Electronic alerts to improve management of heparin-induced thrombocytopenia.

Background: Heparin-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. Objectives: To use electronic health alert interventions to improve provider diagnosis and management of heparin-induced thrombocytopenia through guideline-based, accurate care delivery. Methods: This 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. Results: Intervention 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). Conclusion: Implementation 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.

Heparin is an effective treatment for preventing liver failure after hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) is one of the most important causes of death following liver resection. Heparin, an established anticoagulant, can protect liver function through a number of mechanisms, and thus, prevent liver failure. AIM: To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy. METHODS: The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) v1. 4 pinpointed patients who had undergone hepatectomy for liver cancer, subdividing them into two cohorts: Those who were injected with heparin and those who were not. The statistical evaluations used were unpaired t-tests, Mann-Whitney U tests, chi-square tests, and Fisher's exact tests to assess the effect of heparin administration on PHLF, duration of intensive care unit (ICU) stay, need for mechanical ventilation, use of continuous renal replacement therapy (CRRT), incidence of hypoxemia, development of acute kidney injury, and ICU mortality. Logistic regression was utilized to analyze the factors related to PHLF, with propensity score matching (PSM) aiming to balance the preoperative disparities between the two groups. RESULTS: In this study, 1388 patients who underwent liver cancer hepatectomy were analyzed. PSM yielded 213 matched pairs from the heparin-treated and control groups. Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples. Further analysis in the matched cohorts confirmed a significant association, with heparin reducing the risk of PHLF (odds ratio: 0.518; 95% confidence interval: 0.295-0.910; P = 0.022). Additionally, heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations, diminished requirements for respiratory support and CRRT, and lower incidences of hypoxemia and ICU mortality. CONCLUSION: Liver failure is an important hazard following hepatic surgery. During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure. This indicates that heparin may provide a hopeful option for controlling PHLF.

Heparin-Induced Hemorrhagic Bullous Dermatosis: A Rare Complication of Unfractionated Heparin.

We present a case of an 82-year-old female with a significant medical history of hypertension and Alzheimer's disease who developed heparin-induced hemorrhagic bullous dermatosis during treatment for a subsegmental pulmonary embolism. The patient was admitted with lower extremity edema and cyanosis, diagnosed with a subsegmental pulmonary embolism, and started on therapeutic doses of unfractionated heparin. On the sixth day of heparin therapy, she developed abdominal bloating and a diffuse exanthematous rash, which progressed to hemorrhagic bullae on the plantar and dorsal aspects of her feet, alongside extensive purpura on her legs. Laboratory findings revealed thrombocytopenia. Multidisciplinary consultations confirmed the diagnosis of heparin-induced hemorrhagic bullous dermatosis. Management included continuing unfractionated heparin with close monitoring, supportive topical treatments, and a subsequent transition to rivaroxaban. The patient's condition improved significantly, and she was discharged in stable condition. This case highlights the importance of recognizing rare adverse reactions to heparin and raises the question of preventive measures or risk factors related to this manifestation.

A retrospective study of the management and outcomes of pregnancies with inherited antithrombin deficiency.

INTRODUCTION: Antithrombin (AT) deficiency is a rare but highly thrombogenic inherited thrombophilia. Its association with adverse pregnancy outcomes (APO) is undefined. There is limited guidance on managing AT deficiency in pregnancy. Some significant issues remain controversial, including risk assessment for prophylactic anticoagulation, anticoagulant therapy, and monitoring. Our goal was to examine if the antepartum management of patients with AT deficiency affected their pregnancy outcomes. MATERIALS AND METHODS: This retrospective, single-center observational study included pregnant women with inherited AT deficiency in Peking Union Medical College Hospital between 2013 and 2024. RESULTS: Seventeen pregnancies in 6 women with AT deficiency were identified. A total of 7 pregnancies received adjusted-dose low-molecular-weight heparin (LMWH) and were monitored by anti-Xa level, AT activity, and D-dimer. There were 5 live births (all received LMWH), 7 second-trimester abortions (1 received LMWH), and 5 early pregnancy losses (1 received LMWH). There were 5 abruptio placentae events (3 received LMWH) and 7 thrombotic events (2 received LMWH). CONCLUSIONS: AT deficiency is at least an important partial factor contributing to APO. It is suggested to make a full assessment of AT patients both for venous thrombus embolism and APO risk. We observed a high prevalence of heparin resistance and a positive correlation between adequate anticoagulation and pregnancy outcome based on tight monitoring with anti-Xa level and timely adjustment of the LMWH dosage.

Impact of C-reactive Protein on Anticoagulation Monitoring in Extracorporeal Membrane Oxygenation.

OBJECTIVE: To evaluate the impact of inflammation on anticoagulation monitoring for patients supported with extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective single-center cohort study. SETTING: University-affiliated tertiary care academic medical center. PARTICIPANTS: Adult venovenous and venoarterial ECMO patients anticoagulated with heparin/ MEASUREMENTS AND MAIN RESULTS: C-Reactive protein (CRP) was used as a surrogate for overall inflammation. The relationship between CRP and the partial thromboplastin time (PTT, seconds) was evaluated using a CRP-insensitive PTT assay (PTT-CRP) in addition to measurement using a routine PTT assay. Data from 30 patients anticoagulated with heparin over 371 ECMO days was included. CRP levels (mg/dL) were significantly elevated (median, 17.2; interquartile range [IQR], 9.2-26.1) and 93% of patients had a CRP of ≥5. The median PTT (median 58.9; IQR, 46.9-73.3) was prolonged by 11.3 seconds compared with simultaneously measured PTT-CRP (median, 47.6; IQR, 40.1-55.5; p < 0.001). The difference between PTT and PTT-CRP generally increased with CRP elevation from 2.7 for a CRP of <5.0 to 13.0 for a CRP between 5 and 10, 17.7 for a CRP between 10 and 15, and 15.1 for a CRP of >15 (p < 0.001). In a subgroup of patients, heparin was transitioned to argatroban, and a similar effect was observed (median PTT, 62.1 seconds [IQR, 53.0-78.5 seconds] vs median PTT-CRP, 47.6 seconds [IQR, 41.3-57.7 seconds]; p < 0.001). CONCLUSIONS: Elevations in CRP are common during ECMO and can falsely prolong PTT measured by commonly used assays. The discrepancy due to CRP-interference is important clinically given narrow PTT targets and may contribute to hematological complications.

Macromolecular Interactions of Lipoprotein Lipase (LPL).

Lipoprotein lipase (LPL) is a critical enzyme in humans that provides fuel to peripheral tissues. LPL hydrolyzes triglycerides from the cores of lipoproteins that are circulating in plasma and interacts with receptors to mediate lipoprotein uptake, thus directing lipid distribution via catalytic and non-catalytic functions. Functional losses in LPL or any of its myriad of regulators alter lipid homeostasis and potentially affect the risk of developing cardiovascular disease-either increasing or decreasing the risk depending on the mutated protein. The extensive LPL regulatory network tunes LPL activity to allocate fatty acids according to the energetic needs of the organism and thus is nutritionally responsive and tissue dependent. Multiple pharmaceuticals in development manipulate or mimic these regulators, demonstrating their translational importance. Another facet of LPL biology is that the oligomeric state of the enzyme is also central to its regulation. Recent structural studies have solidified the idea that LPL is regulated not only by interactions with other binding partners but also by self-associations. Here, we review the complexities of the protein-protein and protein-lipid interactions that govern LPL structure and function.

Photoresponsive heparin ionic complexes toward controllable therapeutic efficacy of anticoagulation.

Controllable heparin-release is of great importance and necessity for the precise anticoagulant regulation. Efforts have been made on designing heparin-releasing systems, while, it remains a great challenge for gaining the external-stimuli responsive heparin-release in either intravenous or catheter delivery. In this study, an azobenzene-containing ammonium surfactant is designed and synthesized for the fabrication of photoresponsive heparin ionic complexes through the electrostatic complexation with heparin. Under the assistance of photoinduced trans-cis isomerization of azobenzene, the obtained heparin materials perform reversible athermal phase transition between ordered crystalline and isotropic liquid state at room temperature. Compared to the ordered state, the formation of isotropic state can effectively improve the dissolving of heparin from ionic materials in aqueous condition, which realizes the photo-modulation on the concentration of free heparin molecules. With good biocompatibility, such a heparin-releasing system addresses photoresponsive anticoagulation in both in vitro and in vivo biological studies, confirming its great potential clinical values. This work provides a new designing strategy for gaining anticoagulant regulation by light, also opening new opportunities for the development of photoresponsive drugs and biomedical materials based on biomolecules.

Low-molecular-weight heparin ameliorates intestinal barrier dysfunction in aged male rats via protection of tight junction proteins.

The intestinal barrier weakens and chronic gut inflammation occurs in old age, causing age-related illnesses. Recent research shows that low-molecular-weight heparin (LMWH), besides anticoagulation, also has anti-inflammatory and anti-apoptotic effects, protecting the intestinal barrier. This study aims to analyze the effect of LMWH on the intestinal barrier of old male rodents. This study assigned Sprague-Dawley male rats to four groups: young (3 months), young + LMWH, old (20 months), and old + LMWH. The LMWH groups received 1 mg/kg LMWH via subcutaneous injection for 7 days. Optical and transmission electron microscopy (TEM) were used to examine morphological changes in intestinal mucosa due to aging. Intestinal permeability was measured using fluorescein isothiocyanate (FITC)-dextran. ELISA kits were used to measure serum levels of IL-6 and IL-1ß, while Quantitative RT-PCR detected their mRNA levels in intestinal tissues. Western blotting and immunohistochemistry (IHC) evaluated the tight junction (TJ) protein levels such as occludin, zonula occludens-1 (ZO-1), and claudin-2. Western blotting assessed the expression of the apoptosis marker cleaved caspase 3, while IHC was used to detect LGR5+ intestinal stem cells. The intestinal permeability of aged rats was significantly higher than that of young rats, indicating significant differences. With age, the protein levels of occludin and ZO-1 decreased significantly, while the level of claudin-2 increased significantly. Meanwhile, our study found that the levels of IL-1ß and IL-6 increased significantly with age. LMWH intervention effectively alleviated age-related intestinal barrier dysfunction. In aged rats treated with LMWH, the expression of occludin and ZO-1 proteins in the intestine increased, while the expression of claudin-2 decreased. Furthermore, LMWH administration in aged rats resulted in a decrease in IL-1ß and IL-6 levels. LMWH also reduced age-related cleaved caspase3 expression, but IHC showed no difference in LGR5+ intestinal stem cells between groups. Research suggests that LMWH could potentially be a favorable therapeutic choice for age-related diseases associated with intestinal barrier dysfunction, by protecting TJ proteins, reducing inflammation, and apoptosis.

Factor Xa inhibitors versus low-molecular-weight heparin for preventing coagulopathy following COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Background: Hospitalized patients with COVID-19 have shown a significant occurrence of thromboembolism and a heightened risk of death. It remains unclear whether factor Xa inhibitors are superior to enoxaparin in this context. Hence, there is a need for a direct comparison to assess the preventive effects and safety of factor Xa inhibitors versus enoxaparin in hospitalized COVID-19 patients. Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) or retrospective studies that compared the effectiveness or safety of factor Xa inhibitors and enoxaparin in preventing thromboembolism in hospitalized patients with COVID-19. Embolic incidence, incidence of bleeding, and all-cause mortality were among the outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95 percent CIs. Results: The analysis included six RCTs and two retrospective studies containing 4048 patients. Meta-analysis showed a statistically significant reduction among patients on factor Xa inhibitors compared with low-molecular-weight heparin (LMWH) in the embolic incidence [risk ratio (RR) 0.64 (95%, CI 0.42, 0.98); P=0.04, I2=12%]. Upon subgroup analysis by type of study design, no significant reductions were noted in patients on factor Xa inhibitors in RCTs (RR: 0.62; 95% CI: 0.33-1.17; P=0.14) or observational studies (RR: 0.53; 95% CI: 0.23-1.26; P=0.15) when compared with enoxaparin Factor Xa inhibitors were not significantly associated with incidence of bleeding [RR 0.76 (95% CI 0.36, 1.61); P=0.47, I2=0%] or all-cause mortality (RR: 0.81; 95% CI: 0.48-1.36; P=0.43). Consistent results were obtained upon subgroup analysis by the type of study design. Conclusion: Factor Xa inhibitors are more effective than enoxaparin in preventing thromboembolism among patients with COVID-19 who are not acutely ill and are hospitalized. Additional rigorous RCTs comparing factor Xa inhibitors with enoxaparin are warranted.

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α.

Background: B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.

Characterising glycosaminoglycans in human breastmilk and their potential role in infant health.

Human breastmilk is composed of many well researched bioactive components crucial for infant nutrition and priming of the neonatal microbiome and immune system. Understanding these components gives us crucial insight to the health and wellbeing of infants. Research surrounding glycosaminoglycans (GAGs) previously focused on those produced endogenously; however, recent efforts have shifted to understanding GAGs in human breastmilk. The structural complexity of GAGs makes detection and analysis complicated therefore, research is time consuming and limited to highly specialised teams experienced in carbohydrate analysis. In breastmilk, GAGs are present in varying quantities in four forms; chondroitin sulphate, heparin/heparan sulphate, dermatan sulphate and hyaluronic acid, and are hypothesised to behave similar to other bioactive components with suspected roles in pathogen defense and proliferation of beneficial gut bacteria. Chondroitin sulphate and heparin, being the most abundant, are expected to have the most impact on infant health. Their decreasing concentration over lactation further indicates their role and potential importance during early life.

A randomized crossover trial of regional anticoagulation modalities for intermittent hemodialysis.

INTRODUCTION: The optimal regional anticoagulation (RA) of dialysis filters in patients at risk of bleeding remains elusive. Inducing hypocalcemia within the filter by using a calcium-free dialysate has emerged as an easy-to-use heparin-free RA, including in critically ill patients, but comparative studies are lacking. METHODS: We conducted a multicentre, randomized, crossover trial to compare the efficacy and tolerance of two RAs (heparin-coated membrane (HCM) or calcium free dialysate with calcium reinjection according to ionic dialysance (CFD)) in patients requiring hemodialysis and at risk of bleeding. During the study period, each patient received two dialysis sessions (one with each RA in a randomly assigned order). The primary endpoint was the proportion of dialysis sessions completed (≥ 240 min). RESULTS: 94 patients were included in the intention-to-treat analysis, including 16 critically ill patients (17.0%). Coagulation and inflammation parameters, as well as hemodynamic status at baseline, were balanced between groups. Premature coagulation of the filter occurred in 19 HCM (20.9%) compared to 3 (3.2%) CFD sessions. In half of the sessions with premature termination, coagulation occurred before 180 minutes. The proportion of patients who completed the CFD session while failing to complete the HCM session (n = 17) was significantly higher than the proportion of patients who completed the HCM session while failing to complete the CFD session (n = 1; p < 0.001). Hemodynamic and metabolic tolerance were not different between groups. CONCLUSIONS: In individuals at risk of bleeding, RA with calcium-free dialysate significantly reduces the incidence of premature dialysis termination compared to heparin-coated membrane without safety concerns. Trial registration and statistical analysis plan: ClinicalTrials.gov identifier: NCT03842657.

Heparin-Induced Thrombocytopenia in Patients Suffering Cardiogenic Shock.

OBJECTIVES: Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN: Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING: Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS: In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS: In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS: HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

Efficacy and safety of direct oral anticoagulants for preventing venous thromboembolism in hospitalized cancer patients: a national multicenter retrospective cohort study.

Introduction: Studies on the use of direct oral anticoagulants (DOACs) for preventing venous thromboembolism (VTE) in hospitalized cancer patients are lacking. Therefore, we conducted a multicenter retrospective cohort study to evaluate the efficacy and safety of DOACs versus low-molecular-weight heparin (LMWH) for the primary prevention of VTE in hospitalized cancer patients. Methods: Clinical outcomes included thrombosis, VTE, other thrombosis, all bleeding, major bleeding, nonmajor bleeding, and all-cause death. A 1:1 cohort of rivaroxaban and LMWH patients was created by propensity score matching. Results: A total of 2,385 cancer patients were included in this study. During the 3-month follow-up period, 129 (5.4%) thrombosis events occurred, 63 (2.7%) of which were VTEs and 66 (2.8%) of which were other thrombosis events. All bleeding occurred in 163 (6.8%) patients, 68 (2.9%) had major bleeding, and 95 (4.0%) had nonmajor bleeding. All-cause deaths occurred in 113 (4.7%) patients. After adjusting for various confounders, the incidence of thrombosis and other thromboses was significantly lower in the rivaroxaban group than in the LMWH group [OR 0.543, 95% CI (0.343-0.859), p = 0.009; OR 0.461, 95% CI (0.241-0.883), p = 0.020]. There were no significant differences in incidence of VTE, total bleeding, major bleeding, nonmajor bleeding, or all-cause death. Conclusion: In oncology patients receiving thromboprophylaxis, rivaroxaban has a lower incidence of thrombosis and other thrombosis and a similar incidence of VTE as LMWH and does not increase the risk of bleeding. Rivaroxaban may be an attractive alternative to LMWH for preventing VTE in hospitalized cancer patients.

Heparin-induced thrombocytopenia after cardiac surgery. A single-center, retrospective cohort study.

Background: Cardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting. Objectives: To describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity. Methods: A retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center. Results: HIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause. Conclusion: Although rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.

Heparin-induced thrombocytopenia with very high antibody titer is associated with slower platelet recovery and higher risk of thrombosis.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by platelet-activating antibodies targeting platelet factor 4 (PF4) and heparin complex. A higher antibody titer is reflected in a higher optical density (OD) by enzyme-linked immunosorbent assay for heparin-PF4 antibodies. This single-institution retrospective study of 116 HIT patients examined the effect of heparin-PF4 OD on time to platelet recovery, vascular thrombosis, and in-hospital mortality. Patients were divided into 3 cohorts based on heparin-PF4 OD: cohort 1 had an OD ≥ 2 and ≤ 2.4, cohort 2 had an OD > 2.4 and ≤ 2.8, and cohort 3 had an OD > 2.8. A higher OD titer was associated with significantly increased time to platelet recovery when compared between cohorts 1 versus 2 (HR = 0.599, p = 0.0221) and 1 versus 3 (HR = 0.515, p = 0.0014), as well as an increased risk of thrombosis (79.4%-cohort 3 vs 53.8%-cohort 2 vs 46.1%-cohort 1, p = 0.04), but had no impact on mortality (2.62-alive vs 2.65-deceased, p = 0.7432). A higher OD titer can inform risk assessment and support decision-making in HIT patients; however, prospective studies are needed to further clarify the impact of heparin-PF4 OD on outcomes.

Identification of heparin-binding amino acid residues in antibody HS4C3 with the potential to design antibodies against heparan sulfate domains.

Heparan sulfate (HS) is a linear polysaccharide with high structural and functional diversity. Detection and localization of HS in tissues can be performed using single chain variable fragment (scFv) antibodies. Although several anti-HS antibodies recognizing different sulfation motifs have been identified, little is known about their interaction with HS. In this study the interaction between the scFv antibody HS4C3 and heparin was investigated. Heparin-binding lysine and arginine residues were identified using a protect and label methodology. Site-directed mutagenesis was applied to further identify critical heparin-binding lysine/arginine residues using immunohistochemical and biochemical assays. In addition, computational docking of a heparin tetrasaccharide towards a 3-D homology model of HS4C3 was applied to identify potential heparin-binding sites. Of the 12 lysine and 15 arginine residues within the HS4C3 antibody, 6 and 9, respectively, were identified as heparin-binding. Most of these residues are located within one of the complementarity determining regions (CDR) or in their proximity. All basic amino acid residues in the CDR3 region of the heavy chain were involved in binding. Computational docking showed a heparin tetrasaccharide close to these regions. Mutagenesis of heparin-binding residues reduced or altered reactivity towards HS and heparin. Identification of heparin-binding arginine and lysine residues in HS4C3 allows for better understanding of the interaction with HS and creates a framework to rationally design antibodies targeting specific HS motifs.

The association between heparin sensitivity index and postoperative blood loss in Chinese patients undergoing elective off-pump coronary artery bypass grafting: a single center retrospective study.

BACKGROUND: The heparin sensitivity index (HSI) is closely associated with perioperative ischemic events and increased blood loss in cardiac surgery. Previous studies have produced conflicting results. Therefore, this study aimed to investigate the relationship between HSI and postoperative blood loss specifically in Chinese patients undergoing elective off-pump coronary artery bypass grafting (OPCAB). METHODS: Patients underwent OPCAB between March 2021 and July 2022 were retrospectively included. Enrolled patients were classified into Low-HSI (HSILOW; HSI < 1.3) and Normal-HSI (HSINORM; HSI ≥ 1.3) groups. HSI = [(activated clotting time (ACT) after heparin) - (baseline ACT)] / [loading dose of heparin (IU/kg)]. Primary outcome included postoperative blood loss at 24 h. Secondary outcomes were total postoperative blood loss, transfusion requirement of red blood cell (RBC), fresh frozen plasma (FFP), platelet concentrates (PC), and other complications. RESULTS: We retrospectively analyzed 303 Chinese OPCAB patients. HSILOW group had higher preoperative platelet (PLT) count (221 × 109/L vs. 202 × 109/L; P = 0.041) and platelet crit (PCT) value (0.23% vs. 0.22%; P = 0.040) compared to HSINORM group. Two groups showed no significant differences in postoperative blood loss at 24 h (460 mL vs. 470 mL; P = 0.252), total blood loss (920 mL vs. 980 mL; P = 0.063), RBC transfusion requirement (3.4% vs. 3.1%; P = 1.000), FFP transfusion requirement (3.4% vs. 6.2%; P = 0.380), and other complications. Preoperative high PLT count was associated with low intraoperative HSI value (odds ratio: 1.006; 95% confidence interval: 1.002, 1.011; P = 0.008). CONCLUSIONS: Intraoperative HSI value was not associated with postoperative blood loss in Chinese patients undergoing OPCAB. Preoperative high PLT count was an independent predictor of low intraoperative HSI value.

Plasma exchange and intravenous immunoglobulin for the peri-operative management of type 2 heparin-induced thrombocytopaenia in a patient requiring urgent surgery for critical limb ischaemia.

We report the case of a 61-year-old female who developed heparin-induced thrombocytopaenia following treatment of a submassive pulmonary embolism, and who then required an above knee amputation for critical limb ischaemia. Heparin-induced thrombocytopaenia is a rare, immune-mediated complication associated with an in-hospital mortality rate of 10%. It is more common in surgical patients, with patients undergoing orthopaedic surgery more likely to develop it than patients undergoing cardiac surgery, but heparin-dependent immunoglobulin G antibodies are more likely to be formed in the latter. Peri-operative management remains a challenge. Ideally, it is preferable to wait for the platelet count to improve; but in certain cases, surgery cannot be delayed. Heparin-induced thrombocytopaenia is usually managed with direct thrombin inhibitors, such as argatroban and bivalirudin. Newer therapeutic modalities, such as plasmapheresis and intravenous immunoglobulin, as used in this case, can rapidly remove antibodies, but the certainty of evidence is low. Our case adds to the literature regarding the use of these modalities and highlights the multidisciplinary team approach required to manage such complex cases.

Preferences of pregnant women for postpartum thromboprophylaxis: the bicentric PREFER-PP study.

BACKGROUND: Clinical guidelines for postpartum thromboprophylaxis differ due its uncertain effect and varying preferences of experts. Women's preferences for postpartum thromboprophylaxis are unknown, although they may inform practices and future research. Our aim was to elicit the pregnant women's preferences for postpartum thromboprophylaxis, according to different risks of venous thromboembolism (VTE) and bleeding. METHODS: In two Swiss and French maternity hospitals, we conducted structured interviews of pregnant or postpartum women. Participants were instructed on pulmonary embolism (PE), deep vein thrombosis (DVT), postpartum hemorrhage (PPH) and subcutaneous injections of low-molecular-weight heparin (LMWH). First, we randomized women to either standard gamble or time trade-off (two different validated methods) to estimate the utilities (quality-of-life, from 0-1) of these health states. Second, we elicited the preference for the use of short-term postpartum thromboprophylaxis with LMWH vs. none across different risks of postpartum VTE and bleeding, through direct-choice exercises. RESULTS: Among 122 participants, median (IQR) health states utilities were 0.725 (0.30-0.925) for PE, 0.75 (0.40-0.97) for PPH, 0.85 (0.60-0.97) for DVT and 0.96 (0.96-0.999) for LMWH injections. The median risk of postpartum VTE to prefer the use of postpartum thromboprophylaxis over no treatment was 0.1% (IQR 0.01-0.50%) without LMWH-associated bleeding risk and 0.2% (IQR 0.1-5%) with a 1% bleeding risk. CONCLUSIONS: European pregnant women appear to have a high willingness for 10-day postpartum thromboprophylaxis, preferred over no treatment even for low risks of postpartum VTE. This perspective from patients supports the urgent need for a randomized trial evaluating the efficacy and safety of postpartum thromboprophylaxis.