Heparin-induced Antibodies Research Articles

Pediatric Spontaneous Heparin-Induced Thrombocytopenia and Thrombosis Resulting in Thrombotic Storm

Background: The annual incidence of venous thromboembolism in pediatric patients is approximately 6 out of 1000 in the United States. In rare cases, rapid progression of multifocal thrombosis occurs despite therapeutic anticoagulation with heparin or low molecular weight heparin. Heparin-induced thrombocytopenia (HIT) is a pro-thrombotic disorder caused by an IgG-mediated immune response against platelet factor 4 resulting in platelet activation and risk of thrombosis, classically associated with prior exposure to heparin. The literature reports rare cases of adult patients developing HIT and thrombosis (HITT) without prior exposure. Objective: Aim to describe a case of spontaneous HITT in a pediatric patient which has never previously been published in the literature. Design/Method: Single subject case report developed with literature review. Results: 2-year-old male with no past medical history who presented with 5 days of frontal headaches and irritability. Neuroimaging, including CT, MRI, and MRV demonstrated extensive sinus venous thrombosis requiring initial anticoagulation with heparin. However, within 48 hours of initiation, the patient developed significant thrombocytopenia concerning for HIT. Lab testing was positive for both heparin-induced antibody and serotonin release assay, despite no prior heparin exposure. The remainder of the hypercoagulability workup was negative. Heparin was discontinued and the patient subsequently showed inadequate response to initial treatment with first-generation1 direct thrombin inhibitor (DTI) (Argatroban). Due to ongoing severe progressive symptomatic thrombocytopenia and thrombosis concerning for HIIT with thrombotic storm, the patient was treated with DTI (Bivalirubin), high dose methylprednisolone, and anti-CD20 therapy (Rituximab). This resulted in an improved clinical, laboratory, and neuroimaging response, and the patient was able to be gradually weaned off steroid therapy, and transitioned to anticoagulation with warfarin, with plans to remain on long-term anticoagulation. Conclusion: This is the first reported case in the literature of spontaneous HIIT in a pediatric patient. Spontaneous HITT is the primary explanation due to fulminant thrombosis and positive heparin-induced antibody and serotonin release assay with no prior heparin exposure, thrombocytopenia without immediate improvement upon heparin discontinuation, and blood smear showing normal red blood cell and platelet morphology. Spontaneous HIIT is a rare but important differential to consider in patients presenting with thrombosis and thrombocytopenia as the treatment differs from that of classic HIT, requiring heparin discontinuation, alternative anticoagulation, and immunomodulation.

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.

Incidence of Heparin-Induced Thrombocytopenia in Patients With Newly Implanted Mechanical Circulatory Support Devices.

Heparin exposure and device-related thrombocytopenia complicate the diagnosis of heparin-induced thrombocytopenia (HIT) in patients receiving mechanical circulatory support (MCS). To improve anticoagulation management for patients with newly implanted MCS devices, incidence of confirmed HIT needs to be further characterized. The purpose of this study is to describe the incidence of HIT and clinical utility of the 4Ts score in patients with newly implanted MCS devices. This is a retrospective analysis of MCS patients receiving unfractionated heparin from 2014 to 2017. The primary end point was incidence of laboratory-confirmed HIT. Strong positive, likely positive, low probability, and negative HIT categories were established based on heparin-induced platelet antibody (HIPA) and serotonin release assay (SRA). Secondary end points include characterization of platelet trends, argatroban use, incidence of HIT among each of the MCS devices, and utility of 4Ts score. A total of 342 patient encounters met inclusion criteria, of which 68 HIPA tests and 25 SRAs were ordered. The incidence of HIT was 0.88% (3/342) and 4.4% (3/68) in patients with suspected HIT. Of the 68 HIPA tests, 3 (4.4%) were considered strong positive and 3 of the 25 SRAs were positive. Median 4Ts score was 4 [2.5-4] and optical density 0.19 [0.11-0.54]. The positive predictive value for the 4Ts score was 0.15 (CI = 0.03-0.46) and negative predictive value, 0.93 (CI = 0.82-0.98). HIT occurs infrequently with newly implanted MCS devices. The 4Ts score appears to have a high negative predictive value for ruling out HIT.

Neutrophil extracellular traps and heparin-induced antibodies contribute to vascular access thrombosis in hemodialysis patients.

BackgroundAnti-heparin/platelet factor 4 (PF4) antibodies may trigger severe thrombotic complications in hemodialysis (HD) patients. Tetrameric PF4 has a high affinity for extracellular DNA, which is a key component of neutrophil extracellular traps (NETs); therefore, the interactions between anti-heparin/PF4 antibodies and NETs can contribute to prothrombotic events.MethodsAnti-heparin/PF4 antibody levels were measured by enzyme-linked immunosorbent assay and an optical density > 1.8 was regarded as clinically significant. We additionally measured serum nucleosome levels as representative markers of NETs, and the contributions of anti-heparin/PF4 and increased serum nucleosome levels to the primary functional patency loss of vascular access was assessed.ResultsThe frequency of anti-heparin/PF4 antibodies was significantly higher in incident HD patients compared to prevalent HD patients (23.6% vs. 7.7%). Serum nucleosome levels, as well as the white blood cell counts, neutrophil counts, and high- sensitivity C-reactive protein levels, were significantly higher in anti-heparin/PF4 antibody-positive patients compared to the control. Platelet counts tended to be lower in the patients with anti-heparin/PF4 of >1.8 than in the controls. Relative risk calculations showed that the presence of anti-heparin/PF4 antibodies increased the risk of primary functional patency failure by 4.28-fold, and this risk increased further with higher nucleosome levels. Furthermore, in the anti-heparin/PF4 antibody-positive group, the time to first vascular intervention was much shorter, and the risk of repeated intervention was higher, compared to the controls.ConclusionIn incident HD patients, the presence of anti-heparin/PF4 antibodies was associated with increased NET formation; this could be a strong predictor of vascular access complications

Research on clinical characteristics and prognostic analysis of heparin-induced thrombocytopenia after surgery for acute type a aortic dissection

PurposeThe present study aimed to explore the clinical characteristics of heparin-induced thrombocytopenia (HIT) after surgery for acute type A aortic dissection and perform a relevant prognostic analysis.MethodsAfter continuous observation and analysis of 204 patients who underwent acute type A aortic dissection, we found that blood platelets decreased significantly after surgery and that these patients can be suspected to suffer HIT based on relevant 4Ts scores. For these suspected HIT patients, a latex particle-enhanced immunoturbidimetric assay was conducted to detect heparin-induced antibodies. Perioperative clinical data of patients in HIT and non-HIT groups were recorded as were blood platelet counts, HIT antibody test results, 4Ts scores, thromboembolic complications, clinical prognosis and outcomes.ResultsIn the present study, 38 suspected HIT patients, 16 HIT patients and 188 non-HIT patients were selected in the clinical setting. Among them, HIT patients were found to have prolonged cardiopulmonary bypass time (223 min on average vs. 164 min) and delayed aortic cross-clamp time (128 min on average vs. 107 min), and these differences between HIT patients and non-HIT patients were significant (P < 0.05). Additionally, the HIT group required longer operation time and higher dose of heparin, but showing no statistical differences (P > 0.05). The transfusions of blood platelets in the HIT group and non-HIT group were 18.7 ± 5.0u and 15.6 ± 7.34 u, respectively. In the HIT group, the mechanic ventilation time and the length of ICU stay were longer comparing the non-HIT group(P < 0.05), though no significant differences in total length of stay or In-hospital mortality were observed (P > 0.05). The incidence of continuous renal replacement therapy in HIT group was higher than the non-HIT group (P < 0.05). Additionally,there were no significant differences in 24-h postoperative drainage or reoperation for bleeding in both group(P > 0.05). However, the HIT antibody titer in the HIT group was significantly higher than that in the Suspected HIT group (2.7 ± 0.8 U/mL vs. 0.3 ± 0.2 U/mL) (P < 0.05). Among patients diagnosed with HIT, the incidence of thromboembolism reached 31.5%.For example, two HIT patients newly developed thromboembolism in both lower extremities,and three patients experienced cerebral infarction.ConclusionsAfter surgery for acute type A aortic dissection, HIT patients developed postoperative complications, the duration of ventilatory support and length of ICU stay were extended, and the incidence of thromboembolism increased. HIT antibody detection and risk classification should be implemented for high-risk patients showing early clinical characteristics.

Genome-Wide Association Study Identifies Variation in ABO As Risk Factor for Platelet Reactivity in Heparin-Induced Thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. Genome-wide association studies (GWAS) have the potential to identify genetic risk factors and generate insights into biological mechanisms of adverse drug reactions. However, published HIT GWAS are underpowered and do not include confirmation of HIT using functional assays. We aimed to identify genetic associations with HIT using a GWAS approach in two European ancestry populations tested for functional assay and PF4/heparin antibody levels. Methods: We performed a GWAS with positive functional assay as the outcome in a large discovery cohort of patients, including heparin-induced platelet aggregation (HIPA) positive cases (n=1243), antibody positive but functional assay negative controls (n=1091), and antibody negative controls (n=1718). Logistic regressions were adjusted for age, gender, and first two principal components. Significant associations from the discovery cohort (alpha=5.00x10-8) were then investigated in a replication cohort of serotonin-release assay (SRA)-confirmed HIT cases (n=173), antibody positive controls (n=125), and antibody negative controls (n=488). All patients were genotyped with the HumanOmniExpressExome BeadChip, including 9,065,510 variants after imputation and quality control. Genes near significantly associated loci were resequenced. Results: In the discovery cohort, a genome-wide significant association was observed between common variation in the ABO gene and HIPA positive status (rs505922 odds ratio 0.738 [0.668-0.816], p=2.813x10-9). This variant was also significantly associated with SRA-confirmed HIT in the replication cohort (odds ratio 0.392 [0.172-0.891], p=0.025). Meta-analysis indicated strong association of ABO variation with positive functional assay (Figure 1). Sequencing and fine-mapping of the ABO locus indicated this effect was driven by ABO blood groups, with the O blood group being a risk factor for HIT (odds ratio 1.42 [1.25-1.61], p=6.11x10-8). Conclusions: We identify common variation in ABO as a risk factor for platelet reactivity and HIT. Strong association of ABO variation may have important implications for prediction and understanding of HIT pathogenesis. Figure 1 Disclosures No relevant conflicts of interest to declare.

Detection of Platelet-Activating Antibodies Associated with Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic immune drug reaction caused by platelet-activating antibodies that in most instances recognize platelet factor 4 (PF4)/polyanion complexes. Platelet activation assays (i.e., functional assays) are more specific than immunoassays, since they are able to discern clinically relevant heparin-induced antibodies. All functional assays used for HIT diagnosis share the same principle, as they assess the ability of serum/plasma from suspected HIT patients to activate fresh platelets from healthy donors in the presence of several concentrations of heparin. Depending on the assay, donors’ platelets are stimulated either in whole blood (WB), platelet-rich plasma (PRP), or in a buffer medium (washed platelets, WP). In addition, the activation endpoint studied varies from one assay to another: platelet aggregation, membrane expression of markers of platelet activation, release of platelet granules. Tests with WP are more sensitive and serotonin release assay (SRA) is considered to be the current gold standard, but functional assays suffer from certain limitations regarding their sensitivity, specificity, complexity, and/or accessibility. However, the strict adherence to adequate preanalytical conditions, the use of selected platelet donors and the inclusion of positive and negative controls in each run are key points that ensure their performances.

A Single Institution's Adherence to Heparin-Induced Thrombocytopenia and Thrombosis Testing Guidelines

Introduction:What was once an under-recognized clinical entity, heparin induced thrombocytopenia and thrombosis (HITT) has become a well-recognized and frequently tested disease. HITT is a serious and potentially fatal antibody mediated drug reaction to platelet factor 4 and early identification and treatment is essential. The 4T score is well-validated to guide appropriate testing of HITT where a low-probability score of 0-3 equates to a 99.8% negative predictive value for HITT2,3. In an effort to promote cost-conscious care and efficient use of healthcare resources, the American Society of Hematology (ASH) recommends against testing for HITT if the 4T score is 3 or less4. HITT laboratory testing at our institution is not restricted based on 4T score. We hypothesize that many providers are not following cost-conscious guidelines regarding HITT testing at our institution.Methods:We performed a single-institution retrospective analysis of patients who had a heparin-induced platelet antibody assay with reflexive serotonin release assay ordered between July 1, 2016 to July 1, 2017 at the University of Virginia Medical Center (UVA). We primarily assessed how our institution's ordering of heparin-induced platelet antibody for HITT compared to ASH's Choosing Wisely recommendation of forgoing laboratory testing on patients with a 4T score of 0-3 by retrospectively calculating 4T scores on all patients who had laboratory testing4. Patients were also assessed for episodes of bleeding and clotting and were scored on severity via the CTCAE and ISTH grading systems. Data on anticoagulant used after HITT testing was collected. We also checked to see if the blood specimen for assay was collected 2 hours after last heparin product as recommended by lab. Patients were excluded if they were not inpatient when their heparin-induced platelet antibody assay was drawn or if they were transferred or discharged immediately after assay was collected. Ultimately, of the initial 196 patients who had heparin-induced platelet antibody assay collected during this time frame, 184 patients were included for analysis.Results:Of the 184 patients who had a heparin-induced platelet antibody assay sent and were included in analysis, 55.4% of the patients (n=102) had a low pre-test probability of HITT with a 4T score of less than or equal to 3. Of the patients who had HITT testing sent, only 44% (n=81) received treatment with a non-heparin anticoagulant. Of the 102 patients who had a low pre-test probability of HITT with a 4T score of ≤3, 37.3% (n=38) were placed on an alternative anticoagulant. Of this low pre-test probability of HITT cohort, 7.8% (n=8) experienced bleeding as a complication. Interestingly, 15.5% (n=29) of all patients who had HITT testing continued to receive heparin products while awaiting results. Additionally, 19.3% (n=36) of samples were drawn within 2 hours of receiving heparin products.Conclusion:The guidelines for HITT testing and treatment have been well-validated and widely disseminated. Despite providers' familiarity with this clinical entity, the results depict that ordering practices at our institution do not follow guidelines in cost-conscious ordering nor in standard of treatment. Applying ASH's Choosing Wisely recommendation of not ordering laboratory testing on patients with a 4T low-probability score of 0-3, we see that 55.6% of the HITT assays ordered in this time period were inappropriate and at a cost of $455 to the institution per assay resulted in $46,865 of unnecessary health care costs to our institution in one year's time. This does not include the cost of alternative anticoagulation. Heparin costs just $0.04 per mL while argatroban costs $3.81 per mL and bivalirudin $12 per mL resulting in a 100 to 300 fold cost increase respectively.Standard work regarding HITT assay collection and treatment does not exist at our institution. Of concern, 15.5% of patients continued to receive heparin products after HITT testing was sent. The results of this study prompted implementation of a quality improvement project to decrease inappropriate HITT testing and standardize treatment of suspected HITT via an electronic medical record order set that uses the 4T score to suggest appropriate ordering of assays. We plan to collect data on changes in our ordering practices after this intervention. DisclosuresNo relevant conflicts of interest to declare.

Anti-PF4/Heparin Antibody Levels in Bacteremia, Fungemia and Sepsis

Heparin-induced thrombocytopenia (HIT) is caused by antibodies targeting platelet factor 4 (PF4)/heparin complexes. The immune response leading to HIT remains perplexing with many paradoxes. Unlike other drug induced reactions, anti-PF4/heparin antibody generation does not follow the classic immunologic response. As Greinacher and colleagues have shown, the primary immune response lacks IgM precedence and class switching, and heparin-induced antibodies can induce HIT by day 5 in heparin-naïve patients.Continued exposure to heparin also is puzzling with a weak or declining secondary immune response. Research by Krauel and colleagues suggests that that there is close interplay among infection, PF4 and the immune system. In 2010 they demonstrated that human and murine PF4 bind to Gram positive (S.aureus, S.pneumoniae, L.monocytogenes) and Gram negative (E.coli, N.meningitidis) bacteria in vitro, with bacterial surfaces acting as polyanions. High dose heparin inhibited this binding and anti-PF4/heparin antibodies from patients with HIT reacted with these PF4/bacterial complexes (S. aureus and E. coli). Using a murine model, they went on to show that polymicrobial sepsis in the absence of heparin led to antibody generation. In a separate study, Krauel and colleagues also showed that PF4 binds specifically to the lipid A component of Gram negative bacteria.In this analysis, we report on anti-PF4/heparin antibody levels in groups of patients hospitalized for sepsis, as compared to a control group without sepsis. We examined 200 patients with sepsis, retrospectively identified, from a hospital database of anti-PF4/heparin testing done in medical inpatients with thrombocytopenia but low pretest probability of HIT. This included patients with bacteremia (57), fungemia (7) and sepsis without septicemia (136). For comparison, data from 50 patients without sepsis during the same time period was used. Inclusion criteria for all groups were age 18 years and older and antibody testing within 4 days of admission. Exclusion criteria were diagnosis of HIT or heparin allergy, prior hospitalization or heparin exposure within 90 days of admission, cardiopulmonary bypass or orthopedic surgery within 6 months, hemodialysis, active or past malignancy, antiphospholipid syndrome, autoimmune disease or immunosuppressive therapy.All patients studied were on subcutaneous heparin at prophylactic doses only (i.e. no intravenous use, no therapeutic anticoagulation). UFH use predominated with prevalence of >85% in all groups. Testing was done using a commercially available standardized solid phase enzyme-linked immunoassay (EIA) to detect antibodies (IgG/IgA/IgM) directed against PF4 complexed with polyvinylsulfonate (Genetic Testing Institute, Wisconsin). All assays were performed in the central hospital laboratory according to manufacturer's specifications and measured in optical density (OD) units. The data sets demonstrated continuous unimodal distribution with high OD outliers, indicative of varying immune responses along a continuum. Statistical significance was calculated using independent t-testing with p-value set at 0.05 for significance.Results showed that patients hospitalized with sepsis have higher anti-PF4/heparin antibody levels. Both patients with bacteremia, and sepsis without bacteremia, had significantly higher OD than patients without sepsis (p<0.05). There was no significant difference between Gram negative and Gram positive bacteremia and antibody levels. This suggests that bacterial cell wall components of both classes have similar antigenicity. Interestingly, patients with fungemia had much lower antibody levels compared to bacteremia and sepsis. Despite the small sample size for fungemia, this difference trended strongly towards statistical significance (p=0.05). The threshold for a positive EIA is currently established at OD>0.400, a value based on sensitivity and set by the manufacturer. When the prevalence of a positive EIA was assessed, 16% patients with sepsis and bacteremia tested positive compared to 4% in the control group. In summary, there is an increased prevalence of anti-PF4/heparin antibodies in patients hospitalized with bacterial but not fungal sepsis. These results support the theory that bacterial infection has a role to play in preimmunization leading to anti-PF4/heparin antibody generation. DisclosuresNo relevant conflicts of interest to declare.

Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin

BackgroundHeparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population.MethodsWe examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up.ResultsOverall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400–1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance.ConclusionsThe data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.

The level of heparin-induced antibodies in correlation with the result of the flow cytometric functional assay in the patients with suspected HIT

Heparin can induce the formation of antibodies against a heparin complex with a platelet factor 4 (PF4), leading to platelet activation and the development of heparin-induced thrombocytopaenia (HIT). Because screening...

Is the incidence trend of heparin-induced thrombocytopenia decreased by the increased use of low-molecular-weight-heparin?

BackgroundThe increasing trend of using low-molecular-weight-heparin (LMWH) versus unfractionated heparin (UFH) in hospitalized adult patients is raising concerns about the incidence of heparin-induced thrombocytopenia (HIT).MethodA retrospective study analyzed the requests for heparin-induced antibodies by enzyme-linked immunosorbent assay (ELISA) among adult hospitalized patients during the period from January 2011 to December 2013. These patients received either UFH or LMWH for prevention or therapeutic indications. Those with positive immune-mediated HIT were identified and considered as case patients.ResultThe usage of LMWH and UFH and development of HIT was determined during the study period. The incidence of HIT in patients receiving UFH and those receiving LMWH was 4.09 per thousand patients and 0.48 per thousand patients, respectively, (p<0.0001) with an overall incidence of 2.49 per thousand patients.ConclusionThe increased trend of using LMWH over UFH among hospitalized adult patients was observed and can be said to contribute to the diminished overall incidence of HIT.

A retrospective evaluation of fondaparinux for confirmed or suspected heparin-induced thrombocytopenia in left-ventricular-assist device patients.

BackgroundThrombotic events are a common complication of left ventricular assist device placement and warrant prophylactic anticoagulation. Heparin is the most common anticoagulant used for prophylaxis of thrombotic events in left ventricular assist device patients as a transition to oral anticoagulants but carries the risk of heparin-induced thrombocytopenia. Limited data is available for the treatment of heparin-induced thrombocytopenia in this patient population. We report an evaluation of 8 left ventricular assist device patients with suspected or confirmed HIT started on fondaparinux at the time of heparin-induced platelet-factor-4 antibody positivity.MethodsAdult patients were reported if they were heparin-induced platelet antibody positive, tested via enzyme-linked immunusorbent assay, post-operative after left-ventricular assist device, and were initiated on fondaparinux at the time of heparin-induced platelet antibody positivity. Waiver of informed consent was granted from the institutional review board. Baseline demographics, clinical course of HIT, safety and efficacy variables were collected.ResultsEight patients receiving fondaparinux were identified and included in this report. The patient group was on average 49 years old, weighing 95 kg, with calculated BMI 28.8 and consisted primarily of Caucasian males. Three patients developed new thromboses after initiation of fondaparinux for heparin-induced thrombocytopenia. Only one patient had a major bleeding event of an overt bleed after initiation of fondaparinux therapy.ConclusionsGiven the lack of major bleeding in this evaluation, fondaparinux could be a potentially safe treatment option for left ventricular assist device patients that are heparin-induced platelet antibody positive pending confirmatory testing results. Given the development of new thromboses in 3 of 8 patients, concern exists about the efficacy of fondaparinux in this patient population. Significant limitations exist regarding these conclusions in this evaluation. Controlled, systematic evaluations are necessary to delineate safety and efficacy of fondaparinux for heparin-induced thrombocytopenia in this population.

Elevated Heparin-Induced Antibodies Are More Common in Diabetic Patients with Vascular Disease

Background. Hypercoagulable disorders can lead to deep vein thrombosis (DVT), arterial thrombosis or embolization, and early or recurrent bypass graft failure. The purpose of this study was to identify whether diabetes increased the likelihood of heparin-induced platelet factor 4 antibodies in at risk vascular patients. Methods. We reviewed clinical data on 300 consecutive patients. A hypercoagulable workup was performed if patients presented with (1) early bypass/graft thrombosis (<30 days), (2) multiple bypass/graft thrombosis, and (3) a history of DVT, pulmonary embolus (PE), or native vessel thrombosis. Relevant clinical variables were analyzed and compared between patients with diabetes (DM) and without diabetes (nDM). Results. 85 patients (47 women; age 53 ± 16 years, range 16–82 years) had one of the defined conditions and underwent a hypercoagulable evaluation. Screening was done in 4.7% of patients with early bypass graft thrombosis, 60% of patients were screened because of multiple bypass or graft thrombosis, and 35.3% had a previous history of DVT, PE, or native vessel thrombosis. Of the 43 patients with DM and 42 nDM evaluated, 59 patients (69%) had an abnormal hypercoagulable profile. An elevated heparin antibody level was present in 30% of DM and 12% of nDM patients (chi-squared test P < 0.04). Additionally, DM was associated with a higher likelihood of arterial complications while nDM was associated with a higher rate of venous adverse events (chi-squared test P < 0.003). Conclusions. Diabetes is associated with a higher likelihood of developing heparin-induced antibodies and an increased combined incidence of arterial complications that include early or multiple bypass/graft thrombosis. This finding may influence the choice of anticoagulation in diabetic patients at risk with vascular disease.

Frequency of heparin/platelet factor 4-dependent platelet antibodies in patients undergoing angioplasty and stenting for cardiovascular disease and their role for on-clopidogrel platelet reactivity

The frequency of heparin-induced platelet antibodies (H/PF4 antibodies) following heparin exposure during percutaneous intervention with stent implantation is unknown. These antibodies may activate platelets and therefore contribute to high on-clopidogrel residual platelet reactivity (HRPR). We screened 288 patients after angioplasty and stenting for H/PF4 antibodies by an IgG/A/M ELISA. The 44 (15.3%) positive samples were further evaluated for IgG only antibodies, by the particle gel immunoassay (PaGIA), the heparin induced platelet activation assay (HIPA) and MEA. Further, we determined on-treatment platelet reactivity by multiple electrode aggregometry (MEA) in these patients. In vivo platelet activation was assessed by P-selectin expression. The prevalence of H/PF4 antibodies in the total patients' cohort was 15.3% (95% CI 11.3-20%) by the IgG/A/M ELISA, 9.4% (95% CI 6.3-13.4%) by the IgG ELISA, 11.5% (95% CI 8-15.7%) by PaGIA, 14.2% (95% CI 10.4-18.8%) by MEA, and 2.4% (95% CI 1-4.9%) by HIPA. On-treatment platelet reactivity was similar between patients without and with H/PF4 antibodies [39 AU (6-110 AU) vs. 41 AU (7-91 AU); P = 0.85]. HRPR was seen in 105 patients (37.5%), and occurred to a similar extent in patients without and with H/PF4 antibodies in all test systems (all P > 0.2). Further, there was no difference of the ELISA optical densities using the IgG/A/M or the IgG only ELISA between patients without or with HRPR (all P > 0.3). There was no significant difference of P-selectin expression between patients without or with H/PF4 antibodies (P = 0.97). Noteworthy, none of the patients who developed H/PF4 antibodies had heparin-induced thrombocytopenia or a thromboembolic event. H/PF4 antibodies are not rare in patients undergoing angioplasty and stenting. However, these antibodies are not associated with the occurrence of HRPR.

Pulmonary embolism caused by delayed heparin-induced thrombocytopenia in a patient who received prophylactic LMWH

SummaryBackground:Heparin induced thrombocytopenia (HIT) is a serious complication associated with heparin use. HIT usually develops between 5–14 days after starting heparin. Delayed-onset HIT can still occur 9–45 days after heparin had been discontinued. In patients with delayed HIT, the patient might be admitted to the hospital for new thrombosis and reexposure to heparin further worsens the patient’s condition.Case Report:Our patient is a 71-year old female readmitted for worsening dyspnea 2 weeks after she was discharged from the hospital. On her previous hospitalization, she was diagnosed with bronchiolitis obliterans organizing pneumonia (BOOP). She had received prophylactic doses of LMWH. Dyspnea was initially thought to be secondary to CHF exacerbation secondary to atrial fibrillation with rapid ventricular response. She was started on a heparin. However, the patient’s clinical condition deteriorated and she needed to be intubated. Her platelet counts also decreased rapidly. After CT angiography of the chest showed pulmonary embolism, HIT was strongly considered. All forms of heparin were discontinued and argatroban was started. However, the patient did not improve and she subsequently expired on the 7th hospital day. Heparin-induced antibodies came back positive that same day.Conclusions:HIT is an immune-mediated disorder characterized by formation of antibodies against heparin-platelet factor 4 complex. The major clinical presentation of HIT is arterial and venous thrombosis. Once HIT is suspected, immediate cessation of any form of heparin is needed. Alternative anticoagulation must be started. Early treatment decreases the incidence of new thrombosis and stroke, and improves survival and cost savings.

How I Diagnose and Manage HIT

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4)/polyanion complexes. Platelet activation assays, such as the serotonin-release assay, are superior to PF4-dependent immunoassays in discerning which heparin-induced antibodies are clinically relevant. When HIT is strongly suspected, standard practice includes substituting heparin with an alternative anticoagulant; the 2 US-approved agents are the direct thrombin inhibitors (DTIs) lepirudin and argatroban, which are "niche" agents used only to manage HIT. However, only ~ 10% of patients who undergo serological investigation for HIT actually have this diagnosis. Indeed, depending on the clinical setting, only 10%-50% of patients with positive PF4-dependent immunoassays have platelet-activating antibodies. Therefore, overdiagnosis of HIT can be minimized by insisting that a positive platelet activation assay be required for definitive diagnosis of HIT. For these reasons, a management strategy that considers the real possibility of non-HIT thrombocytopenia is warranted. One approach that I suggest is to administer an indirect, antithrombin (AT)-dependent factor Xa inhibitor (danaparoid or fondaparinux) based upon the following rationale: (1) effectiveness in treating and preventing HIT-associated thrombosis; (2) effectiveness in treating and preventing thrombosis in diverse non-HIT situations; (3) both prophylactic- and therapeutic-dose protocols exist, permitting dosing appropriate for the clinical situation; (4) body weight-adjusted dosing protocols and availability of specific anti-factor Xa monitoring reduce risk of under- or overdosing (as can occur with partial thromboplastin time [PTT]-adjusted DTI therapy); (5) their long half-lives reduce risk of rebound hypercoagulability; (6) easy coumarin overlap; and (7) relatively low cost.

Prevalence and Clinical Significance of Heparin Induced Antibodies in Chronic Hemodialysis Patients and Cardiac Surgery Patients

The prevalence of heparin-induced antibodies (HIA) varies widely among reported series, but is generally higher in cardiac surgery than hemodialysis patients. This study was designed to explore the reasons behind the different prevalence of HIA in these two populations. Blood samples from all hemodialysis and cardiac surgery patients in our hospital were examined for HIA. Heparin-induced thrombocytopenia (HIT) was suspected when platelet count was <150,000 in the hemodialysis group, and >50% decline in platelet count in the cardiac surgery group. 79 hemodialysis and 40 cardiac surgery patients were studied. HIA prevalence was significantly higher in cardiac surgery than in hemodialysis patients (65% v 10.1%, respectively, P<0.00001). Conversely, the prevalence of suspected clinical HIT was 37.5% in the hemodialysis and 11.5% in the cardiac surgery group. Prevalence of HIA was higher in patients who were tested during the first 90 days of hemodialysis than in those tested at later times. One-year mortality was 37% in HIA positive and 19% in HIA negative hemodialysis patients. Prevalence of HIA was significantly lower in hemodialysis as compared with cardiac surgery patients. Our data suggest that the observed difference in HIA prevalence was either population dependent, or due to different timing of heparin administration in the two groups.

Successful Use of Hirudin During Cardiac Surgery Using Minimized Extracorporeal Circulation in Patients With Heparin-Induced Thrombocytopenia

In this case series, we describe our successful use of a reduced hirudin dosage as an anticoagulant during cardiac surgery using minimized extracorporeal circulation in patients with heparin-induced thrombocytopenia.