Heparin-induced Thrombocytopenia Group Research Articles

Similarities of antiphospholipid antibodies in HIT and APS patients with heparin-platelet factor 4 antibodies

Heparin-induced thrombocytopenia (HIT) is a prothrombotic autoimmune disorder confirmed by the existence of Heparin-Platelet Factor 4 (HPF4) antibodies. The aim of this work is to study the possible relationship between anti-HPF4 and antiphospholipid antibodies (aPLs) that may explain the discrepancies observed in patients with a suspected HIT (HIT group) with positive immunoassay (HPF4-Elisa) and negative functional assay (heparin-induced platelet aggregation test). So, we performed H-PF4 antibodies research in 31 APS confirmed patients (APL group). All tests performed have been compared to normal controls (n = 34). We found anti-H-PF4 in 7/31 patients of APL group. In parallel, we search for aPLs in 9/34 patients tested positive for anti-HPF4 in HIT group, all of them were positive. All specificities were observed in the two anti-HPF4 positive groups (aβ2GP1 IgM/IgG/IgA, aCL (IgM/IgG/IgA, aPS-PT IgM/IgG). The most associated antibodies with anti-HPF4 are the anti ß2Glycoprotein1 (Odds ratio = 50.1). We suggest that the presence of aPLs in HIT group with anti-HPF4 could be the cause of the discrepancies. In addition, we performed the Heparin Neutralization Assay (HNA) which is specific for anti-HPF4, neutralization was obtained for patients exposed to heparin. Furthermore, we suggest that we should performed a larger cohort to confirm the causal relationship of aPLs and also to expand the tests allowing the differentiation between these autoantibodies.

Abstract 10166: Incidence and Outcomes of Heparin-Induced Thrombocytopenia Among Patients Undergoing Left Ventricular Assist Device Implantation

Background and Objectives: Heparin-induced thrombocytopenia (HIT) increases the risk of thromboembolic and bleeding events. HIT is also a well-known complication in patients undergoing left ventricular assist device (LVAD) implantation, although most studies are limited to case reports/series and single-center experiences. The main objective of this study is to examine the incidence and impact of HIT on outcomes in LVAD implants using a nationwide database. Methods: Using the National Inpatient Sample database (2007-2014), we identified patients ≥ 18 years that underwent LVAD implants using ICD-9 codes. LVAD implants were stratified by the presence of HIT. The primary and secondary endpoints were the impact of HIT on mortality and other outcomes respectively. Results: Out of the 15,083 LVAD implantations, HIT occurred in 331 (2.2%). Although not statistically significant, the annual incidence of HIT rose from 1.3% in 2009, peaked at 3.3% in 2012 and decreased to 2.0% (ptrend = 0.6171). In-hospital mortality (OR 2.21, 95% CI 1.30-3.74, p = 0.0034) and post-operative DVT/PE (OR 2.45, 95% CI 1.09-5.51, p = 0.0303) were significantly associated with HIT. Our analysis did not show any differences in the incidence of vascular complications, post-op stroke/TIA, hemorrhage requiring transfusion and acute kidney injury between HIT and non-HIT group. The HIT group stayed longer in the hospital (30 vs 27 days, p < 0.0001) and incurred higher total hospital charges ($695,834 vs. $640,089 p < 0.0001). Conclusion: Among patients undergoing LVAD implants, HIT was associated with higher risk of in-hospital mortality, post-op DVT/PE, higher hospital charges and longer hospital stay.

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.

Incidence, Outcomes and Risk Factors of Heparin-Induced Thrombocytopenia After Total Joint Arthroplasty: A National Inpatient Sample Database Study

Backgrounds: Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated complication of heparin exposure, leading to negative consequences after total hip (THA) and knee arthroplasty (TKA). Materials and Methods: A retrospective study was conducted using the National Inpatient Sample (NIS) database from 2005 to 2014. The incidence and outcomes of HIT after THA or TKA were documented. Logistic regression analysis was performed to identify the postoperative HIT risk factors. Results: A total of 59 3045 patients who underwent THA and 1228 707 patients who underwent TKA were identified. The cumulative incidences were 0.02% and 0.01%, respectively. The HIT group presented significantly higher Charlson Comorbidity Index and Elixhauser Comorbidity Index scores, longer hospital stays (LOS), and higher medical costs. HIT led to a significantly higher mortality rate after THA (2.17% vs 0.16%, P = .0091). In THA, the HIT risk factors were racial minority, AIDS, pulmonary circulation disorders (PCD), psychoses, and hypertension. In TKA, the HIT risk factors were racial minority, PCD, and weight loss. Conclusion: The incidence of HIT after THA and TKA is relatively low; however, HIT significantly increases inpatient mortality, LOS, and medical cost.

Outcomes With Heparin-Induced Thrombocytopenia After Cardiac Surgery

Heparin-induced thrombocytopenia (HIT) is an immune-mediated reaction to heparin that provokes a prothrombotic state and causes a decline in platelet count. Data describing outcomes of HIT after cardiac surgeryare limited. This study sought to determine theimpact of HIT on short-term outcomes after cardiac surgery. This was an observational study of cardiac surgeries from 2010 to 2018. Patients with HIT were matched against patients without HIT using 2:1 nearest-neighbor propensity matching. Matching was performed to assess the impact of HIT on operative mortality (The Society of Thoracic Surgeons definition) and thromboembolic events (including deep vein thrombosis, pulmonary embolism, stroke, and/or acute limb ischemia), which were the primary outcomes of interest. Of 11,820 patients undergoing a Society of Thoracic Surgeons indexed cardiac surgery, 131 (1.1%) developed HIT after their index operation. After matching operative mortality was 21.8% in HIT patients compared with 5.3% in non-HIT patients. Thromboembolic events occurred in 29.1% of HIT patients compared with 2.9% in non-HIT patients. On subanalysis operative mortality was significantly higher for the HIT group without thromboembolic events (16.7%) and the HIT group with thromboembolic events (34.4%) compared with the non-HIT group (5.3%). However operative mortality was not significantly higher in the HIT group with thromboembolic events compared with the HIT group without thromboembolic events, after Bonferroni correction. Although uncommon, HIT is a highly morbid and potentially lethal complication, which should reinforce the importance of timely recognition and treatment of this adverse outcome.

Incidence and outcomes of heparin-induced thrombocytopenia in solid malignancy: an analysis of the National Inpatient Sample Database.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction to heparin products characterized by thrombocytopenia with or without thrombosis. This study aimed to determine the incidence, morbidity, mortality and economic burden of HIT in solid-malignancy-related hospitalizations. We analyzed the National Inpatient Sample Database (NIS), the largest public database of hospital admissions in the United States, from January 2012 to September 2015. The primary outcome of the study was the incidence of HIT. Secondary outcomes included incidence of venous thrombosis (acute deep venous thrombosis and pulmonary embolism), arterial thrombosis (thrombotic stroke, myocardial infarctions and other arterial thromboembolism), mortality associated with HIT, length of stay, total hospital charges and disposition. During the study period, 7437049 hospitalizations had an associated diagnosis of solid malignancy. Approximately 0·08% (n=6225) hospitalizations had a secondary diagnosis of HIT in this population. The standardized incidence of total thrombotic events was higher in the solid malignancy with HIT compared to the solid malignancy without HIT group (24·7% vs. 6·8%, P<0·001). The standardized mortality rate was 4·8% in solid malignancy with HIT compared to 3·4% in the without HIT group (OR, 1·53; 95% CI, 1·25-1·89; P<0·001). HIT in solid malignancy is a rare condition but associated with increased morbidity and mortality.

Heparin-induced Thrombocytopenia in Acute Coronary Syndrome.

IntroductionHeparin-induced thrombocytopenia (HIT) is by far the most relevant pathological association of it encountered by clinicians. It is an immune-mediated phenomenon caused by antibodies directed against complexes of heparin molecules and platelet factor 4 (PF4). HIT is a considerable side effect in patients of acute coronary syndromes (ACS). Its prevalence and associated outcomes in ACS patients have not been studied sufficiently except for clinical trials. The objective of this study was to assess the frequency of HIT in patients presenting with ACS.MethodsThis was an observational study with 272 patients between 40 and 70 years of either gender presenting with ACS within 24 hours of the first appearance of symptoms. Blood samples for baseline platelet count were taken before heparin therapy. Then, patients were subsequently administered low molecular weight heparin 5000 units stat, followed by 12 units/kg/hr for 72 hours of intravenous infusion. Blood samples were repeated for platelet count on Day 5. Thrombocytopenia was defined as per the recommendation of American College of Cardiology as " ≥50% decline in platelets (below 150 x 109/L in most patients), which may occur immediately following heparin exposure (rapid presentation) or up to three weeks following exposure (delayed presentation)." Reports were assessed for the level of platelets. Data were entered and analyzed using SPSS version 22 (IBMCorp, Armonk, NY, US).ResultsThe incidence of HIT was observed in 9.56% (n=26). In the HIT group, the mean platelet count on Day 5 was 109.81 ± 78.06 x 109/L. The incidence of HIT in ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) were equal but higher than that in unstable angina (UA) (p-value=0.01). The incidence of HIT was also significantly higher in the group that presented late to the hospital (after 12 hours of symptom onset) (p-value=0.001).ConclusionThe risk of HIT is more prominent in patients with myocardial infarction and in those who have a duration of symptoms more than 12 hours at the time of hospital presentation. Cardiologists and specialists of internal medicine have to take precautions while administrating heparin therapy in these high-risk patients, to avoid any complications.

Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review

AbstractDirect oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score ≥4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non-heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4%-11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban.

Clinical outcomes in a cohort of patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder usually prompting treatment with non-heparin anticoagulants. The benefits and risks of such treatments have not been fully assessed. We analyzed data for 442 patients having a positive heparin-platelet factor 4 antibody test and recent heparin exposure. The primary outcome was a composite endpoint (death, limb amputation/gangrene, or new thrombosis). Secondary outcomes included bleeding and the effect of anticoagulation. Seventy-one patients (16%) had HIT with thrombosis (HIT-T); 284 (64%) had HIT without thrombosis (isolated HIT); 87 (20%) did not have HIT. An intermediate or high "4T" score was found in 85%, 58%, and 8% of the three respective groups. Non-heparin anticoagulation was begun in 80%, 56%, and 45%. The composite endpoint occurred in 48%, 36%, and 17% (P = .01) of which 61%, 38%, and 40% were receiving non-heparin anticoagulation. Compared with the no HIT group, the composite endpoint was significantly more likely in HIT-T [HR 2.48 (1.35-4.55), P = .003)] and marginally more likely in isolated HIT [HR 1.66 (0.96-2.85), P = .071]. Importantly, risk increased (HR 1.77, P = .02) after platelet transfusion. Major bleeding occurred in 48%, 36%, and 16% of the three groups (P = .005). Non-heparin anticoagulation was not associated with a reduction in composite endpoint events in either HIT group. HIT patients have high risks of death, limb amputation/gangrene, thrombosis, and bleeding. Non-heparin anticoagulant treatment may not benefit all patients and should be considered only after careful assessment of the relative risks of thrombosis and bleeding in individual patients.

Clinical analysis of heparin induced thrombocytopenia after liver transplantation in children

Objective To analyze the clinical features and the impact of heparin induced thrombocytopenia (HIT) after liver transplantation in children. Methods The clinical data of 64 patients who underwent liver transplantation from June 2006 to March 2015 in the Children's Hospital of Chongqing Medical University were retrospectively analyzed. The aims were to investigate the risks of HIT, and its impact on prognosis of liver transplantation. Results 64 patients were enrolled in this study. Five patients (5/41, 12.1%) progressed to develop HIT postoperatively in the unfractionated heparin (UFH) group. This group included 2 patients who were aged under 3 years (2/33, 6.1%) and 3 patients who were aged over 3 years (3/8, 37.5%). No patient progressed to develop HIT in the low molecular weight heparin (LMWH) group. For the perioperative mortality, 3 patients (3/5, 60%) died in the HIT group including 2 patients had hepatic artery thrombosis. Six patients (8/59, 13.6%) died in the Non-HIT group. Conclusions HIT was one of the death causes after liver transplantation in children. Children aged over 3 years had a higher incidence of HIT. Key words: Children; Liver transplantation; Heparin; Thrombocytopenia

Impact of renal function on argatroban therapy during percutaneous coronary intervention

Argatroban, a hepatically metabolized direct thrombin inhibitor, is approved for anticoagulation in patients with or at risk of heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention (PCI). We investigated the effect of renal function on argatroban therapy during PCI. From previous argatroban studies in PCI, we evaluated relationships between estimated creatinine clearance (CrCl) and activated clotting times (ACTs), dosage, and outcomes in 219 patients with or at risk of HIT (HIT group, n = 67) or administered glycoprotein IIb/IIIa inhibition (non-HIT group, n = 152). Patients received an argatroban bolus (350 mcg/kg, HIT group; 250 or 300 mcg/kg, non-HIT group) then 25-30 mcg/kg/min (adjusted to achieve ACTs 300-450 s, HIT group) or 15 mcg/kg/min (target ACTs 275-325 s, non-HIT group), with additional 150-mcg/kg boluses if needed. Of 219 patients, 55 (25%) had CrCl <or= 60 ml/min (8 with CrCl <or= 30 ml/min). Regression analyses detected no association between CrCl (range 7-231 ml/min) and initial ACT (by bolus) or mean infusion dose. Multi-bolus usage was similar in patients with, versus without, CrCl <or= 60 ml/min. In the non-HIT group, CrCl was associated (P = 0.01) with the time to ACT <or= 160 s after argatroban cessation (approximately 17 min slower per 30-ml/min CrCl decrease). Eight patients (none with CrCl <or= 60 ml/min) had ischemic complications. Three patients (1 with CrCl 40 ml/min) experienced major bleeding. Argatroban dose adjustment for renal function appears unnecessary during PCI. Renal dysfunction may be associated with slower (by minutes) ACT effect decay after argatroban cessation. Argatroban is well tolerated in PCI patients with renal impairment.

Polymorphisms in TNFA and CTLA-4 Genes and the Risk of Heparin Induced Thrombocytopenia.

Backgroud and objectives: The formation of antibodies (Abs) to heparin platelet factor 4 complexes (H/PF4) associated with heparin-induced thrombocytopenia (HIT) is a T-helper cell dependent event that involves antigen presenting cells (APC) and B-lymphocytes. Polymorphisms of the CTLA-4 (cytotoxic T lymphocyte antigen 4) gene have been described as a risk factor in several autoimmune diseases. In addition, TNFα is a major inflammatory cytokine with potent regulatory functions and polymorphisms in TNFA have also been associated with autoimmune antibody-mediated diseases. We therefore evaluated the possibility that an association between polymorphisms in CTLA-4 (−318 C/T and +49 A/G) or TNFA (−308 G/A) and the development of Abs to H/PF4 and HIT might exist.Methods: Eighty-three patients identified as having developed definite HIT with significant levels of Abs to PVS/PF4 in ELISA (HAT 45, GTI, Brookfield, WI, USA) and positive serotonin release assay were studied (HIT group). Two control groups were studied: the Abneg group consisted of 83 patients who had undergone heart surgery with high doses of unfractionated heparin administered during cardiopulmonary bypass (CPB), and who were tested negative for Abs to PVS/PF4 at the 8th post operative day. The Abpos group consisted of 58 patients who had also undergone CPB but had developed high levels of Abs to PVS/PF4 without significant change in the platelet count post-operatively. Three single nucleotide polymorphisms (SNPs), one in TNFA (−308G/A) and two in CTLA-4 (−318 C/T and +49A/G) were studied by conventional RFLP analysis as described (Astermark et al, Blood 2006 and Astermark et al, Thromb Haemost 2007).Results: The CTLA-4 +49 A/G and −318 C/T genotypes and allele distributions were similar in the 3 groups of patients (Table). In contrast, the frequency of TNFA –308 G/G homozygotes was higher in the HIT group compared to patients without HIT whether they had developed PF4-specific Abs or not (p=0.035). Therefore, the A allele was less frequent in HIT patients (p=0.026, OR 0.49; CI95% 0.26–0.93) but there was no significant difference when comparing patients with and without PF4-dependent antibodies.Genotype Allele frequencyAbneg (n = 82)Abpos (n = 58)HIT (n = 82)CTLA-4(+49)A/A31 (38%)24 (41%)35 (43%)A/G40 (49%)26 (45%)41 (50%)G/G11 (13%)8 (14%)6 (7%)CTLA-4(−318)C/C63 (77%)49 (84%)67 (82%)C/T19 (23%)9 (16%)17 (21%)T/T000 (0%)TNFα(−308)G/G59 (72%)41 (71%)68 (84%)G/A20 (24%)15 (26%)12 (15%)A/A3 (4%)2 (3%)1 (1%)A Allele0.1600.1600.09G Allele0.8400.8400.910Conclusion: The TNFA –308 A allele appears to be protective regarding the risk of heparin-induced thrombocytopenia in patients having developed PF4-specific antibodies. A similar effect has been suggested in immune thrombocytopenic purpura (Foster et al, Brit J Haematol 2001) despite individuals with this allele have been identified as high TNFα producers. Therefore, the mechanisms involved for explaining this apparent protective effect of the TNFA −308A allele in patients at risk for HIT have to be identified.

Heparin-induced thrombocytopenia (HIT): Clinical and economic outcomes

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that occurs following exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). HIT with thrombosis (HITT) can cause devastating venous thromboembolism or arterial clots, prolonged hospitalization, and increased costs. To explore the economic and clinical implications of HIT and HITT, we initiated a single-center patient registry. In this report, we describe patient characteristics, comorbidities, management strategies, clinical outcomes, and costs. We enrolled 349 hospitalized patients with an enzyme immunoassay-confirmed diagnosis of HIT over a 40-month period. Patients were assessed for the primary outcome of 30-day mortality, as well as baseline characteristics, development of thrombosis, and the economic impact of HIT. The primary outcome measure was 30-day mortality and occurred in 58 (16.6%) patients, 40 (15.3%) in the HIT group versus 18 (20.7%) in the HITT group (p = 0.25). The frequency of HIT was greater in patients exposed to UFH than in patients exposed to LMWH (0.8% vs. 0.2%, respectively, p < 0.001). Both HIT and HITT patients who were exposed to UFH had higher hospital costs than those exposed to LMWH ($113,100 vs. $56,352, respectively, p < 0.001). HIT remains an important clinical problem with a high mortality rate and significant cost, regardless of development of thrombosis. Prospective controlled trials need to be conducted to determine the optimal strategy to reduce the frequency of HIT.

A Unique Biomarker Is Associated with the Prevalence of Functional Heparin Induced Thrombocytopenia (HIT) Associated Antibodies: Results from Proteomic (ProteinChip Array) Profiling of ELISA Positive HIT Plasma Samples.

Heparin induced thrombocytopenia (HIT) represents a complex immunopathologic syndrome resulting in the activation of coagulation, inflammatory and cellular processes, which contribute to the overall pathogenesis. Protease mediated transformation of endogenous proteins resulting in the generation of certain mediators and specific cleavage products may be used to understand the pathogenesis of this syndrome. It was hypothesized that unique biomarkers may be generated in patients who develop HIT antibodies upon exposure to heparins. The identification of unique biomarkers and their prevalence in heparin exposed patients may provide an additional parameter in the prognosis of this syndrome. To profile the proteomic biomarkers in serum, specimens were selected from archived sera that had been referred to Loyola University Medical Center for the quantitation of HIT antibodies and 14C Serotonin Release Assay (SRA). All of these specimens were positive in the GTI PF4 Enhanced ELISA for the presence of anti-heparin platelet factor 4 antibodies with a broad range of antibody titers absorbance range (0.4 – 2.5). Eleven of these specimens were positive in the SRA. All of these samples were proteomic profiled utilizing a ProteinChip Array method using a Gold (AU) Chip in the molecular weight range of 0 – 150 kDa. The normal sera samples (n = 40) were also analyzed simultaneously in a crossover fashion along with the patients' specimens. Surface enhanced laser desorption/ionization (SELDI) technique utilizing Ciphergen PBS II (Fremont, CA) was used for mass profiling. Proteomic profiling is widely used to identify unique biomarkers in various hemotologic disorders. Although electrophoretic methods identify biomarkers at molecular weights ≥ 25 kDa, the SELDI technique provides a complete spectrum in the lower molecular weight range. The ProteinChip Software for mass profiling was used to analyze the data. Proteins such as albumin were used as control proteins throughout the study. Of the 54 HIT samples profiled, 36 showed a unique biomarker peak at 11.9 kDa (67%) whereas none of the normal sera (n = 40) showed this peak. All of the SRA positive samples also showed the 11.9 kDa biomarker peak. Several biomarker peaks in the range of 5 – 10 kDa were present in the HIT positive sera suggesting increased proteolysis. While no other unique biomarkers were obvious in the HIT samples, the relative proportion of some of the biomarker peaks in the range of 15 – 20 kDa were differentiable in the HIT group. These studies demonstrate that HIT patients' sera exhibit a unique biomarker profile, which is distinguishable from normal serum samples. Combined usage of the ProteinChip Array analysis of the HIT patients' sera with other diagnostic methods may further enhance the diagnostic process for this syndrome. Additional molecular characterization of these biomarkers will also help in the understanding of the pathogenesis of HIT with particular reference to the protease activation processes.

Effect of body mass index on Argatroban therapy during percutaneous coronary intervention

Obesity is common in patients undergoing percutaneous coronary intervention (PCI). Argatroban, a direct thrombin inhibitor, is used during PCI in patients with or at risk of heparin-induced thrombocytopenia (HIT) and also has been evaluated in conjunction with glycoprotein IIb/IIIa inhibition in nonHIT patients. We investigated the effect of body mass index (BMI), and specifically obesity (BMI>30 kg/m2), on argatroban therapy during PCI. From previously reported studies of argatroban therapy during PCI in patients with or at risk of HIT (ie, HIT group) or in conjunction with glycoprotein IIb/IIIa inhibition (ie, nonHIT group), we identified patients with sufficient data to determine BMI. After an initial bolus of 350 microg/kg (HIT group) or 300 or 250 microg/kg (nonHIT group), patients received continuous argatroban 25-30 microg/kg/min (adjusted to achieve ACTs of 300-450 s, HIT group) or 15 microg/kg/min (target ACTs of 275-325 s, nonHIT group) during PCI, with additional 150 microg/kg boluses allowed if needed. Regression analyses evaluated relationships between patient BMI and ACT response to initial bolus administration, mean infusion dose (HIT group only), and rate of ACT decline after PCI. Frequencies of additional bolus usage and clinical outcomes were compared between obese and nonobese patients. Our analysis population included 225 patients (85 obese) in total: 73 in the HIT group and 152 in the nonHIT group (300 microg/kg bolus, n=101; 250 microg/kg bolus, n=51), with BMIs of 16.3-50.9 kg/m2. No association was detected between BMI and the first ACT after bolus administration (median ACTs of 361, 298, and 289 s, respectively, following 350, 300, and 250 microg/kg bolus), mean infusion dose (24.2+/-4.9 microg/kg/min overall in HIT group), or time to ACTs<or=160 s after argatroban cessation (median 4.4 h in HIT group and 1.7-2.1 h in nonHIT group). Fifteen (5 obese) patients in the HIT group and 36 (13 obese) in the nonHIT group required additional boluses, without differences by obesity versus nonobesity (P>or=0.35). Clinical outcomes did not differ (P>or=0.09) between obese and nonobese individuals: 4 (3 obese) patients in the HIT group and 4 (2 obese) in the nonHIT group had ischemic complications; 1 nonobese patient in the HIT group and 2 (1 obese) in the nonHIT group experienced major bleeding. These findings support the use of actual body weight-adjusted (and ACT-targeted) argatroban therapy during PCI and suggest that dose adjustment for obesity (BMI up to 50.9 kg/m2) is unnecessary.

The homozygous FcγRIIIa-158V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes

AbstractWe hypothesized that Fcγ receptor IIIa (FcγRIIIa), a polymorphic receptor for the Fc portion of immunoglobulin G (IgG) other than FcγRIIa, was involved in heparin-induced thrombocytopenia (HIT). FcγRIIa-131 and FcγRIIIa-158 genotypes were determined in 102 patients with definite HIT and in 2 control groups of patients treated by heparin (86 subjects without detectable antibodies [Abs] to heparin-platelet factor 4 [H/PF4], Ab- group; 84 patients with Abs to H/PF4 without HIT, Ab+ group). There were no significant differences in genotype distribution or allele frequencies between the 3 groups for FcγRIIa-131H/R polymorphism. In contrast, FcγRIIIa-158V homozygotes were more frequent in the HIT group than in the Ab+ group (P = .02), a difference that was more pronounced in patients with high levels of anti-H/PF4 Abs (P = .01). Since anti-H/PF4 Abs are mainly IgG1 and IgG3, clearance of sensitized platelets may be increased in patients homozygous for the FcγRIIIa-158V allotype, thus contributing to the development of thrombocytopenia. (Blood. 2004;104:2791-2793)

Thrombosis and hemorrhage in heparin-induced thrombocytopenia in seriously ill patients.

Heparin-induced thrombocytopenia (HIT) is the most common form of drug-induced immune-mediated thrombocytopenia. HIT may be aggravated by life-threatening arterial and venous thrombosis and, to a lesser extent, hemorrhagic complications. We investigated the incidence of thromboembolic and hemorrhagic complications in critically ill patients with the multiple organ dysfunction syndrome and HIT. Case-control study. A 33-bed general intensive care unit in a university-affiliated teaching hospital. Twenty consecutive patients with laboratory-proven HIT compared with 20 contemporary, consecutive patients without HIT. Unfractionated heparin or low-molecular-weight heparin were replaced by danaparoid sodium in patients with HIT. Heparin-induced thrombocytopenia was proven by a positive platelet aggregation test. The HIT group consisted of 14 males and 6 females aged 65.2+/-10.8 years (mean +/- standard deviation) with APACHE II scores of 26.7+/-5.4. Thrombocytopenia less than 100 x 10(9)/l developed within 6.4+/-7.0 days. In 12 patients thrombocytopenia resolved after discontinuation of unfractionated heparin in 8.8+/-6.4 days. Arterial and venous thromboembolic complications occurred more frequently in HIT patients than in non-HIT patients (10/20 (50%) versus 0/20 (0%); chi-square p<0.001). Hemorrhagic complications also occurred more frequently in HIT patients than in non-HIT patients (17/20 (85%) versus 7/20 (35%); chi-square p=0.001). In critically ill patients with HIT, the incidence of thromboembolic complications and hemorrhagic complications was remarkably high.

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia.

As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immune-mediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS. We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died. Amongst HIT patients three died from causes unrelated to HIT. No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P=0.01), a significantly lower platelet count nadir (43 +/- 32 vs. 75 +/- 63 x 109/L; P=0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 +/- 1024 vs. 1277 +/- 858; P=0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, chi2 8.4, P=0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, chi2 4.6, P=0.03). Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.