Conventional Coagulation Parameters Research Articles

Critical hematological parameters in bleeding during extracorporeal membrane oxygenation support.

Bleeding complications are frequently observed in patients undergoing extracorporeal membrane oxygenation and are associated with increased mortality. Due to the complex mechanisms, managing bleeding during ECMO remains a challenge. Acquired von Willebrand syndrome (AVWS) in ECMO highlights a potentially reduced affinity of von Willebrand factor (vWF) for binding to platelets and collagen in response to vascular damage, thus contributing to increased bleeding in ECMO patients. Conventional coagulation parameters are incomplete predictors for bleeding in ECMO patients, whereas AVWS is often overlooked due to the absence of vWF evaluation in the coagulation profile. Therefore, clinical physicians should evaluate AVWS in patients experiencing bleeding complications during ECMO support.

Increased clot strength following transcatheter aortic valve replacement

Abstract Background Patients treated with transcatheter aortic valve replacement (TAVR) are at high risk for bleeding and ischemic events. Thrombelastography (TEG) parameters are associated with thromboembolic and bleeding risk. TEG may be used to risk-stratify TAVR patients. The variability of TEG over time and the association of TEG parameters with antithrombotic medication in these patients has not been studied. Aim To assess the changes in platelet function and global hemostasis between periprocedural and long-term measurement in patients undergoing TAVR. Methods We performed a prospective, single center cohort study and included patients after TAVR. TEG was performed during the index hospitalization (T0) and 6 (± 2) months after TAVR (T1). TEG was used to determine the maximum blood clot strength as maximum amplitude (MA) after stimulation with kaolin + tissue factor (CRT) and kaolin + heparinase (CKH). Platelet count and thromboplastin time (INR) were determined as conventional coagulation parameters. At time of the measurements, patients were treated with acetylsalicylic acid (ASA), dual antiplatelet therapy (DAPT), oral anticoagulation (OAC) or a combination of these medications. We compared TEG parameters, thrombocytes and INR between measurements T0 and T1 and stratified patients according to the antithrombotic regimen. Results From December 2021 to April 2022, 64 patients were enrolled and measured after TAVR: T0 at median on day 4 (min. 2, max.17) and T1 at a median of 6 months (min. 4 max. 8). The median age was 81 years (interquartile range IQR 78-83) and 28 (47%) patients were male. 59 of 64 patients had no change in indication for anticoagulation between measurements T0 and T1, thus taking either OAC (28 of 59) or antiplatelet (AP) without OAC (31 of 59) at measurements T0 and T1. MA was higher in patients at T0 compared with T1 and was observed independently of antithrombotic therapy. OAC: [MA-CRT 66.5mm (IQR 64.5-69.1mm) vs. 63.8mm (IQR 59.7-66.0mm); p<0.0001] and [MA-CKH 64.5mm (61.3-68.0mm) vs. 60.1mm (56.4-64.7mm); p<0.0001)]. AP: [MA-CRT 66.8mm (IQR 63.75-69.9mm) vs 64.2mm (IQR 60.7.7-66.1mm); p<0.0001] and [MA-CKH 64.5mm (61.3-68.0mm) vs 60.1mm (56.4-64.7mm); p<0.0001]. Platelet count (Tc) was not significantly different at T0 vs. T1 in patients with OAC and those with AP. [Tc (OAC) 162.5103/µl (IQR 131.2-223.2 103/µl) vs.178tsd/µl (IQR 152-209.75103/µl); p=0.29] and [Tc (AP) 181tsd/µl (IQR 128-243103/µl) vs. 202tsd/µl (IQR 175-247103/µl), respectively; p=0.056, Figure 1]. Conclusion Compared with long-term measurements, clot strength measured during the index hospitalization after TAVR was significantly increased. The increased clot strength was independent of baseline antithrombotic therapy. Whether this corresponds to an early procoagulant state that favors the occurrence of valvular thrombosis or cardiovascular events needs to be investigated in prospective studies.

Coagulation parameters for the differential diagnosis of pancreatic cancer in the early stage: a retrospective study

BackgroundIn recent years, conventional coagulation (CC) and thromboelastography (TEG) parameters have been reported to be closely related to the progression of pancreatic cancer (PC). However, the potential utility of these parameters in differentiating benign and malignant pancreatic diseases is still unclear.ObjectivesA retrospective study was conducted to evaluate the efficacy of coagulation parameters in differentiating pancreatic cancer/early stage pancreatic cancer (EPC, TNM stages I and II) from benign control conditions, and to further explore whether coagulation parameters could improve the differential value of CA199.MethodsReceiver operating characteristic (ROC) curves and logistic regression analysis were used to identify the diagnostic value of each coagulation parameter or combination of parameters.ResultsCompared with benign pancreatic disease (BPD), patients with pancreatic malignant tumors had significant coagulation disorders, specifically manifested as abnormal increases or decreases in several CC and TEG parameters (such as activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer (DD2), K time, R time, Angle, maximum amplitude (MA), coagulation index (CI), and Ly30). In the training group, ROC curve showed that FIB, DD2, Angle, MA, and CI had favorable efficacy at differentiating PC or EPC from BPD (for PC, AUC = 0.737, 0.654, 0.627, 0.602, 0.648; for EPC, AUC = 0.723, 0.635, 0.630, 0.614, 0.648). However, several combined diagnostic indicators based on FIB, DD2 and CI failed to outperform the individual coagulation indexes in diagnostic efficiency. Combinations of certain coagulation indexes with CA199 outperformed CA199 alone at identifying PC or EPC, especially FIB + CA199 (for PC, AUC = 0.904; for EPC, AUC = 0.905), FIB + DD2 + CA199 (for PC, AUC = 0.902; for EPC, AUC = 0.900), FIB + CI + CA199 (for PC, AUC = 0.906; for EPC, AUC = 0.906), and FIB + DD2 + CI + CA199 (for PC, AUC = 0.905; for EPC, AUC = 0.900). The results from a validation set also confirmed that these combinations have advantageous diagnostic value for PC and EPC.ConclusionsA significant hypercoagulable state was common in PC. Some CC and TEG parameters are valuable in the differential diagnosis of benign and malignant pancreatic diseases. In addition, coagulation indexes combined with CA199 can further enhance the differential diagnosis efficacy of CA199 in PC and EPC.

Comparisons of coagulation characteristics between elderly and non-elderly patients with sepsis: A prospective study

BackgroundA blunt host defense response in older patients may contribute to different coagulation responses during sepsis. We aimed to investigate the differences in coagulation parameters between elderly and non-elderly patients with sepsis. MethodsAdult patients diagnosed with sepsis within 24 hours after admission to the intensive care unit between September 2018 and December 2020 were prospectively enrolled. Patients were categorized into the adult (18–64 years) and elderly (age ≥65 years) groups. Conventional coagulation parameters and inflammatory markers were measured on intensive care unit admission and on Days 3 and 7. Thromboelastography was performed on intensive care unit admission. The differences in the coagulation parameters between the 2 groups were evaluated. The adult and elderly patients were matched to adjust for baseline characteristics. Correlations between inflammatory markers and coagulation-related parameters were also analyzed. ResultsOf the 567 patients, 303 (53.4%) were elderly. Compared with adult patients, elderly patients had lower prothrombin time elevation, lower fibrinogen, D-dimer, and fibrin/Fib degradation product levels, and lower proportion of disseminated intravascular coagulation on intensive care unit admission; and, they had lower dynamic platelet, lower fibrinogen, and D-dimer levels during the first week in the intensive care unit. Thromboelastography parameters were generally within the normal range, although elderly patients had lower R and K values and a higher alpha angle. Comparisons of coagulation parameters between the 2 groups revealed similar results in the matched cohort. The inflammatory markers correlated with prothrombin time, activated partial thromboplastin time, and antithrombin III. ConclusionElderly patients had milder coagulation activation, accompanied by a decreased inflammatory response during sepsis, compared to non-elderly patients.

The effect of recombinant versus plasma-derived von Willebrand factor on prolonged PFA closure times in ECMO patients with acquired von Willebrand syndrome – an observational study

BackgroundExtracorporeal membrane oxygenation (ECMO) is applied in patients with respiratory or cardiopulmonary failure, but bleeding is a frequent complication contributing to the high mortality rates in this patient collective. A major factor predisposing patients to bleeding events is an acquired von Willebrand syndrome (aVWS). So far, specific treatment options for this phenomenon are lacking. In hereditary von Willebrand disease (VWD), treatment with recombinant or plasma-derived von Willebrand factor (rVWF or pVWF) is common practice. Closure time measured by the Platelet Function Analyser-200 (PFA-200) is an established assay to detect defects in primary hemostasis and the method is useful to monitor the effect of hemostatic therapy. The aim of this study was to assess the effect of recombinant (rVWF) vs. plasma-derived von Willebrand factor (pVWF) on closure times measured by PFA in blood obtained from ECMO patients with aVWS.MethodsBlood was sampled from thirteen patients receiving extracorporeal membrane oxygenation and three patients with hereditary VWD. Diagnosis of aVWS was made by conventional coagulation parameters and by multimeric structure analysis. PFA analysis of blood spiked with rVWF or pVWF was performed.ResultsThirteen patients receiving ECMO were recruited. Ten patients survived and three patients suffered major bleeding complications. PFA closure times in ECMO patients with aVWS spiked with rVWF were significantly shorter at all concentrations than with pVWF (e.g., rVWF vs. pVWF: 1 U/ml: 150.4 ± 21.7 s vs. 263.8 ± 11.7 s; 4 U/ml: 97.8 ± 9.8 s vs. 195.8 ± 15.4 s, p<0.001). PFA closure times were also significantly shorter in three patients with hereditary VWD treated with rVWF compared to pVWF (e.g., 1 U/ml rVWF vs. pVWF: 73.7±1.33 s vs. 231.3±43.4 s, p<0.01)ConclusionIn summary, this study shows that rVWF compared to pVWF more effectively reduced PFA closures times in blood samples of ECMO patients with aVWS. Higher doses of VWF are needed to normalize PFA closure time in blood samples of patients with ECMO-induced aVWS compared to hereditary VWD. These data support the use of PFA-200 to monitor hemostatic effects in a future clinical trial involving ECMO patients with aVWS.

Association between Functional Parameters of Coagulation and Conventional Coagulation Tests in the Setting of Fluid Resuscitation with Balanced Crystalloid or Gelatine: A Secondary Analysis of an In Vivo Prospective Randomized Crossover Study.

Functional point-of-care tests (POCTs) have evolved into useful tools for diagnosing disorders of blood coagulation and fibrinolysis. We aimed to describe the in vivo association between standard and functional parameters of coagulation and fibrinolysis in the setting of acute hemodilution induced by an infusion of balanced crystalloid or synthetic gelatine solutions. This prospective randomized crossover in vivo study included healthy male volunteers aged 18–30 years. Enrolled participants were randomly assigned to receive either the Optilyte® or Geloplasma® infusion. Laboratory analysis included conventional coagulation parameters and rotational thromboelastometry (ROTEM) assays. A total of 25 healthy Caucasian males were included. ROTEM viscoelastic assays presented moderate to strong correlations with conventional coagulation tests, regardless of the fluid type utilized. Irrespectively of the extent of hemodilution, significant correlations remained unaffected. The strongest associations were found between the ROTEM clot formation and clot strength and the fibrinogen concentration and platelet count, and between the ROTEM clotting time and the APTT and PT. This in vivo experimental study in healthy male volunteers demonstrated that ROTEM may be used as a credible alternative to standard laboratory tests to assess blood coagulation and fibrinolysis in the setting of fluid resuscitation with both crystalloid and colloid solutions. The study was registered online in the ClinicalTrials.gov database (NCT05148650).

In Vivo Effects of Balanced Crystalloid or Gelatine Infusions on Functional Parameters of Coagulation and Fibrinolysis: A Prospective Randomized Crossover Study.

Prudent administration of fluids helps restore or maintain hemodynamic stability in the setting of perioperative blood loss. However, fluids may arguably exacerbate the existing coagulopathy. We sought to investigate the influence of balanced crystalloid and synthetic gelatine infusions on coagulation and fibrinolysis in healthy volunteers. This prospective randomized crossover study included 25 males aged 18–30 years. Infusions performed included 20 mL/kg of a balanced crystalloid solution (Optilyte®) or 20 mL/kg of gelatine 26.500 Da (Geloplasma®) in a random order over a period of 2 weeks. Laboratory analysis included conventional coagulation parameters and rotational thromboelastometry (ROTEM) assays. We confirmed a decrease in fibrinogen concentration and the number of platelets, and prolongation of PT after infusions. Compared to baseline values, differences in the ROTEM assays’ results after infusions signified the decrease in coagulation factors and fibrinogen concentration, causing impaired fibrin polymerization and clot structure. The ROTEM indicator of clot lysis remained unaffected. In the case of both Optilyte® and Geloplasma®, the results suggested relevant dilution. Gelatine disrupted the process of clot formation more than balanced crystalloid. Infusions of both crystalloid and saline-free colloid solutions causing up to 30% blood dilution cause significant dilution of the coagulation factors, platelets, and fibrinogen. However, balanced crystalloid infusion provides less infusion-induced coagulopathy compared to gelatine.

Serial Thromboelastography and the Development of Venous Thromboembolism in Critically Ill Patients With COVID-19.

Prospective, observational cohort study. Tertiary care, academic medical center in Nashville, TN. Patients with acute respiratory failure from COVID-19 pneumonia admitted to the adult medical ICU without known VTE at enrollment. None. Ninety-eight consecutive critically ill adults with laboratory-confirmed COVID-19 were enrolled. Thromboelastography parameters and conventional coagulation parameters were measured on days 0 (within 48 hr of ICU admission), 3, 5, and 7 after enrollment. The primary outcome was diagnosis of VTE with confirmed deep venous thrombosis and/or pulmonary embolism by clinical imaging or autopsy. Twenty-six patients developed a VTE. Multivariable regression controlling for antiplatelet exposure and anticoagulation dose with death as a competing risk found that lower MA was associated with increased risk of VTE. Each 1 mm increase in enrollment and peak MA was associated with an 8% and 14% decrease in the risk of VTE, respectively (enrollment MA: subdistribution hazard ratio [SHR], 0.92; 95% CI, 0.87-0.97; p = 0.003 and peak MA: SHR, 0.86; 95% CI, 0.81-0.91; p < 0.001). Lower enrollment platelet counts and fibrinogen levels were also associated with increased risk of VTE (p = 0.002 and p = 0.01, respectively). Platelet count and fibrinogen level were positively associated with MA (multivariable model: adjusted R 2 = 0.51; p < 0.001). When controlling for the competing risk of death, lower enrollment and peak MA were associated with increased risk of VTE. Lower platelet counts and fibrinogen levels at enrollment were associated with increased risk of VTE. The association of diminished MA, platelet counts, and fibrinogen with VTE may suggest a relative consumptive coagulopathy in critically ill patients with COVID-19.

Pattern of Conventional Coagulation and Thromboelastographic Parameters in Patients with COVID-19 Diseases and Association of COVID-Associated Coagulopathy with Mortality in Intensive Care Unit.

Background:Knowledge of underlying pathophysiology of coagulopathy is evolving and the pattern of coagulation parameters in coronavirus disease 2019 (COVID-19)–associated diseases is still not very clear.Aims:In the present study, we aimed to find out the pattern and distribution of conventional coagulation parameters and thromboelastographic (TEG) parameters in COVID-19–associated coagulopathy (CAC) in survivors and nonsurvivors at 28 days.Setting and Design:The present prospective observational study was conducted at a tertiary care COVID-19 intensive care unit (ICU) facility from March 21, 2020, to July 15, 2021.Materials and Methods:Admission clinical and laboratory data (conventional coagulation, inflammatory and TEG parameters, and disease severity parameters) of 64 COVID-19 patients admitted to the ICU were collected. Patients were divided into two groups, i.e., survivors and nonsurvivors.Statistical Analysis:Data were compared between two groups, i.e., survivors versus no survivors on 28 days using Student's t-test/Mann–Whitney U-test or Chi-square test/Fisher's exact test.Results:Admission mean plasma fibrinogen levels (474.82 ± 167.41 mg.dL−1) and D-dimer were elevated (1.78 [0.66, 3.62] mg.mL−1) in the COVID-19 ICU patients. Overall, COVID-19 patients had mean lower normal platelet count (150 ± 50 × 103 cells.mm−3), with marginally elevated prothrombin time (16.25 ± 3.76 s) and activated partial thromboplastin time (38.22 ± 16.72 s). A 65.6% (42/64) TEG profile analysis showed a normal coagulation profile, and the rest 21.9% (14/64) and 12.5% (8/64) had hypercoagulable and hypocoagulable states, respectively. Plasma D-dimer level was markedly elevated in nonsurvivors compared to survivors (P < 0.05), while no other conventional coagulation parameters and TEG profile demonstrated statistically significant between the two groups.Conclusion:Markedly elevated plasma D-dimer level was observed in nonsurvivors of COVID-19 ICU patients. A large portion of COVID-19 ICU patients had a normal TEG profile. Conventional coagulation parameters and TEG profile were similar between survivors and nonsurvivors.

Peri-Operative Thrombophilia in Patients Undergoing Liver Resection for Colorectal Metastases

Introduction: Routine peri-operative chemical venous thromboembolism (VTE) prophylaxis for liver surgery remains controversial, and is often delayed post-operatively until conventional coagulation parameters have normalised, due to perceived risks of bleeding. This study asked whether patients undergoing liver resection for colorectal metastases (CRM) were at risk from VTE pre-operatively, and the impact of liver resection on that risk. Method: A single-centre prospective observational cohort study of patients undergoing open liver resections for CRM, comparing pre-, peri- and post-operative haemostasis variables. Patients with cirrhosis, previous VTE or anticoagulated were excluded. Coagulation assays were measured pre-operatively, peri-operatively (after transection) and first post-operative day. Tissue Factor messenger ribonucleic acid (TFmRNA) activation was measured from peripheral blood mononuclear cells (PBMCs) pre- and post-operatively. Chemical thromboprophylaxis commenced on the first post-operative day after venesection. Results: Of 336 hepatectomies performed October 2017-December 2019, 60 resections in 57 patients were prospectively recruited (Table 1). Patients had raised Factor VIIIC and thrombin generation velocity index pre-operatively, which significantly increased post-operatively. Post-operative Factor VIIIC and von Willebrand Factor (vWF) were higher and Protein C lower following major resections. Longer transections exhibited greater PMBC-TFmRNA expression. Conclusions: These data show the risk of major haemorrhage in elective liver resection in a high-volume unit is low, and administration of chemical thromboprophylaxis within 13-20 hours of surgery is safe and effective. Furthermore, patients with CRM are prothrombotic pre-operatively, an effect exacerbated by liver resection, particularly in patients with longer, more complex resections, suggesting chemical thromboprophylaxis should be considered earlier in the patient pathway.

Suppressed Fibrinolytic Activity Demonstrated By Simultaneous Thrombin and Plasmin Generation Assay during Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy

Introduction: Infusion T cells engineering to express CD19-specific chimeric antigen receptor T cells (CAR-T) following lymphodepleting chemotherapy has shown promising efficacy in patients with relapsed and/or refractory CD19-positive B-cell malignancies including B-cell acute lymphoblastic leukemia (B-ALL), and diffuse large B-cell lymphoma (DLBCL). CAR-T therapy can often be associated with cytokine release syndrome (CRS), which has been reported to present severe coagulopathy. Conventional coagulation and fibrinolysis parameters have been reported to worsen in correlation with CRS grading [Hay KA et al. Blood 2017]. In the present study, we hypothesized that the change of balance between coagulation and fibrinolysis due to coagulopathy is associated with CRS after CAR-T therapy. To clarify our hypothesis, we investigated the global coagulation and fibrinolytic function of patients receiving CD19 CAR-T therapy using simultaneous thrombin and plasmin generation assay (T/P-GA). Patients: We enrolled 13 consecutive patients aged 23-69 years (8 males and 5 females, DLBCL; n = 11, B-ALL; n = 2) receiving CD19 CAR-T therapy from May 2020 to December 2020 at a single center in Japan. Due to a history of internal jugular venous thrombosis, one patient received edoxaban, an anticoagulant. Methods: We evaluated the global functions of coagulation and fibrinolysis using T/P-GA [Matsumoto et al. TH 2013]. This clotting was initiated by the mixture of recombinant human tissue factor (Innovin ®, f.c. 1 pM), phospholipid vesicles (f.c. 4 μM), and tissue-type plasminogen activator (f.c. 3.2 nM). We simultaneously monitored thrombin and plasmin generation using thrombin- and plasmin-specific fluorogenic substrate (Z-Gly-Gly-Arg-AMC and BOC-Glu-Lys-Lys-MAC, respectively) in separate microtiter wells. The first derivatives (velocity) of thrombin and plasmin generation were utilized to derive the parameters, lag time (LT), endogenous potential (EP), peak levels (Peak), and time to peak (ttPeak). In this study, EP of thrombin generation (T-EP) and plasmin-peak (P-Peak) were selected as parameters for evaluation. We calculated the ratio of T-EP and P-Peak of patients' plasmas to those of control normal plasma. A ratio > 1.0 was defined as high coagulation or fibrinolytic potential relative to normal. Using fibrinogen (Fbg), D-dimer, and antithrombin (AT), we also monitored the conventional laboratory markers of hemostasis. Soluble IL-2 receptor (sIL-2R) was also measured as a marker of inflammatory cytokines. Day 0 was defined as the day of CAR-T infusion. Plasmas were collected at T0; pre-lymphodepleting chemotherapy, T1; Days -2-0, T2; Days 1-3, T3; Days 4-6, T4; Days 7-9, T5; Days 10-12, T6; Days 13-18, and T7; Days 19-23. Results: All patients had Grade ≤ 2 CRS. Two cases developed CRS-associated coagulopathy, one of whom required fresh frozen plasma transfusion and cryoprecipitate for low Fbg level, and the other required tranexamic acid for hemorrhagic cystitis. The median values of AT remained within the reference value (RV). The median Fbg values were 229-525 mg/dL, and which were significantly greater at T0-T3 than at T5-T7 (p < 0.05). The median D-dimer values were 0.45-3.9 µg/mL, which were within or above the RV with no significant change between time points. The median values of sIL-2R were 819-3,953 U/mL, and which were significantly increased at T3-T4 than at T0-T1 (p < 0.05). T-EP/P-Peak revealed a median of 1,877/21.9, 1,659/18.6, 1,731/19.8, 1,856/15.0, 1,931/16.3, 1,758/18.5, 1,600/19.1, 1,634/20.3, and 1,594/17.4 nM for T0-T7 and control plasma, respectively, indicating the reduced P-Peak ratios (Fig. 1). T-EP ratios showed consistently maintaining > 1 with no significant difference between time points, while P-Peak ratios were significantly lower at T3 and T4 than at T0 (p < 0.01) (median ratios of T-EP/P-peak; T0; 1.23/1.22, T1; 1.08/1.05, T2; 1.12/1.09, T3; 1.23/0.81, T4; 1.27/0.91, T5; 1.19/1.11, T6; 1.07/1.12, and T7; 1.20/1.15, respectively). Conclusion: The results of T/P-GA showed that hemostatic kinetics in patients with Grade ≤ 2 CRS were likely to shift to hypercoagulable states throughout the entire period and that they were likely to experience hypofibrinolytic activity during the CRS phase. These results suggest that the imbalance of coagulation and fibrinolysis might cause organ disorder due to thrombotic tendency associated with CRS after CAR-T therapy. [Display omitted] DisclosuresTakaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding.

Tocilizumab mitigates hypercoagulability after out-of-hospital cardiac arrest – results from a randomized controlled trial (IMICA)

Abstract Background Systemic inflammation constitutes a key element of the post cardiac arrest syndrome (PCAS) which affects initially comatose resuscitated cardiac arrest patients. We have recently shown that treatment with tocilizumab, an IL-6 receptor antagonist, reduces systemic inflammation and myocardial injury after out-of-hospital cardiac arrest (OHCA). Inflammation and coagulation are interconnected, and changes in coagulation often accompany inflammatory states. Purpose To investigate if conventional coagulation parameters or a viscoelastic hemostatic assay differ in patients treated with tocilizumab compared to placebo. Methods Eighty comatose OHCA patients were randomized 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Trial registration: Clinicaltrials.gov NCT03863015. Endpoints were plasma fibrinogen, platelet count, and Thrombelastography (TEG) variables. TEG analysis was performed utilizing whole blood in a citrated kaolin assay with heparinase (to neutralize any unfractionated or low molecular weight heparin that had been administered), and the following variables were analyzed: reaction time (R), angle, maximum amplitude (MA), and lysis at 30 minutes (Ly30) which represents clot initiation, propagation, strength and dissolution respectively. Data reported as median (Q1; Q3), statistical analysis performed by constrained linear mixed models, and a p&amp;lt;0.05 was considered statistically significant. Results Admission median levels of the investigated coagulation parameters were within normal levels for both the tocilizumab and placebo group. At 48 hours, for the placebo group, fibrinogen levels (figure 1) had risen to supra-normal levels, TEG angle had increased from 64 (10; 67) till 72 (69; 74), and TEG MA (figure 2) had increased to the hypercoagulable range (all p&amp;lt;0.05), while for the tocilizumab group fibrinogen levels and TEG MA remained within normal values. Both groups had a significant fall in platelet count from admission till 48h [placebo: from 252 109/L (208; 282) till 151 (126; 189); tocilizumab from 217 (183; 260) till 152 (127; 183)], with no group differences. Also for both groups there was significant shortening of the TEG R time [placebo: from 8 min (6; 10) till 6 (6; 8); tocilizumab from 8 (6; 9) till 7 (6; 8)], again with no difference between groups. Ly30 did not change over time or differ between groups. Conclusion Treatment with tocilizumab following resuscitated OHCA aids in maintaining a normo-coagulable state, whereas placebo patients developed supra-normal fibrinogen levels and a hypercoagulable TEG clot strength. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The Danish Heart Foundation (Reference no. 19-R135-A9302-22125); Region Hovedstadens Forskningsfond til sundhedsforskning (CapitalRegion Research Foundation, Denmark; reference no. A6030) Figure 1. FibrinogenFigure 2. Thrombelastography MA

The Procoagulant Effect of COVID-19 on the Thrombotic Risk of Patients with Hip Fractures Due to Enhanced Clot Strength and Fibrinolysis Shutdown

Introduction: Coronavirus disease 2019 (COVID-19) in patients with hip fractures is associated with increased incidence of venous thromboembolism (VTE). The purpose of this study was to evaluate the hemostatic alterations of COVID-19 that are associated with a higher thrombotic risk using rotational thromboelastometry (ROTEM). Methods: A retrospective observational study was performed including 20 COVID-19 patients with hip fractures. To compare the coagulopathy of patients with mild COVID-19 and hip fractures with the coagulopathy associated with each of these two conditions separately, we used two previously recruited groups of patients; 198 hip fracture patients without COVID-19 and 21 COVID-19 patients without hip fractures. The demographics, clinical parameters, conventional coagulation parameters and ROTEM findings of the three groups were analyzed and compared. Results: COVID-19 hip fracture patients had higher amplitude of clot firmness at 10 min (p < 0.001), higher alpha angle (p < 0.001), higher lysis index at 60 min (p < 0.001), and shorter clot formation time (p < 0.001) than non-COVID-19 hip fracture patients, indicating increased clot strength and impaired fibrinolysis due to COVID-19. The value of lysis index at 60 min (99%) in COVID-19 patients with hip fractures was consistent with fibrinolysis shut down. Multivariable linear regression analysis further confirmed that COVID-19 resulted in increased amplitude of clot firmness at 10 min (p < 0.001), increased maximum clot firmness (p < 0.001), increased lysis index at 60 min (p < 0.001) and increased alpha angle (p < 0.001), but significantly shortened clot formation time (p < 0.001). Discussion: The higher thrombotic risk in COVID-19 patients with hip fractures is characterized by increased clot strength and fibrinolysis shutdown, as shown by ROTEM findings. Further prospective studies are warranted to evaluate the need for modification of thromboprophylaxis to balance the hemostatic derangements of COVID-19 patients with hip fractures.

Predictive value of coagulation factor XIII on bleeding risk in ischemic stroke patients treated with intravenous thrombolysis.

Intravenous thrombolysis (IVT) therapy with recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke (AIS) has a known risk of intracerebral hemorrhage (ICH). We aimed to identify the predictive value of coagulation factor XIII (FXIII) on post-thrombolytic ICH risk in AIS patients. The study cohort included 69 diagnosed AIS patients undergoing IVT treatment within 24 hours of symptom onset. Blood samples taken on admission were analyzed for FXIII antigen levels with an automated latex enhanced immunoassay. Conventional coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-dimer (DD) were also tested. Of the 69 AIS patients, 23 (33.3%) developed post-thrombolytic ICH. Plasma FXIII levels showed a significant decrease, accompanied with elevated FIB and DD levels in AIS patients with post-thrombolytic ICH. Multivariable logistic regression (LR) revealed that FXIII and FIB were independently associated with post-thrombolytic ICH progression. Area under receiver operating characteristic curve of FXIII selected by the further forward logistic regression was 0.823 [95% confidence interval (CI): 0.712-0.904], and the cutoff value of 76.6% yielded good sensitivity at 91.3% and good negative predictive value (NPV) at 93.9%. Our findings indicated that plasma FXIII level may be an independent determinant for predicting post-thrombolytic bleeding risk in AIS patients.

A retrospective comparison of thromboelastography and conventional coagulation parameters for periprosthetic joint infection diagnosis and reimplantation timing

PurposeThe diagnostic significance of coagulation parameters in periprosthetic joint infection (PJI) is currently attracting increasing attention. We assessed the diagnostic accuracy of thromboelastography (TEG) for PJI and compared the values of various coagulation indicators for PJI diagnosis and reimplantation timing. MethodsWe enrolled 250 patients undergoing revision for aseptic failure (Group A), revision for PJI (Group B), or reimplantation (Group C) during 2013–2020. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), representative coagulation-related indicators (reaction time [R], clotting time [K], angle and maximum amplitude [MA]) of TEG and routine coagulation indicators, including fibrinogen, D-dimer, fibrin degradation product (FDP), platelets count (PC), mean platelet volume (MPV), distribution width (PDW) and plateletcrit (PCT) as well as PC/MPV ratio(PVR)were measured preoperatively. Receiver operating characteristic (ROC) curves were used to evaluate the utility of all tested indicators for assessing infection. ResultsAll the indicators showed significant differences between groups A and B (P < 0.05) and, except for D-dimer, FDP, MPV and R, between groups B and C (P < 0.05). Similar differences were also observed in biomarkers before first-stage revision and second-stage reimplantation. ROC curves showed that fibrinogen, K, angle and MA outperformed the other coagulation indicators, with areas under the curve of 0.864 to 0.893 and threshold values of 3.55 g/L, 1.2 min, 72.4 deg and 69.1 mm, respectively. The multiple tests of TEG indices (K, angle and MA) and traditional inflammatory markers (CRP and ESR) or conventional coagulation indicators (fibrinogen, PC and PVR) had good sensitivity and specificity for PJI diagnosis, and the diagnostic values of TEG and platelet-associated indicators (PC and PVR) varied in the different subgroups. ConclusionTEG was closely related to PJI and could serve as a valuable technique for identifying residual infection before reimplantation. Fibrinogen showed high diagnostic accuracy for PJI and effectively guided the timing of reimplantation.

Prognostic Value of Antithrombin Levels in COVID-19 Patients and Impact of Fresh Frozen Plasma Treatment: A Retrospective Study

Objective:The defective interplay between coagulation and inflammation may be the leading cause of intravascular coagulation and organ dysfunction in coronavirus disease-19 (COVID-19) patients. Abnormal coagulation profiles were reported to be associated with poor outcomes. In this study, we assessed the prognostic values of antithrombin (AT) activity levels and the impact of fresh frozen plasma (FFP) treatment on outcome.Materials and Methods:Conventional coagulation parameters as well as AT activity levels and outcomes of 104 consecutive critically ill acute respiratory distress syndrome (ARDS) patients with laboratory-confirmed COVID-19 disease were retrospectively analyzed. Patients with AT activity below 75% were treated with FFP. Maximum AT activity levels achieved in those patients were recorded.Results:AT activity levels at admission were significantly lower in nonsurvivors than survivors (73% vs. 81%). The cutoff level for admission AT activity was 79% and 58% was the lowest AT for survival. The outcome in those patients who had AT activity levels above 75% after FFP treatment was better than that of the nonresponding group. As well as AT, admission values of D-dimer, C-reactive protein, and procalcitonin were coagulation and inflammatory parameters among the mortality risk factors.Conclusion:AT activity could be used as a prognostic marker for survival and organ failure in COVID-19-associated ARDS patients. AT supplementation therapy with FFP in patients with COVID-19-induced hypercoagulopathy may improve thrombosis prophylaxis and thus have an impact on survival.

Continuous renal replacement therapy without anticoagulation in critically ill patients at high risk of bleeding: A systematic review and meta-analysis.

The current clinical guideline recommends continuous renal replacement therapy (CRRT) proceed without anticoagulation in patients with contraindication to citrate and increased bleeding risk. Nevertheless, the efficacy of anticoagulation-free CRRT remains inconsistent. The purpose of our present systematic review is to evaluate the efficacy and safety of anticoagulant-free CRRT based on the current literatures. The primary outcomes were filter lifespan and risk factors for filter failure. Seventeen observational studies and three randomized controlled trials were included in our present meta-analysis. There was no significant difference in filter lifespan and azotemic control between the anticoagulation-free and systemic heparin group. The regional citrate anticoagulation (RCA) protocol seems to be superior to the anticoagulation-free protocol in terms of filter lifespan (WMD -23.01, 95% CI [-28.62, -17.39], p<0.001; I2 =0%, p=0.53) and azotemic control. Nafamostat protocol could significantly prolong filter lifespan (WMD -8.4, 95% CI [-9.9, -6.9], p<0.001; I2 =33.7%, p=0.21) as compared with anticoagulation-free protocol without better azotemic control. The conventional coagulation parameters showed poor predictive performence for filter failure and the necessity of anticoagulants use before CRRT. Currently, the optimal choice of anticoagulation strategy for critically ill patients with increased bleeding risk could be RCA under close monitoring.

A gottingen minipig model of radiation-induced coagulopathy

Purpose Total body irradiation of the Gottingen minipig results in a characteristic hematopoietic response, including anemia, neutropenia, lymphocytopenia, and thrombocytopenia. Currently, there are no well-characterized large or small animal models for radiation-induced thrombocytopenia. The study described here using the Gottingen minipig was focused on understanding which aspects of the coagulation cascade leads to radiation-induced coagulopathy. In this study, multiple clinical pathology parameters were determined prior to and for 45-days following total body irradiation using a 6 MV photon linear accelerator. Materials and methods Following irradiation, frequent analyses of conventional hematology and coagulation parameters provided time-course information on the onset and recovery of thrombocytopenia. In addition, thromboelastography (TEG) was utilized to monitor coagulation dysfunction, namely clotting time, clot formation time, clot strength, and fibrinolysis. Coagulation factor activity levels were measured for factors II, V, VII, VIII, IX, X, XI, XII, XIII, Protein C, fibrin monomers, antiplasmin and D-dimer using a Siemen’s coagulation analyzer to provide time course information of changes in activity post irradiation exposure. Results These analyses revealed that in total body irradiated minipigs, TEG tracings demonstrate long R (time to initial clot formation) and K (time to achieve a certain clot strength) times, and low alpha-angle (rate of clot formation) and MA (overall stability of the clot) during onset of thrombocytopenia (typically post irradiation day 10–15). Low alpha-angle and MA directly correlated with decreased platelet counts. A long R time is suggestive of a deficiency in clotting factors and was compared to measured activity levels of individual coagulation factors. The data indicates that coagulation factors are significantly changed early after irradiation exposure prior to thrombocytopenia and factors VIII, XI, XII and XIII are markedly altered during the critical point of thrombocytopenia. Conclusion These data support the continued use of multiple approaches to evaluate the coagulation cascade in order to provide the most meaningful interpretation of the hematopoietic changes that occur post irradiation.

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

BackgroundThree months ago, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) broke out in Wuhan, China, and spread rapidly around the world. Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism (VTE) prevalence is still rarely mentioned. ObjectivesTo determine the incidence of VTE in patients with severe NCP. MethodsIn this study, 81 severe NCP patients in the intensive care unit (ICU) of Union Hospital (Wuhan, China) were enrolled. The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed. ResultsThe incidence of VTE in these patients was 25% (20/81), of which 8 patients with VTE events died. The VTE group was different from the non‐VTE group in age, lymphocyte counts, activated partial thromboplastin time (APTT), D‐dimer, etc. If 1.5 µg/mL was used as the D‐dimer cut‐off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%. ConclusionsThe incidence of VTE in patients with severe NCP is 25% (20/81), which may be related to poor prognosis. The significant increase of D‐dimer in severe NCP patients is a good index for identifying high‐risk groups of VTE.

COVID-19 and coagulative axis: review of emerging aspects in a novel disease.

Latest evidences from literature suggest that SARS-CoV-2 disease 2019 (COVID-19) is commonly complicated with coagulopathy and that disseminated intravascular coagulation is present in the majority of deceased patients. Particularly, conventional coagulation parameters appear to be significantly altered in patients with poor prognosis. A wide-ranging cross- talk between coagulative haemostasis and inflammation, as well as the activation of coagulation cascade during viral infections, are well established. Another important evidence which may explain coagulation disorders in COVID-19 is the increase of thrombus formation under conditions of hypoxia. Despite the exact pathophysiological mechanism of coronavirus-induced thromboembolism needs to be further investigated, this finding suggests that it is good practice to assess the risk of thrombosis in COVID-19 patients to improvethe clinical management in terms of anticoagulation therapy. Anticoagulants, mainly low-molecular-weight heparin (LMWH), should be tailored in patients meeting sepsis induced coagulopathy (SIC) criteria or with markedly elevated D-dimer. In this context, further studies are needed to optimise the decision making in therapeutic approach.