International Society Of Thrombosis And Haemostasis Research Articles

Combining rivaroxaban with aspirin for peripheral artery disease: an in-depth systematic review and meta-analysis

Abstract Funding Acknowledgements None. Introduction Peripheral artery disease (PAD) poses a significant challenge in the realm of cardiovascular medicine, necessitating a multifaceted approach to mitigate its impact and enhance patient outcomes. One treatment approach involves the combined use of rivaroxaban, a direct oral anticoagulant, and aspirin, a commonly used antiplatelet agent in decreasing possible complications that can develop in patients with PAD. Methods An extensive search of randomized controlled trials (RCTs) comparing the efficacy of rivaroxaban in combination with aspirin versus aspirin monotherapy among individuals diagnosed with peripheral artery disease. The assessment of this treatment approach involved evaluating the following primary outcomes: a decrease in major adverse cardiovascular events (MACE) and the need for major amputation. Safety profile was also evaluated by examining the rate of major bleeding, utilizing the scoring tool from International Society of Thrombosis and Hemostasis (ISTH). The analyses were performed using a random effects analysis approach via Review Manager V5.4. Results This meta-analysis encompassed three studies involving a total of 9,352 participants. There was reduction of MACE in rivaroxaban with aspirin therapy (RR 0.83 [95% CI: 0.71-0.97] I2 = 29%, p = 0.02] but there was no significant difference in terms of major amputation rates (RR 0.96 [95% CI: 0.80-1.14] I2 = 0%, p = 0.62). However, there was increased risk of bleeding in rivaroxaban with aspirin therapy (RR 1.46 [95% CI: 1.17-1.82] I2=0, p = 0.0009) compared to aspirin alone. Conclusion Rivaroxaban combined with aspirin therapy demonstrated a 17% reduction in MACE compared with aspirin monotherapy but didn’t reduce major amputation rates. Also, doing this strategy poses a higher risk of bleeding. Therefore, a balance between the risks and benefits of this combined therapy necessitates a thorough assessment of individual patient profiles, considering factors such as overall cardiovascular risk, comorbidities, and bleeding tendencies. Further research and long-term studies are needed to establish comprehensive guidelines for the appropriate utilization of this combination therapy in various patient populations.

Thromboprophylaxis with Intermediate Dose Low Molecular Weight Heparin in Adults Undergoing Induction with L-Asparaginase for Acute Lymphoblastic Leukemia

Introduction Adolescents and young adults (AYA, defined as age 15-39 years) with acute lymphoblastic leukemia (ALL) have a poorer prognosis than their pediatric counterparts. To replicate the success of ALL treatment in children, pediatric-inspired regimens have been incorporated into the treatment of AYA and often include the use of L-asparaginase. Rates of thrombosis in adults receiving L-asparaginase for treatment of ALL have been reported to be as high as 34%, compared to only about 5% in pediatric patients. The risk of thrombosis is elevated primarily during the induction phase of treatment. Several strategies have been studied in adults, including antithrombin III replacement, fresh frozen plasma replacement, and prophylactic dosing of anticoagulation, however no clear guidelines exist on how to prevent thrombosis in these high-risk patients. To prevent L-asparaginase-induced thrombotic events, our institution implemented a standard practice of 1mg/kg/day of low molecular weight heparin (LMWH), a dose in-between prophylactic and therapeutic dosing, administered to all adults with ALL who were treated with L-asparaginase during induction chemotherapy. In this current study, we report data from patients who have been treated with this strategy from 2012 to present, focusing on the antithrombotic efficacy and safety of 1mg/kg/day LMWH in this population. Methods This retrospective chart review included 62 patients who received prophylactic anticoagulation with the LMWH enoxaparin (1mg/kg/day) while undergoing induction chemotherapy with L-asparaginase for ALL at the Oregon Health & Science University from 2012 to present. Anticoagulation with enoxaparin was initiated with the first dose of L-asparaginase and continued until the day of discharge or day 30 of induction. The primary outcome was the incidence of thrombosis within the first 30 days of L-asparaginase administration. Minor and major bleeding events, as defined by the International Society of Thrombosis and Haemostasis (ISTH), were recorded. Statistical analysis with univariate regression models was performed to evaluate the association of thrombotic events with demographic, disease and treatment variables. Results Sixty-two patients received 1mg/kg/day LMWH prophylaxis during ALL induction between January 2012 and June 2023 (43 with B-ALL and 19 with T-ALL). Median age at induction was 25.7 years (range 18-39 years). A majority of patients (83.9%) received the maximum dose of 2500mg/m 2 of L-asparaginase. Four patients (6.5%; 95% CI 1.8%-15.7%) experienced a thrombotic event within the first 30 days of induction with L-asparaginase; 3 of the events were catheter-associated and were treated supportively or with catheter removal, and 1 patient developed a distal lower extremity deep vein thrombosis related to myositis. Median time to thrombosis was 13.5 days (range 11-22 days). There were no significant associations between development of thrombotic events with age, gender, B- or T-cell precursor, or dose of L-asparaginase. No thrombosis-related deaths or major bleeding events occurred. Conclusions Prophylactic anticoagulation with intermediate dose 1mg/kg/day LMWH in adults with ALL undergoing induction chemotherapy with L-asparaginase is a safe and an effective strategy to prevent serious thrombotic events. Our institutional rate of 6.5% of patients experiencing thrombotic events during induction with L-asparaginase, with all of the events being clinically low risk, compares favorably to historically reported rates in adults and approaches the low rates reported in children. Further prospective research is warranted.

Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy.

In patients with sepsis-induced coagulopathy (SIC), the Chinese DIC scoring system (CDSS) of the Chinese Society of Thrombosis and Hemostasis score, the Japanese Association for Acute Medicine (JAAM) score, the International Society of Thrombosis and Hemostasis (ISTH), and the Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA Guidelines (CRUSADE) score were compared for their predictive significance (SIC). From August 2021 through August 2022, 92 SIC patients hospitalized in our hospital's Department of Critical Care Medicine served as study participants. Groups of patients were created with a bad prognosis (n = 35) and a favorable prognosis (n = 57) 14 days following admission. Electronic medical records were used to compile patient information such as demographics (gender, age, and body mass index), medical history (hypertension, diabetes, chronic obstructive pulmonary disease, and chronic kidney disease), treatment (mechanical ventilation, APACHE II score at admission), and outcomes (results). All patients' JAAM, CDSS, ISTH, and CRUSADE scores were recorded. The APACHE II scores of the group with a poor prognosis were noticeably (p < 0.05) higher upon admission than those of the group with a favorable prognosis. The poor prognosis group had higher JAAM, ISTH, CDSS, and CRUSADE scores than the good prognosis group (all p < 0.05). Partial coagulation indicators in fibrinogen, D-dimer, activated partial thromboplastin time, and prothrombin time were positively linked with JAAM, ISTH, CDSS, and CRUSADE (all p < 0.05). At admission, the JAAM, ISTH, CDSS, CRUSADE, and APACHE II scores were independently linked with SIC patients' prognosis (all p < 0.05) in a multivariate logistic regression analysis. According to receiver operating characteristic analysis, the area under the curve for predicting the prognosis of SIC patients using the JAAM, ISTH, CDSS, and CRUSADE4 scores was 0.896, 0.870, 0.852, and 0.737, respectively, with 95% CI being 0.840-0.952, 0.805-0.936, 0.783-0.922 and 0.629-0.845, respectively (all p < 0.05). The prognosis of SIC patients may be predicted in part by their JAAM, ISTH, CDSS, and CRUSADE4 scores, with the CDSS score being the most accurate. This research provides important recommendations for improving the care of patients with SIC.

The International Society of Thrombosis and Hemostasis (ISTH) criteria in intensive care units

BackgroundDisseminated Intravascular Coagulation (DIC) has been assessed by the International Society of Thrombosis and Hemostasis (ISTH) 2001 and the ISTH 2018-modified version. More investigations are needed to assess usability and visibility of those DIC scoring systems in the intensive care units (ICU). AimsThis study investigated the predictive performance of the ISTH–Overt DIC versions of 28–day mortality in ICUs compared to SOFA as a gold standard assessment tool of sepsis. MethodsA retrospective design (2015–2017) included 220 adult patients enrolled from medical and surgical ICUs in two major hospitals in Jordan. We calculated ISTH–Overt DIC scores and SOFA score on time of DIC diagnosis. Overt DIC was categorized based on a score of ≥ five for ISTH DIC 2001; and ≥ 4 for ISTH DIC 2018. Provided, a score > 12 was categorized as Multiple–Organ– Dysfunction–Syndrome (MODS) for Sequential Organ Failure Assessment (SOFA) score. Then, 28–day mortality follow-up was performed. ResultsMore than half of sample died before 28–days of follow–up. The analysis of Receiver Operating Characteristic (ROC) showed that higher scores of ISTH DIC 2001(≥ 5), ISTH DIC 2018 (≥ 4), and SOFA score (>12) were highly associated with 28–day mortality. The ISTH DIC 2001 and SOFA score were superior on the modified ISTH 2018 in predicting 28–day mortality, with an Area Under the Curve (AUC) of (0.724 vs. 0.822 vs. 0.507, respectively). Yet, the accuracy of the SOFA score was better than the ISTH DIC 2001. Conclusion: This study suggests that ISTH DIC 2001 score is helpful when applied on medical and surgical ICU Jordanian populations. It showed better results compared to the Modified ISTH DIC 2018 in mortality prediction, regardless of the underlying diseases.

Diagnosis of Disseminated Intravascular Coagulation in Patients Suffering from Sepsis using the Modified International Society of Thrombosis and Haemostasis Criteria and Japanese Association of Acute Medicine Criteria

Introduction: The international task force defines sepsis as ‘life- threatening organ dysfunction caused by a dysregulated host response to infection’. Disseminated Intravascular Coagulation (DIC) is a coagulopathy syndrome that causes microvascular and macrovascular thrombosis and increases the risk of bleeding due to consumptive coagulopathy. Sepsis causes dysfunction in coagulation due to release of inflammatory markers which leads to inappropriate deposition of intravascular fibrin. In order to facilitate the diagnostic process for detecting DIC, the scoring system recommended by International Society of Thrombosis and Haemostasis (ISTH) and Japanese Association of Acute Medicine (JAAM) were used which are based on the global coagulation tests such as the platelet count, Prothrombin time, International Normalised Ratio (INR) and Fibrin Degradation Products (FDPs)/D-dimer. Aim: To determine the prevalence and outcome of DIC in patients suffering from sepsis using ISTH criteria and JAAM criteria. Materials and Methods: A prospective cohort was carried out from January 2021 to July 2022 in the haematology section of pathology department of Government Medical College and Hospital, Aurangabad, Maharashtra, India. Hundred patients suffering from clinically suspected sepsis were included in the study. Venous blood was collected from patients in Ethylene Diamine Tetra-acetic Acid (EDTA) and Citrate bulbs. The tests performed were Complete Blood Count (CBC), Prothrombin Time (PT), INR and D-Dimer. CBC was performed on Fully automated three part cell counter. PT, INR, D-Dimer testing was done on fully automated coagulometer. The above test results were used to diagnose DIC in patients suffering from sepsis using the modified ISTH and JAAM criterias. The results were analysed using Microsoft excel 2019 i.e., chi-square test was applied for p-value calculation. Results: Out of 100 patients with clinically suspected sepsis 35 patients (35%) suffered from Overt DIC using ISTH criteria and 58 patients (58%) suffered from DIC using JAAM criteria. The total mortality in patients with sepsis in the present study was 40%. The mortality in patients with DIC in sepsis using the ISTH criteria was 26 patients (74.28%) and 37 patients (63.79%) using the JAAM criteria. Conclusion: Coagulation abnormalities are widely prevalent in patients with sepsis and are likely to play a key role in multi- organ dysfunction. Both ISTH and JAAM criteria are good predictors of mortality.

Risk of Bleeding Associated With Outpatient Use of Rivaroxaban in VTE Management at a National Referral Hospital in Western Kenya.

There is limited data on the bleeding safety profile of direct oral anticoagulants, such as rivaroxaban, in low- and middle-income country settings like Kenya. In this prospective observational study, patients newly started on rivaroxaban or switching to rivaroxaban from warfarin for the management of venous thromboembolism (VTE) within the national referral hospital in western Kenya were assessed to determine the frequency of bleeding during treatment. Bleeding events were assessed at the 1- and 3-month visits, as well as at the end of follow-up. The International Society of Thrombosis and Hemostasis (ISTH) and the Bleeding Academic Research Consortium (BARC) criteria were used to categorize the bleeding events, and descriptive statistics were used to summarize categorical variables. Univariate and multivariate logistic regression model was used to calculate unadjusted and adjusted associations between patient characteristics and bleeding. The frequency of any type of bleeding was 14.4% (95% CI: 9.3%-20.8%) for an incidence rate of 30.9 bleeding events (95% CI: 20.1-45.6) per 100 patient-years of follow-up. The frequency of major bleeding was 1.9% while that of clinically relevant non-major bleeding was 13.8%. In the multivariate logistic regression model, being a beneficiary of the national insurance plan was associated with a lower risk of bleeding, while being unemployed was associated with a higher bleeding risk. The use of rivaroxaban in the management of VTE was associated with a higher frequency of bleeding. These findings warrant confirmation in larger and more targeted investigations in a similar population.

Recurrent Venous Thromboembolism with Direct-Acting Oral Anticoagulants and Body Mass Index: A Single Institutional Study

Introduction: Obesity is a known risk factor for development and worsening of venous thromboembolic episodes (VTEs). The 2016 International Society of Thrombosis and Hemostasis (ISTH) guidelines recommend caution using direct-acting oral anticoagulants (DOACs) in patients with morbid obesity (BMI >40 kg/m2 or weight > 120 kg) due to limited clinical efficacy and safety data supporting their use in this population. The ISTH recommends laboratory monitoring and dose adjustment as needed, if DOACs are being used in these patients. Unfortunately, most health systems do not have timely access to these tests, and the laboratory monitoring of DOACs remains a non-validated concept. Although the review of the currently available data does not reveal a significantly higher risk of recurrent VTE when using DOACs in these patients, the data is limited due to their retrospective and non-randomized nature and are thus hypothesis generating. We hypothesize that recurrent VTEs are higher in patients with morbid obesity and sought to investigate the differences in VTE recurrences in these patients when compared to the other patients. Methods: After institutional review board approval, we conducted a retrospective chart review for 1 year period (Jan 1, 2020 - Dec 31, 2020) on all patients >/= 18 years of age who were seen at our institution, who received a DOAC (Apixaban, Rivaroxaban, Edoxaban or Dabigatran). Patients who did not have any documentation of the outcome of interest, and those who were non-compliant with the DOACs were excluded. In the remainder of the cohort, data on BMI and recurrence of VTE after starting DOACs was collected and analyzed. Fisher's exact test was used to compare VTE recurrence in the different BMI groups. VTE recurrence in BMI groups taking the same DOAC was also compared individually. SPSS version 28 was used for statistical analysis. Results: A total of 549 patients were initially collected and reviewed. 15 patients who did not have any documentation regarding VTE recurrence were excluded. 60 patients who were non-compliant with DOACs were excluded as well. The remaining 474 were including in the final study, out of which 288 (60.7%) were female, and 186 (39.3%) were male. Median age was 60, ±24. 400 (84.3%) had BMI <40 kg/m2, and 74 (15.7%) had BMI ≥40 kg/m2. 388 (81.9%) patients were on Apixaban, 6 (1.2%) on Dabigatran, 79 (16.7%) on Rivaroxaban, and 1 (0.2%) on Edoxaban. Recurrence of VTE while on the DOAC was observed in 4 (1%) patients with BMI <40 kg/m2, compared to 3 (4.1%) patients with ≥40 kg/m2 (p=0.080). Among those taking Apixaban, 3 (0.9%) patients with BMI <40 kg/m2 had recurrence, compared to 2 (3.4%) with ≥40 kg/m2 (p=0.16). For those on Rivaroxaban, 1 (1.6%) patient with BMI <40 kg/m2 had recurrence, compared to 1 (6.7%) patient with ≥40 kg/m2 (p=0.346). No recurrences were observed in patients on Dabigatran and Edoxaban. [Table 1] Conclusions: There was a numerically higher but statistically insignificant increased risk of recurrent VTE while on a DOAC in patients with BMI ≥40 kg/m2 compared to those with BMI <40 kg/m2 (4.1% vs 1%). This increased risk was similar with comparison of individual DOACs as well (3.4% vs 0.9% in the Apixaban group; 6.7% vs 1.6% in the Rivaroxaban group). Our study did not achieve statistical significance to prove our hypothesis, possibly because the analysis was underpowered. Further prospective studies with a larger sample size are needed to establish the safety of DOACs in morbidly obese patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diagnostic value of multigene sequencing for inherited thrombocytopenia.

Multigene testing for inherited thrombocytopenia can detect an unexpected diagnosis as demonstrated in the case report from Ming-Ping et al., where the mode of inheritance and clinical phenotype did not point towards dominant Schlafen family member 14 (SLFN14) moderate thrombocytopenia. They describe two siblings with very severe thrombocytopenia due a pathogenic SLFN14 variant and gonosomal mosaicism in their healthy mother. In their paper Ming-Ping et al. describe two siblings with severe thrombocytopenia (platelets counts <15 × 109/l) and bleeding symptoms, born from healthy non-consanguineous parents.1 The first child died at the age of 5 months due to intracranial haemorrhage. This child also had larger platelets, while this was not found for his affected sister. She has received regular platelet transfusions since birth. Neonatal and immune thrombocytopenia were ruled out. Their diagnosis was made after using whole-exome sequencing with the detection of a heterozygous pathogenic SLFN14 variant that is responsible for dominant thrombocytopenia. Interestingly, gonosomal mosaicism for this variant was detected in the mother who has normal platelet counts. This case report nicely demonstrates the power of multigene sequencing for the diagnosis of inherited thrombocytopenia, which is an extremely heterogenous disorder with already 40 diagnostic-grade genes as potential underlying cause (Figure 1).2, 3 Using only textbook knowledge, the diagnosis of SLFN14-related thrombocytopenia could probably never have been made for these patients. Based on the clinical phenotypes present in the family members, a recessive form of inherited (macro)thrombocytopenia was expected as parents have a normal platelet count. In addition, SLFN14-related thrombocytopenia is an ultrarare disorder and clinical and laboratory data have only been described for four unrelated pedigrees.4 All patients with pathogenic SLFN14 variants have platelet counts >65 × 109/l (moderate thrombocytopenia) and highly variable degrees of bleeding symptoms and International Society of Thrombosis and Haemostasis (ISTH) bleeding scores ranging between 2 and 20. The children in this case report have a much more severe phenotype and still they carry the same genetic variant as previously described.4 In the past, several diagnostic algorithms have been proposed to assist clinicians in the differential diagnosis of inherited thrombocytopenia. The classification of inherited thrombocytopenia was typically driven by the presence or absence of other clinical features besides a platelet defect (syndromic versus non-syndromic), the mode of inheritance (recessive, dominant and X-linked) and the platelet size (macro, micro and normal size platelets) (Figure 1).5 Applying such an algorithm was very useful, as the numbers of genes implicated in inherited thrombocytopenia was less than half of the genes we know today. However, this algorithm would have missed the diagnosis in the family. Since the discovery of many novel genes for inherited thrombocytopenia using next-generation sequencing approaches over the last decade, phenotype–genotype associations for this disorder have become very complex.6 In addition, the mode of inheritance has expanded for well-known genes (e.g., dominant mild Bernard–Soulier syndrome versus the classical recessive form and recessive Fli-1 proto-oncogene, ETS transcription factor [FLI1] and growth factor-independent 1B transcriptional repressor [GFI1B] variants versus the known dominant forms of this type of thrombocytopenia). To date, multigene panel testing is typically used to diagnose inherited thrombocytopenia by investigating all the known genes involved in this pathology in a single analysis.7 Providing detailed clinical and laboratory information to genetic laboratories remains very important for the interpretation of this test as it assists in the variant classification to decide if a variant is pathogenic or not. The major drawbacks of performing a multigene panel test for inherited thrombocytopenia are the detection of many variants of unknown significance than cannot be used for clinical management and unsolicited findings. If for example pathogenic variants are detected in either RUNX family transcription factor 1 (RUNX1), ETS variant transcription factor 6 (ETV6) or ankyrin repeat domain-containing 26 (ANKRD26) in a patient with thrombocytopenia without a family history of leukaemia, such variants can be considered as an unsolicited finding if the patient was not aware about these genetic risk factors for leukaemia before initiating the multigene test. On the other hand, a multigene test allows the detection of ‘the unexpected diagnosis’. This case report provides such an example as a SLFN14 defect was not really expected based on the known disease phenotypes associated with pathogenic variants in this gene.

Association of coagulation markers and antiphospholipid antibodies with ischemic and bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention

Abstract Background Antiphospholipid antibodies and other coagulation markers are associated with ischemic risk in patients with coronary artery disease without oral anticoagulation (OAC). Aim To assess the association of antiphospholipid antibodies (aPL) and conventional markers of coagulation with ischemic and bleeding risk in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). Patients and methods In this prospective single center observational cohort study, patients with AF and an indication for OAC were enrolled after PCI. Dilute Russell's viper venom time (DRVVT) was used to determine lupus anticoagulants (LA) in direct OAC-free plasma. Anti-cardiolipin IgG (aCL), IgM and anti-beta2GP-1-IgG (aβ2GP1) were analyzed by enzyme linked immunosorbent assay (ELISA). Fibrinogen C (FIBC), d-dimers and prothrombin fragments 1 and 2 (PF1+2) were measured in citrated plasma. Immature platelet fraction (IPF [%]) and absolute (IPF abs. [103/μl]) were measured in EDTA-blood. The primary ischemic outcome was defined as time to major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, or stroke) assessed at 6 months. Bleeding was defined according to the International Society of Thrombosis and Haemostasis (ISTH) and the Bleeding Academic Research Consortium (BARC). Results 158 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 72–82), 111 (70%) were male, and 39 (25%) presented with acute coronary syndrome. All Patients were treated with clopidogrel and OAC, 145 (92%) in addition with acetylsalicylic acid (ASA). 32 patients (20%) had ≥1 antiphospholipid antibody (aPL; LA: 19 [12%], aCL: 14 [9%], aβ2GP1: 2 [1%]). D-dimers were elevated in 74 patients (47%), FIBC was increased in 40 (25%) and PF1+2 in 68 patients (43%). IPF [%] was elevated in 28 (18%) and IPF abs. [103/μl] in 11 (7%). The presence of aPL was neither significantly associated with MACE, nor with bleeding risk. Elevated d-dimers were significantly associated with higher risk for MACE (HR=5.1, 95% CI [1.1; 23.4], p=0.04), major ISTH bleeding events (HR= 6.9, 95% CI [1.5; 30.8], p=0.01) and BARC bleeding type 3 or 5 (HR=6.4, 95% CI [1.4; 28.7], p=0.02). Increased levels of FIBC were associated with risk of MACE (HR= 3.6, 95% CI [1.1; 12.0], p=0.03 (Table 1). Conclusion In patients with AF undergoing PCI, high levels of d-dimers and fibrinogen C indicate an increased ischemic risk. Elevated d-dimers are associated with higher risk for bleeding. aPL positivity was not significantly associated with outcome possibly due to low sample size. A combined panel of biomarkers might be suitable to assess ischemic and bleeding risk in patients with AF following PCI. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Faculty of Medicine, Freiburg

The Role of Fibrin-Related Markers in Disseminated Intravascular Coagulation Due to Sepsis

Sepsis leads to local and systemic activation of different response systems, including coagulation and fibrinolysis. An overwhelming inflammatory response may lead to organ failure, and the coagulation and fibrinolysis involvement may lead to Disseminated Intravascular Coagulation (DIC). Special regard is given to the diagnosis of DIC by the use of scoring systems, which are, APACHE II, SAPS II, International Society of Thrombosis and Hemostasis (ISTH), and Japanese Ministry of Health and Welfare (JMHW). A large variety of fibrin compounds can be detected in plasma from septic patients with intravascular coagulation activation. Coagulation activation is indicated by elevated plasma levels of D-dimer, prothrombin fragments, and Thrombin-Antithrombin (TAT) complexes. Fibrin-Related Markers (FRMs) identified in sepsis are D-dimer, fibrinogen, Soluble Fibrin Monomer (SFM), and Fibrin Degradation Products (FDP). Hemostatic molecular markers, such as TAT, Plasmin-Plasmin Inhibitor Complex (PPIC), D-dimer, and SFM are better for the diagnosis of pre-DIC. No single biomarker of sepsis may be ideal, but many are helpful in terms of at least identifying critically ill patients who need more careful monitoring. As each biomarker has limited sensitivity and specificity, it may be interesting to combine several biomarkers. The purpose of this literature review was to increase knowledge about laboratory tests of FRMs and provide current knowledge and insight into these biomarkers related to DIC-sepsis. The method used in this literature review was a traditional review. Search, identify, and select relevant literature on PubMed–CBI and Google Scholar based on keywords, 30 journals were obtained from the two search engines.

Distinguishing and overlapping laboratory results of thrombotic microangiopathies in HIV infection: Can scoring systems assist?

Patients with Human Immunodeficiency Virus (HIV) infection are at risk of thrombotic microangiopathies (TMAs) notably thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC). Overlap between laboratory results exists resulting in diagnostic ambiguity. Routine laboratory results of 71 patients with HIV-associated TTP (HIV-TTP) and 81 with DIC with concomitant HIV infection (HIV-DIC) admitted between 2015 and 2021 to academic hospitals in Johannesburg, South Africa were retrospectively reviewed. Both the PLASMIC and the International Society of Thrombosis and Haemostasis (ISTH) DIC scores were calculated. Patients with HIV-TTP had significantly (P < .001) increased schistocytes and features of hemolysis including elevated lactate dehydrogenase (LDH)/upper-limit-of-normal ratio (median of 9 (interquartile range [IQR] 5-12) vs 3 (IQR 2-5)) but unexpectedly lower fibrinogen (median 2.8 (IQR 2.2-3.4) vs 4g/L (IQR 2.5-9.2)) and higher D-dimer (median 4.8 (IQR 2.4-8.1) vs 3.6g/L (IQR 1.7-6.2)) levels vs the HIV-DIC cohort. Patients with HIV-DIC were more immunocompromised with frequent secondary infections, higher platelet and hemoglobin levels, more deranged coagulation parameters and less hemolysis. Overlap in scoring systems was however observed. The laboratory parameter overlap between HIV-DIC and HIV-TTP might reflect a shared pathogenesis including endothelial dysfunction and inflammation and further research is required. Fibrinogen in DIC may be elevated as an acute phase reactant and D-dimers may reflect the extensive hemostatic activation in HIV-TTP. Inclusion of additional parameters in TMA scoring systems such the LDH/upper-limit-of-normal ratio, schistocytes count and wider access to ADAMTS-13 testing may enhance diagnostic accuracy and ensure appropriate utilization of plasma.

Comparing Safety and Efficacy of Direct Oral Anticoagulants Versus Warfarin in Extreme Obesity

Background: Limited clinical data exists regarding use of direct oral anticoagulants (DOACs) in extreme obesity, specifically those ≥140 kg or having a body mass index (BMI) ≥ 50 kg/m2. Objective: Evaluate the safety and efficacy of DOACs in extreme obesity. Patients/Methods: A retrospective chart review was performed at a single center of patients aged 18-89 years and weight ≥140 kg or BMI ≥50 kg/m2 receiving warfarin or DOAC therapy. Patients were followed for 1 year from prescribing/study inclusion. The primary outcome was the difference in rates of any bleed (composite of major, nonmajor clinically relevant, or minor bleeding events as defined by International Society of Thrombosis and Haemostasis (ISTH) criteria) between groups. Secondary outcomes included individual components of the composite primary outcome and effectiveness in preventing thrombotic events within 12 months. Post-hoc multivariate analysis evaluated potential predictors of bleeding events within overall patient population. Results: Two-hundred eighty-five patients were included, 80 and 205 in the DOAC and warfarin groups, respectively. Rates of any documented bleeding event were comparable in DOAC and warfarin groups (17.5% vs 17.1%, P > .05). No significant difference in rates of minor (P = .067), nonmajor clinically relevant (P = .825), and major (P = 1) bleeding events were observed. Two thrombotic events occurred in the warfarin group compared to none in the DOAC group. Increasing weight was associated with bleeding events in multivariate analysis. Conclusions: This data did not demonstrate a difference in safety or efficacy outcomes between DOACs and warfarin when utilized in patients with extreme obesity.

P1673: THROMBOTIC COMPLICATIONS IN MERS-COV COMPARED TO COVID-19

Background: Several observational studies have reported the rate of thrombotic events in patients infected with coronavirus disease 2019 (COVID-19), with conflicting results. Middle east respiratory syndrome (MERS-COV) is another coronavirus had been initially reported in Saudi Arabia in 2012. A genome scan has shown a 50% similarity between covid-19 and. Several common features of covid-19 and MERS-COV including transmissibility, and clinical presentation have been identified. However, data about thrombotic complications in patients with MERS-COV are limited. Aims: To compare the rate of thrombotic events between COVID-19 and MERS-COV. Methods: We included all confirmed COVID-19 patients who were admitted to intensive care unit (ICU) in 3 major hospitals in Saudi Arabia between February to July 2020. We included all confirmed cases of MERS-COV who were admitted to ICU from these centers between March to May 2014. Patients were excluded if they were transferred in or out from one of these three hospital to another hospitals. Patients also excluded is they were admitted for less than 24 hours. Data were collected retrospectively from the first day of admission until discharge or death. The primary outcome was the rate of venous thromboembolism (VTE). The secondary outcomes were the rate of arterial events, the rate of composite events (venous and arterial) and the rate of bleeding. VTE included all symptomatic or incidentally diagnosed cases of pulmonary embolism (PE), deep vein thrombosis (DVT) and thrombosis in unusual sites (cerebral, mesenteric, portal, splenic, hepatic, and renal veins). Screening for VTE in asymptomatic patients was not performed. If more than on type of VTE occurred in the same patient, it was considered one event. Arterial events included cerebrovascular accidents (CVAs), mesenteric ischemia, and limb ischemia and were confirmed by the appropriate imaging modality. Myocardial infarction (MI) was diagnosed based on the suspicion of the attending physician using clinical criteria as well as biomarker elevations or electrocardiographic changes. Composite events were defined as any VTE or arterial event. Bleeding events were classified as major and nonmajor based on the definition of international society of thrombosis and hemostasis (ISTH)5. Informed consent was waived. Results: After exclusion, 234 COVID-19 and 58 MERS-COV patients were included. The majority of patients with COVID-19 (97%, n=230) and more than (67%,n =39) of those with MERS-COV group received pharmacological prophylaxis according to local hospital practice. The most frequently prescribed regimen in both groups was enoxaparin (40 mg twice per day). Over a median length of stay in the COVID-19 group of 22 days, the rate of VTE 9.8 (6.64–14.3) and was 3.4 (0.95–11.7) in the MESR-COV group over median length of stay of 10 days. Image:Summary/Conclusion: Conclusions: To our knowledge, this is the first study compared thrombotic risk between COVID-19 and MERS-COV critically ill patients. We found unexpected similar rate of composite thrombotic events (venous and arterial) between COVID-19 and MERS-COV with higher rate of venous thrombosis in COVID-19 and higher arterial thrombosis in MERS-COV. This may indicate that thrombotic complication is a unique complication of coronaviruses. These result needs to be confirmed in studies with larger sample size. Helms J, et al. Intensive Care Med. 2020;46:1089-98. Schulman S, et al. J Thromb Haemost. 2005;3:692-4.

Pulmonary embolism bleeding score index (PEBSI): A new tool for the detection of patients with low risk for major bleeding on thrombolytic therapy

BackgroundEstimation of bleeding risk is an unmet need for individualized therapy in acute pulmonary embolism (PE) patients with increased mortality risk. MethodsWe analyzed the association between various patients' characteristics and occurrence of major bleeding (MB) according to the modified International Society of Thrombosis and Hemostasis (ISTH) criteria (“overt” bleeding is the only modification from the original criteria) at 7 days from admission to the hospital and thrombolytic therapy with a tissue-plasminogen activator (tPA). Pulmonary embolism bleeding score index (PEBSI) was created using multivariate regression analyses, and finely, dichotomous index was used for the discrimination of patients with low risk for MB from those with high risk. ResultsDuring the 6-year period (2015–2021) 367 PE patients were treated with tPA and included in the Regional PE registry. Among them, 29 (7.9%) fulfilled the criteria for MB. Five factors were identified as significantly associated with MB and were used to build the PEBSI score: previous bleeding, recent surgery, diabetes, the use of drugs that could be associated with bleeding, and anemia. PEBSI score showed c-index for 7-day MB 0.794 (95CI% 0.698–0.889). Patients with PEBSI scores of 0 or 1 had a low risk for MB (2.8%) and those with scores>1 had a high risk for MB (18.6%) (p < 0.001). Internal validation of PEBSI score using a randomly, equally split method confirmed the discriminative value of the PEBSI score. ConclusionNovel PEBSI score has significant power to discriminate patients with low risk for MB on thrombolytic therapy from those with high risk.

The utility of flow cytometric platelet forward scatter as an alternative to mean platelet volume

The use of mean platelet diameter (MPD) to classify inherited thrombocytopenia (IT) has been demonstrated in several studies. Alternatively, the mean platelet volume (MPV) may be used, but in macrothrombocytopenia this may not be available. We hypothesized that platelet forward scatter (FSC) measurements using flow cytometry may be used for the size-based classification of IT. The study aimed to assess the ability of platelet FSC to measure platelet size and whether it could be used as an alternative to the MPD or MPV. Blood samples were obtained from individuals undergoing investigation for inherited platelet function disorders (IPFD, n = 40) or platelet number disorders (IPND, n = 46). A hematology analyzer was used to obtain MPV and platelet counts, flow cytometry to measure platelet FSC and ImageJ software to measure MPD from stained blood smears. The International Society of Thrombosis and Hemostasis (ISTH) Bleeding Assessment Tool (BAT) was used to calculate bleeding scores. Twenty-nine(63%) of IPND patients had an MPV that could not be reported. A significant correlation to platelet FSC was found to the MPD (p < .0001) and MPV (p < .0001) and an inverse correlation with platelet count (p < .0001). No significant correlation was found between FSC and bleeding history. In conclusion, platelet FSC is an alternative to MPV and may be used in macrothrombocytopenia where the MPV is not recorded

Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhages

BackgroundExisting research recommends either andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) as an antidote for major bleeding events due to apixaban or rivaroxaban. Currently, there is limited published research that directly compares the risks and benefits of the two agents in patients with oral factor Xa inhibitor related traumatic and spontaneous intracerebral hemorrhages. Additional head-to-head data is needed to support favoring either AA or 4F-PCC when it comes to efficacy, safety, and cost. MethodsA retrospective chart review was conducted to assess patients admitted to a multi-center healthcare system and a stand-alone teaching hospital in central Florida from June 2016 to December 2020. Patients included in the study were at least 18 years of age, taking apixaban or rivaroxaban prior to admission, had radiographical evidence of an intracranial hemorrhage, and received either AA or 4F-PCC as a reversal agent. The primary outcome analyzed was the level of excellent hemostasis achieved, based on a standardized rating system for effective hemostasis defined by the International Society of Thrombosis and Hemostasis (ISTH), after administration of AA or 4F-PCC. Secondary outcomes analyzed included changes in the initial hemorrhage volume as reported on computed tomography (CT) scan and at 12 to 24 h post treatment, rate of thromboembolic events, rate of inpatient mortality, and total cost of treatment after AA or 4F-PCC administration. ResultsA total of 109 patients were included in the study with 47 in the AA group (43.1%) and 62 in the 4F-PCC group (56.9%). There were no statistically significant differences between AA and 4F-PCC in terms of the primary and secondary outcomes with the exception of total cost of treatment. The level of excellent hemostasis achieved after reversal administration of AA was seen in 27 patients (71.1%) and 41 patients (70.7%) after 4F-PCC administration (p = 1, p adjusted = 0.654 after controlling for age, ICH score, regional mass effect, and midline shift). There was no statistically significant difference in the median percentage change in hemorrhagic volume from baseline to 12–24 h after reversal treatment (0 [−0.17–-0.24] vs. 0 [−0.021–0.29], p = 0.439, adjusted p = 0.601) in the AA and 4F-PCC groups, respectively. The total incidence of thromboembolic events (4 [8.5%] vs. 6 [9.7%], p = 1, adjusted p = 0.973) and rate of inpatient mortality was similar between the two groups (16 [34.0%] vs. 13 [21.0%], p = 0.134, adjusted p = 0.283). A statistically significant difference was observed with the total cost of reversal treatment: $23,602 for treatment with AA and $6692 for treatment with 4F-PCC. ConclusionsNo statistically significant differences were identified in primary or secondary outcomes between the two agents with the exception of total treatment cost. There is insufficient evidence based on this study to recommend AA over 4F-PCC for patients with intracranial hemorrhages associated with the use of apixaban or rivaroxaban.

Risk stratification for predicting recurrent venous thromboembolism after discontinuation of anticoagulation: a post hoc analysis of a French prospective multicentre study.

We aimed to validate and to refine current recurrent venous thromboembolism (VTE) risk classification. We performed a post hoc analysis of a multicentre cohort including 1881 patients with a first symptomatic VTE prospectively followed after anticoagulation discontinuation. The primary objective was to validate the International Society of Thrombosis and Haemostasis (ISTH) risk classification in predicting recurrence risk. The secondary objective was to evaluate a refined ISTH classification based on the recurrence risk estimate for each individual risk factor. During a 4.8-year median follow-up after anticoagulation discontinuation, symptomatic recurrent VTE occurred in 230 patients (12.2%). Based on the ISTH classification, patients with unprovoked VTE or VTE with minor or major persistent risk factors had a 2-fold increased recurrence risk compared with those with VTE and major transient risk factors. Recurrence risk was not increased in patients with minor transient factors (hazard ratio (HR) 1.31, 95% CI 0.84-2.06). Individual risk factors analysis identified hormone-related VTE (pregnancy: HR 0.26, 95% CI 0.08-0.82; oestrogens: HR 0.25, 95% CI 0.14-0.47) and amyotrophic lateral sclerosis (HR 5.84, 95% CI 1.82-18.70). After reclassification of these factors as major transient for the former and major persistent for the latter, the modified ISTH classification allowed us to accurately discriminate between patients at low risk of recurrence (i.e. with major transient risk factors) and those at high risk of recurrence (i.e. without major transient risk factors). Among patients who stopped anticoagulation after a first VTE, a refined ISTH classification based on recurrence risk intensity of individual factors allowed discrimination between patients at low recurrence risk, including hormonal exposure in women, and patients at high recurrence risk.

The evaluation of risk factors leading to early deaths in patients with acute promyelocytic leukemia: a retrospective study.

Acute promyelocytic leukemia (APL) differs from other forms of acute myeloid leukemia (AML), including coagulopathy, hemorrhage, disseminated intravascular coagulation (DIC), and treatment success with all-trans retinoic acid (ATRA). Despite ATRA, early deaths (ED) are still common in APL. Here, we evaluated factors associated with ED and applicability of scoring systems used to diagnose DIC. Ninety-one APL patients (55 females, 36 males, and median age 40 years) were included. ED was defined as deaths attributable to any cause between day of diagnosis and following 30th day. DIC was assessed based on DIC scoring system released by the International Society of Thrombosis and Hemostasis (ISTH) and Chinese Diagnostic Scoring System (CDSS). Patients' median follow-up time was 49.2 months, and ED developed in 14 (15.4% of) cases. Patients succumbing to ED had higher levels of the Eastern Cooperative Oncology Group Performance Status (ECOG PS), lactate dehydrogenase (LDH), and ISTH DIC, and lower fibrinogen levels (p <0.05). In multivariate Cox regression analysis, age >55 and ECOG PS ≥2 rates were revealed to be associated with ED. Based on ISTH and CDSS scores, DIC was reported in 47.3 and 58.2% of the patients, respectively. Despite advances in APL, ED is still a major obstacle. Besides the prompt recognition and correction of coagulopathy, those at high ED risk are recommended to be detected rapidly. Implementation of local treatment plans and creating awareness should be achieved in hematological centers. Common utilization of ATRA and arsenic trioxide (ATO) may be beneficial to overcome ED and coagulopathy in APL patients.

Diagnosis of human immunodeficiency virus associated disseminated intravascular coagulation.

Disseminated intravascular Coagulation (DIC) is a thrombotic microangiopathy which may complicate a number of severe disease processes including sepsis. Development of microvascular thromboses results in consumption of coagulation factors and platelets and ultimate bleeding. Patients with HIV infection (PWH) often present with baseline dysregulation of the coagulation system which may increase severity and derangement of DIC presentation. Previously, we have shown that HIV is a significant risk factor for development of DIC. We conducted a retrospective record review of all DIC screens submitted to our tertiary coagulation laboratory in Johannesburg, South Africa, over a one year period and compared the laboratory presentation of DIC in PWH with presentation of DIC in patients without HIV infection. Over the year, 246 patients fulfilled the International Society of Thrombosis and Haemostasis (ISTH) diagnostic criteria for DIC- 108 were confirmed HIV-infected and 77 were confirmed uninfected. PWH and DIC presented at a significantly earlier age (41 vs 46 years respectively, p<0.02). The prothrombin time was significantly more prolonged (30.1s vs 26.s), the d-dimer levels were substantially higher (5.89mg/L vs 4.52mg/L) and the fibrinogen (3.92g/L vs 1.73g/L) and platelet levels (64.8 vs 114.8x109/l) were significantly lower in PWH. PWH also showed significant synthetic liver dysfunction and higher background inflammation. PWH who fulfil the diagnostic criteria for DIC show significantly more dysregulation of the haemostatic system. This may reflect baseline abnormalities including endothelial dysfunction in the context of inflammation and liver dysfunction.

Anticoagulation Changes Following Major and Clinically Relevant Nonmajor Bleeding Events in Non-valvular Atrial Fibrillation Patients

Background: Bleeding events are common complications of oral anticoagulant drugs, including both warfarin and the direct oral anticoagulants (DOACs). Some patients have their anticoagulant changed or discontinued after experiencing a bleeding event, while others continue the same treatment. Differences in anticoagulation management between warfarin- and DOAC-treated patients following a bleeding event are unknown. Methods: Patients with non-valvular atrial fibrillation from six anticoagulation clinics taking warfarin or DOAC therapy who experienced an International Society of Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant non-major (CRNM) bleeding event were identified between 2016 and 2020. The primary outcome was management of the anticoagulant following bleeding (discontinuation, change in drug class, and restarting of same drug class). DOAC- and warfarin-treated patients were propensity matched based on the individual elements of the CHA2DS2-VASc and HAS-BLED scores as well as the severity of the bleeding event. Results: Of the 509 patients on warfarin therapy and 246 on DOAC therapy who experienced a major or CRNM bleeding event, the majority of patients continued anticoagulation therapy. The majority of warfarin (231, 62.6%) and DOAC patients (201, 81.7%) restarted their previous anticoagulation. Conclusion: Following a bleeding event, most patients restarted anticoagulation therapy, most often with the same type of anticoagulant that they previously had been taking.