence of HIT occurred during the total follow-up period. Conclusion Dabigatran is safe and efficient as first-line treatment for HIT and can be used as the only one anticoagulant in this challenging, clinical scenario. Funding Acknowledgement Type of funding sources: None.

Screening and diagnosis of heparin-induced thrombocytopenia in the pediatric population: A tertiary centre experience

IntroductionHeparin-induced thrombocytopenia (HIT) is a life-threatening side effect of heparin necessitating immediate heparin discontinuation. A missed diagnosis of HIT carries significant morbidity and mortality, while overdiagnosis may result in unnecessary and potentially harmful use of alternative anticoagulants in the pediatric population. We aimed to determine the proportion of HIT screening tests at our pediatric tertiary care centre ultimately leading to a diagnosis of HIT by functional assay (either lumi-aggregometry or serotonin-release assay). We hypothesized that the frequency of HIT at our centre would be lower than that reported in the literature. Materials and methodsWe conducted a retrospective review including children aged 0 to 18 years who had HIT testing performed at our centre between 2010 and 2018 (N = 189; 51% female). A screening enzyme immunoassay, if positive, is followed by a functional assay which must be positive to establish the diagnosis of HIT. Data were analyzed to establish trends in demographic and clinical features of patients with a positive HIT screening test. Our primary outcome was the rate of HIT confirmed by functional testing amongst children screened for HIT from 2010 to 2018. Results and conclusionsThere were 233 screening tests performed on 189 distinct patients. Only one patient (0.4%) received a diagnosis of HIT based on functional assay. This patient was a 16-year-old female later found to have a JAK2 mutation. The false positive rate of the enzyme immunoassay was 9.4% (N = 22). There were no positive enzyme immunoassay tests in the neonatal age group (N = 49). These results reinforce that HIT is rare in children.

Diagnosing heparin-induced thrombocytopenia: The need for accuracy and speed.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition resulting from pathogenic antibodies to complexes of heparin and platelet factor 4 (PF4). The diagnosis of HIT can be challenging due to the widespread use of heparin and the frequency of thrombocytopenia in hospitalized patients. Laboratory testing for HIT typically includes an immunoassay to detect antibodies to PF4-heparin and a functional assay. Current HIT diagnostic algorithms recommend using the 4Ts score to determine the need for HIT laboratory testing. Automated calculation of HIT clinical prediction scores in the electronic health record may improve the identification of patients who should undergo HIT testing. Another challenge in the management of patients with suspected HIT is the turnaround time of the laboratory testing needed to confirm the diagnosis. Due to the high daily thrombotic risk of HIT, clinicians must treat patients with intermediate to high pretest likelihood of HIT empirically while awaiting the test results. Treatment for HIT often involves alternative anticoagulants that lack reversal agents, which may increase bleeding risk, prolong hospital stays, and increase costs for patients suspected of having HIT. Rapid immunoassays hold promise to improve the speed of HIT diagnosis. These assays must retain a very high sensitivity for this "can't miss" diagnosis, yet have sufficient specificity to be of diagnostic value. A Bayesian approach has been proposed using two rapid immunoassays in succession, which decreased analytic turnaround time to 60minutes. Such an approach has the potential to be a much-needed clinical advance in improving accuracy and speed in the diagnosis of HIT.

Heparin-Induced Thrombocytopenia with Very High Antibody Titer Is Associated with Slower Platelet Recovery

Introduction: HIT is a relatively common and potentially catastrophic prothrombotic disorder caused by platelet activating antibodies targeting complexes of platelet factor 4 (PF4) and heparin. Diagnosis rests on clinical features coupled with serologic assays, most commonly an ELISA for heparin-PF4 antibodies. The ELISA optical density (OD) is a surrogate for antibody titer, an OD < 1 conveying a likelihood for pathogenic platelet-activating antibodies of < 1%, while OD > 2.0 confirms clinically suspected platelet activating antibodies in about 90%. The treatment for HIT is alternative anticoagulation, effecting platelet recovery >100,000 usually within 3 days and in the great majority within 7 days. We and others have observed very delayed platelet recovery (sometimes for weeks; “persisting HIT”) and this appeared more common with high titer antibodies. We did a retrospective analysis of 116 patients with HIT from single institution to investigate whether high titres of antibodies in HIT is associated with prolong time to platelet recovery and its potential impact on overall survival.Method: We retrospectively reviewed 116 patients diagnosed with HIT in our institution from 2009 to 2017 using our hospital database. Charts were reviewed for clinical comorbidities, association of surgery, thromboembolic events, type of alternative anticoagulation used on HIT diagnosis, platelet nadir count and time to recovery, and the relationship to ELISA OD. For statistical analysis, patients with HIT were categorized into 3 cohorts based on OD 1 to OD equal or less than 2.5, OD 2.5 to OD equal or less than 3 and OD more than 3 (Table 1). Patients with OD less than or equal to 2.5 was chosen as the reference group. A competing risk analysis based on the Fine & Gray method investigated differences in cumulative incidence of platelet recovery among the cohorts. Death before recovery was treated as a competing risk. Pooled t- test analysis was used to study correlation between OD and survival.Results: Median age of 116 patients was 65 years (63-68 ; 95% CI). 60.3% of the patients were male. Median value of initial platelet count during admission was 212k. Median value of nadir platelet count after diagnosis of HIT was 47k. 90% had surgery prior to diagnosis of HITT. 57% of patients with HIT had thromboembolic disease. 53%; 15% and 9% of patients were transitioned to Coumadin, NOACs and Arixtra respectively after initially getting treated with alternative anticoagulation Bivalirudin for HIT. Out of 116 patients, 101 patients (87%) of patients had platelet recovery in median of 6 days. The heparin OD value is significantly different between the two cohorts (p=0.0485) based on a pooled t-test. We further categorized all the patients into 3 cohorts based on their PF4 OD to study its impact on time to platelet recovery as shown in Table 1.There was no significant difference in recovery time between patients with OD between 2.5 and 3.0 and those less than 2.5 (p = 0.7207). The estimated hazard ratio of 0.921 [95% CI: (0.588, 1.444)], implying that patients with a higher OD value were likely to take slightly longer to recover their platelet count. However there was a statistically significant difference in platelet recovery time for patients OD greater than 3.0 (p = 0.0260) with hazard ratio 0.598 [95% CI: (0.380, 0.940)] compared to the reference group (see Figure 1). In-hospital mortality was 24.14% (28 patients) but was not significantly different by ELISA OD (p=0.7432). There is ongoing analysis of relationship of ELISA OD to thrombotic complications.Conclusion: Time to platelet recovery was significantly increased in HIT patients with heparin-PF4 OD value > 3. The lack of impact on overall survival probably relates to the fact that most deaths with HIT are related to underlying disorders (multiorgan failure, severe cardiac disease, cancer) rather than complications of HIT per se. A larger prospective study might further clarify the impact of PF4 OD on HIT treatment and outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Recognizing the Existence of Heparin Induced Thrombocytopenia and Thrombosis in the Setting of High-Dose Melphalan and Autologous Stem Cell Transplantation: A Single Institution Case Series

Background: Heparin induced thrombocytopenia and thrombosis (HIT/HITT) is a disorder characterized by transient hypercoagulability, with increased risk of venous or arterial thrombosis, related to the development of antibodies directed against the heparin-PF4 complex. HIT can occur in any patient receiving heparin but has rarely been described in the setting of high dose melphalan and autologous stem cell transplantation (HDM/SCT) so the true incidence in this population is unknown. Clinical suspicion of HIT in this setting is often clouded by the increased frequency of thrombocytopenia due to stem cell collection or high dose chemotherapy, as well as the increased risk of thrombosis in hematologic malignancies. We report five such cases, with clinically apparent and laboratory confirmed HIT that were diagnosed while undergoing treatment with high dose melphalan and autologous stem cell transplantation.Results: Five patients pursuing treatment with HDM/SCT were diagnosed with HIT during a five year period at our institution. Four patients were being treated for AL amyloidosis and one for multiple myeloma. The average patient age was 64 years (range, 59 to 69), including four males and 1 female. At the time of HIT diagnosis one patient was receiving prophylactic doses of enoxaparin due to a history of line-associated deep vein thrombosis. The other four patients had only been exposed to heparin as part of standard practice for central line placement, line flushes, or stem cell collection. Suspicion of HIT arose in all cases when the patient had delayed platelet recovery during the days following stem cell collection. Only one patient had proceeded with melphalan treatment before HIT was diagnosed. The average platelet nadir was 29, with a range of 6 to 68 x 109/L (Table 1). In two patients the development of thrombosis prompted the work-up for HIT: one with an internal jugular thrombosis and the other with limb threatening aortoiliac thrombosis requiring aortoiliac and femoral artery embolectomy with fasciotomy. All five patients had confirmation of diagnosis with heparin-PF4 antibody (optical density range, 0.5 to 3.3) and a positive serotonin release assay (SRA). Four patients were started on anticoagulation with fondaparinux or argatroban with appropriate platelet recovery in all patients. Three patients proceeded with HDM/SCT, while the remaining two patients received alternative therapies because the previously collected stem cells had been processed with heparin and could not be given to the patients.Conclusions: Herein we have describe five cases of HIT confirmed by the presence of a heparin-PF4 antibody and SRA testing. In all five cases the cause of thrombocytopenia was initially thought to be related to stem cell collection, which is known to cause a decline in platelets. It is notable that the platelet nadir in these patients, was frequently much lower than the nadir that is typically expected in HIT (50 to 80 x 109/L). Despite the development of thrombosis in two patients and the known increase in mortality in patients with HIT, the long term outcome in each of these patients was favorable. This is potentially attributable to rapid diagnosis, cessation of heparin, and initiation of alternative anticoagulation. In reaction to the initial cases, our institution has changed practices to eliminate heparin in the processing of stem cells so that all patients are able to receive their collected stem cells even in the setting of HIT. These cases highlight the existence of HIT during the process of HDM/SCT and the need for increased diligence in monitoring for unexpected thrombocytopenia or sluggish platelet recovery, in particular immediately after stem cell collection. Clinicians should have a low threshold to send diagnostic testing, begin alternative anticoagulation and postpone high dose chemotherapy in order to prevent life threatening complications. [Display omitted] DisclosuresSloan:Molecular Templates, Inc.: Consultancy; Stemline Pharmaceuticals: Consultancy.

COVID‐19 patients often show high‐titer non‐platelet‐activating anti‐PF4/heparin IgG antibodies

BackgroundHeparin‐induced thrombocytopenia (HIT) is a severe adverse reaction to heparin caused by heparin‐dependent, platelet‐activating anti‐platelet factor 4 (PF4)/heparin antibodies. Heparin is a cornerstone of treatment in critically ill COVID‐19 patients. HIT antibodies can be detected by antigen tests and functional tests. Often strong reactivity in the antigen test is used as a surrogate marker for the presence of clinically relevant, platelet‐activating antibodies. We observed an unexpectedly high percentage of COVID‐19 patients, clinically suspected to have HIT, with high titer anti‐PF4/heparin antibodies, but a negative functional test. ObjectiveWe investigated whether in COVID‐19 patients a serum‐derived factor inhibits the heparin‐induced platelet activation test (HIPA). Methods and ResultsTwelve COVID‐19 patients with suspected HIT were tested. Three samples tested negative in all assays; nine samples tested positive by antigen tests, among which only three tested also positive by HIPA. When we spiked COVID‐19 serum or control serum with the human HIT antibody like monoclonal antibody 5B9, reactivity of 5B9 remained the same. Also, the purified IgG fractions of COVID‐19 sera testing strongly positive in the PF4/heparin antigen test but negative in the functional test did not show increased reactivity in the functional test in comparison to the original serum. Both results make a functionally inhibitory factor in the serum/plasma of COVID‐19 patients highly unlikely. ConclusionCOVID‐19 patients often present with strong reactivity in PF4/heparin antigen tests without the presence of platelet‐activating antibodies. Diagnosis of HIT requires confirmation of heparin‐dependent, platelets activating antibodies to avoid overdiagnosis and overtreatment with non‐heparin anticoagulants.

Decreased Platelet Count Due to Heparin in Covid-19

COVID-19 (coronavirus disease-2019) infection may be a extremely prothrombotic state, ensuing from a dysregulation of the coagulation cascade. Therefore, thromboprophylaxis is powerfully suggested in these patients, with some consultants even advocating for therapeutic dosing to forestall thromboembolic events. Heparin-induced blood disorder (HIT) may be a well-known complication of heparin therapy. during this article, we tend to report a case of HIT in a patient with COVID-19. A 52-year-old male with history of one week of dry cough and loose stools. He had a positive COVID-19 reverse-transcriptase–polymerase chain reaction. On admission, the platelet count and liver function test were within normal limits. Throughout his hospitalization, he developed a right femoral deep venous thrombosis and was started on therapeutic anticoagulations. Due to worsening respiratory failure, he was intubated and mechanically ventilated. Between days eight and nine of hospitalization, platelet count decreased from 294000 to 89000 cells/μL. He had a high pretest likelihood for HIT with a 4T score of 6 and a positive anti-PF4/ heparin antibody. Heparin drip was interrupted and was switched to Argatroban. The serotinin assay eventually came back positive, that confirmed the diagnosis of HIT.

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis

AbstractHeparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14–labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

Challenges in Detecting Clinically Relevant Heparin-Induced Thrombocytopenia Antibodies.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated hypercoagulable state featuring high thrombosis risk and distinct pathogenesis involving immunoglobulin G-mediated platelet activation. The target of the immune response is a cationic “self” protein, platelet factor 4 (PF4), rendered antigenic by heparin. A key problem is that only a minority of anti-PF4/polyanion antibodies induced by heparin are pathogenic, i.e., capable of causing platelet activation and thereby clinical HIT. Since thrombocytopenia occurs frequently in hospitalized, heparin-treated patients, testing for “HIT antibodies” is common; thus, the problem of distinguishing between pathogenic and nonpathogenic antibodies is important. The central concept is that those antibodies that have platelet-activating properties demonstrable in vitro correlate well with pathogenicity, as shown by platelet activation tests such as the serotonin-release assay (SRA) and heparin-induced platelet activation assay. However, in most circumstances, immunoassays are used for first-line testing, and so it is important for clinicians to appreciate which immunoassay result profiles—in the appropriate clinical context—predict the presence of platelet-activating antibodies (Bayesian analysis). Clinicians with access to rapid, on-demand HIT immunoassays (e.g., particle gel immunoassay, latex immunoturbidimetric assay, chemiluminescent immunoassay) can look beyond simple dichotomous result interpretation (“negative”/“positive”) and incorporate semiquantitative interpretation, where, for example, a strong-positive immunoassay result (or even combination of two immunoassays) points to a greater probability of detecting platelet-activating antibodies, and hence supporting a diagnosis of HIT. Recent recognition of “SRA-negative HIT” has increased the importance of semiquantitative interpretation of immunoassays, given that strong immunoassay reactivity is a potential clue indicating possible HIT despite a (false) negative platelet activation assay.

Computerised risk scores to guide recognition and diagnosis in patients with possible heparin-induced thrombocytopenia.

The heparin-induced thrombocytopenia computerised risk (HIT-CR) score is designed to aid in the diagnosis of HIT. We sought to evaluate its potential clinical utility. In this retrospective cohort study, we collected HIT-CR scores on all inpatients receiving heparin over a 4-month period and performed chart reviews on the subset who independently underwent clinical diagnostic testing for HIT to identify patients with HIT. In all, 34342 patients received heparin, 1744 had high-risk HIT-CR scores of ≥3 and 220 had the maximal risk score of 4. Only 6% of high-risk and 10% of maximal-risk patients underwent testing for HIT. Conversely, among all 317 patients who underwent independent testing for HIT, 67% had low-risk HIT-CR scores (<3). Among patients independently tested, the positive predictive value (PPV) was 6·6% [95% confidence interval (CI) 4·9-8·8%] and the negative predictive value (NPV) was 99·5% (95% CI 97·1-99·9%) at a HIT-CR score cut-off of 3, and the PPV was 22·7% (95% CI 12·7-37·4%) and NPV was 99·0% (95% CI 97·6-99·6%) at a cut-off of 4. This study suggests clinicians fail to test most high-risk patients and unnecessarily test many low-risk patients for HIT. A reasonable approach to clinical application of HIT-CR scores would be recommending no testing for patients with a score of <3 and recommend testing for patients with a score of 4.

Heparin-induced thrombocytopenia in COVID-19 patients with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation: two case reports

Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly used in Coronavirus disease-19 (COVID-19) patients with the most severe forms of acute respiratory distress syndrome (ARDS). Its use is associated with a significant hemostatic challenge, especially in COVID- 19 patients who have been demonstrated to otherwise present a COVID-19-associated coagulopathy. The systematic use of unfractionated heparin therapy to prevent circuit thrombosis is warranted during ECMO support. The clinical presentation and management of heparin-induced thrombocytopenia, which is a rare but life-threatening complication of heparin therapy, has not been described in those patients yet. We report herein two cases of laboratory-confirmed HIT in COVID-19 patients with severe ARDS admitted to our intensive care unit for VV-ECMO support and the successful use of argatroban as an alternative therapy. We also provide a brief literature review of best evidence for managing such patients. The diagnosis and management of HIT is particularly challenging in COVID-19 patients receiving ECMO support. An increased awareness is warranted in those patients who already present a procoagulant state leading to higher rates of thrombotic events which can confuse the issues. Argatroban seems to be an appropriate and safe therapeutic option in COVID-19 patients with HIT while on VV-ECMO.

Heparin 'flush' induced thrombocytopenia triggered by total hip replacement: a case report.

BackgroundHeparin-induced thrombocytopenia (HIT) typically responds to heparin termination. Some types of HIT can persist after heparin discontinuation.Case summaryA 95-year-old woman was referred to the cardiology from orthopaedics because of acute limb ischaemia (ALI) 1 day after surgery of a femoral neck fracture. Despite thrombectomy, ALI relapsed the next day. She had been treated with intravenous antibiotics with a diagnosis of aspiration pneumonia for 1 week until 3 days before surgery, together with heparin flush twice a day. Of note, no intra-/post-operative heparin was administered, no cell salvage device, central venous, nor arterial catheters were used before development of ALI. The patient and her family refused reattempting invasive therapies; consequently, the patient continued to worsen and died on post-operative day 3. Diagnosis of autoimmune HIT, which was prompted by surgery without re-exposure to heparin, was confirmed posthumously.DiscussionThis case emphasizes the significance of suspecting autoimmune HIT in any patient presenting with thrombosis, even if the heparin exposure dates back more than a few days or even without heparin exposure.

Heparin-induced thrombocytopenia: Diagnostic challenges in intensive care patients especially with extracorporeal circulation

BackgroundHeparin-induced thrombocytopenia (HIT) is a serious drug induced reaction that may be associated with life threatening complications. Platelet-activating antibodies directed against platelet factor 4 (PF4)/heparin complexes cause the disease. The diagnosis of HIT is challenging, as thrombocytopenia is a frequent finding in intensive care (ICU) patient population, especially during extracorporeal membrane oxygenation. ObjectiveTo investigate the performance of a diagnostic algorithm for HIT in ICU patients. MethodsICU patients who developed thrombocytopenia or thrombosis under heparin treatment were included in this study. The pretest probability for HIT was estimated using the 4Ts-score and patient's sera were tested using two rapid immunoassays (RA) LFI-HIT and PaGIA (from Milenia Biotec and DiaMed), and within 72 h using the IgG enzyme immunoassay (EIA) from Hyphen and the heparin induced platelet activation assay (HIPA). Results392 consecutive ICU patients with suspected HIT were enrolled in this study, of whom 83/392 (21.2%) patients had extracorporeal circulation. Sera from 120/392 (30.6%) and 98/392 (25.0%) patients revealed positive results in RA and IgG EIA, respectively. The HIPA test revealed heparin-dependent platelet activation in a total of 15/392 (3.8%) ICU patients (3 medical and 12 surgical patients). In addition, sera from 7 patients revealed indeterminate HIPA results, of whom 2 patients had a clinical course compatible with HIT. ConclusionsData from our study confirm the high frequency of IgG PF4/heparin antibodies in ICU patients under unfractionated heparin and shows that the combination of 4Ts-score and RA does not reduce the laboratory overinvestigation for HIT in these patients.