Hemostatic Abnormalities Research Articles

Von Willebrand Factor Expression in Endothelium in a Co-Culturing System of Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most common cause of cancer and death from cancer among children, with an incidence of 1 in 1,750 children. A previous Dutch cohort study highlighted that 7.6% of children with ALL also developed venous thromboembolism (VTE; n=55/778). VTE increases the risk of morbidity and mortality in cancer patients. However, the mechanisms of hemostatic abnormality in ALL is not well understood. Von Willebrand factor (vWF) is involved in thrombosis and is a well-established marker for endothelial dysfunction. High vWF levels and qualitative abnormality of the protein have been documented in patients with ALL and may contribute to the prothrombotic state observed in these patients.Objective: To determine whether co-culturing cancerous ALL cells with healthy human umbilical vein endothelial cells (HUVECs) may increase vWF secretion from endothelial cells.Methods: HUVECs were obtained from Lonza Bioscience Solutions (Basel, Switzerland) and leukemic B-lymphoblasts (ALL cells) derived from bone marrow were obtained from ATCC (Manassas, Virginia, USA). Passages 3 to 5 were used in this study and cell lines were grown as per manufacturer's instruction. A confluent monolayer of HUVECs was established before the co-culturing experiments. Firstly, ALL cells and HUVECs were grown together (co-cultured) at a 1:1 ratio. Then, the conditioned media and cell lysates were harvested at three different time points and the vWF levels were quantitated by a vWF-ELISA. To further evaluate the effect of leukemic cells on the endothelium, ALL cells were also co-cultured at a 10:1 ratio to endothelial cells. All experiments were conducted in biological triplicates.Results: Cells were monitored throughout the study period and no morphological changes to the endothelial cells were observed. An accumulation of vWF was recorded over time in both the conditioned media and cell lysates. The differences in vWF levels between the co-culture group and HUVEC-only group at three time points (24, 48 and 72 hours) were not statistically significant. In addition, 10-fold differences in ratio between leukemic and endothelial cells did not have a meaningful effect on vWF levels.Discussions: In an in vitro co-culture system, ALL cells do not appear to induce an increase vWF secretion in HUVECs. Contrary to prior evidence, this study suggests that increased vWF secretion from endothelial cells may not be a contributor to the prothrombotic state observed in ALL. The circulating lymphoblasts may have a more pronounced effect on other endothelial layers where vWFs are highly expressed such as the pulmonary endothelium. On the other hand, peripheral blood pediatric leukemic lymphoblasts have been demonstrated to produce hemostatic factors, which may contribute the hemostatic imbalance in the progression of disease. In addition, the pathogenesis of thrombosis in ALL is likely to be therapeutically related since thrombosis rarely occurs at presentation. Alternative mechanisms, such as ADAMST13 and hemostatic factors' level and function or the use of chemotherapeutic agents, ought to be explored. [Display omitted] DisclosuresMatino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees.

Potential value of the calibrated automated thrombogram in patients after a cerebral venous sinus thrombosis; an exploratory study

BackgroundCerebral venous sinus thrombosis (CVST) is a relatively rare, but potentially lethal condition. In approximately 15% of the patients, the cause of CVST remains unclear. Conventional clotting tests such as prothrombin time and activated partial thromboplastin time are not sensitive enough to detect prothrombotic conditions nor mild haemostatic abnormalities. The calibrated automated thrombogram (CAT) is a physiological function test that might be able to detect minor aberrations in haemostasis. Therefore, we aimed to detect the presence of a prothrombotic state in patients who endured idiopathic CVST with the CAT assay.MethodsFive adult patients with an idiopathic, radiologically proven CVST that had been admitted during the past 3 years were included in this study. The control group consisted of five age/gender matched healthy volunteers. Exclusion criteria were known haematological disorders, malignancy (current/past) or hormonal and anticoagulant therapy recipients. We obtained venous blood samples from all participants following cessation of anticoagulation. Using the CAT assay, we determined lag time, normalized endogenous thrombin potential (ETP), ETP reduction and normalized peak height. In addition, prothrombin concentrations were determined.ResultsWe found no significant differences in lag time (4.7 min [4.5–4.9] vs 5.3 min [3.7–5.7], p = 0.691), normalized ETP (142% [124–148] vs 124% [88–138], p = 0.222), ETP reduction (29% [26–35] vs 28% [24–58], p > 0.999), and normalized peak height (155% [153–175] vs 137 [94–154], p = 0.056) between patients and their age/gender matched controls. In addition, prothrombin concentrations did not significantly differ between patients and controls (120% [105–132] vs 127% [87–139], p > 0.999).ConclusionReasons for absent overt hypercoagulability within this study population may be the small patient sample, long time since the event (e.g. 3 years) and avoidance of acquired risk factors like oral contraception. Given the fact that CVST is a serious condition with a more than negligible risk of venous thrombosis event recurrence, exclusion of clinically relevant hypercoagulability remains a challenging topic to further study at the acute and later time points, particularly in patients with idiopathic CVST.

The Reevaluation of Thrombin Time Using a Clot Waveform Analysis.

Object: Although thrombin burst has attracted attention as a physiological coagulation mechanism, clinical evidence from a routine assay for it is scarce. This mechanism was therefore evaluated by a clot waveform analysis (CWA) to assess the thrombin time (TT). Material and Methods: The TT with a low concentration of thrombin was evaluated using a CWA. We evaluated the CWA-TT of plasma deficient in various clotting factors, calibration plasma, platelet-poor plasma (PPP), and platelet-rich plasma (PRP) obtained from healthy volunteers, patients with thrombocytopenia, and patients with malignant disease. Results: Although the TT-CWA of calibration plasma was able to be evaluated with 0.01 IU/mL of thrombin, that of FVIII-deficient plasma could not be evaluated. The peak time of CWA-TT was significantly longer, and the peak height significantly lower, in various deficient plasma, especially in FVIII-deficient plasma compared to calibration plasma. The second peak of the first derivative (1st DP-2) was detected in PPP from healthy volunteers, and was shorter and higher in PRP than in PPP. The 1st DP-2 was not detected in PPP from patients with thrombocytopenia, and the 1st DP-2 in PRP was significantly lower in patients with thrombocytopenia and significantly higher in patients with malignant disease than in healthy volunteers. Conclusion: The CWA-TT became abnormal in plasma deficient in various clotting factors, and was significantly affected by platelets, suggesting that the CWA-TT may be a useful test for hemostatic abnormalities.

Assessment of Von Willebrand factor antigen and activity levels in inflammatory bowel diseases

Background There is a close interaction between inflammation and coagulation. Hemostatic abnormalities are common in inflammatory bowel disease (IBD) with higher risk for a hypercoagulable state and prothrombotic conditions. In addition, a few cases of acquired coagulopathy with higher risk of bleeding have been reported. The involved pathophysiologic mechanisms are complex and incompletely understood. Objective This is a case–control study that aimed to assess the levels of Von Willebrand factor (VWF) in IBD as a marker of disease activity and its relation to higher risk of bleeding or thrombotic events. Patients and methods A total of 46 patients with IBD aged 18 years or older were enrolled in the study. After consenting, patients were divided into two groups: one group included 23 patients with active IBD and the other group included 23 patients with inactive IBD. Activity of Crohn's disease was assessed through the Harvey-Bradshaw index and activity in patients with ulcerative colitis was evaluated with the simple clinical colitis activity index. The white blood cell count, hemoglobin level, platelet count, activated partial thromboplastin time, C-reactive protein, erythrocyte sedimentation rate, albumin, fecal calprotectin, VWF antigen level (VWF:Ag), and VWF ristocetin cofactor activity (VWF:RCo) were measured. The VWF:RCo/VWF:Ag ratio was calculated. Results There were significant differences in the mean±SD of vWF antigen and vWF:RCo levels between active IBD group (189.30±62.83 and 101.73±23.42, respectively, P=0.001) and inactive IBD group 177.30±64.90 and 97.08±24.21, respectively, P=0.001). The IBD activity index was correlated with VWF antigen (r=0.78 P=0.001) and VWF:RCo levels (r=0.74 P=0.001). VWF antigen and VWF:RCo were correlated with fecal calprotectin (r=0.65, P=0.001, and r=0.67, P=0.001, respectively). The odds ratio of an elevated vWF antigen greater than 150% was 24 (95% confidence interval: 4.38–131.47) in the group with active IBD compared with the inactive IBD group. The VWF:RCo/VWF:Ag ratio of less than 0.7 which reflects the possibility of acquired Von Willebrand syndrome was detected in five patients (21.7%) with active IBD in comparison with only one patient (4.3%) in the inactive IBD group, with odds ratio of 6.1 (95% confidence interval: 0.65–57.1). Conclusion VWF antigen and activity levels can be used as markers for evaluation of IBD activity. Assessment of VWF in IBD could be significant for better hemostatic control of such patients. Activated coagulation system in IBD is well known; however, precautions for coexisting acquired functional coagulopathy should be considered.

Do platelet indices play a role in assessing severity of pre-eclampsia and eclampsia?

Background: Pre-eclampsia and eclampsia is a multisystem disorder affecting approximately 2-7% of all pregnancies and is a significant cause of maternal and fetal morbidity and mortality. Many hemostatic abnormalities have been reported in association with hypertensive disorder of pregnancy. We conducted this prospective case-control study to assess and analyze the platelet parameters in 3rd-trimester normotensives, pre-eclamptic, and eclamptic pregnant women. Materials and methods: This study was conducted in the hematology division of the Department of Pathology, in a rural population-based medical institute over 2 years. In all subjects (cases and controls) 2 ml of blood sample was collected in EDTA vials for platelet counts and platelet indices. The blood samples were run on an automated blood cell counter (Beckman coulter) within 2 hours of collection. The data obtained were tabulated and statistical analyses were performed. Results: The mean platelet count was significantly decreased in cases as compared to controls with increased frequency of thrombocytopenia associated with progression of the disease. Platelet indices, mean platelet volume, and platelet distribution width were increased, whereas the plateletcrit was decreased in cases as compared to the controls. However, the statistically significant difference was found only in platelet distribution width and plateletcrit. Conclusions: We concluded that platelet indices like platelet distribution width and plateletcrit can be useful along with platelet count in early detection of pre-eclampsia and eclampsia instead of relying on platelet count alone.

P14.33 Preoperative Lactate Dehydrogenase levels as a predictor of venous thromboembolism development in glioblastoma patients

Abstract BACKGROUND Venous thromboembolism (VTE) is a common complication in patients with glioblastoma. Despite high incidence of up to 30% per year, concerns about bleeding complications have limited the use of primary anticoagulant prophylaxis. Finding a suitable biomarker to assess the risk of occurrence is therefore of utmost clinical interest. We performed an exploratory study of preoperative routinely used haematological markers as predictor for the development of VTE in glioblastoma patients. MATERIAL AND METHODS Data was retrospectively collected from an existing database of 307 patients diagnosed with glioblastoma by the Oncology Network South-East Netherlands (OnzoZON) between 2006 and 2020. Collected preoperative haematological markers included: haemoglobin, platelets, lactate dehydrogenase, neutrophils, lymphocytes, albumin and derived ratios. In addition, type and date of VTE were retrieved from medical records. Receiver operating curve was used to identify the optimal cut-off values of the preoperative haematological markers. Univariate and multivariate logistic regression analyses were performed to predict VTE for each haematologic marker independently. Variables included in the multivariate analyses were age, gender, type of surgery, Karnofsky performance score, MGMT status, weight, height and BMI, already available from the primary database. RESULTS In the total dataset, 45 patients (15%) suffered from a VTE, most common pulmonary embolism (51%) followed by deep vein thrombosis (31%). Mean time from diagnosis until VTE was 4.3 months (SD = 5.5). Preoperative haemoglobin value was available for analyses in 265 patients, platelets value in 226, lactate dehydrogenase in 98, neutrophils in 133, lymphocytes in 133 and albumin in 56 patients. A preoperative lactate dehydrogenase value > 243 U/L was found to increase the risk of VTE in both univariate and multivariate analysis (P <0.05). Seventeen out of 98 patients of whom lactate dehydrogenase level was available suffered from a VTE, most common pulmonary embolism (59%), followed by deep vein thrombosis (29%) and cerebral venous sinus thrombosis (12%). An elevated lactate dehydrogenase in serum increased the odds for getting a VTE by 3.2 (1.1–9.4). None of the other investigated haematological markers or ratios were found to be significantly correlated with the occurrence of VTE in our study. CONCLUSION Glioblastoma initiates locally haemostatic abnormalities, that propagate systemically though circulating mediators. Our exploratory analysis shows for the first time that preoperative lactate dehydrogenase levels might aid clinicians in identifying patients at risk for a venous thromboembolism. Ultimately this could lead to preventive measures and patient education, but larger and prospective validation of these findings is warranted.

Coagulation Profile in Non-Haematological Malignancies

A variety of Coagulation abnormalities have been reported in patients with malignant lesions especially in the form of Thromboembolic phenomena. These can be detected with simple and inexpensive tests and can help prevent complications. The aim of the present study is to evaluate the coagulation profile in patients with non-Haematological malignancies with respect to the changes in Prothrombin Time (PT), activated Partial. Thromboplastin Time (aPTT) and fibrinogen levels to elucidate any prognostic significance of haemostatic abnormalities in non-haematological malignancies. A total of 70 cases of non-haematological malignancies were evaluated for changes in PT, aPTT and fibrinogen levels and compared to the normal control values. Significant higher levels of Fibrinogen levels were observed in patient group values when compared to normal control values.

Coagulation Abnormalities in Renal Pathology of Chronic Kidney Disease: The Interplay between Blood Cells and Soluble Factors.

Coagulation abnormalities in renal pathology are associated with a high thrombotic and hemorrhagic risk. This study aims to investigate the hemostatic abnormalities that are related to the interaction between soluble coagulation factors and blood cells, and the effects of hemodialysis (HD) on it, in end stage renal disease (ESRD) patients. Thirty-two ESRD patients under HD treatment and fifteen healthy controls were included in the study. Whole blood samples from the healthy and ESRD subjects were collected before and after the HD session. Evaluation of coagulation included primary and secondary hemostasis screening tests, proteins of coagulation, fibrinolytic and inhibitory system, and ADAMTS-13 activity. Phosphatidylserine (PS) exposure and intracellular reactive oxygen species (iROS) levels were also examined in red blood cells and platelets, in addition to the platelet activation marker CD62P. Platelet function analysis showed pathological values in ESRD patients despite the increased levels of activation markers (PS, CD62P, iROS). Activities of most coagulation, fibrinolytic, and inhibitory system proteins were within the normal range, but HD triggered an increase in half of them. Additionally, the increased baseline levels of ADAMTS-13 inhibitor were further augmented by the dialysis session. Finally, pathological levels of PS and iROS were measured in red blood cells in close correlation with variations in several coagulation factors and platelet characteristics. This study provides evidence for a complex coagulation phenotype in ESRD. Signs of increased bleeding risk coexisted with prothrombotic features of soluble factors and blood cells in a general hyperfibrinolytic state. Hemodialysis seems to augment the prothrombotic potential, while the persisted platelet dysfunction might counteract the increased predisposition to thrombotic events post-dialysis. The interaction of red blood cells with platelets, the thrombus, the endothelium, the soluble components of the coagulation pathways, and the contribution of extracellular vesicles on hemostasis as well as the identification of the unknown origin ADAMTS-13 inhibitor deserve further investigation in uremia.

Evaluation of Levels of Some Inflammatory Cytokines in Preeclamptic Women in Owerri

Preeclampsia is a serious and life-threatening pregnancy complication. In this study, the levels of inflammatory cytokines were measured in preeclamptic women in Owerri, Imo State. A total of 120 pregnant women aged 18-45 years at 20-40 weeks of pregnancy were recruited; 60 were preeclamptic women (test group) while 60 were normotensive pregnant women (control group). Preeclampsia was determined by the presence of ≥2+ protein in the urine using combi 2 dipstick for urinalysis and sphygmomanometer blood pressure reading of ≥ 140/90 mmHg. From the demographic data obtained in the studied subject through questionnaire, it showed that nulliparity and family history of high blood pressure were the most dominant risk factor of preeclampsia. The mean of the pro-inflammatory cytokines (IL-6 and TNF-α) in the test group were 4.33±1.42 pg/ml and 8.23±2.73 pg/ml while that of the control group were 3.38±1.22 pg/ml and 6.89±1.88 pg/ml. There was a significant increase in the pro-inflammatory cytokines of the preeclamptic women when compared to the control group. The mean of the anti-inflammatory cytokines (IL-10 & IL-4) of the group were 78.88±14.28 pg/ml and 27.92±7.22pg/ml while the control group was 91.39± 18.46 pg/ml and 31.25±6.90 pg/ml. There was a significant decrease in the result obtained from the test group when compared to the control group. The levels of the pro-inflammatory cytokines were higher than the levels of the anti-inflammatory cytokines of the test group when compared with the control group. Hence there is need to manage the disorder with an anti inflammatory drugs in order to enhance obstetric care, thereby reducing maternal mortality and morbidity that may occur from haemostatic abnormalities.

Evaluation of Biomarkers of Severity in Patients with COVID-19 Infection.

Object: Although many Japanese patients infected with coronavirus disease 2019 (COVID-19) only experience mild symptoms, in some cases a patient’s condition deteriorates, resulting in a poor outcome. This study examines the behavior of biomarkers in patients with mild to severe COVID-19. Methods: The disease severity of 152 COVID-19 patients was classified into mild, moderate I, moderate II, and severe, and the behavior of laboratory biomarkers was examined across these four disease stages. Results: The median age and male/female ratio increased with severity. The mortality rate was 12.5% in both moderate II and severe stages. Underlying diseases, which were not observed in 45% of mild stage patients, increased with severity. An ROC analysis showed that C-reactive protein (CRP), ferritin, procalcitonin (PCT), hemoglobin (Hb) A1c, albumin, and lactate dehydrogenase (LDH) levels were significantly useful for the differential diagnosis of mild/moderate I stage and moderate II/severe stage. In the severe stage, Hb levels, coagulation time, total protein, and albumin were significantly different on the day of worsening from those observed on the day of admission. The frequency of hemostatic biomarker abnormalities was high in the severe disease stage. Conclusion: The evaluation of severity is valuable, as the mortality rate was high in the moderate II and severe stages. The levels of CRP, ferritin, PCT, albumin, and LDH were useful markers of severity, and hemostatic abnormalities were frequently observed in patients in the severe disease stage.

Laboratory manifestations of COVID-19 associated with hemostatic abnormalities

Hemostatic abnormalities had been reported in COVID-19 patients, which may include disseminated intravascular coagulation (DIC), hypercoagulability, and alterations in platelets parameters. Articles that investigate the alterations of hemostatic abnormalities during the COVID-19 disease (2020-2021) and their predictive value of disease outcome have been thoroughly reviewed. Among the reviewed articles, thrombocytopenia is observed in 5.0-41.7% of COVID-19 patients, which is related to disease severity. Moreover, other platelets parameters, including Platelets/lymphocytes ratio (PLR), Mean platelets volume (MPV), and aggregation, may also be affected. On the other hand, findings of coagulation tests such as D dimer; fibrinogen, Antithrombin (AT), and Fibrin degradation products (FDP) are significantly elevated in COVID-19 patients, while in a single study, most of the patients had positive Lupus anticoagulants (LA) and normal protein C (PC). In the same perspective, these alterations showed significant correlations with disease severity. Overall, hemostatic laboratory markers are significant predictors of COVID-19 disease outcome as indicated by the increased risk of venous and arterial thrombotic events, especially in ICU patients.

Hemostasis and fibrinolysis in COVID‐19 survivors 6 months after intensive care unit discharge

BackgroundThe prothrombotic phenotype has been extensively described in patients with acute coronavirus disease 2019 (COVID‐19). However, potential long‐term hemostatic abnormalities are unknown. ObjectiveTo evaluate the changes in routine hemostasis laboratory parameters and tissue‐type plasminogen activator (tPA) rotational thromboelastometry (ROTEM) 6 months after COVID‐19 intensive care unit (ICU) discharge in patients with and without venous thromboembolism (VTE) during admission. MethodsPatients with COVID‐19 of the Maastricht Intensive Care COVID cohort with tPA ROTEM measurement at ICU and 6‐month follow‐up were included. TPA ROTEM is a whole blood viscoelastic assay that illustrates both clot development and fibrinolysis due to simultaneous addition of tissue factor and tPA. Analyzed ROTEM parameters include clotting time, maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT). ResultsTwenty‐two patients with COVID‐19 were included and showed extensive hemostatic abnormalities before ICU discharge. TPA ROTEM MCF (75 mm [interquartile range, 68‐78]‐59 mm [49‐63]; P ≤ .001), LOT (3690 seconds [2963‐4418]‐1786 seconds [1465‐2650]; P ≤ .001), and LT (7200 seconds [6144‐7200]‐3138 seconds [2591‐4389]; P ≤ .001) normalized 6 months after ICU discharge. Of note, eight and four patients still had elevated fibrinogen and D‐dimer concentrations at follow‐up, respectively. In general, no difference in median hemostasis parameters at 6‐month follow‐up was observed between patients with (n=14) and without (n=8) VTE, although fibrinogen appeared to be lower in the VTE group (VTE–, 4.3 g/L [3.7‐4.7] vs VTE+, 3.4 g/L [3.2‐4.2]; P = .05). ConclusionsSix months after COVID‐19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased D‐dimer and fibrinogen concentrations persist up to 6 months in some patients, warranting further exploration of the role of hemostasis in long‐term morbidity after hospital discharge.

Plasma, platelet and red blood cell transfusion ratios for life-threatening non-traumatic haemorrhage in medical and post-surgical patients: An observational study.

Despite the broad utilization of component-based transfusion strategies that aim to reconstitute whole blood during acute traumatic haemorrhage, data for haemorrhage occurring outside of trauma and surgery are limited. This is an observational cohort study of adults experiencing critical non-traumatic, non-intraoperative haemorrhage during hospitalization at an academic medical centre from 2011 to 2015. The primary goal was to evaluate differences in plasma and platelet to red blood cell (RBC) transfusion ratios across patient demographic, clinical and laboratory characteristics. Secondarily, associations between transfusion ratios and clinical outcomes were assessed. Seven hundred nine patients were included: 498 (70.2%) medical and 211 (29.8%) post surgical. The gastrointestinal tract (36.7%) was the most common site of bleeding. Most patients received RBCs without plasma (35.5%) or platelets (54.2%). Among those receiving plasma, 82.3% received a plasma to RBC ratio < 1:1 at 24 h. For platelets, the most common ratio was 1-2:1 (52.9%). Transfusion ratios were generally consistent across comorbid disease severity, admission type and anatomic sites of bleeding. Higher plasma utilization was observed in the emergency department, while greater platelet utilization occurred in intensive care units. Higher transfusion ratios were observed in those with greater laboratory haemostatic abnormalities prior to the haemorrhagic event. Clinical outcome differences were limited, though greater platelet utilization in the first 24 h was associated with higher mortality and fewer hospital-free days. Transfusion ratios for critical non-traumatic haemorrhage were primarily related to laboratory abnormalities preceding the haemorrhagic event and practice environments. Clinical outcome differences across ratios were limited.

Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study

Despite therapeutic advances, early death (ED) remains a major factor curtailing survival of acute promyelocytic leukemia (APL). Studies examining factors that cause early death (ED; within 30 days of admission) and the correlation of survival with the timing of administration of all-trans retinoic acid (ATRA) and hemostatic parameters are scarce. We performed a cohort analysis of nonselect patients with newly diagnosed APL who presented to the health care system in Hong Kong, where oral arsenic trioxide was used. From 1 January 2007 to 30 April 2020, 358 patients (median age, 47 [1-97] years) with newly diagnosed APL were identified. ED occurred in 56 patients (16%): 11 (3%) died in the first 2 days after admission (intracranial hemorrhage [ICH], n = 6; APL-differentiation syndrome [APL-DS], n = 4; infection, n = 1); 22 (6%) died within 3 to 7 days (ICH, n = 12; APL-DS, n = 8; infections, n = 2), and 23 (6%) died within 8 to 30 days (ICH, n = 7; APL-DS, n = 11; infection, n = 5). Factors significantly associated with ED by multivariate analysis included male sex (P = .01); presenting leukocyte count ≥10 × 109/L (P = .03); fibrinogen <1.5 g/L (P = .02); and ATRA administration >24 hours after hospital admission (P < .001). After a median follow-up of 47 (0-166) months, the 5- and 10-year overall survival (OS) was 68.6% and 61.2%, respectively. Excluding EDs, the 5- and 10-year post–30-day OS improved to 81.3% and 72.5%. Early administration of ATRA (<24 hours) and vigorous correction of hemostatic abnormalities, including hypofibrinogenemia, are key to reducing ED.

Usefulness of Thromboelastography for Perioperative Evaluation of Hemostatic Profile in Patients with Primary Brain Tumors Undergoing Surgery.

Context:Hemostatic abnormalities are more common in patients with brain tumors than systemic malignant diseases. Conventional coagulation tests (CCT) are poor assays for dynamic assessment of clot strength in whole blood. Thromboelastography (TEG) gives us detailed information on the dynamics of clot development, stabilization, and dissolution reflecting in vivo hemostasis. TEG can assess both thrombosis and fibrinolysis.Aims:This study aimed to investigate the temporal trends in hemostatic profile occurring during surgery for primary brain tumors, using a combination of TEG and CCT, and to assess perioperative blood component support.Subjects and Methods:A prospective, observational study was done on 40 patients with primary brain tumors larger than 4 cm in maximum diameter on computed tomography or magnetic resonance imaging. The tests (TEG and CCT [PT, INR, activated partial thromboplastin time, and platelet count]) were performed preoperatively (on the day of surgery), intraoperatively (2 h into surgery), and postoperatively (the day after surgery).Statistical Analysis:SPSS Version 21.0 statistical analysis software was used.Results:We found a universal trend toward hypercoagulability (persistent decrease in R-time, K-time and increase in MA, α-angle, Coagulation Index) in all the TEG parameters measured intraoperatively and postoperatively even though the values were within normal limits. Results of CCT had poor correlation with TEG parameters. The mean intraoperative blood loss was 737.7 ± 185.6 mL, for which PRBC was transfused in 17 patients, FFP in 13, but no platelet transfusion was done intraoperatively.Conclusions:We found a trend toward hypercoagulability in our study in intraoperative and postoperative period using TEG which was not evident on CCT. TEG was a useful diagnostic tool to identify coagulation abnormalities and to guide perioperative blood transfusion.

Endothelium Activation Markers in Severe Hospitalized COVID-19 Patients: Role in Mortality Risk Prediction.

Introduction Endothelial damage and hypercoagulability are major players behind the hemostatic derangement of SARS-CoV-2 infection. Aim In this prospective study we assessed endothelial and inflammatory biomarkers in a cohort of COVID-19 patients, aiming to identify predictive factors of in-hospital mortality. Methods COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were enrolled. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, C reactive protein (CRP) and procalcitonin were assessed. Results Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of D-dimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/FiO2 were significantly associated with death. Using these variables, a linear score with 3-risk groups was generated that provided a cumulative incidence of death of 0% in the low-, 32% in the intermediate-, and 78% in the high-risk group. Conclusions COVID-19-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the inflammatory status, underlying the link between coagulation, endothelial activation, and inflammation. Our study provides evidence for a role of vWF, together with neutrophils and PaO2/FiO2, as a significant predictor of in-hospital mortality by SARSCoV-2 infection.

Perioperative management of post-COVID-19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

Perioperative management of post-COVID-19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement.

High-sensitivity cardiac troponin I and D-dimer are risk factors for in-hospital mortality of adult patients with COVID-19: A retrospective cohort study

Aim: This study aimed to evaluate the impact of high-sensitivity cardiac troponin I (Hs-cTnI) and D-dimer on in-hospital mortality of adult patients with Coronavirus disease 2019 (COVID-19). Materials and Methods: The COVID-19 outbreak, a global health disaster, has resulted in significant morbidity and mortality around the world since it emerged in December 2019. The outbreak has gradually spread nationwide. COVID-19 is associated with hemostatic abnormalities and cardiac injury. This retrospective cohort study included a total of 221 adult inpatients. The diagnosis of COVID-19 was made according to the World Health Organization's interim guideline and confirmed by RNA detection of SARS-CoV-2. Participants were divided into 2 groups, survivors and non-survivors. Results: Hs-cTnI and D-dimer levels on admission were significantly higher in non-survivors COVID-19 patients (p&amp;lt;0.05 for each). Forward stepwise logistic regression analysis demonstrated that age (OR=1.140, 95% CI: 1.045-1.244, p=0.003), baseline hs-cTnI level (OR=1.022, 95% CI: 1.004-1.041, p=0.018), and baseline D-dimer level (OR=1.790, 95% CI: 1.078-2.972, p=0.024) were independent predictors of in-hospital mortality of adult patients with COVID-19. The receiver operating characteristic curve analysis provided a cut-off value of &amp;gt;18.6 ng/L for hs-cTnI to predict in-hospital mortality of adult patients with COVID-19 with 100% sensitivity and 74% specificity, and a cut-off value of &amp;gt; 1.41 mg/L for D-dimer with 93.3% sensitivity and 71.5% specificity. Conclusion: High-sensitivity cardiac troponin I and D-dimer levels on admission predict in-hospital mortality of adult patients with COVID-19.

Compromised Lung Volume and Hemostatic Abnormalities in COVID-19 Pneumonia: Results from an Observational Study on 510 Consecutive Patients.

Background: Hemostatic abnormalities have been described in COVID-19, and pulmonary microthrombosis was consistently found at autopsy with concomitant severe lung damage. Methods: This is a retrospective observational cross-sectional study including consecutive patients with COVID-19 pneumonia who underwent unenhanced chest CT upon admittance at the emergency room (ER) in one large academic hospital. QCT was used for the calculation of compromised lung volume (%CL). Clinical data were retrieved from patients’ files. Laboratory data were obtained upon presentation at the ER. Aim: The aim of this study was to evaluate the correlation between hemostatic abnormalities and lung involvement in patients affected by COVID-19 pneumonia as described using computer-aided quantitative evaluation of chest CT (quantitative CT (QCT)). Results: A total of 510 consecutive patients (68% males), aged 67 years in median, diagnosed with COVID-19 pneumonia, who underwent unenhanced CT scan upon admission to the ER, were included. In all, 115 patients had %CL > 23%; compared to those with %CL < 23%, they showed higher levels of D-dimer, fibrinogen, and CRP, greater platelet count, and longer PT ratio. Via multivariate regression analysis, BMI ≥ 30 kg/m2, D-dimer levels > 500 ng/mL, CRP > 5.0 ng/mL and PT ratio > 1.2 were found to be independent predictors of a %CL > 23% (adjusted odds ratios (95% confidence intervals): 2.1 (1.1–4.0), 3.1 (1.6–5.8), 2.4 (1.3–4.5), and 3.4 (1.4–8.5), respectively). Conclusions: Hemostatic abnormalities in patients affected by COVID-19 correlate with the severity of lung injury as measured by %CL. Our results underline the pathogenetic role of hemostasis in COVID-19 pneumonia beyond the presence of clinically evident thromboembolic complications.

Acquired Factor X Deficiency in Systemic Light Chain Amyloidosis: Factor X Recovery after Bleeding Complications, Splenectomy, Chemotherapy and Remission

Aim: Acquired factor X deficiency is one of the more frequent coagulation abnormalities (8.7 to 14 %) in systemic light chain amyloidosis with about half of the patients presenting bleeding symptoms. The therapeutic options are replacement of factor X with plasma products, removal of the factor X -binding amyloid deposits (splenectomy) or chemotherapy. We report on an adult male patient with acquired factor X deficiency who presented severe bleeding complications. The course of factor X activity after splenectomy, chemotherapy and administration of prothrombin complex concentrate (PCC) is reported.Methods: We report a case of a 75-years-old male patient who was diagnosed with severe haemostatic abnormalities. Coagulation screening revealed an INR of 6.6 and the factor X activity was reduced to 2 %. Traumatic splenic rupture with intraabdominal bleeding necessitated splenectomy followed by daily administration of 3,000 IU PCC. Histopathologic examination of the removed spleen established amyloidosis. Two days after splenectomy, the patient presented lower gastrointestinal bleeding in the context of a gastrointestinal infection and a right hemicolectomy was performed. After two cycles of chemotherapy neither organ manifestations of amyloidosis nor pathological free light chain assay results were present. No further bleeding episodes occurred. However, the follow up examination showed an increase of factor X activity (111.1 %) to normal levels (77-128%) after two years.Results: A recovery study with PCC was performed. After a single dose of 40 IU/kg, factor X activity level increased from 3.8 % to 12 % and the INR decreased from 2.9 to 1.7. Within 2 hours the factor X activity level dropped to 5.8 % and the INR was 2.1. In addition, the factor X antigen-levels rise from 6.9 % to 12.5 % within one hour after PCC administration and only decrease to 11.4 % after two hours.Conclusion: Even after splenectomy, chemotherapy and following remission of systemic light chain amyloidosis, the results demonstrate a rapid decrease of factor X after PCC administration. We suspect elimination and adsorption of factor X to areas of amyloid deposition other than the spleen going undetected by imaging techniques. The estimate bleeding risk and efficacy of treatment is still difficult to say. However factor X recovered after 1 year of time of remission. DisclosuresNo relevant conflicts of interest to declare.