Low Levels Of Antithrombin Research Articles

Acquired antithrombin deficiency in adult patients with postcardiotomy extracorporeal membrane oxygenation.

This study aimed to investigate the relationship between acquired antithrombin deficiency in patients undergoing postcardiotomy extracorporeal membrane oxygenation (PC-ECMO) and thromboembolic or haemorrhagic events such as bleeding, peripheral arterial thromboembolism, and ischemic cerebrovascular events. The study was designed as a single-center, prospective study and conducted at our hospital between November 2019 and June 2021. 50 patients who underwent ECMO due to postcardiotomy cardiogenic shock were included in the study. Antithrombin (AT) activity testing was performed immediately after ECMO placement and continued for 5 days. The total of haemorrhagic or thromboembolic events was defined as morbidity. The entire patient population was assessed daily for AT measurements according to morbidity status, and ROC analysis was applied to determine the cut-off point. The correlation between clinical outcomes and morbidities with antithrombin levels was analysed. In our study, we identified a cut-off for AT levels on the first postoperative day. The risk of both bleeding (p = .006) and thromboembolism (p = .012) was significantly higher in patients below the 48.9% cut-off value. AT levels were compared with data on separation from PC-ECMO. The rate of separation from ECMO was 7.969 times higher in cases with AT levels above 51.8 on the third postoperative day and 5.6 times higher in cases with AT levels above 47.5 on the fourth postoperative day. Acquired antithrombin deficiency may develop in adults undergoing PC-ECMO. In our study, we demonstrated that in patients with low antithrombin levels, the risk of bleeding and thromboembolism increased. Additionally, since AT levels were higher in survivors, this can be considered an indicator of severity. This study is the first prospective study related to determining target antithrombin levels in adult patients undergoing PC-ECMO.

The First ABO Incompatible Kidney Transplantation without Splenectomy in India - A Review at 12 Years.

The First ABO Incompatible Kidney Transplantation without Splenectomy in India - A Review at 12 Years.

The Rise and Fall of Antithrombin Supplementation in Cardiac Surgery.

Various cohort studies, both retrospective and prospective, showed that low antithrombin levels after cardiac surgery (at the arrival in the intensive care unit and during the next days) were associated with a number of adverse outcomes, including surgical reexploration and thromboembolic events, eventually leading to prolonged stay in the intensive care. Values lower than 58% to 64% of antithrombin activity were indicative of this higher morbidity with good sensitivity and specificity. The scenario generated the hypothesis that low antithrombin levels needed to be corrected by supplementation to improve postoperative outcome. However, randomized controlled studies run to test this idea failed to demonstrate any benefit of antithrombin supplementation, showing no effects on outcome, neither as preemptive preoperative strategy nor for treating postoperative low antithrombin values. In addition, randomized trials highlighted that those patients who received antithrombin experienced significantly higher incidence of acute kidney injury with a pooled odds ratio of 4.41 (95% CI, 1.90-10.23; P = .001). A strongly decreased thrombin activity after antithrombin correction may eventually affect the efficiency of the glomerular filtration and cause the deterioration of kidney function, but underlying biological mechanisms remain unclear. In conclusion, low levels of antithrombin activity after cardiac surgery should be considered as a marker of greater severity of the patient's conditions and/or of the complexity of the surgical procedure. There are no indications for antithrombin supplementation in cardiac surgery unless for correcting heparin resistance.

Resolving DOAC interference on antithrombin activity testing on a FXa based method by the use of activated carbon

BackgroundDirect oral anticoagulants (DOACs) may cause falsely increased levels of antithrombin (AT) activity depending on the AT activity method and the specific target of the DOAC. Activated carbon (AC) has proven to remove DOAC interference on PT, aPTT and LA assays. We evaluate whether AC could be useful to resolve DOAC interference on AT assays. MethodsNormal pooled plasma (NPP) was diluted to obtain AT activity of 25 %, 50 % and 75 % respectively. The diluted NPPs were spiked with DOACs (apixaban, edoxaban, dabigatran and rivaroxaban) in concentrations of respectively 100, 250 and 500 ng/ml. DOAC concentrations and AT activity were tested at baseline and after treatment with 20 mg/ml AC. AT activity was measured with a FXa-based method (HemosIL Liquid Antithrombin®, Werfen). ResultsAll DOAC concentrations were below the limit of quantification (LoQ) after addition of AC. DOAC interference on AT activity testing was removed by adding AC, resulting in correctly diagnosing low levels of AT for all dilutions. The influence of DOACs on AT activity was directly correlated to the concentration of the DOAC. As expected, only the anti-FXa DOACs influenced the used assay. ConclusionsAC effectively removes anti-FXa DOAC interference on FXa-based AT assays.

Mathematical Modeling to Identify Clotting Factor Combinations That Modify Thrombin Generation in Hemophilia

Background: In previous work, we used our mathematical model to identify modifiers of thrombin generation in hemophilia A (Link, JTH, 18, 2020). We performed thousands of simulations that varied clotting factors and inhibitors between 50 and 150% of their baseline plasma levels. From those simulations, we identified the combinations of factors and inhibitors that led to enhanced thrombin generation. We found that factor V (FV), at low normal levels (50%-75%), was a major contributor of the thrombin enhancement. The model elucidated an underlying mechanism to be substrate competition between factors V and VIII for activated factor X (FXa), which occurred early in the thrombin generation process. That study was focused on hemophilia A. Aims: To identify factor combinations that enhance or attenuate thrombin generation in mild, moderate, and severe hemophilia A, B, and C. Methods: Plasma levels for factors II, V, VII, VIII, IX, X, XI, tissue factor pathway inhibitor (TFPI), and antithrombin (AT) were fixed at one of three values: 50%, 100%, or 150% of normal. We simulated all possible combinations of these three factor levels for normal blood, and mild, moderate, and severe hemophilia A, B, and C type blood, characterized by deficiencies of 10, 5, and 1% of normal plasma levels. For each combination of factor levels, tissue factor (TF) was varied, and combinations of factor levels were identified as thrombin enhancing (or attenuating) when they resulted in at least a 10-fold increase (or decrease) in detectable thrombin levels. We used an updated version of our mathematical model that includes interactions between TFPI and partially cleaved FV. Results: For simulations of severe hemophilia A and B, combinations of low normal levels (50%) of FV and TFPI and high normal levels (150%) of FII and FX lead to an increase in total thrombin. Interestingly, the opposite combinations (high normal FV and TFPI, low normal FII and FX) led to a decrease in total thrombin for simulations of mild hemophilia A and B. In some of the severe deficiency cases, high normal FVIII levels in hemophilia B and low normal FIX levels in hemophilia A were found to enhance thrombin generation. In normal blood and hemophilia C, combinations of low normal levels (50%) of FV and TFPI and high normal levels (150%) of FVIII and FIX led to an increase in total thrombin, and again the opposite levels attenuated thrombin generation. In some cases, low normal levels of AT also enhanced thrombin generation. Conclusion(s): Our mathematical model identified new and testable combinations of parameters that enhance thrombin generation in severe hemophilia and attenuated thrombin generation in mild hemophilia.

Fibrinogen and antithrombin III are associated with in-hospital mortality among critically ill patients with acute kidney injury

Objectives Coagulation factors participates in the inflammatory cascade, known to play a crucial role in the development of acute kidney injury (AKI). Thus, it’s likely that some factors may be associated with AKI. Among them, low levels of fibrinogen and antithrombin III (ATIII) activity have been proved to increase mortality in patients with sepsis. Moreover, they are also reported to be associated with higher incidence of AKI. However, the association between coagulation parameters, especially fibrinogen and ATIII, and prognosis of AKI has not been examined. Methods Data were acquired from Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC-IV) version 1.0. Cox proportional hazards regression model was used to estimate the relationship between coagulation parameters and in-hospital mortality in critically ill patients with AKI. Subgroup analysis was also conducted to assess the robustness of the association. Restricted cubic spline (RCS) curve was utilized to examine the nonlinear relationships between fibrinogen or ATIII and in-hospital mortality. Kaplan–Meier method was used to estimate cumulative incidence of mortality by fibrinogen or ATIII levels. Receiver-operating characteristic (ROC) curve was plotted and area under curve was calculated to evaluate predictive ability of fibrinogen or ATIII. Results A total of 5914 eligible patients were enrolled in fibrinogen cohort study and 115 patients were eligible for ATIII cohort study. The baseline of low fibrinogen (<150 mg/dL) or ATIII (<80%) activity was associated with significantly higher in-hospital mortality (fibrinogen HR [95% CIs] 2.01 [1.79, 2.27]; ATIII 3.73 [1.11, 12.54]). The HR [95% CIs] of low fibrinogen remained significant 1.29 (1.13, 1.48) in multivariate analysis. The RCS curve showed nearly linear relationship. Subgroup analysis also proved the robustness of the association between fibrinogen and in-hospital mortality. Kaplan–Meier survival curve and ROC demonstrated the predictive capability of fibrinogen and ATIII. Conclusion Low fibrinogen is an independent predictor of in-hospital mortality in critically ill patients with AKI. Low ATIII activity is also likely to impact the risk of in-hospital death.

Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.

Low antithrombin levels are associated with low risk of cardiovascular death but are a risk factor for cancer mortality

BackgroundThrombosis is common in subjects suffering from cardiovascular diseases (CVD) and cancer. Hypercoagulation plays a pivotal role in the pathophysiology of thrombosis. Therefore, the inactivation of thrombin, the key enzyme in coagulation, is tightly regulated via antithrombin (AT). AT deficiency is related to thrombosis and cardiovascular death. In this study we investigated the association between AT levels and mortality, in particularly cardiovascular-related and cancer-related death in the general population.MethodsWe studied the association of AT levels and mortality in a prospective cohort sampled from the general Italian population (n = 19,676). AT levels were measured in the baseline samples, and mortality was recorded during a median follow-up period of 8.2 years. Cox regression was performed to investigate the association of all-cause, CVD-related and cancer-related mortality with variations in AT levels.ResultsIn total, 989 subjects died during follow-up, of which 373 subjects of CVD and 353 of cancer-related causes. Cox analysis revealed that, after adjustment for age, sex, current smoking, BMI, diabetes, hypertension, hypercholesterolemia, history of cardiovascular disease, history of cancer, vitamin K antagonists, antiplatelet medication, heparin and oral contraceptives AT levels were not associated with all-cause mortality (HRQ1vsQ5: 0.92, 95% CI:0.74–1.15). Interestingly, the risk of CVD-related mortality was reduced in subjects with low AT levels compared to subjects with higher AT levels, after adjustment for age and sex and other confounders did not change the association (HRQ1vsQ5: 0.64, 95% CI:0.44–0.91). Moreover, low AT levels were associated with increased cancer mortality in a fully adjusted model (HRQ1vsQ2-5: 1.26, 95% CI:0.88–1.81).ConclusionsLow AT levels are associated to a lower risk of fatal cardiovascular events in the general population, regardless of age, sex and medication use. In contrast, low AT levels are associated with lower cancer survival. For the first time we show that AT levels lower than the normal range in the general population, even before the development or diagnosis of cancer, are associated with an elevated risk of cancer death.

Hemostatic rebalance in neonatal intrahepatic cholestasis with citrin deficiency.

Neonatal intrahepatic cholestasis with citrin deficiency (NICCD) results in coagulopathy due to decreased levels of vitamin (V)K-dependent clotting factors, similar to biliary atresia (BA). However, the involvement of VK-independent coagulant and anticoagulant factor(s) remains unknown. We examined relationships between coagulant and anticoagulant potential before and after nutritional treatment in NICCD. Three cases (aged 12, 21, and 45 days) with NICCD-associated coagulopathy were evaluated with standard coagulation/anticoagulation tests and comprehensive coagulation assays, rotational thromboelastometry, and protein C/protein S (PC/PS) pathway function assay (ThromboPath® ), before and after nutritional treatment. In all cases, activated partial thromboplastin time and prothrombin time were significantly prolonged, which is associated with very low levels of VK-independent fibrinogen and antithrombin. The initiation of nutritional treatment of medium-chain triglycerides oil improved these levels within the normal range, although low levels of other clotting factors were modestly increased. Whole blood- rotational thromboelastometry analysis revealed near-normal coagulation potential, even before treatment, comparable to healthy adults, and supportive of their non-bleeding symptoms. The introduction of nutritional treatment had further improved comprehensive coagulation potential. The global PC/PS-pathway function assay demonstrated the absence of the features of this function associated with the pathogenesis of NICCD. Compared to BA, the plasma levels of fibrinogen and antithrombin in all cases were markedly low, whilst those after treatment improved, especially to similar level of BA. Neonatal intrahepatic cholestasis with citrin deficiency has the characteristic of rebalancing hemostatic mechanisms associated with coagulant and anticoagulant potential involving low levels of fibrinogen and antithrombin, suggesting a pathophysiological coagulopathy distinct from BA.

ASPARAGINASE INDUCED SINUS VEIN THROMBOSIS IN AN ADULT YOUNG ALL PATIENT

Asparaginase has a very important role in ALL treatment among increasing of remission rate and duration. Multiple side effects prevent its regulatory use. Asparaginase reduce antithrombin 3, heparin cofactor II, protein C and plasminogen synthesis. By the way, P-selectin, PAI 1, tissue factor activity, and vWF antigen levels increase. Hypofibrinogenemia may be a marker of of hemostasis disturbances and decreased protein synthesis. A 25-year-old male patient with acute T-cell lymphoblastic leukemia diagnosis was initiated on induction chemotherapy according to augmented BFM protocol. After 4 weeks, remission was confirmed. During consolidation with the third dose of standard L-asparaginase of 10000 units, headache, nausea and vomiting started and confusion developed. Biochemical investigations, PT, aPTT were within normal limits. Fibrinogen was 92 mg/dL and D-dimer was high.Contrast-enhanced MRI showed a thrombus occluding. the superior sagittal sinus. He was intubated and followed up in the intensive care unit due to a rapid decline in the Glasgow score and epileptic seizures. Correction of fibrinogen with cryoprecipitate anticoagulation treatment contributed to symptoms improvement. unfortunately, asparaginase was removed from the protocol. During maintenance therapy, he has had severe COVID-19 pneumonia and during this time he did not experience any thrombosis related complications. Asparaginase therapy is associated with low antithrombin and fibrinogen levels and 7% of thrombosis rate. Previous studies showed that, in ALL patients, thrombosis occurred far more frequently during cycles that contained asparaginase than those that did not. Therefore, studies have investigated the role of fresh frozen plasma or cryoprecipitate supplementation to reduce the thrombohemorrhagic risk of therapy. Retrospective studies suggest antithrombin concentrates may have a beneficial effect on the outcomes of adults treated with asparaginase for ALL.

BUDD-CHIARI SYNDROME IN PATIENTS WITH ULCERATIVE COLITIS: A SYSTEMATIC LITERATURE REVIEW

Objective Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction that can lead to hepatic congestion, portal hypertension, ascites, esophageal varices, and liver failure. This syndrome is deeply associated with acquired or inherited hypercoagulation states; such as myeloproliferative disorders, factor V Leiden, deficiency of protein C, pregnancy, and systemic inflammation. Ulcerative colitis (UC) is an inflammatory bowel disease that leads to chronic systemic inflammation. Therefore, the aim of this study was to conduct a systematic literature review to analyze the association between Budd-Chiari syndrome and ulcerative colitis. Materials and methods A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Papers were selected searching PubMed/Medline, SciELO, and LILACS databases in August 2021 using the search terms [Budd-Chiari syndrome] AND [ulcerative colitis]. The inclusion criterion was limited to observational studies, case reports, or case series that reported an association between Budd-Chiari syndrome and ulcerative colitis. Language was restricted to English, Spanish or Portuguese. Results Among the 33 papers initially identified, 17 were eligible for this review after full texts were read. The selected studies were all case reports or case series. Budd-Chiari syndrome has been described as a rare extraintestinal complication of ulcerative colitis. Regarding gender, 12 patients were female and 5 were male. Seven articles reported cases of BCS in pediatric patients with UC. Three articles reported the diagnosis of BCS before the clinical manifestations and diagnosis of UC. Two cases also described the occurrence of severe thrombotic storm (development of multiple thrombi in different sites in quick succession) in patients with UC and no other coagulopathy. Discussion The studies suggest that patients with ulcerative colitis have a higher risk of Budd-Chiari syndrome and thromboembolic events. This risk can be eight times higher during a flare-up, which can be explained by the increased systemic levels of cytokines (e.g. IL-1, 1L-6, and TNF-alpha) that can modulate the coagulation cascade leading to a hypercoagulation state. In addition, the increased intestinal epithelial permeability can promote bacterial translocation and systemic endotoxemia, which further accelerates the coagulation cascade activation. Still, studies have shown that patients with UC have higher rates of thrombocytosis, fibrinogen levels, and low antithrombin levels. Conclusion Budd-Chiari syndrome can be a rare extraintestinal complication of ulcerative colitis in pediatric and adult patients. This complication can occur even before the diagnosis of inflammatory bowel disease.

Evaluation of plasma protein C and antithrombin levels in patients with tuberculosis

Background Tuberculosis (TB) is a global health problem and thromboembolic complications, when occurring, are often fatal, with no proven markers to predict. The most common type is latent tuberculosis infection (LTBI); however, patients can develop active TB disease and become infectious. Managing LTBI properly can prevent active disease evolution, and exclusion of active TB is the main primary question in LTBI management. Protein C (PC) and antithrombin (AT) are natural anticoagulants with anti-inflammatory properties, so they are suggested to have a role in hypercoagulability due to inflammatory processes. Aim To correlate PC and AT levels in TB patients with patients’ coagulable and clinical state. Patients and methods Sixty patients (20 pretreatment, 20 posttreatment active TB, and 20 LTBI) and 20 normal-controls were included. Activity levels of PC and AT were measured and correlated to patients’ coagulable and clinical states, and routine laboratory results. Results Activity levels of PC and AT are significantly low in active TB, increasing with treatment, and normal in LTBI. No thromboembolic events were detected in all patients included, so correlation with PC and AT could not be verified. Conclusion Active TB is associated with hypercoagulable state, with low activity levels of PC and AT. Both proteins are suggested to be used as adjuvant markers of activation of LTBI and during their pretreatment assessment, together with monitoring therapeutic response in patients with active TB.

Prevalence of low antithrombin levels in preeclamptic women and perinatal outcome

Prevalence of low antithrombin levels in preeclamptic women and perinatal outcome

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Low level of postoperative plasma antithrombin III is associated with portal vein thrombosis after liver surgery.

Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy. Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics. Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489). Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.

Low Level of Postoperative Plasma Antithrombin III Is Associated with Portal Vein Thrombosis after Liver Surgery

Background: Decreased antithrombin-III (AT-III) is a risk factor of portal vein thrombosis (PVT) in patients with liver cirrhosis. The association between PVT and postoperative AT-III is controversial in patients who underwent liver surgery. The efficacy of postoperative AT-III supplementation on PVT is also uncertain. Methods: Patients who underwent hepatectomy for hepato-biliary disease between 2015-2018 were retrospectively analyzed. Donors and recipients for liver transplantation were excluded. Postoperative PVT was assessed on computed tomography on the day 6-9 after hepatectomy. Results: Of the 325 patients included in this analysis, 19 patients (5.8%) were diagnosed as postoperative PVT. AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (area under the curve, 0.644; cut-off value, 60%; p=0.032). Univariate analysis revealed that AT-III level ≤60% on POD3 was the only significant risk factor for postoperative PVT (Table). Postoperative AT-III supplementation was not associated with reduced incidence of PVT. Although postoperative AT-III supplementation and major hepatectomy were the significant risk factors for postoperative hemorrhagic complications in univariate analysis, multivariate analysis revealed that major hepatectomy was the only significant risk factor for hemorrhagic complications. Conclusion: Patients with AT-III level ≤60% on POD3 should be given careful attention to postoperative PVT. Although postoperative supplementation of AT-III is safe without increased risk of hemorrhagic complication, the efficacy of it on PVT is still controversial.

Prothrombotic changes in patients with COVID‐19 are associated with disease severity and mortality

Background and AimsPatients with severe coronavirus disease 2019 (COVID‐19) are at significant risk of thrombotic complications. However, their prothrombotic state is incompletely understood. Therefore, we measured in vivo activation markers of hemostasis, plasma levels of hemostatic proteins, and functional assays of coagulation and fibrinolysis in plasma from patients with COVID‐19 and determined their association with disease severity and 30‐day mortality. MethodsWe included 102 patients with COVID‐19 receiving various levels of respiratory support admitted to general wards, intermediate units, or intensive care units and collected plasma samples shortly after hospital admission. ResultsPatients with COVID‐19 with higher respiratory support had increased in vivo activation of coagulation and fibrinolysis, as reflected by higher plasma levels of d‐dimer, thrombin‐antithrombin, and plasmin‐antiplasmin complexes as compared to patients with no to minimal respiratory support and healthy controls. Moreover, the patients with COVID‐19 with higher respiratory support exhibited substantial ex vivo thrombin generation and lower ex vivo fibrinolytic capacity, despite higher doses of anticoagulant therapy compared to less severely ill patients. Fibrinogen, factor VIII, and von Willebrand factor levels increased, and ADAMTS13 levels decreased with increasing respiratory support in patients with COVID‐19. Low platelet count; low levels of prothrombin, antithrombin, and ADAMTS13; and high levels of von Willebrand factor were associated with short‐term mortality. ConclusionsSevere COVID‐19 is associated with prothrombotic changes with increased in vivo activation of coagulation and fibrinolysis, despite anticoagulant therapy.

Derivation and Validation of a Predictive Score for Disease Worsening Inpatients with COVID-19

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease. COVID-19 is associated with excessive inflammation, platelet activation, endothelial dysfunction, blood coagulation activation and fibrin formation. Current management of patients hospitalized in an intensive care unit (ICU) is based on supportive care and the mortality rate is high. Blood hypercoagulability -documented by increase in D-Dimers and decrease in antithrombin (AT) -is frequently encountered among COVID-19 patients.Aim: Identification of patients with COVID-19 being at high risk for clinical deterioration is a challenging issue for an earlier adapted treatment and positive clinical outcome. we aimed to identify the most relevant clinical and haematological risk factors for worsening of COVID-19 in hospitalized patients by and constructing an accurate risk assessment tool, COMPASS-COVID-19.Methods: Patients with confirmed COVID-19 (n=430) were divided in derivation (n=310) and validation (n=120) cohorts. They were stratified to those hospitalized at the conventional ward (C-group) and those with worsening disease (W-group) admitted in ICU. The study endpoint was disease worsening. All patients were routinely evaluated with full blood count, prothrombin time, fibrinogen, D-Dimers, antithrombin and protein C activity. Data from the first hospitalization day at the conventional ward or the ICU were analyzed. Cardiovascular risk factors and comorbidities were routinely registered.Results: In the derivation cohort, compensated DIC was diagnosed in 8.2% of patients in the C-group and in 28.2% of patients in the W-group (p=0.001). Compared to the C-group, the patients in the W-group had significantly lower levels of AT, PC, platelets, lymphocyte, monocyte and red blood cell counts as well as, hemoglobin and hematocrit. They had significantly higher levels of fibrinogen, DDimers, white blood cells and neutrophils counts. No difference was noted in eosinophil and basophil counts. Hematological predictors for disease worsening: Increase of fibrinogen (OR= 9.50, 95% CI:2.23-40.54) and D-Dimer levels (OR=7.65, 95% CI:2.67-21.87), a platelet count lower than 100x109/L (OR=7.60, 95% CI:1.55-37.35) and a positive compensated DIC-ISTH score (OR=4.58, CI:2.09-10.07) were major determinants of disease worsening risk. Deficiency of AT activity (OR = 2.13, 95%CI: 1.18-3.85), PT prolongation (OR=2.43, 95% CI:1.15-5.13), leukocytosis (OR=1.86, 95%CI:1.04-3.33), lymphopenia with lymphocyte count lower than 1.5 G/L (OR=3.37, CI:1.58-7.21) were significant risk factors for worsening disease. The multivariate analysis retained obesity- BMI≥30, (OR=6.56, 95%CI: 2.98-14.46; p<0.001), male gender (OR=2.59, 95% CI:1.29-5.21; p=0.007), compensated DICISTH score ≥5 (OR=2.58, 95% CI:1.07-6.21; p=0.034), lymphocyte count <1 G/L (OR=2.21, 95% CI:1.17-4.19; p=0.015) and Hb<11 g/dL (OR=2.25, 95% CI: 1.13-4.48; p=0.021) as significant predictors of worsening disease . The score at 18 points cut-off value identified as high risk for disease worsening 90% of patients at the W-group and 38% of the patients at the C-group. The sensitivity and the specificity of the score were 94% and 58% respectively and the negative and positive predictive values were 96% and 45% respectively.Conclusion: The COMPASS-COVID- 19 score derived from multivariate analysis and includes obesity, gender, hemoglobin, lymphocyte and the cDIC-ISTH score (including platelet count, prothrombin time, D-Dimers antithrombin and protein C levels). The score has a very good discriminating capacity to stratify patients at high and low risk for worsening disease, with AUC value at 0.77, sensitivity 81% and specificity 60%. Application of the COMPASS-COVID-19 score at the validation cohort showed 96% sensitivity. The COMPASS-COVID-19 score is an accurate clinical decision tool for an easy identification of COVID-19 patients being at high risk for diseaseDisclosuresNo relevant conflicts of interest to declare.

Intracranial haemorrhage associated with systemic anticoagulation in ventilated COVID-19 Intensive care patients

IntroductionCOVID-19 induces a pro-inflammatory, hypercoagulable state with marked elevations of ferritin, C-reactive protein, interleukin, and D-dimers. Observed consequences include pro-thrombotic disseminated intravascular coagulation (DIC) with a high rate of venous thromboembolism (VTE) and elevated D-dimers with high fibrinogen and low anti-thrombin levels. Pulmonary congestion appears to be due to micro-vascular thrombosis and occlusion on pathological examination.1 The acquired pro-thrombotic state and associated poorer outcomes seen in critically ill COVID-19 patients 2,3 have led to such patients being treated empirically with systemic anticoagulants. Unfractionated heparin (UFH) or low molecular weight heparin (LMWH) have both been used.2,3MethodsReview of COVID-19 positive adult patients admitted to the critical care unit between 10th March and 13th May 2020 with severe respiratory failure requiring invasive ventilation.ResultsIn that period we admitted 59 patients. 6 (10%) females, 56 (90%) males. 45 (76%) patients required therapeutic anticoagulation (27 UFH, 14 LMWH, 4 argatroban). 4 (8.9%) of the 45 anticoagulated patients suffered catastrophic intracranial haemorrhage and subsequently died.DiscussionThe risk for any significant haemorrhage in patients systemically anticoagulated for VTE with unfractionated heparin (UFH) is 2-3%, 4 and that of anticoagulant-related intracranial haemorrhage (AICH) in patients systemically anticoagulated with UFH is 1-2.7% (in patients treated for ischaemic stroke) and 4% with argatroban.5 We report a much higher incidence of nearly 9%. The cases we present fulfilled the advised criteria for systemic anticoagulation. Despite four-hourly monitoring of APPT and anti-Xa activity on the intensive care unit there were significant fluxes in these laboratory markers of anticoagulation. These may be associated with the uncharted nature of this disease process.It is impossible to disassociate the necessary therapeutic-intensity anticoagulation with the observed heightened frequency of life-ending intracranial haemorrhage in these patients.

Коррекция дефицита антитромбина в периоперационном периоде у кардиохирургических пациентов

Введение: В качестве антикоагулянта у пациентов с сочетанием порока митрального клапана (МК) и ишемической болезнью сердца (ИБС) в периоперационном периоде используется гепарин. Терапевтическая активность гепарина зависит от уровня активности антитромбина (АТ). Дефицит АТ увеличивает риск тромбоза. Цель исследования: оценить эффективность и безопасность препаратной коррекции дефицита АТ в интраоперационном периоде у пациентов с сочетанием по рока МК и ИБС. Материалы и методы: Обследовано 30 доноров и 46 пациентов с ИБС и патологией МК. Измерение аналитов проводили на 3 этапах: до кожного разреза, после ушивания операционной раны, через 24 ч после начала операции. В зависимости от уровня активности АТ (cut-off 60%) пациенты с этапа 2 были разделены на 2 группы. Пациенты обеих групп получали лечение в соответствии со стандартным анестезиологическим протоколом, пациентам группы 2 дополнительно для коррекции дефицита АТ вводили препарат Антитромбин- III (Бакстер АГ, Австрия). Результаты: Не обнаружено разницы между группами по объему послеоперационной кровопотери, продолжительности искусственной вентиляции легких и времени пребывания в отделении реанимации и интенсивной терапии. Более низкая активность АТ в группе 2 сохранялась на всех этапах исследования. При нормировании снижения уровня АТ в группе 2 обнаружена более выраженная динамика. Аналогичные результаты получены для этапов 2 и 3 при нормировании восстановления активности АТ. Обнаружена умеренная отрицательная корреляция снижения активности АТ и времени пережатия аорты, уровня Д-димера и активности АТ на этапе окончания операции. Заключение: Исходная активность АТ у всех обследованных пациентов была ниже, чем в группе доноров. У пациентов с исходно низким уровнем АТ документирована более выраженная динамика его снижения. Восстановление активности АТ после препаратной коррекции его дефицита происходило значимо эффективнее. Пациентам с сочетанием порока МК и ИБС рекомендуется интраоперационная коррекция Антитромбином при снижении активности &lt; 60% к моменту окончания операции. Применение препарата безопасно и не ведет к увеличению кровопотери. Background: Heparin is used as an anticoagulant perioperatively in patients with combined cardiac pathology. The heparin therapeutic activity depends on the level of antithrombin (AT) activity. AT defi ciency increases the risk of thrombosis. Objectives: to access the effectiveness and safety of drug correction of AT defi ciency in the intraoperative period in patients with combined mitral valve defect (MVD) and ischemic heart disease (IHD). Patients/Methods: 30 healthy blood donors and 46 patients with IHD and MVD were examined. The analytes were measured at 3 stages: before the skin incision, after suturing the operating wound, and 24 hours after the start of the operation. Depending on the AT activity at the second stage (cut-off 60%) patients were divided into 2 groups. All patients received treatment according to the standard anesthetic protocol; group 2 patients were given Antithrombin III (Baxter AG, Austria) to correct AT defi ciency. Results: There was no difference between the groups in the postoperative blood loss, duration of ventilation and ICU stay. The lower activity of AT in group 2 patients remained at all study stages. When the decrease in AT level was rationed, more pronounced dynamics was found in group 2. Similar results were found at stages 2 and 3 after the AT activity restoration also was rationed. Moderate negative correlation at the stage 2 was found between the drop of AT activity and the time of aortic clamping, and between the D-dimer level and AT activity. Conclusions: The initial AT activity in all examined patients was lower than in the blood donor group. In patients with an initially low AT level a more pronounced dynamic of its decrease was documented. Recovery of AT activity was significantly more effective after drug correction of its defi ciency. For patients with MVD and IHD combination intraoperative correction with Antithrombin is recommended if the activity decreases by &lt; 60% by the end of the operation. The use of the drug is safe and does not lead to increased blood loss.