Heparin Products Research Articles

Outcomes among patients with non-ST-elevation myocardial infarction on chronic anticoagulation: Insights from the National Inpatient Sample.

Chronic systemic anticoagulation use is prevalent for various thromboembolic conditions. Anticoagulation (usually through heparin products) is also recommended for the initial management of non-ST-elevation myocardial infarction (NSTEMI). To evaluate the in-hospital outcomes of patients with NSTEMI who have been on chronic anticoagulation. Using the National Inpatient Sample (NIS) years 2016-2020, NSTEMI patients and patients with chronic anticoagulation were identified using the appropriate International Classification of Diseases, 10th version (ICD-10) appropriate codes. The primary outcome was all-cause in-hospital mortality while the secondary outcomes included major bleeding, ischemic cerebrovascular accident (CVA), early percutaneous coronary intervention (PCI) (i.e., within 24 h of admission), coronary artery bypass graft (CABG) during hospitalization, length of stay (LOS), and total charges. Multivariate logistic or linear regression analyses were performed after adjusting for patient-level and hospital-level factors. Among 2,251,914 adult patients with NSTEMI, 190,540 (8.5%) were on chronic anticoagulation. Chronic anticoagulation use was associated with a lower incidence of in-hospital mortality (adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.65-0.73, p < 0.001). There was no significant difference in major bleeding (aOR: 0.95, 95% CI: 0.88-1.0, p = 0.15) or ischemic CVA (aOR: 0.23, 95% CI: 0.03-1.69, p = 0.15). Chronic anticoagulation use was associated with a lower incidence of early PCI (aOR: 0.78, 95% CI: 0.76-0.80, p < 0.001) and CABG (aOR: 0.43, 95% CI: 0.41-0.45, p < 0.001). Chronic anticoagulation was also associated with decreased LOS and total charges (adjusted mean difference [aMD]: -0.8 days, 95% CI: -0.86 to -0.75, p < 0.001) and (aMD:$-19,340, 95% CI: -20,692 to -17,988, p < 0.001). Among patients admitted with NSTEMI, chronic anticoagulation use was associated with lower in-hospital mortality, LOS, and total charges, with no difference in the incidence of major bleeding.

Perioperative Management of Antiplatelet and Anticoagulation in Brain Tumor Surgery: A Survey of International Practices

Perioperative management of antithrombotic therapy is a necessary preprocedural consideration for patients prescribed direct oral anticoagulants (DOACs), vitamin K antagonists, or antiplatelet medications. There is a lack of evidence-based guidelines to help inform decision-making in managing antiplatelet and anticoagulation medications in the perioperative period around brain tumor resection. The objective of this study was to provide an example of the heterogeneity in practice and raise awareness for the need to create standardized guidelines for managing these medications. A survey was sent to a list of over 800 international neurosurgeons who are members of the Neurosurgery Research Listserv. The survey comprised 70 questions assessing individual practices for managing thromboprophylaxis, antiplatelet medications, and anticoagulation in the perioperative period. The survey was sent via e-mail invitation between March 2021 and June2021. A total of 72 surgeons responded to the survey. There was no difference in medication management preoperatively or postoperatively when comparing intra- and extra-axial tumor resections. Cessation of antiplatelet medications varied between 3 and 11 days while restart varied between 1 and 14 days. Preoperative management of vitamin K antagonists varied between indication for use (P < 0.001) while DOAC management did not. In our group of respondents, 90% started heparin products within 5 days of surgery, while the same fraction restarted DOAC within 14 days. Respondents demonstrated significant heterogeneity in their perioperative management of antiplatelet and anticoagulation medication in brain tumor resection. This may lead to an unacceptable level of heterogeneity in practice that has the potential to cause patient harm due to errors in medication management.

Electronic alerts to improve management of heparin-induced thrombocytopenia

BackgroundHeparin-induced thrombocytopenia (HIT) is a difficult clinicopathologic diagnosis to make and to treat. Delays in identification and appropriate treatment can lead to increased morbidity and mortality. ObjectivesTo use electronic health alert interventions to improve provider diagnosis and management of heparin-induced thrombocytopenia through guideline-based, accurate care delivery. MethodsThis quality improvement initiative developed 3 electronic health record-based interventions at our 750-bed academic medical center to improve the initial management of suspected HIT between 2018 and 2021: 1. an interruptive alert to recommend discontinuation of active heparin products when signing a heparin-platelet factor 4 test (PF4) order, 2. integrated 4T score calculation in the heparin-PF4 test order, and 3. interruptive alert suggesting not to order heparin-PF4 tests when the 4T score is <4. Changes in practice were assessed over defined time periods pre and post each intervention. ResultsIntervention 1 resulted in heparin discontinuation in more patients, with 65% (191 heparin orders/293 heparin-PF4 enzyme-linked immunosorbent assay tests) of cases continuing heparin prealert and only 54% (127 heparin orders/235 heparin-PF4 enzyme-linked immunosorbent assay tests) postinterruptive alert (95% CI 2.3-19.9; P = .015). Intervention 2 increased appropriate heparin-PF4 test ordering from 40.4% (110/272) preintervention to 79.1% (246/311) (95% CI 30.9-46.4; P < .00001) postintervention, with inappropriate PF4 ordering defined as testing when 4T score was <4. Intervention 3 did not lead to reduction in heparin-PF4 testing in the control group (96 inappropriate orders/402 total orders, 24%) compared to the randomized alert group (56 inappropriate orders/298 total orders; 19%) (95% CI −1.2 to 11.5; P = .13). ConclusionImplementation of unique electronic health record interventions, including both diagnostic and management interventions, led to improved guideline-based, accurate care delivery with 4T score calculation and cessation of heparin for patients with suspected HIT.

Alpha gal syndrome, a relative not absolute contraindication to the use of bovine pericardium to close an intracardiac septal defect: a case report

BackgroundAlpha-gal syndrome is an allergic condition in which individuals develop an immune-mediated hypersensitivity response when consuming red meat and its derived products. Its diagnosis is important in individuals undergoing cardiac surgery, as patients frequently require large doses of unfractionated heparin or the insertion of surgical implants, both of which are porcine or bovine in origin. There are currently no guidelines for heparin administration in alpha-gal patients, with even less knowledge regarding the long-term clinical implications of these patients after receiving bioprosthetic valve replacements or other prostheses.Case presentationWe present the case of a 31-year-old male who underwent cardiac surgery in the setting of alpha-gal syndrome for a large atrial septal defect (ASD) and mitral valve prolapse (MVP). The patient continues to do well one year after undergoing a mitral valve repair, tricuspid valve repair and an ASD closure using bovine pericardium. He sustained no adverse reaction to the use of heparin products or the presence of a bovine pericardial patch. This rare case was managed by a multidisciplinary team consisting of cardiothoracic surgery, cardiac anesthesiology, and allergy/immunology that led to an optimal outcome despite the patient’s pertinent allergic history.ConclusionsThis case highlights that the use of bovine pericardium and porcine heparin to close septal defects in patients with milder forms of alpha-gal allergy can be considered if other options are not available. Further studies are warranted to investigate the long-term outcomes of such potential alpha-gal containing prostheses and heparin exposure and establish the optimal decision making algorithm and prophylactic regimen.

Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin

Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored N-sulfoheparosan with N-sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products.

Anticoagulation management in patients tested for heparin-induced thrombocytopenia in the cardiothoracic intensive care unit diverges from expert guidelines

Abstract Heparin-induced thrombocytopenia (HIT) is a rare, life-threatening complication in patients receiving heparin products. Clinical scoring tools, such as the ‘4T’ score, aim to help identify patients at risk for HIT and are recommended by expert guidelines. For example, the American Society of Hematology (ASH) recommends that patients with an intermediate or high-risk 4T score are presumptively treated for HIT by withdrawing heparin and starting an alternative anticoagulant. At our institution, laboratory HIT testing involves an in-house latex immunoassay (LIA) that, if positive, reflexes to a send-out serotonin release assay (SRA) at the Blood Center of Wisconsin. This confirmation may take several days to result, underscoring the importance of presumptive treatment. Anecdotally, we have observed that clinicians have expressed reservations about the use of the 4T score in the cardiothoracic intensive care unit (CTICU). These reservations may lead to increased HIT testing in patients with low 4T scores and delays in the initiation of alternative anticoagulants. We set out to objectively determine if clinical practice in the CTICU is aligned with ASH guidelines. To do so, we used anticoagulant usage as a proxy for medical decisions made at the time of order for HIT laboratory testing. Data was extracted from the electronic medical records of all patients who were admitted to the CTICU between 5/2018 and 7/2022 and administered a heparin product (n = 1,602). Patients that were not tested for HIT (n = 1,449) were excluded. The remaining patients’ (n = 153) medication record timings were normalized such that the time of their first LIA was set to zero to allow for relative comparisons. 25 (16%) of the LIAs were positive, of which 5 (20%) were confirmed by SRA. Of the 153 patients, 136 (89%) received heparin within 24 hours prior to LIA order, while 6 (4%) were already on alternative anticoagulation (bivalirudin). Of the patients on heparin prior to LIA, 18 (13%) were switched to bivalirudin upon LIA order, 66 (49%) had heparin discontinued without an alternative, and 52 (39%) were continued on heparin. Our results suggest that the prevalence of HIT in this cohort is 3.3% by SRA, much lower than the expected pretest probability estimated for intermediate- and high-risk 4T scores in published meta-analyses. In addition, the observed anticoagulation practices varied widely and diverged from ASH guidelines, where only 17% of patients were on alternative anticoagulation when the testing was ordered. Future work will investigate these patterns across LIA positivity and 4T scores while attempting to address the clinical outcomes of these treatment decisions.

Characteristics of Patients with Cirrhosis and Impact on Outcomes Following Heparin-Induced Thrombocytopenia; A Retrospective National Population-Based Study between 2016 and 2019

Introduction: Heparin-induced thrombocytopenia (HIT) is characterized by thrombocytopenia and a prothrombotic state. It can occur following the use of heparin products of any form or dosage. Various factors predispose cirrhosis patients to thrombocytopenia, such as splenic platelet sequestration, lower levels and activity of thrombopoietin (TPO), bone marrow suppression secondary to chronic viral infections(e.g., Hepatitis C), and use of antiviral therapies such as interferons. As there is a paucity of data on the impact that cirrhosis confers on the outcomes following HIT, we conducted a retrospective nationwide analysis. Methods: A retrospective study of adult patients with HIT was performed using the2016-2019 National Inpatient Sample(NIS), a set of annual hospitalization databases produced by HCUP, AHRQ, and multiple partners. Patients with HIT were identified via the ICD-10 code “D7582”. We studied the differences in patient characteristics and multiple comorbidities among patients with and without cirrhosis, along with the impact on outcomes. Results: Our study included a total of 60800 cases of HIT, which included 3020(5.0%) cases with a diagnosis of cirrhosis (Table 1). The majority of cases involved patients classified as White, were Medicare-insured and underwent treatment in Urban-teaching centers. While patients with cirrhosis were younger (mean age 61.71 years vs. 64.39 years, p&amp;lt;0.01), they also reported disparities in patient characteristics and comorbidities. Cirrhosis cohort had fewer females (43.9% vs. 46.9%, p&amp;lt;0.01), lower prevalence of hypertension (22.2% vs. 29.4%, p&amp;lt;0.01), peripheral vascular disease (7.0% vs. 10.6%, p&amp;lt;0.01), lipid disorders (24.2% vs. 42.1%, p&amp;lt;0.01), and were overall younger (mean age 61.71 vs. 64.39 years, p&amp;lt;0.01). However, cirrhosis patients showed a higher prevalence of smoking (39.4% vs. 35.1%, p&amp;lt;0.01), chronic kidney disease (39.4% vs. 36.4%, p&amp;lt;0.01), and alcohol abuse ( 24.2% vs. 4.8%, p&amp;lt;0.01). Moreover, 4.1% of cirrhosis patients had a diagnosis of hepatocellular carcinoma (vs. 0.4% of non-cirrhosis patients, p&amp;lt;0.01). No differences in the two groups were observed for diabetes and obesity. Overall, cirrhosis patients reported a higher mean Charlson Comorbidity Index (CCI) score (6.21 vs. 4.58, p&amp;lt;0.01) but had a shorter stay (13.84 days vs. 14.64 days, p&amp;lt;0.01), with a lower mean hospital charge ($167196 vs. $225959, p&amp;lt;0.01). After careful adjustment of confounders, lower odds of Major adverse cardiovascular events (MACEs) were seen among cirrhosis patients (14.2% vs. 19.3%,aOR 0.531, 95% CI 0.474-0.595, p&amp;lt;0.01). Moreover, cirrhosis patients also had lower odds of in-hospital death following events of HIT (11.4% vs. 10.9%, aOR 0.875, 95% CI 0.770-0.994, p=0.040). Conclusion: Our study found lower odds of MACEs and mortality among cirrhosis patients in cases of HIT. However, as the NIS has multiple limitations, such as the unavailability of medication codes and the inability to evaluate post-discharge outcomes, we highly encourage more in-depth studies to improve our understanding of the impact of cirrhosis in patients with HIT.

Bleeding Associated with Prophylactic Anticoagulation for Hospital Related Venous Thromboembolism Prevention: A Case Series

The use of heparin products for prophylaxis of venous thromboembolism (VTE) have decreased the prevalence of VTE in all hospitalized patients, however the possibility of bleeding from prophylactic heparin cannot be disregarded. While life-threatening bleeding is less common with prophylactic doses, it can occur in the presence of other risk factors for bleeding. We aim to describe characteristics that may increase bleeding risk from prophylactic use of heparin. We present a single-center, retrospective case series of patients who received protamine for bleeding complications from prophylactic heparin administration at our facility between 2016-2020. We assessed patient demographics, medical history, types of heparin formulations administered, and patient outcomes. We observed that all patients were female. Patients who developed bleeding events from VTE prophylaxis had at least two of these attributes; BMI &amp;lt;18.5 kg/m2, weight &amp;lt;50kg, trauma within 1-month, surgery within 1-month or were taking anti-platelet agents. We suggest that the collective presence of two or more of these characteristics should lend consideration to dose adjustment and/or closer monitoring. In the absence of rigorous research comparing alternative doses to standard doses for prophylaxis in these patients, these decisions fall largely to the discretion of individual physicians. Designing larger studies following patients over long periods of time can help conclusively identify risk factors that predispose patients to bleeding.

Trends in Heparin-Induced Thrombocytopenia in the Pre-Pandemic and Peak-Pandemic Era, and Impact of COVID-19 on Mortality; An Analysis Via the National Inpatient Sample

Introduction: The recent pandemic of COVID-19 caused a significant upheaval in access to healthcare and resources across the world. The COVID-19 infection has also been associated with a hypercoagulable state that can alter multiple coagulation pathways and cause various cerebrovascular and cardiovascular insults, thus requiring the need for heparin products. While a recent study found a decreasing trend of Heparin-induced thrombocytopenia(HIT) between 2011-2014, there have yet to be any recent studies investigating the pandemic's role on HIT trends and the overall effect of COVID-19 on the mortality of these patients. We, therefore, used the National Inpatient Sample (NIS) to assess the impact of the pandemic on HIT. Methods: The 2016-2020 NIS, a set of yearly discharge records released in de-identified form with various patient characteristics, discharge and procedural codes, was used for our study. We included cases with a diagnosis for HIT via the International Classification of Diseases, Tenth Revision (ICD-10) code “D7582”. Patients with COVID-19 and other comorbidities that can influence the outcomes were also identified via their respective ICD-10 codes from past studies. The incidence of HIT per 100,000 hospitalizations between 2016-2020 was compared and linear-by-linear analysis was used to assess trends, as in previous studies. We further proceeded to compare the trends in mortality rates among HIT patients. Finally, the odds of mortality among HIT patients with and without COVID-19, restricting the sample to HIT patients from 2020, were estimated via multivariable regression models. SPSS 29.0 was used for our analyses, and a p-value &amp;lt;0.05 was set for statistical significance. Results: Our study included a total of 72930 cases of HIT between January 1st 2016- December 31st 2020, with 16780 cases in 2016, 16450 cases in 2017, 14590 cases in 2018, 12980 cases in 2019, and 12130 cases in 2020. The overall adjusted incidence of HIT dropped between 2016-2019 from 55.6 cases per 100,000 (in 2016) hospitalizations to 43.0 cases per 100,000 hospitalizations (in 2019). However, a rise was seen in 2020 with 43.9 cases per 100,000 hospitalizations (ptrend&amp;lt;0.01). On average, HIT was reported in 49.1 cases per 100,000 adult hospitalizations. However, in 2020, among the 12130 cases of HIT, there were 1745(14.4%) COVID-19 positive patients. The adjusted incidence of HIT in 2020 without COVID-19 cases of HIT was 37.6 cases per 100,000 hospitalizations. The adjusted analysis (excluding COVID-19 positive HIT cases), showed a continuous decrease in incidence of HIT between 2016-2020 (Figure 1a). Meanwhile, the mortality rates among HIT patients were 10.2% in 2016, 11.9% in 2017, 11.0% in 2018, 10.5% in 2019 and 16.2% in 2020 (ptrend&amp;lt;0.01). However, in 2020 the mortality rate among non-COVID-19 positive HIT patients was 10.4%, with no statistical differences between the years (ptrend=0.440) (Figure 1b). Finally, among the HIT cases of 2020, concurrent presence of COVID-19 was linked with a higher odds of mortality (50.4% vs. 10.4%, aOR 8.471, 95% CI 7.405-9.690, p&amp;lt;0.01). Conclusion: Our study provides a fresh analysis of the burden of the COVID-19 pandemic on the incidence and outcomes of HIT in the United States. While a decreasing incidence of HIT was seen between 2016-2020 for cases without COVID-19, in 2020, patients with the virus contributed to a rise in the overall incidence and mortality rates. COVID-19 infection has a massive impact on coagulation profiles, and while our data covers the pre-vaccination period, we strongly advocate for research via future NIS databases to better understand the progress of the pandemic on HIT in 2021 and onwards.

New insights into the binding of PF4 to long heparin oligosaccharides in ultralarge complexes using mass spectrometry

BackgroundHeparin-induced thrombocytopenia (HIT) is a serious complication caused by heparin drugs. The ultralarge complexes formed by platelet factor 4 (PF4) with heparin or low molecular weight heparins (LMWHs) are important participants in inducing the immune response and HIT. ObjectivesWe aim at characterizing the interaction between PF4 and long-chain heparin oligosaccharides and providing robust analytical methods for the analysis of PF4–heparin complexes. MethodsIn this work, the characteristics of PF4–enoxaparin complexes after incubation in different molar ratios and concentrations were analyzed by multiple analytical methods, especially liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry with multiple reaction monitoring were developed to qualitatively and quantitatively monitor heparin oligosaccharides and PF4 in HIT-inducing complexes. ResultsThe results showed that the largest proportion of ultralarge complexes formed by PF4 and enoxaparin was at a specific molar ratio, ie, a PF4/enoxaparin ratio of 2:1, while the ultralarge complexes contained PF4 tetramer and enoxaparin at a molar ratio of approximately 2:1. ConclusionA binding model of PF4 and enoxaparin in ultralarge complexes is proposed with one heparin oligosaccharide chain (∼ dp18) bound to 2 PF4 tetramers in different morphologies to form ultralarge complexes, while PF4 tetramer is surrounded by multiple heparin chains in smaller complexes. Our study provides new insights into the structural mechanism of PF4–LMWH interaction, which help to further understand the mechanism of LMWH immunogenicity and develop safer heparin products.

Clinical decision support to reduce unnecessary diagnostic testing for heparin-induced thrombocytopaenia.

Appropriate evaluation of heparin-induced thrombocytopaenia (HIT) is imperative because of the potentially life-threatening complications. However, overtesting and overdiagnosis of HIT are common. Our goal was to evaluate the impact of clinical decision support (CDS) based on the HIT computerized-risk (HIT-CR) score, designed to reduce unnecessary diagnostic testing. This retrospective observational study evaluated CDS that presented a platelet count versus time graph and 4Ts score calculator to clinicians who initiated a HIT immunoassay order in patients with predicted low risk (HIT-CR score 0-2). The primary outcome was the proportion of immunoassay orders initiated but cancelled after firing of the CDS advisory. Chart reviews were conducted to assess anticoagulation usage, 4Ts scores and the proportion of patients who had HIT. In a 20-week period, 319 CDS advisories were presented to users who initiated potentially unnecessary HIT diagnostic testing. The diagnostic test order was discontinued in 80 (25%) patients. Heparin products were continued in 139 (44%) patients, and alternative anticoagulation was not given to 264 (83%). The negative predictive value of the advisory was 98.8% (95% CI: 97.2-99.5). HIT-CR score-based CDS can reduce unnecessary diagnostic testing for HIT in patients with a low pretest probability of HIT.

Clinical characteristics of pregnancy and lactation associated osteoporosis: An online survey study.

Pregnancy and lactationassociated osteoporosis (PLO) is a rare form of early-onset osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. Little information is available about etiology, clinical characteristics, risk factors and predictors of disease severity. PLO patients were recruited to complete an anonymized online questionnaire. Disease severity was defined as total number of fractures during or after the first pregnancy associated with a fracture(s). Analyses related disease severity to potential predictors including diseases/conditions or medication exposures. 177 completed surveys were received between 5/29/2018 and 1/12/2022. Average age at initial PLO fracture event was 32 ± 5years. The majority were primiparous with singleton pregnancy and 79% fractured during lactation. Subjects reported 4.7 ± 2.7 total PLO fractures, with 48% reporting ≥ 5 fractures. Vertebral fractures, reported by 164/177 responders (93%), were the most common fracture type. Conditions and medications most commonly reported included vitamin D deficiency, amenorrhea unrelated to pregnancy, nephrolithiasis, celiac disease (CD), oral steroid use, heparin products during pregnancy and progestin only contraceptive after pregnancy. CD and heparins exposure during pregnancy were significantly related to disease severity. This is the largest study characterizing clinical features of PLO to date. The large number of participants and broad range of clinical and fracture characteristics queried has yielded novel information on the characteristics of PLO and potential risk factors for its severity, including primiparity, exposure to heparin and CD. These findings provide important preliminary data that can help target future mechanistic investigations.

Considerations for the Bioanalytical Part of Equivalence Studies of Biosimilar Nadroparin Calcium

According to current regulatory views, a comparative study of the pharmacodynamics (PD) of low molecular weight heparin (LMWH) products and confirmation of their equivalence require comparing three PD markers: the anti-Xa activity, the anti-IIa activity, and the tissue factor pathway inhibitor (TFPI) concentration. The aim of this study was to analyse the features specific to the bioanalytical part of an equivalence study of a nadroparin calcium biosimilar after single subcutaneous administration. Material and methods: the anti-Xa and anti-IIa activity values and TFPI content were determined in human plasma samples obtained after single subcutaneous administration of the test and the reference product in the same dose, using commercially available reagent kits and pre-validated assays. The authors calculated the main PD parameters (surrogate pharmacokinetic markers), namely the maximum activity or concentration (Amax or Cmax), time to maximum activity or concentration (Tmax), area under the activity–time (or concentration–time) curve (AUC ), and half-life period (T1/2), by means of model-independent statistical moment analysis and carried out further statistical testing of the parameters. Results: the anti-Xa activity and TFPI concentration results provided for the possibility of calculating and comparing the PD parameters (Amax or Cmax, AUC0-24, AUC0-∞, Tmax, T1/2) and estimating the confidence intervals that are necessary to confirm the bioequivalence of the studied products. The anti-IIa activity data had a characteristic pattern of slight fluctuations around one level, which prevented the calculation and comparison of PD parameters. Conclusion: the study identified specific features to consider when planning comparative PD studies of nadroparin calcium products. Firstly, it is feasible to divide samples into two test aliquots (one for anti-Xa and anti-IIa activity determination, the other for TFPI analysis) at the moment of collection in order to perform the analytical step correctly. Secondly, there is no need in full validation for the bioanalytical assays of the anti-Xa and anti-II activity and TFPI content in human plasma validated in the concentration ranges of 0.024–0.182 IU/mL, 0.0069–0.052 IU/mL and 1.56–100 ng/mL, respectively; a confirmation that the active ingredient does not interfere with the analytical procedure is adequate for the purpose. Finally, the data obtained may not allow for calculating PD parameters and comparing confidence intervals for all three markers. The listed considerations may be relevant for other LMWH products as well.

Heparin-induced Thrombocytopenia Associated With A Heparin-bonded Stent: A Novel Stent-preserving Strategy

Heparin Induced Thrombocytopenia (HIT) resulting from exposure to heparin products is well known, but there is scarce literature regarding HIT resulting from heparin-bonded stent grafts, and limited data supporting the possibility of graft preservation in these patients.

Spontaneous Heparin-Induced Thrombocytopenia Presenting as Concomitant Bilateral Cerebrovascular Infarction and Acute Coronary Syndrome

Background: Spontaneous heparin-induced thrombocytopenia is a pro-thrombotic syndrome in which anti-heparin antibodies develop without heparin exposure. Case presentation: A 78-year-old man who underwent a successful lumbar laminectomy presented to the hospital 5 days after discharge for stroke-like symptoms and was found to have acute infarcts of the bilateral frontal lobes. The patient was found to be severely thrombocytopenic and was incidentally found to have an inferior wall myocardial infarction. Further investigation led to the diagnosis of bilateral lower extremity deep vein thromboses. His overall clinical presentation prompted a detailed hematologic workup that indicated positivity for heparin-induced thrombocytopenia despite no previous exposure to heparin products. Conclusions: This case illustrates a patient with no prior lifetime heparin exposure who underwent laminectomy with subsequent development of acute infarcts of the bilateral frontal lobes, an inferior wall myocardial infarction, and bilateral lower extremity deep vein thromboses, with concern for sequelae of spontaneous heparin-induced thrombocytopenia.

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.

Implementation of Electronic Alerts to Improve Clinician Management of Heparin Induced Thrombocytopenia

Introduction: Heparin induced thrombocytopenia (HIT) is often a difficult clinicopathologic diagnosis to make, which can result in poor patient outcomes due to delays in identification and treatment. Platelet factor 4 (PF4) antibody ELISA tests are routinely used to diagnose HIT. PF4 ELISAs have high sensitivity but low specificity; therefore, to guide appropriate ordering of PF4 tests ASH guidelines recommend calculating a 4T score to assess the pre-test probability, but this is not always done. We implemented and studied the impact of three electronic health record (EHR) based strategies to improve diagnosis and treatment of HIT at our institution. Methods: At Brigham and Women's Hospital, we created 1. an interruptive alert to recommend discontinuation of active heparin products when signing a PF4 order (Figure 1), 2. integrated 4T score calculations with PF4 test ordering, and 3. through randomization, investigation of the efficacy of an interruptive alert advising clinicians not to order the PF4 test if the 4T score was low. Pre and post implementation groups for each intervention were identified and compared. The heparin discontinuation alert went live on December 20, 2018; the pre-intervention group included patients with PF4 tests in the previous 12 months, and the post-intervention group for 12 months following. The 4T score elements were integrated into the PF4 ELISA order on August 31, 2020; the pre-intervention group included patients with PF4 tests ordered 9 months prior and the post-intervention for 9 months following. In the pre-intervention group, we performed chart review to assess whether the ordering provider documented a 4T score; if a 4T score was not documented in the EHR, it was calculated retrospectively by the research team. Groups were compared to determine the proportion of appropriate PF4 orders (4T score > 3), and the efficacy of the randomized alert recommending no PF4 ordering if the 4T score was < 4. For both alert-based interventions, Chi-squared analysis was performed to determine statistical significance between defined groups. Results: 1. Heparin discontinuation: For the heparin discontinuation alert analysis, of 781 orders for PF4 tests in the pre-heparin discontinuation alert group, 293 eligible orders were used, and of 708 orders in the post-alert group, 235 orders were included. Eligible orders were those that had heparin ordered at the time of PF4 testing and those that were not cancelled. Implementation of the heparin discontinuation alert increased heparin discontinuation from 35% to 46 % (p = 0.015) (Figure 2). 2. 4T Score Documentation and Associated PF4 Appropriateness: Of the patient charts reviewed prior to integration of the 4T score elements into the PF4 order, only 31% (85/272) had a 4T score documented in the EHR. Of the 547 patients post-intervention, by design 100% had a documented 4T score. In the pre-intervention group, of those with calculated 4T scores before PF4 test ordering, 69.4% (59/85) were appropriate, while for those without a 4T score calculated just 27.2% (51/187) were appropriate based on retrospective 4T calculation, for a composite 40.4% appropriate pre-intervention PF4 test ordering, as compared to 79.1% (246/311) appropriate PF4 test ordering post-intervention (p <0.00001). Subspecialties with the highest inappropriate ordering of PF4 tests were: Surgical ICU (32.3%), Oncology (25.6%), the Cardiac Critical Care Unit (24.5%), and Adult Medicine (23.8%). 3. Alert to Not Order PF4 With Low 4T Score: Rates of appropriate PF4 ordering were similar between the group randomized to see the interruptive alert advising clinicians not to order the PF4 test if the 4T score <4 (242 appropriate orders/ 298 completed orders, 81%) and the control group that did not see the alert (306 appropriate orders/ 402 completed orders, 76%; p=0.13). Conclusions: Heparin product continuation can be life-threatening in patients with HIT. Implementation of electronic decision support significantly increased discontinuation of heparin products in patients in whom HIT was suspected. Forced calculation of the 4T score resulted in increased appropriateness of PF4 test orders by 40%. The impact of randomized guidance not to order a PF4 test when the 4T score was low was not as successful. Overall, the EHR interventions resulted in improved patient care for those suspected of having HIT at our institution. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

New CMC Algorithm for Evaluation of Lupus Anticoagulant

Introduction: Lupus Anticoagulant (LA) is an autoantibody that in vitro inhibit phospholipid-dependent coagulation reactions in the absence of specific coagulation factor inhibition Primary laboratory criteria for LA detection include prolonged clotting time of a phospholipid dependent test, failure of correction on mixing study, shortening of the clotting time in the presence of high phospholipid concentrations & absence of other inhibitors. (1) According to guidelines,for diagnosing LA two tests based on different principles should be used- dRVVT(Dilute Russel's Viper Venom Time) should be the first test considered. Second test should be a sensitive aPTT (Activate Partial Thromboplastin Time).LA is a multistep procedure with screening, mixing and confirmation tests. Devreese et al recently concluded that integration of screening and confirmation in a single procedure and skipping the mixing tests result in a poor diagnostic efficacy for LA (2).LA is an in-vitro inhibitor and elevated Screening test without mixing studies does not prove inhibitor effect & it wastes time & resources to perform confirmatory tests skipping the mixing. Hence, we devised a new algorithm- Christian Medical College (CMC) Algorithm as shown in figure-1 which starts with DRVVT Screen Mix. To identify interferences due to anticoagulants like heparin and fibrin degradation products (FDP) thrombin time (TT) was also included. If Screen Mix is normal APTT Screen Mix was performed. Aim of our new algorithm was to reduce false positives and avoid interferences in LA Materials and methods: Four hundred and ninety-one (491) samples were analysed retrospectively for a period of 5 months from January 2022 to May 2022. The new algorithm was incorporated into STA R Max2 (Diagnostica Stago) analyser and automatic calculation of ratios and interpretation of results were done based on flow charts. LA testing was performed using DRVVT screen and confirm reagents (STA-Staclot DRVV Screen and STA-Staclot DRVV Confirm) and/or APTT reagent (STA-PTT Synthasil). LA test was considered positive when Screen/ Confirm(S/C) ratio was >1.2. We compared this result to the three hundred forty seven(347) samples, over a period of 4 months(September 2021 - December 2021) analyzed in old algorithm where DRVVT screen & APTT were done as the initial steps instead of DRVVT mixing studies as the 1st step. Results: In the new algorithm result were classified into 7 categories. Category 1 had normal DRVVT screen Mix and normal APTT; these represent true negative cases comprising 68.8 % of the cases. Category 2 had normal DRVVT screen Mix, prolonged APTT Screen Mix with normal TT. 1 case in this category had other Antiphosholipid Antibody (APLA) negative & repeat testing for LA was advised. Category 3 had normal DRVVT Screen mix, prolonged APTT Screen Mix with prolonged TT. There was 1 case in this category, who was on heparin, APLA antibody was negative. Repeat testing was advised at a later date. Category 4 had prolonged DRVVT Screen Mix, normal S/C ratio , with normal TT. There were 61 cases (12%) in this category among which 5 cases had normal DRVVT Screen with prolonged Mix Category 5 had Prolonged DRVVT Screen Mix, with normal S/C Ratio, prolonged TT and this category had 13 (2 %) cases. On further evaluation they were found to be on anticoagulants. Category 6 had prolonged S/C Ratio with normal TT, which are the true positive cases, n=67 (13.6%). There were 4 cases where Screen mix was more prolonged than Screen, and Screen fell below the cut off & could have been missed if mixing step was not done Category 7 had prolonged S/C ratio with prolonged TT. There were 10 cases (2%) in this category. On further evaluation 6 patients had history of anticoagulants and 2 had features of DIC. These 8 patients could represent false positive LA and would have been misclassified if TT was not done. Old algorithm had 20 % positive cases & 80 % negative cases. Since the algorithm were incorporated into STA R Max2 hands on time decreased from 240 minutes to 80 minutes. Cost of the reagents were similar by 2 algorithms. Conclusion: The new algorithm gives better clarity in classification of patients into true positive and true negative & detection of interference due to heparin as thrombin time is also done in parallel. Possible false positive cases could be identified at the onset even before repeat confirmatory lupus testing. This study concludes the importance of mixing studies in avoiding false negatives. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

VTE Prophylaxis in Sickle Cell Disease/Trait Patients Who Underwent Total Joint Replacement, a Single Center Experience

Background Sickle cell disease is a known risk factor for venous thromboembolism (VTE) due to multiple factors including orthopedic surgeries, such as total knee arthroplasty (THA) or total hip arthroplasty (THA), that are frequently undertaken in this population due to complications such as avascular necrosis of the hip and other procedures such as gall-bladder removal and splenectomy.3 These risks, combined with the inherit hypercoagulability in these patients due to increased platelet activation, intravascular hemolysis, and impaired fibrinolysis, leads to an increased risk of VTE in these patients particularly in the periods of increased stress such as during a TKA or THA.4 There is a paucity of published data in regards to the optimum anticoagulation for this patient population and practices remain to be heavily influenced by expert opinion and personal experience by extrapolating data from other patient populations to be used in this higher risk population.2 The incidence of VTE in hospitalized sickle cell patients is higher than that of the general population and likely underdiagnosed 2 There is some data to suggest an odds ratio as high as 7.37 for pulmonary embolism in sickle cell patients undergoing spinal fusion operations (C.I. 4.27- 12.71 , p-value 0.001).1 Given these observations and underlying pathophysiology there is a need for more information regarding the optimum anticoagulation for these patients as well as the need to describe the association of sickle cell disease and VTE which is not very well established in literature.3 Methods Data was requested from MARCQI and compared to EPIC to identify patients with Hemoglobin SS disease, sickle cell trait and Hb C disease who underwent THA or TKA. Patients were analyzed for perioperative anticoagulants, including medication type, dosage, and length of administration. Patients were then assessed for postoperative VTE incidences, including deep vein thromboses, pulmonary emboli, or strokes. Results Overall, 15 patients were included in the study who met our inclusion criteria for analysis (Above 18 years or age with SS disease or sickle trait of Hb C who underwent TKA or THA between the years 2011-2021), patients who were previously receiving anticoagulation with Heparin products DOACs or Coumadin were excluded from the study, and VTE events were defined as events occurring within 3 months after the initial surgical intervention. Of the 15 patients that were chosen for the study there were 10 females and 5 males included with a median age of 54 (Range 24-79) , there were 12 cases of Sickle Cell Trait and 3 cases of HbSS disease ,of these patients 13 had undergone a total knee replacement and two had undergone a total hip replacement, interestingly none of our 15 selected patients had a thromboembolic event within 3 months of their surgical procedure regardless of method of VTE prophylaxis or duration used. There was significant Heterogenicity in terms of methods or VTE prophylaxis used with the majority of the patients ( 6 patients ) having been prescribed ASA at a dose of 325MG BID on discharge along with Pneumatic compression devices while being in the hospital , 4 patients were prescribed a DOAC (Xarelto was used in all 4 patients), 2 patients were prescribed low dose LMWH , while 3 patients did not receive any form of VTE prophylaxis on discharge and only had Pneumatic compression devices while inpatient , all of which were knee replacement patients. Of all therapies chosen the average duration of therapy ranged between 21-28 days in patients who were sent home with VTE prophylaxis. Conclusions: While our smaller sample size was not able to identify VTE occurring in sickle cell disease/trait/HbC disease patients undergoing TKA or THA there was significant lack of standardization in the choice of the type and duration of anticoagulation prophylaxis which stems from a lack of useful guidelines with regards to this high-risk population. Given paucity of data with regards to the subject at hand our data can perhaps be expanded to include more patients through bigger databases to better enhance our understanding on how to best manage these patients to improve clinical outcomes and serve as a basis for future prospective trials.

Quantum chemical calculations of IR spectra of heparin disaccharide subunits

Heparin is a natural polysaccharide, which plays essential role in many biological processes. Alterations in building blocks can modify biological roles of commercial heparin products, due to significant changes in the conformation of the polymer chain. The variability structure of heparin leads to difficulty in quality control using different analytical methods, including infrared (IR) spectroscopy. In this paper molecular modelling of heparin disaccharide subunits was performed using quantum chemistry. The structural and spectral parameters of these disaccharides have been calculated using RHF/6-311G. In addition, over-sulphated chondroitin sulphate disaccharide was studied as one of the most widespread contaminants of heparin. Calculated IR spectra were analyzed with respect to specific structure parameters. IR spectroscopic fingerprint was found to be sensitive to substitution pattern of disaccharide subunits. Vibrational assignments of calculated spectra were correlated with experimental IR spectral bands of native heparin. Chemometrics was used to perform multivariate analysis of simulated spectral data.