Prior Heparin Exposure Research Articles

HR-pQCT reveals marked trabecular and cortical structural deficits in women with pregnancy and lactation associated osteoporosis (PLO).

Pregnancy and lactation associated osteoporosis (PLO) is a rare presentation of early-onset osteoporosis characterized by low trauma, spontaneous fractures during late pregnancy/lactation. Herein, we report areal BMD (aBMD) by DXA and volumetric BMD (vBMD), microarchitecture and strength at the distal radius and tibia by HR-pQCT in 59 women with PLO - in comparison to both healthy premenopausal Controls (n= 28) and premenopausal women with idiopathic osteoporotic fractures not associated with pregnancy/lactation (Non-PLO IOP;n= 50). Women with PLO (aged 34 ± 6yrs) had a more severe clinical presentation than Non-PLO IOP: 80% had vertebral and 92% had multiple fractures (P<.001). They had lower DXA aBMD at all sites vs Controls (all P<.001) and non-PLO IOP (all P<.05). By HR-pQCT, PLO had deficits in all radial/tibial density and most microarchitecture parameters, and lower bone strength than Controls (all P<.001). Compared to non-PLO IOP, PLO had lower total and trabecular density at radius and tibia (all P≤.01) and significant deficits in trabecular microstructure and cortical thickness at the radius only. We studied PLO subgroups with clinical factors potentially related to bone physiology: Within PLO, women with vertebral fractures had lower spine aBMD and higher tibial cortical porosity but were otherwise structurally similar to the nonvertebral group. Those with prior heparin exposure had larger bone size and trabecular area, and those with renal stones had smaller bone size and lower 1/3radius aBMD. We also compared groups based on postpartum timing: Recent PLO (n= 25) evaluated ≤12M postpartum, before expected recovery of pregnancy/lactation bone loss, had significantly lower aBMD than Distant PLO (n= 34) evaluated >12M postpartum. However, radial/tibial HR-pQCT measures did not differ, suggesting pre-existing and/or persistent structural deficits. This structural study increases our mechanistic understanding of the severe bone fragility presentation that characterizes PLO and also highlights areas of potential mechanistic heterogeneity that require additional investigation.

Evaluating the effectiveness of pseudothrombocytopenia (PTCP) panel with alternative anticoagulants on clinically suspicious EDTA-dependent PTCP: a single tertiary hospital experience

Abstract EDTA is considered the most common anticoagulant to induce pseudothrombocytopenia (PTCP). PTCP panel with alternative anticoagulants (heparin and citrate) has been ordered by clinicians in our hospital for suspicious EDTA-dependent PTCP cases to obtain the correct platelet count (PC). In this study, we aimed to evaluate the effectiveness of alternative anticoagulants on clinically suspicious EDTA-PTCP. We retrospectively identified cases for which PTCP panel (EDTA, heparin, and citrate) was performed from June 2021 to March 2022 using the SAP business intelligence tool. PC was considered significantly different when the difference is more than 25% comparing heparin or citrate to EDTA tubes. Representative cases were chosen for chart review and/or peripheral blood smear review. 200 cases were included in the study. 76 cases had similar PCs in all 3 tubes which represent either true thrombocytopenia or PTCP in all 3 tubes. 17 cases had higher PC on heparin and/or citrate than EDTA which are EDTA-PTCP corrected by alternative anticoagulants (confirmed by smear review). Among those 17 cases: 6/17 had high PC on citrate only, 2/17 on heparin only and 9/17 had higher PC on citrate/heparin. 82 cases had lower PC on heparin only compared to EDTA and 62/82 had heparin exposure. There was 1 case with lower PC on citrate only (no heparin tube) compared to EDTA. 24 cases had lower PC in both heparin and citrate than EDTA tubes (lowest PC on Heparin) and 21/24 have heparin exposure. Peripheral blood smears were reviewed in 39 representative cases. Platelet clumps were identified in the corresponding tubes of all cases. Our study shows that heparin-PTCP is common in hospitalized patients and confirms that heparin is not a suitable alternative anticoagulant for EDTA-PTCP as shown by previous literature. However, many laboratories still use it for EDTA-PTCP. Heparin is known to promote platelet activation which may cause PTCP. The low PC in the heparin tube also seems to be associated with prior heparin exposure. Citrate is a better alternative to EDTA-PTCP. Among cases with low PCs on citrate, nearly all have low PCs on heparin as well. It is interesting to note those cases usually have lower PCs on heparin versus citrate and have prior exposure to heparin. The low PCs on citrate might be partially due to insufficient correction (110%) of PC by the dilution factor of the anticoagulant. Literature showed that a higher corrective factor of PCs is required for citrate. Therefore, a correlation study of PCs in EDTA versus citrate in each lab is needed to establish the corrective factor. Furthermore, delayed processing might be contributing as PCs on citrate are less stable and must be processed within 3 hours.

Never too soon to be thinking about heparin-induced thrombocytopenia! A case report of early onset heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a serious complication that can affect a small percentage of patients receiving heparin. Atypical HIT presentations like delayed onset HIT have been described. We present an atypical case of early onset HIT in a patient presenting with ACS with no prior heparin exposure and shed light on the various atypical HIT and HIT-like presentations.

336: EVALUATION OF A PHARMACY-MANAGED HEPARIN-INDUCED THROMBOCYTOPENIA STANDARD OPERATING PROCEDURE

Introduction: Heparin-induced thrombocytopenia (HIT) is associated with significant morbidity and mortality, necessitating early identification and timely diagnosis. The objective of this study was to evaluate a pharmacy-managed HIT standard operating procedure (SOP). Methods: A retrospective analysis of HIT laboratory testing at Nebraska Medicine before (April 2018 to August 2019) and after (April 2020 to August 2021) SOP implementation was performed on patients admitted to the ICU. Patients were included if an anti-PF4 antibody and/or SRA test was ordered during hospitalization with prior heparin exposure. Exclusion criteria were age < 19, no heparin product exposure prior to HIT laboratory testing, or if lab testing was ordered ≥15 days from receiving heparin. The primary outcome was appropriately documented heparin allergy field in the medical record. Secondary outcomes include false positive anti-PF4 antibody assays, time from heparin initiation to HIT laboratory testing, duration of direct thrombin inhibitor (DTI) use, hospital length of stay, and in-hospital all-cause mortality. Results: 226 patients were evaluated, 110 in the pre- and 116 in the post-cohort. Baseline characteristics demonstrated most patients were male (58.8%), white (81.4%), and were anticoagulated with an indication of VTE prophylaxis (61.1%). Acute trauma/surgical procedure was the most common reason for admission (31%). Appropriate heparin allergy documentation occurred in 95.5% of patients in the pre- and 97.4% of patients in the post- cohort (p=0.528). No difference was found in the incidence of false positive anti-PF4 antibody assays (9.1% vs 8.6%) or time from heparin initiation to HIT laboratory testing (3.2 vs 3.6 days). DTI’s were utilized for a longer duration of time in the pre- cohort compared to the post-cohort (4.9 vs 2.8 days). There was no difference in hospital length of stay (17.9 vs 17.4 days), but in-hospital all-cause mortality was observed more frequently in the post-cohort than the pre-cohort (36.2% vs 23.6%). Conclusions: The implementation of a pharmacist-driven heparin-induced thrombocytopenia standard operating procedure demonstrated a similar incidence of appropriate heparin allergy documentation in the medical record compared to a physician-driven approach.

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.

Organ transplantation from deceased donors with vaccine-induced thrombosis and thrombocytopenia

Vaccine-induced thrombosis and thrombocytopenia (VITT) may follow immunisation with the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Autoantibodies to platelet factor 4 (PF4) may mediate VITT through antibody-dependent platelet activation, though the underlying etiology is uncertain. Anti-PF4 antibodies are also seen in heparin-induced thrombocytopenia, though most cases of VITT do not have prior heparin exposure. More than 20 million people in the United Kingdom (UK) have received the ChAdOx1 nCoV-19 vaccine.

Spontaneous Heparin-Induced Thrombocytopenia and COVID-19 Infection

Background and Objective: Heparin-induced thrombocytopenia (HIT) can develop if immune responses to infections become pathologic in the presence of heparins. Low molecular weight heparin or unfractionated heparin are recommended for prophylaxis and treatment of venous thromboembolic disease in hospitalized patients with Covid-19 infection but may trigger HIT. Our aim is to alert clinicians that HIT occurs in association with Covid-19 infections even in the absence of prior exposure and may not be easily recognized without a high index of suspicion. Case Summary: A 33-year-old previously healthy male was initially evaluated for low grade fever, dyspnea without hypoxia and cough. A Covid-19 PCR swab was negative despite a recent exposure. He was treated with azithromycin. However, his symptoms did not improve, he then developed right leg swelling and hypoxia, so he was re-evaluated. CTA of the chest showed bilateral pulmonary emboli and ground-glass opacities at the lung bases. Venous Duplex Ultrasound showed non-occlusive thrombus in the deep veins of right lower extremity. He was hospitalized and placed on oxygen and heparin. Covid-19 swab was negative again. Laboratory tests before heparin showed a decreased platelet count of 64,000 k/ul, elevated prothrombin time of 16.4 seconds, normal aPTT at 30.8 seconds, decreased serum fibrinogen at 120 mg/dl and markedly elevated D-dimer at 59,966 ng/ml. Lupus anticoagulant and anti-phospholipid antibody tests were negative. On heparin at the desired therapeutic aPTT target range, the right leg became significantly swollen and painful by day five. Platelet count had decreased further to 39,000 k/ul. Repeat doppler examination of the right leg now showed more severe and extensive deep venous thrombosis. D-dimer had increased to 125,133 ng/ml. The HIT 4T score was 4, suggesting intermediate probability. Rapid HIT immunoassays on 2 separate samples were positive. Heparin was discontinued and he was placed on argatroban. Serotonin release assays on 2 separate samples came back positive. Suspicion for Covid-19 infection remained high and so a Covid-19 serology sample was obtained which was positive for IgG. A repeat nasopharyngeal swab at this time turned positive. He did not receive any COVID specific treatments. As viability of his leg appeared threatened, he underwent right iliofemoral vein thrombectomy with arteriovenous fistula creation. He improved on argatroban and was transitioned to apixaban with gradual normalization of hemostasis laboratory parameters, improvement in hypoxemia and fading clinical symptoms, he was discharged home on day 15. Conclusion: Current consensus guidelines for thromboprophylaxis and treatment of thromboembolism in hospitalized patients with Covid-19 infection recommend heparins as primary therapy to reduce morbidity and mortality. However, our report in addition to the two previous reports of HIT in Covid-19 patients illustrate that HIT can be a complication in the setting of Covid-19 infection. Further, our report also highlights that HIT with thrombosis can occur in a spontaneous manner in the absence of prior heparin exposure, which has been so far studied only in bacterial infection with the hypothesis that Platelet factor 4 (PF4) can bind to negatively charged polysaccharides on the surface of bacteria, triggering an immune response. DisclosuresNo relevant conflicts of interest to declare.

The first known case of vaccine‐induced thrombotic thrombocytopenia in Australia

The first known case of vaccine‐induced thrombotic thrombocytopenia in Australia

HIT in the head: a systematic review of cerebral venous sinus thrombosis in classical and autoimmune heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) causes thrombosis and thrombocytopenia, usually due to prior heparin exposure, so-called classical HIT. However, in the autoimmune form, the signs and symptoms of HIT occur without prior heparin exposure. Development of cerebral venous sinus thrombosis (CVST) secondary to HIT is a rare occurrence, with relatively few reports in the literature. There is a need to better understand the clinical presentation and treatment paradigms in these rare cases. Therefore, we present the first systematic review of CVST occurring in classical and autoimmune HIT. Cases of HIT-induced CVST were identified through a systematic search of Pubmed from the date of inception to March 2021. Literature search revealed 21 cases of HIT and associated CVST with six cases (28.6%) of autoimmune HIT. Patients presented with signs and symptoms consistent with increased intracranial pressure, intracerebral hemorrhage (ICH), and/or focal neurologic deficits. Headache was the most common symptom with 12 patients (60.0%) presenting as such. 10 patients (47.6%) included in the study developed ICH. Non-heparin anticoagulants, especially direct thrombin inhibitors, were the first-line treatment for the majority of patients (55.6%). Intravenous immunoglobulin (IVIG) was used as treatment for select patients (16.7%) with autoimmune HIT. Few patients received surgical intervention for CVST (14.3%) or ICH (30.0%). Four patients had a full recovery, four patients had residual deficits, and seven patients ultimately expired. Symptoms of HIT-induced CVST are often related to CNS dysfunction. Non-heparin anticoagulants are important to treat CVST, even when patients have concomitant ICH, and may be supplemented with IVIG if treating autoimmune HIT. Rapid identification and treatment of HIT-induced CVST is imperative in order to prevent morbidity and mortality.

US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021

Cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare and serious condition, has been described in Europe following receipt of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca), which uses a chimpanzee adenoviral vector. A mechanism similar to autoimmune heparin-induced thrombocytopenia (HIT) has been proposed. In the US, the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson), which uses a human adenoviral vector, received Emergency Use Authorization (EUA) on February 27, 2021. By April 12, 2021, approximately 7 million Ad26.COV2.S vaccine doses had been given in the US, and 6 cases of CVST with thrombocytopenia had been identified among the recipients, resulting in a temporary national pause in vaccination with this product on April 13, 2021. To describe reports of CVST with thrombocytopenia following Ad26.COV2.S vaccine receipt. Case series of 12 US patients with CVST and thrombocytopenia following use of Ad26.COV2.S vaccine under EUA reported to the Vaccine Adverse Event Reporting System (VAERS) from March 2 to April 21, 2021 (with follow-up reported through April 21, 2021). Receipt of Ad26.COV2.S vaccine. Clinical course, imaging, laboratory tests, and outcomes after CVST diagnosis obtained from VAERS reports, medical record review, and discussion with clinicians. Patients' ages ranged from 18 to younger than 60 years; all were White women, reported from 11 states. Seven patients had at least 1 CVST risk factor, including obesity (n = 6), hypothyroidism (n = 1), and oral contraceptive use (n = 1); none had documented prior heparin exposure. Time from Ad26.COV2.S vaccination to symptom onset ranged from 6 to 15 days. Eleven patients initially presented with headache; 1 patient initially presented with back pain and later developed headache. Of the 12 patients with CVST, 7 also had intracerebral hemorrhage; 8 had non-CVST thromboses. After diagnosis of CVST, 6 patients initially received heparin treatment. Platelet nadir ranged from 9 ×103/µL to 127 ×103/µL. All 11 patients tested for the heparin-platelet factor 4 HIT antibody by enzyme-linked immunosorbent assay (ELISA) screening had positive results. All patients were hospitalized (10 in an intensive care unit [ICU]). As of April 21, 2021, outcomes were death (n = 3), continued ICU care (n = 3), continued non-ICU hospitalization (n = 2), and discharged home (n = 4). The initial 12 US cases of CVST with thrombocytopenia after Ad26.COV2.S vaccination represent serious events. This case series may inform clinical guidance as Ad26.COV2.S vaccination resumes in the US as well as investigations into the potential relationship between Ad26.COV2.S vaccine and CVST with thrombocytopenia.

Enforcing the 4T: Including a Hard Stop 4T Calculator into the Electronic Medical Record for Heparin Induced Thrombocytopenia

Background: Among many causes of thrombocytopenia acquired during hospitalization, heparin-induced thrombocytopenia (HIT), an immune complex-mediated thrombogenic state with high morbidity and mortality, is one of the most feared etiologies. The clinical ‘4T’ score is an established method to assess risk for HIT and guide immediate management(Lo, Juhl et al. 2006). However, the 4T score is not consistently used by clinicians, leading to potential over-testing and suboptimal management of suspected HIT. Our objective in this Quality Improvement (QI) project was to implement a mandatory 4T calculator (4TC) into the electronic medical record (EMR) to improve the positive predictive value of HIT antibody (HITA) testing, decrease the incidence of testing of low-risk patients, and to improve clinical management of suspected HIT.Methods: We developed a 4TC that assisted clinicians by integrating EMR-derived data on heparin exposure and the five most recent platelet counts with a link to an online calculator as well as clinical suggestions (Figure). As a part of this QI project, clinicians were required to enter the calculated 4T score before ordering a polyspecific HITA assay, which serves as the screening test for HIT in our institution. We reviewed laboratory records for all HITA tests performed over a six-month period, including 3 months before and after the implementation of a “hard stop” for HITA order in the EMR. We extracted data on the ordering hospital service team, 4T score documented in notes (if any), as well as quality of care indicators including rates of clinically recommended heparin cessation and initiation of alternative anticoagulation in the subgroup of patients with intermediate or high 4T score at the time of HITA order. In this QI project, we refrained from any statistical testing and summarized pre-specified outcome measures: incidence of HITA testing, positive predictive value of the HITA assay, and quality of care indicators.Results: We identified 99 (53 prior to the 4TC and 46 post) cases of HITA orders in the study period, among which there were 4 cases of confirmed HIT (either with positive IgG or positive serotonin-release assay [SRA]). Three HIT cases occurred after the 4TC was implemented. After the implementation of the 4TC, the positive predictive value for the HITA assay increased from 9% to 21%. The rate of clinically appropriate heparin order discontinuation increased from 72% to 88%, as did the initiation of alternative anticoagulation from 14% to 27%.HITA assay was most commonly ordered by the internal medicine service (35% of tests), non-cardiac intensive care service (30%), coronary care and cardiothoracic surgery services (21%), neurology (5%), and general surgery/other services (9%). Implementation of the 4TC did not significantly change this distribution, but the overall incidence of HITA orders decreased from 4.0 to 3.4 per 1000 admissions. We observed a high frequency of confirmatory SRA testing requested (18%), which is the reflex confirmatory test performed at our institution, even in cases of negative polyspecific HITA or HIT IgG.Conclusions: Addition of a 4T score calculator into the EMR which provides immediate feedback on patient's prior heparin exposure and recent platelet counts allows clinicians to consistently use the 4T score when considering HIT. Importantly, it also helps to educate non-hematologists on the proper management of HIT. Improved predictive value of the HITA assay suggests that our 4TC led to ordering HITA in a more appropriate patient population. We also demonstrated improved quality of care for suspected HIT, with increased rates of heparin cessation and initiation of alternative anticoagulation in patients with intermediate or high pre-test probability. Identifying clinical teams that order a disproportionate number of HITA assays will help us to direct education to improve clinical management. This QI project has led to other areas of improvement, particularly with regard to rational ordering of the SRA. At only three months of review since implementation of the 4TC, we have noted an improvement in the management of suspected HIT and a slight reduction in the incidence of testing. With continued review, we hope to demonstrate further improvement, as practitioners continue to use the 4TC and rely on clinical rationale rather than reflexive laboratory testing when evaluating thrombocytopenia in the hospital. [Display omitted] DisclosuresOlszewski:TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding.

A CASE OF SPONTANEOUS HEPARIN-INDUCED THROMBOCYTOPENIA AND THROMBOSIS (HITT)

SESSION TITLE: Critical Care 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Spontaneous heparin-induced thrombocytopenia and thrombosis (HITT) is established with positive serum platelet factor 4 (PF4) antibody, thrombosis, and without prior heparin exposure. Only a handful of spontaneous HITT cases have been reported. Due to history of no exposure to heparin products, diagnosis is often challenging and treatment delayed leading to increased patient morbidity and mortality. Here we present a case of spontaneous HIT and thrombosis after a left total knee arthroplasty (TKA). CASE PRESENTATION: A 71 year old male presented on postoperative day (POD) 7 from left TKA with acute onset abdominal pain, bright red blood per rectum, and coffee ground emesis. Prior to his TKA, he was noted to have a platelet count of 185 x 103/uL. Post-operatively he was discharged on Clindamycin 600mg and Aspirin 325mg twice daily for deep venous thrombosis (DVT) prophylaxis. On admission, he was found to have a platelet count of 47 x 103/uL and further work-up revealed splenic vein and bilateral lower extremity deep venous thrombosis. Due to acute bleeding patient was not started on anticoagulation and an inferior vena cava filter was placed. On hospital day 3, patient became acutely short of breath and computed tomography angiogram of the chest revealed bilateral pulmonary artery emboli. Serum PF4 [define PF4 here] antibody resulted strongly positive at 3.004 optical density (OD) (Range: 0.0 – 0.4 OD) indicating HITT associated thrombosis. Once the serum PF4 antibody titer was resulted positive, patient was started on Argatroban drip with eventual increase in platelet count past 150 x 103/uL. DISCUSSION: HIT is a complication of exposure to heparin that could be life threatening. It is caused by autoantibodies that recognize and bind to highly antigenic multi-molecular complexes formed of heparin binding to endogenous protein PF4 and causing platelet activation.1 Multiple theories have been proposed but the exact mechanism behind spontaneous HIT remains unclear. In vitro studies have shown that heparin antibodies are not specific to heparin and can also recognize PF4 bound to other polyanions and have shown to be elicited by reaction with lipopolysaccharides from gram negative bacteria.2 This may explain why cases of spontaneous HIT are seen in patient following total knee or hip arthroplasty where significant limb ischemia and tissue injury occur. CONCLUSIONS: Although exceedingly rare, spontaneous HITT is important to be recognized early to reduce patient morbidity and mortality. Patients without prior exposure to heparin who have undergone orthopedic procedures and present with worsening platelet count or new arterial/venous thrombosis should be considered to have spontaneous HITT and treated accordingly. Reference #1: Rauova L, Zhai L, Kowalska MA, et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood 2006; 107:2346. Reference #2: G. Pongas, S. K. Dasgupta, and P. Thiagarajan, “Antiplatelet factor 4/heparin antibodies in patients with gram negative bacteremia,” Thrombosis Research, vol. 132, no. 2, pp. 217–220, 2013. Reference #3: Warkentin T.E., Cook R.J., Marder V.J., Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of nondrug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost. 2010; 8:504. DISCLOSURES: No relevant relationships by Bryan Anderson, source=Web Response No relevant relationships by Chinthaka Bulathsinghala, source=Web Response No relevant relationships by Palla De Silva, source=Web Response No relevant relationships by Ahmed Hassan, source=Web Response No relevant relationships by aftab mahmood, source=Web Response No relevant relationships by Chirag Patel, source=Web Response Speaker/Speaker's Bureau relationship with Sunovian Please note: $5001 - $20000 Added 11/20/2017 by Salim Surani, source=Web Response, value=Honoraria Advisory Committee Member relationship with Astra Zeneca Please note: $5001 - $20000 Added 11/20/2017 by Salim Surani, source=Web Response, value=Consulting fee No relevant relationships by Deanna Yamamura, source=Web Response

Nadroparin carries a potentially high risk of inducing cutaneous delayed-type hypersensitivity responses.

Heparins are widely used for the prophylaxis/treatment of thromboembolic events. As adverse effects, heparin-induced skin lesions occur frequently (in 7.5-39% of patients). Skin lesions may be the only clinical manifestation of life-threatening immune-mediated heparin-induced thrombocytopenia, but are commonly caused by a delayed-type hypersensitivity response [heparin-induced delayed-type hypersensitivity (HIHS)]. Risk factors have not been prospectively identified. To identify possible risk factors for heparin-induced skin lesions from three independent clinical trials in a combined analysis. A pooled analysis from prospective studies was performed, and possible risk factors were included in a multiple logistic regression analysis. Obesity (body mass index of > 25), prolonged anticoagulant therapy, prior heparin exposure and younger age (< 55 years) were confirmed as independent risk factors for HIHS. The choice of anticoagulant preparation had the greatest influence. On comparison of dalteparin, enoxaparin, fondaparinux, unfractionated heparin, and nadroparin, the latter was associated with the highest risk of eliciting HIHS (odds ratio of 30.2, 95%CI: 11.7-77.9). The high risk associated with nadroparin has been validated in controlled trials, and this emphasizes the singularity of each heparin preparation in terms of allergenicity and that individualized anticoagulation is required.

Testing for Heparin Induced Thrombocytopenia: Comparison of Practice at an Academic Center with Choosing Wisely Guidelines

▪Background: The American Society of Hematology Choosing Wisely Guidelines 2014 recommend against testing for treatment of Heparin Induced Thrombocytopenia (HIT) in individuals at low risk, defined by a 4T score ≤ 3. Diagnosis of HIT relies on a combination of clinical characteristics and laboratory testing. The 4T score is a pretest probability score that defines clinical characteristics of HIT with reported negative predictive value of 99.8%. A new scoring model, the HIT Expert Probability (HEP) score, was introduced in 2010 and postulated to reduce inter-observer variability. The primary objective of this study was to examine compliance with guidelines at our institution; a 456 bed university hospital. Secondary objectives were to compare the performance of the 4T and HEP score in regards to inter-observer variability and the predictive value of low risk scores.Methods: Local practice is initial testing with anti-PF4 antibody enzyme immunoassay (EIA), and subsequent reflex serotonin release assay (SRA) if the EIA is positive or indeterminate. Consecutive patients with requests for HIT testing were identified from laboratory records. With Research Ethics Board approval, retrospective chart review was conducted by 3 reviewers who independently applied 4T and HEP scores; discrepancies were resolved by consensus. Adverse events including thrombosis, skin necrosis, heparin infusion reactions, bleeding (classified as major by ISTH criteria) and mortality were recorded. Inter-observer variability was assessed using the intraclass correlation (ICC).Results: Between 2013 January 1 and 2015 Feb 21, 76 patients were referred for EIA testing. Excluded from this analysis were 7 patients with prior history of HIT or with testing requested from an outside institution. Of the remaining 69, median age was 67 years (range 24-90), 36 (56%) were male, 49 (71%) admitted with a medical diagnosis and 20 (29%) under a surgical service. Hematology service was consulted at some point during admission in 25 (36%). Pretest probability was documented in 16 (23%). A greater percentage of patients with documented pre-test probability had a hematology consult 11 (69%) than patients without 5 (31%). Also, 36 (86%) patients without a documented pre-test probability were considered low risk by the 4T score. Table 1Scoring systemPre-test probabilityTotalN=69 (%)EIA positiveSRA positive*4TLow (≤3)42 (61)9 (13)1* (1)Intermediate (4-5)25 (36)10 (14)4 (6)High (6-8)2 (3)2 (3)1 (1)HEPLow (≤2)35 (51)7 (10)1* (1)Intermediate (2-5)20 (29)17 (25)1 (1)High (≥6)14 (20)7 (10)4 (6)*If SRA inconclusive, result confirmed with anti-PF4 IgG**Admitted with ischemic leg requiring catheter directed thrombolysis. Rapid onset thrombocytopenia within 24 hours of heparin exposure. Prior heparin exposure 150 days prior. Heparin stopped. No alternative anti-coagulation. No sequelae of HIT.The ICC for the pre-test probabilityscores was0.796(95% CI 0.714- 0.860) for 4T and 0.742 (95% CI- 0.645-0.821) for HEP score. By risk category, ICC for 4T score was 0.667 (95% CI 0.553 - 0.765) and HEP score was 0.702 (95% CI 0.553 - 0.765). HIT testing was performed in patients classified as low risk; 42 (61%) according to 4T and 35 (45%) according to HEP score. Among the 42 classified as low risk by 4T score, heparin was held in 26 (55) % pending results of testing and alternative anticoagulation commenced in 14 (33%) (fondaparinux 13, argatroban 1), at prophylactic dose in 12 and at therapeutic dose in 1 without a separate indication for anticoagulation. One low risk patient suffered major bleeding and 2 had thrombotic events. Overall, bleeding occurred in 10 (14%), major in 6 (9%), and thrombotic events occurred in 9 (13%). One patient presenting with septic shock, who developed thrombocytopenia with 4T score of 4, received argatroban and died on the same day from intracranial hemorrhage. All cause mortality during admission was 23 (33%).Conclusion: Compliance with Choosing Wisely Guidelines at our institution is low, and potentially associated with unnecessary financial expenditure and patient harm due to over-testing and over-treatment. We did not observe benefit of the more complex HEP score over the 4T score. Efforts are underway to increase awareness and align practice with recommendations. DisclosuresJames:Biogen Idec: Honoraria; Bayer: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Baxter: Honoraria; CSL Behring: Honoraria, Research Funding.

Clinical Features of Heparin-Induced Thrombocytopenia Diagnosed By Lumi-Aggregometry

Background: Heparin-induced thrombocytopenia (HIT) is associated with anti-platelet factor-4 (PF4)/heparin antibodies that activate platelets, resulting in thrombocytopenia and a pro-thrombotic state. At our institution antibody-mediated platelet activation is demonstrated by lumi-aggregometry, which is a method previously validated against the gold standard serotonin-release assay (SRA). Lumi-aggregometry does not involve radioactive isotopes, which is its major advantage over the SRA. The clinical course of HIT diagnosed via SRA and ELISA has been previously described, and clinical prediction tools such as the 4-T score were validated using these diagnostic tests. However, the clinical picture of HIT diagnosed by lumi-aggregometry has not been previously described.Aims: The objective of this study is to describe the clinical and laboratory presentation of patients diagnosed with HIT by lumi-aggregometry.Methods: Patients with clinically suspected HIT and quantitative anti-PF4 IgG-specific ELISA OD ≥0.400 (Gen-Probe, San Diego) received confirmatory HIT testing by lumi-aggregometry. Briefly, HIT antibody-induced activation of washed healthy donor platelets was tested at therapeutic (0.1U/mL and 0.5U/mL) and high (100U/mL) porcine heparin concentration. The degree of platelet activation was quantitated luminographically based on the light flash reaction of ATP (released from platelet dense-granules) with luciferin luciferase reagent. A ratio of therapeutic to high heparin luminescence amplitude of >5.0 and platelet aggregation at therapeutic, but not high, concentrations was considered a positive result. The results of assays performed by our regional HIT testing referral laboratory from June 2009 to July 2012 were reviewed to identify patients with positive HIT testing by lumi-aggregometry. Patient records were retrospectively reviewed to obtain predefined data on baseline patient characteristics, heparin exposure, platelet counts, and thrombotic events occurring in the 5 days preceding or the 30 days following the date of positive HIT testing.Results: We identified 43 patients diagnosed with HIT by lumi-aggregometry (median age 68.0, 49% male) while under the care of local academic (46%) or urban community hospitals (37.2% medical; 53.5% surgical; 9.3% intensive care). Median baseline platelet count was 187 (14-349). Median date of platelet drop post-heparin exposure was 6 days (range 3-14) in patients without prior heparin exposure or platelet transfusions (Figure 1). Platelet drop >50% and platelet nadir ≥20x109/L were present in the majority of patients (Table 1). Thrombocytopenia occurred prior to (70.5%) or the same day (23.5%) as thrombosis in 16/17 patients with serial platelet counts who developed HIT-associated thromboembolism.Conclusion: Patients diagnosed with HIT by lumi-aggregometry present with similar findings to those described in SRA-confirmed HIT. These findings lend support to the use of lumi-aggregometry as an accurate diagnostic assay for the clinico-pathologic syndrome of HIT. [Display omitted] Table 1Percentage platelet drop from baseline and platelet nadirPercent platelet dropPlatelet nadir>50%30-50%<30%≥20 x 109/L283210-19 x 109/L510<10 x 109/L110 DisclosuresSzkotak:Alexion Pharmaceuticals: Research Funding. Sandhu:Celgene: Honoraria; Jansen: Honoraria; Novartis: Honoraria.

Prognostic importance of preoperative anti-PF4/heparin antibodies in patients undergoing cardiac surgery

It was the objective of this study to obtain best estimates of the prevalence of anti-PF4/heparin antibodies in patients not suspected to have clinical heparin-induced thrombocytopenia (HIT) prior to undergoing cardiac surgery and to determine whether preoperative antibody status and antibody class is predictive of postoperative thromboembolic outcomes, non-thromboembolic outcomes, length of stay, and mortality. PubMed and EMBASE online databases were searched up to July 2011, and we included studies involving adults undergoing cardiac surgery examining the relationship between preoperative anti-PF4/heparin antibodies (ELISA) and postoperative clinical outcomes. Five studies involving a combined total of 2,332 patients met our inclusion criteria. Preoperative anti-PF4/heparin antibodies were detected in 5-22% of patients. No study demonstrated an association between preoperative anti-PF4/heparin antibodies and postoperative thromboembolic outcomes or mortality. Three studies demonstrated a statistically significant association between preoperative anti-PF4/heparin antibodies and length of stay while two showed an association with non-thromboembolic complications. In the one study that examined outcomes by anti-PF4/heparin antibody class, IgM antibodies predicted non-thromboembolic complications and length-of-stay. None of the studies reported prior heparin exposure, and most studies did not examine the relationship of the absolute value of antibody titres (ELISA OD) and risk, nor the incidence of true/clinical HIT in preoperative positive or negative patients. In conclusion, pre-formed anti-PF4/heparin antibodies are common in patients undergoing cardiac surgery, but the available literature does not support that they predict postoperative thromboembolic complications or death. There does appear to be an association between anti-PF4/heparin antibodies and non-thromboembolic adverse events, but a causal relationship is unlikely.

Seroprevalence of PF4/Heparin Antibodies among Blood Bank Donors

Heparin-Induced Thrombocytopenia (HIT) is classically viewed as a drug-induced immune disorder triggered by exposure to the anticoagulant drug, heparin. However, HIT may also be considered a dysregulated autoimmune response to two naturally occurring substances, Platelet Factor 4 (PF4), a platelet protein, and heparin, a tissuederived glycosaminoglycan. Until recently, studies of HIT and PF4/heparin antibody seroconversion have been exclusively focused on patients exposed to heparin or heparinlike drugs, including low-molecular weight heparin, the heparinoids and the synthetic agent, fondaparinux. Recent reports, however, indicate that PF4/heparin antibodies may arise spontaneously in some individuals in the absence of heparin (Warkentin Am J Med 2008; Hursting J Thromb Thrombolysis, 2008). We undertook this study to document the seroprevalance of “naturally-occurring” PF4/heparin antibodies in healthy subjects without prior heparin exposure. To study “healthy” subjects, we used blood bank donors as a surrogate population. Samples from blood bank units were obtained through Duke Transfusion services/American Red Cross (ARC). Donors met eligibility criteria for blood donation to the ARC and generally, represent a healthy population (http://www.redcross.org/services/biomed/0,1082,0_557_,00.html#hem). A Duke IRB waiver was issued due to use of anonymous samples. Plasma from donor units/segments were assayed in duplicate for the presence of PF4/heparin antibodies using a commercially available PF4/heparin ELISA (PF4 enhanced IgG,A,M kits, Genetics Technology Institute, Waukesha, WY). Positivity was defined by the manufacturer as A405nm ≥0.4. Positive samples were stratified into low, (A405nm=0.4–0.6), intermediate (A405nm=0.61–0.99) or high-positive values (A405nm≥1.0). High and intermediate positive samples were further isotyped using IgG and IgM specific antibodies (Sigma, St. Louis, MO). Of the 970 blood bank donors tested to date, 31 samples (3.2%) were positive using the manufacturer's cut-off value. Repeat testing confirmed positivity in all 31 samples. Of those testing positive, 26 were low-positive (2.3% of overall cohort; 84% of all positive samples), 1 sample was intermediate positive (0.1% of overall cohort; 3.2% of positive samples) and 5 samples were high-positive (0.5% overall cohort; 16% of positive samples). Isotyping of 6 high/intermediate positive samples revealed IgG in 3 patients, IgM in the remainder. There was no correlation between antibody positivity and ABO blood type. In summary, our data reveals a high prevalence of PF4/heparin antibodies, the majority of which are low-positive values (~84%). Many of these low-positive samples likely reflect background “noise” of the assay and could be eliminated using a higher cut-off for positivity. We also found a seroprevalance of 0.5% of high positive antibodies, of IgG and IgM isotype, supporting the notion that some individuals may have “naturally-occuring”

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Sir: We appreciate the comments by Dr. Knobloch and colleagues on our article entitled “Incidence of Hematoma Complication with Heparin Venous Thrombosis Prophylaxis after TRAM Flap Breast Reconstruction,” raising the question of heparin-induced thrombocytopenia. It has been well established by numerous studies across surgical and medical disciplines that venous thrombosis chemoprophylaxis with heparin is effective, and it has been well reviewed in practice guidelines.1,2 Nevertheless, plastic surgeons are often concerned with the use of heparin in patients after procedures that involve extensive soft-tissue undermining. The goal of our study was to determine whether the use of heparin actually increased the rate of hematoma requiring operative intervention, studying patients after transverse rectus abdominis musculocutaneous flap breast reconstruction as a model population. Our data showed that the hematoma rate did not increase with heparin chemoprophylaxis, suggesting that heparin use is worthwhile, because venous thrombosis is common and pulmonary embolus often fatal. Heparin-induced thrombocytopenia is an increasingly recognized clinical entity, most often in cardiac surgery patients. Knobloch and colleagues succinctly summarized the cause of heparin-induced thrombocytopenia. We did recognize the importance of heparin-induced thrombocytopenia and examined its incidence in our patient population. We studied 392 patients who received subcutaneous heparin: 375 patients received unfractionated and 17 received low-molecular-weight heparin. There were 61 patients who received an intravenous heparin bolus in the context of free transverse rectus abdominis musculocutaneous flap reconstruction. As we noted at the end of the Results section, we specifically looked for but detected no cases of heparin-induced thrombocytopenia. Therefore, our study provides the first large case series in plastic surgery demonstrating that the incidence of heparin-induced thrombocytopenia is quite low, less than 0.26 percent. Several studies on the incidence of heparin-induced thrombocytopenia offer guidance in preoperative risk stratification. Smythe and colleagues conducted a retrospective study of over 24,000 patients and found the overall incidence of heparin-induced thrombocytopenia to be 0.2 percent.3 The incidence of heparin-induced thrombocytopenia is 3.8 times greater in patients exposed to intravenous versus subcutaneous heparin administration. Moreover, over 50 percent of heparin-induced thrombocytopenia cases were in cardiac surgery patients. It has been shown that the incidence of heparin-induced thrombocytopenia is lower in patients treated with low-molecular-weight heparin, as compared with unfractionated heparin.4 Therefore, although heparin-induced thrombocytopenia can have devastating consequences, it is a clinical entity we rarely encounter in plastic surgery. Balanced against the relatively common occurrence of venous thrombosis, we maintain that chemoprophylaxis with heparinoids should be considered in patients at risk, mindful of heparin-induced thrombocytopenia as a rare complication. In the average patient without prior heparin exposure, heparin-induced thrombocytopenia concern should not dissuade one from venous thrombosis chemoprophylaxis. Eric C. Liao, M.D., Ph.D. Division of Plastic Surgery Brigham and Women’s Hospital Harvard Medical School Amir H. Taghinia, M.D. Harvard Medical School James W. May, Jr., M.D. Division of Plastic Surgery Massachusetts General Hospital Harvard Medical School Dennis P. Orgill, M.D., Ph.D. Division of Plastic Surgery Brigham and Women’s Hospital Harvard Medical School Boston, Mass.

Antibodies to Platelet Factor 4/Heparin are Associated with Elevated Endothelial Cell Activation Markers in Patients with Acute Coronary Ischemic Syndromes

We postulated that antibodies to platelet factor 4/heparin complex lead to a heightened inflammatory state, contributing to an increased risk of recurrent thrombotic events. We analyzed serum from a subset of patients in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had prior heparin exposure. We selected 109 patients with the 30 day primary endpoint (death, MI or revascularization) and an equal number of controls, excluding patients with thrombocytopenia. Anti-platelet factor 4/heparin antibodies and inflammatory markers (sVCAM-1, sICAM-1, sE-selectin, sP-selectin, us-CRP, IL-6) were measured on serum samples. Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% vs. 11.3%, p = 0.01), or MI (21.7% vs. 6.2%, p = 0.01) than patients who were antibody negative. In a multiple logistic regression model that included inflammatory markers and clinical risk factors, antibody to PF4/heparin was a strong predictor of 30 day MI (odds ratio: 9.0; 95% confidence intervals 2.1-38.6; p < 0.01), with IL-6 being the only other predictor (odds ratio: 1.1; 95% confidence intervals 1.0-1.2; p = 0.03). Antibody positive patients had higher levels of sVCAM-1 (892 +/- 263 microg/l versus 780 +/- 228 microg/l; p = 0.04) and sICAM-1(246 +/- 50 microg/l versus 222 +/- 71microg/l; p = 0.02) than antibody-negative patients. Antibodies to the platelet factor 4/heparin complex were associated with elevated levels of endothelial but not platelet activation markers, or markers of a systemic inflammatory state. Anti-PF4/heparin antibodies were associated with a 9-fold increased risk of recurrent MI at 30 days. We measured soluble cell adhesion molecules, CRP and IL-6 from 218 non-thrombocytopenic patients, 23 of whom had antibodies to PF4/heparin. Antibody positive patients had higher levels of sVCAM-1 (892 +/- 263 microg/l versus 780 +/- 228 microg/l; p = 0.04) and sICAM-1(246 +/- 50 microg/l versus 222 +/- 71 microg/l; p = 0.02). In a multiple logistic regression model, antibody to PF4/heparin was a predictor of 30 day MI (odds ratio: 9.0; 95% CI: 2.1-38.6; p < 0.01). The presence of antibodies to PF4/heparin, even in the absence of thrombocytopenia, is a stronger predictor of 30 day MI than clinical variables or inflammatory markers.

Anti-platelet factor 4/heparin antibodies: an independent predictor of 30-day myocardial infarction after acute coronary ischemic syndromes.

We postulated that antibodies to platelet factor 4/heparin complex might contribute to recurrent ischemic events in patients with acute coronary syndrome. We analyzed serum from patients enrolled in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had high likelihood of prior heparin exposure. We selected 109 patients without thrombocytopenia with the 30-day primary end point (death, myocardial infarction [MI], or revascularization) and 109 age-, gender-, and race-matched controls who did not achieve the primary end point. An ELISA for anti-platelet factor 4/heparin antibodies was performed using 48-hour serum samples. The analyses were done by blinded investigators, and the results were correlated with clinical outcomes. Twenty-three of 218 patients (10.6%) had anti-PF4/heparin antibodies. Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% versus 11.3%, P=0.011) or MI (21.7% versus 6.2%, P=0.008) than patients who were negative for the antibody. After multiple logistic regression analysis, anti-PF4/heparin antibodies remained a predictor of 30-day death or MI (odds ratio, 4.0; 95% CI, 1.4 to 11.3; P=0.0093) and MI (odds ratio, 4.6; 95% CI, 1.4 to 15.0; P=0.0108). The antibody was not associated with the composite end point (death, MI, or revascularization) or with death or revascularization alone. Antibodies to the platelet factor 4/heparin complex are a novel, independent predictor of myocardial infarction at 30 days in patients presenting with acute coronary ischemic syndromes. This finding may explain the previous association between thrombocytopenia and adverse events in patients with acute coronary syndrome and may have important implications for the choice of anticoagulant regimens.