Hypercoagulable Profile Research Articles

P085 Hypercoagulability in patients undergoing abdominopelvic surgery for inflammatory bowel disease: insights from thromboelastography

BACKGROUND: Hypercoagulability in patients with inflammatory bowel disease (IBD) is a hematological extra-intestinal manifestation thought to be driven by the gut inflammatory response. However, mechanisms driving the coagulation abnormalities are poorly understood. The aim of this study is to characterize coagulation profiles in IBD surgical patients using thromboelastography (TEG). METHODS: A single center, single surgeon retrospective study was performed after IRB approval. Consecutive patients with Crohn's disease (CD) or ulcerative colitis (UC) who underwent bowel surgery from June to September 2018 were included. All patients (100%) received perioperative VTE chemoprophylaxis. Clinical data was collected by retrospective chart review. Hypercoagulability profile based on TEG results was defined by any combination of: (1) low R-value, (2) high degree angle, (3) high maximum amplitude (MA), (4) elevated coagulation index. Short-term (30-day) surgical outcomes including length of stay (LOS), readmission, reoperations, and major (Clavien-Dindo grade 3/4) complications were reported. Figures represent frequency (proportion) or median (range). RESULTS: A total of 19 IBD patients had a TEG prior to surgery. The age was 33 (23–70), more were women (63%, n = 12) and most patients had CD (78%, n = 15). Overall 11 (58%) of patients were receiving steroids and 10 (53%) had were receiving biologics, while 6 (32%) of patients were hospitalized pre-operatively. Surgery was laparoscopic in 11 (58%) with 1 conversion to laparotomy. All patients (100%) received VTE chemoprophylaxis peri-operatively. Overall, 14 (74%) patients had a hypercoagulable TEG profile with 7 of these patients (50%, or 37% overall) having more than one hypercoagulable TEG parameter. A high MA (platelet hyperfunction) in 7 (37%) patients, and 8 (42%) patients had high degree angle (increased fibrinogen concentration/function), and 8 (42%) patient had low R-value (hyperfunctioning coagulation cascade). The coagulation index, indicating hypercoagulability, was abnormally high in 2 (10%) patients. The overall median LOS was 7 days (1, 42). Clavien-Dindo grade 3 complications occurred in 3 (16%) patients; there were no unplanned reoperations, while 3 (16%) of patients were re-admitted. A total of 16 of 18 eligible patients (88%) received extended post-discharge VTE chemoprophylaxis; one patient (5.5%) with unexplained tachycardia was diagnosed with a groin VTE 14 days post-operatively prior to discharge and required anticoagulation (TEG parameters: low R-value, high degree angle, and high coagulation index. Another patient had superficial thrombophlebitis related to a midline but did not require anticoagulation; this patient had a low R-value. Thus any VTE occurred in 2 (14%) of those with hypercoagulable TEG profiles and in zero of those with normal TEG profiles. CONCLUSION(S): We observed that the majority of surgical IBD patients have a hypercoagulable TEG profile, and patients with evidence of hypercoagulability on thromboelastography may be at increased risk of post-operative VTE. Our data suggests, given the mutlifactorial nature of hypercoaguability in these patients, novel VTE chemoprophylaxis approaches are needed.

PB2192 GLOBAL COAGULATION CAPACITY OF ESSENTIAL THROMBOCYTHEMIA PATIENTS BY ROTEM ANALYSIS ADJUSTED FOR PLATELET COUNT CORRELATES WITH THROMBOTIC RISK CLASS

Background:Essential Thrombocythemia (ET) is characterized by hypercoagulability and increased risk of arterial and venous thrombosis. The thromboelastometry profile by ROTEM, a point of care system for assessment of global coagulation in whole blood, has never been investigated in these patients, who have abnormalities in blood cell counts. This approach is attractive in that the test reflects the activity of both soluble and cellular components of hemostasis. Furthermore, the test is rapid, does not require blood sample centrifugation and may be useful in prospective studies of thrombotic risk assessment in ET patients.Aims:To evaluate the global clotting process in ET patients by thromboelastometry with ROTEM and establish whether and to what extent elevated platelet count and mutational status affect the global hemostasis evaluation.MethodsAnalysis was performed in 52 ET patients using INTEM and EXTEM reagents, to evaluate the intrinsic and extrinsic pathway, respectively. Maximum clot firmness (MCF, [mm]), which reflects the maximum tensile strength of the thrombus, clotting formation time (CFT [sec]), namely the time that clot takes to increase from 2 mm to 20 mm above baseline, and clotting time (CT [sec]), the time to clot initiation, were recorded. Patient thrombotic risk was classified as, i.e.: very low risk (age≤60 yrs, no thrombosis history, JAK2/MPL−), low risk (age≤60 yrs, no thrombosis history, JAK2/MPL+), intermediate risk (age > 60 yrs, no thrombosis history, JAK2/MPL−), and high risk (thrombosis history or age >60 yrs with JAK2/MPL+).Results:ROTEM analysis with both EXTEM and INTEM reagents showed that ET patients had a hypercoagulable profile, characterized by significant (p < 0.01) short CFT and high MCF values compared to healthy subjects. None of the ROTEM parameters per se correlated with classes of thrombotic risk. However, a strong correlation (p < 0.01) was present between platelet count and CFT or MCF (both with EXTEM and INTEM reagents). Therefore, the parameters were adjusted for platelet count. After adjustment, corrected CFT (cCFT) significantly correlated with the patient thrombotic risk category (p < 0.05). Furthermore, corrected MCF (cMCF) was significantly increased in JAK2V617F+/MPL+ compared to CalR+ subjects (p < 0.01).Summary/Conclusion:This study confirms the occurrence of a hypercoagulable state in ET patients and shows that ROTEM parameters are significantly influenced by platelet count. Correction of CFT and MCF values allows a better understanding of global coagulation of ET patients and may potentially better reflect the thrombotic risk in these patients.

Analytical and clinical performance evaluation and comparison of automated urinalysis analyzers

This study has investigated whether high levels of Reticulocytes-C4d (R-C4d) and Platelets-C4d (P-C4d) reflecting recent activity in SLE patients are correlated with changes in natural anticoagulation components, coagulation activation and endothelial injury markers.This study included three groups: 1) healthy women (control, n = 30); 2) women with low activity of the disease (SLEDAI 2 K ≤ 4, n = 30); 3) women with active disease (moderate or high activity) (SLEDAI 2 K > 4, n = 30). Median fluorescence intensity (MFI) of R-C4d and P-C4d were determined by flow cytometry using double labeling with specific monoclonal antibodies. Endothelial injury and hypercoagulability were evaluated by measuring Thrombomodulin and D-dimer levels.Higher MFI index of R-C4d were related to the recent activity of SLE, and higher expression of P-C4d indicated an elevated risk of thrombotic complications. Increased levels of soluble thrombomodulin and D-dimer were observed in patients with active SLE.R-C4d is helpful to monitor early disease activity and PC4-d may be an important tool to detect a prothrombotic phenotype in SLE. Elevated levels of D-dimer and thrombomodulin add value to P-C4d data and corroborate a hypercoagulable profile in women with SLE, contributing to an increased prothrombotic risk associated with inflammation.

Prospective assessment of fibrinolysis in morbid obesity: tissue plasminogen activator resistance improves after bariatric surgery

BackgroundMorbid obesity is associated with an increased risk of thrombotic events, which has been attributed to increased thrombotic activity. Multiple mechanisms have been proposed to explain this increased risk, including an inflammatory state with upregulation of procoagulant and antifibrinolytic proteins. We therefore hypothesize that patients with morbid obesity are hypercoagulable and will revert to normal after bariatric surgery. ObjectivesTo evaluate changes in the hypercoagulable state after bariatric surgery. SettingUniversity Hospital, Bariatric Center of Excellence, United States. MethodsThromboelastography (TEG) data were collected on 72 subjects with morbid obesity, with 36 who had 6 months of follow-up after bariatric surgery. TEG data of 75 healthy subjects (HS) without obesity, recent trauma or surgery, acute infection, or chronic conditions (e.g., liver, cardiovascular, or kidney disease; cancer; diabetes; autoimmune or inflammatory disorders; and disorders of coagulation) were used for comparison. TEG was performed alone and with the addition of 75 and 150 ng/mL tissue plasminogen activator (tPA) to quantify fibrinolysis resistance (tPA-challenged TEG). ResultsThe bariatric surgery cohort had a median age of 40.5 years, a median body mass index of 44.6 kg/m2, and 90% female patients. Median body mass index reduced significantly 6 months post surgery but remained elevated compared with the HS group (31.4 versus 25.4 kg/m2, P < .0001). At 6 months post surgery, subjects had longer reaction time (mean difference, 1.3; P = .02), lower maximum amplitude (–2.4, P = .01), and increased fibrinolysis with low-dose (3.1, P < .0001) and high-dose tPA-challenged TEG (9, P < .0001). Compared with HS, the postsurgery TEG values were still more likely to be abnormal (all P < .05). ConclusionsPatients with morbid obesity form stronger clots more rapidly and are more resistant to fibrinolysis than subjects without obesity. Bariatric surgery significantly improved the hypercoagulable profile and fibrinolysis resistance of morbid obesity.

Trauma Resuscitation Consideration: Sex Matters

Sex dimorphisms in coagulation have been recognized, but whole blood assessment of these dimorphisms and their relationship to outcomes in trauma have not been investigated. This study characterizes the viscoelastic hemostatic profile of severely injured patients by sex, and examines how sex-specific coagulation differences affect clinical outcomes, specifically, massive transfusion (MT) and death. We hypothesized that severely injured females are more hypercoagulable and therefore, have lower rates of MT and mortality. Hemostatic profiles and clinical outcomes from all trauma activation patients from 2 level I trauma centers were examined, with sex as an experimental variable. As part of a prospective study, whole blood was collected and thrombelastography (TEG) was performed. Coagulation profiles were compared between sexes, and association with MT and mortality were examined. Poisson regression with robust standard errors was performed. Overall, 464 patients (23% female) were included. By TEG, females had a more hypercoagulable profile, with a higher angle (clot propagation) and maximum amplitude (MA, clot strength). Females were less likely to present with hyperfibrinolysis or prolonged activating clotting time than males. In the setting of depressed clot strength (abnormal MA), female sex conferred a survival benefit, and hyperfibrinolysis was associated with higher case-fatality rate in males. Severely injured females have a more hypercoagulable profile than males. This hypercoagulable status conferred a protective effect against mortality in the setting of diminished clot strength. The mechanism behind these dimorphisms needs to be elucidated and may have treatment implications for sex-specific trauma resuscitation.

Dynamic Thromboembolic Risk Modelling to Target Appropriate Preventative Strategies for Patients with Non-Small Cell Lung Cancer.

Prevention of cancer-associated thromboembolism (TE) remains a significant clinical challenge and priority world-wide safety initiative. In this prospective non-small cell lung cancer (NSCLC) cohort, longitudinal TE risk profiling (clinical and biomarker) was undertaken to develop risk stratification models for targeted TE prevention. These were compared with published models from Khorana, CATS, PROTECHT, CONKO, and CATS/MICA. The NSCLC cohort of 129 patients, median follow-up 22.0 months (range 5.6—31.3), demonstrated a hypercoagulable profile in >75% patients and TE incidence of 19%. High TE risk patients were those receiving chemotherapy with baseline fibrinogen ≥ 4 g/L and d-dimer ≥ 0.5 mg/L; or baseline d-dimer ≥ 1.5 mg/L; or month 1 d-dimer ≥ 1.5 mg/L. The model predicted TE with 100% sensitivity and 34% specificity (c-index 0.67), with TE incidence 27% vs. 0% for high vs. low-risk. A comparison using the Khorana, PROTECHT, and CONKO methods were not discriminatory; TE incidence 17–25% vs. 14–19% for high vs. low-risk (c-index 0.51–0.59). Continuous d-dimer (CATS/MICA model) was also not predictive of TE. Independent of tumour stage, high TE risk was associated with cancer progression (HR 1.9, p = 0.01) and mortality (HR 2.2, p = 0.02). The model was tested for scalability in a prospective gastrointestinal cancer cohort with equipotency demonstrated; 80% sensitivity and 39% specificity. This proposed TE risk prediction model is simple, practical, potent and can be used in the clinic for real-time, decision-making for targeted thromboprophylaxis. Validation in a multicentre randomised interventional study is underway (ACTRN12618000811202).

Haemostatic Profiles are Similar across All Aetiologies of Cirrhosis

Patients with cirrhosis may acquire profound changes in haemostasis. Although haemostatic changes in cirrhosis have been extensively studied, most studies were performed in groups of patients with mixed aetiology. As thrombotic events appear more common in some aetiologies of disease, notably non-alcoholic steatohepatitis (NASH) and cholestatic disease, we hypothesized that haemostatic changes might be different across aetiologies. We studied 109 patients with cirrhosis (31 cholestatic liver disease, 23 NASH, 37 alcoholic liver disease [ALD], 18 viral hepatitis) and 44 healthy controls. Patients with malignancy were excluded. Routine diagnostic tests of haemostasis, thrombin generation assays, fibrin permeability assays and a plasma-based fibrinolytic assay were performed. All patients had comparable severity of disease according to their Model for End-Stage Liver Disease score (9 [7-11]). Plasma levels of von Willebrand factor were substantially elevated across all aetiologies, with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 levels comparable to controls. Thrombin generation capacity was elevated in all aetiologies, most profoundly in ALD. Fibrin permeability was decreased in all aetiologies, which was accompanied by elevated fibrinogen levels. Clot lysis times were prolonged in NASH and cholestatic disease. Plasma levels of individual proteins were similarly altered in all aetiologies. Our in-depth haemostatic profiling of primary, secondary and tertiary haemostasis in a group of patients with Childs-Turcotte-Pugh A/B cirrhosis showed no large differences between aetiologies, and was consistent with a general hypercoagulable profile in patients with mild cirrhosis. These results suggest that patients with cirrhosis have an increased risk of thrombosis, irrespective of their aetiology.

Impact of Nonmalignant Portal Vein Thrombosis in Transplant Recipients With Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease is an increasingly prevalent condition, and its more severe progressive state, nonalcoholic steatohepatitis (NASH), is currently the second most common indication for wait-listed adults in the United States. The association of portal vein thrombosis (PVT) prior to or at transplant and poor graft and patient outcomes is not well established, particularly among NASH patients who inherently have an increased hypercoagulable profile. Using the United Network for Organ Sharing data set, we analyzed graft and patient outcomes of patients transplanted for the indication of NASH with and without PVT. Of 3689 NASH transplant recipients, the prevalence of PVT was 12% (450 with PVT and 3239 without PVT). NASH transplant recipients with PVT had inferior graft and patient survival compared with NASH transplant recipients without PVT, even after adjusting for recipient and donor demographic characteristics, body mass index, synthetic dysfunction, and presence of diabetes. In a multivariate Cox regression model, NASH transplant recipients with PVT had a 37% increased risk of graft failure (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.15-1.63; P < 0.001) and 31% increased risk of overall death (HR, 1.31; 95% CI, 1.09-1.58; P < 0.001) compared with NASH transplant recipients without PVT at transplant. This difference in graft and patient survival was most pronounced in the early posttransplant period. These results demonstrate that NASH patients with PVT have decreased graft and patient survival independent of recipient and donor factors.

Correlation between active disease and hypercoagulability state in patients with systemic lupus erythematosus

ObjectiveThis study has investigated whether high levels of Reticulocytes-C4d (R-C4d) and Platelets-C4d (P-C4d) reflecting recent activity in SLE patients are correlated with changes in natural anticoagulation components, coagulation activation and endothelial injury markers. MethodsThis study included three groups: 1) healthy women (control, n = 30); 2) women with low activity of the disease (SLEDAI 2 K ≤ 4, n = 30); 3) women with active disease (moderate or high activity) (SLEDAI 2 K > 4, n = 30). Median fluorescence intensity (MFI) of R-C4d and P-C4d were determined by flow cytometry using double labeling with specific monoclonal antibodies. Endothelial injury and hypercoagulability were evaluated by measuring Thrombomodulin and D-dimer levels. ResultsHigher MFI index of R-C4d were related to the recent activity of SLE, and higher expression of P-C4d indicated an elevated risk of thrombotic complications. Increased levels of soluble thrombomodulin and D-dimer were observed in patients with active SLE. ConclusionR-C4d is helpful to monitor early disease activity and PC4-d may be an important tool to detect a prothrombotic phenotype in SLE. Elevated levels of D-dimer and thrombomodulin add value to P-C4d data and corroborate a hypercoagulable profile in women with SLE, contributing to an increased prothrombotic risk associated with inflammation.

Significance and Prognostic Value of The Coagulation Profile in Patients with Glioblastoma: Implications for Personalized Therapy

Coagulation is an important aspect of the vascular microenvironment in which brain tumors evolve. Patients with tumor often show aberrant coagulation and fibrinolysis activation. In particular, glioblastoma (GBM), the most aggressive primary brain tumor, is associated with a state of hypercoagulability, and venous thromboembolism is a common complication of this cancer and its treatment. Our study aims to investigate the clinical and prognostic significance of routine laboratory tests to assess the coagulative state of patients with brain tumors, to identify potential new prognostic factors and targets for personalized therapy. Blood samples were collected from patients with GBM (n= 58) and patients with meningioma (MNG, n= 22), before any treatment. The parameters analyzed were prothrombin time (PT), activated partial thromboplastin time (aPTT), D dimer (DD), fibrinogen, von Willebrand factor (VWF), leukocyte count, and hemoglobin levels. Plasma levels of PT and aPTT were significantly reduced in GBMs compared with MNGs (P < 0.05), whereas DD, VWF:Ag levels, and leukocyte count were significantly higher in GBMs than in MNGs (P < 0.01). Furthermore, we observed that patients with GBM with reduced PT and aPTT and high levels of DD and VWF, defined as hypercoagulable patients, showed reduced overall survival (P < 0.05) compared with nonhypercoagulable patients. Our data support the assumption that patients with GBM show a plasma hypercoagulable profile and that coagulation profile is related to adverse outcome in patients with GBM. If confirmed, hypercoagulability could play an important role as a prognostic factor of the disease and in the decision of an antithrombotic prophylaxis.

Preoperative Thromboelastographic Profile of Patients with Congenital Heart Disease: Association of Hypercoagulability and Decreased Heparin Response

To describe the demographic and thromboelastographic characteristics of patients with congenital heart disease presenting with decreased heparin response before cardiac surgery. Retrospective, observational study. Single institution, tertiary, academic, university hospital. The study comprised 496 pediatric and adult patients undergoing cardiac surgery for congenital heart disease. Retrospective review of medical records. Data on preoperative thromboelastography (TEG), demographics, and response to heparin were collected retrospectively. Logistic regression analysis was used to study the association between TEG and response to heparin. Decreased heparin response (defined as activated clotting time <480 s initial bolus of 300 U/kg heparin) was observed in 23.6% of patients presenting for surgery. Age distribution and preoperative coagulation profiles were similar for both nonresponders and responders to heparin. Preoperatively, nonresponders demonstrated all thromboelastrographic characteristics consistent with a hypercoagulable profile (shorter reaction time, K value, wider angle, and maximum amplitude). Univariate logistic regression identified all TEG variables significantly associated with decreased heparin response. After adjustment for age, procedure type, and the presence of cyanosis, a multivariate logistic regression model identified the TEG variable K (≤1.3 min) as being significantly associated with decreased heparin response (odds ratio 3.7; confidence interval 2.3-5.8; p < 0.0001). Decreased response to heparin before cardiac surgery in patients with congenital heart disease is associated with preoperative hypercoagulability identified using a viscoelastic test. Additional studies are needed to better understand the etiology of decreased heparin response and potential clinical strategies to improve anticoagulation management.

Posterior reversible encephalopathy syndrome following blood transfusion in a patient with factor X deficiency: Is it an unusual systemic manifestation of an adverse transfusion reaction?

Adverse neurological transfusion reactions including posterior reversible encephalopathy syndrome (PRES) following blood transfusion are rare. Our case an 18-year-female with known Factor X deficiency with menorrhagia developed severe hypertension, followed by generalised tonic clonic convulsions apparently after blood component transfusion. She had earlier received 4 units of red blood cells (RBC) for anaemia and 10 units of fresh frozen plasma (FFP) for menorrhagia (with prolonged PT and APTT) within short span of time at another hospital. There was no history of hypertension, convulsions, any cardiovascular, renal or neurological disease before transfusion. The clinical features and magnetic resonance imaging findings led to the diagnosis of PRES. Abnormal electroencephalogram and a hypercoagulable haemostatic profile on thromboelastography along with derangement in blood glucose and liver function tests were also observed. Patient responded well to the anticonvulsants and antihypertensive agents prescribed and was discharged in a stable condition. Our patient had a systemic transfusion reaction involving predominantly neurological system, however, cardiovascular, hepatic, haemostatic and endocrine systems were also affected. This case is unusual being the first report of PRES occurring in a patient with factor X deficiency presenting with an array of clinical and laboratory features which have not been reported in earlier studies involving PRES. Presumably the initial aggressive red cell transfusion to treat anaemia initiated the crisis and further large volumes of transfused FFP contributed to this adverse transfusion reaction in our case. Clinicians and Transfusion Medicine specialists should be aware about this uncommon clinical entity.

Coagulation profile following liver resection: Does liver cirrhosis affect thromboelastography?

BackgroundThromboelastography has called into question the coagulopathy seen following partial hepatectomy. However the coagulation profile in cirrhotic livers has not been studied. Our objective was to determine the coagulation profile following partial hepatectomy in normal and cirrhotic livers. MethodsPatients undergoing liver resection were prospectively enrolled in the study. The prothrombin time and international normalized ratio, as well as the thromboelastogram, were obtained preoperatively, post-operatively, and on post-operative days 1, 3, and 5. Results22 noncirrhotic and 11 cirrhotic patients undergoing liver resection were enrolled. Postoperatively the thromboelastogram demonstrated a hypercoagulable profile in 64%, 33%, 39% and 36% of patients on post-operative days 0, 1, 3 and 5 respectively. There was no difference between patients with cirrhosis and those without underlying liver disease. ConclusionPatients appear to have a similar coagulation profile after liver resection regardless of underlying cirrhosis with many having a hypercoagulable profile.

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability.

Reference values for kaolin-activated thromboelastography in volunteers of Anhui Province in China.

The assessment of the coagulation status using thromboelastography (TEG) in Chinese population has less been reported. This study aimed to establish reliable reference values for kaolin-activated TEG in Chinese volunteers. A total of 1681 Chinese adult individuals were recruited for this study. The reference individuals were stratified by gender and age, and the TEG values were measured on the basis of strict quality control. The 95% reference values were determined using nonparametric statistical methods. The sex-related 95% reference values were reaction time (R):4.2-8.7minutes; clotting time (K): 1.2-3.2minutes; alpha angle (α): 47.0-72.3 degree; maximum amplitude (MA): 49.1-70.5mm for males, and R: 3.7-9.0minutes; K: 1.0-3.2minutes; α: 48.4-74.4 degree; MA: 46.8-72.4mm for females. Also, the TEG parameters indicated a relatively more hypercoagulable profile in both female and elder groups. This study established the reference values for kaolin-activated TEG in the target Chinese population, which might provide a reference for both clinical and laboratory studies.

Pro-coagulant activity during exercise testing in patients with coronary artery disease

BackgroundStrenuous exercise may trigger myocardial infarction through increased pro-coagulant activity. We aimed to investigate whether patients referred for exercise testing, who were found to have angiographically verified coronary artery disease (CAD), have a more hypercoagulable profile during exercise testing than those without CAD.MethodsPatients with symptoms of stable CAD were examined with exercise electrocardiography on bicycle ergometer. Venous blood samples were taken at rest and within 5 min after end of exercise. The following haemostatic variables were analyzed: tissue factor pathway inhibitor (TFPI) activity and antigen, prothrombin fragment 1 + 2 (F1 + 2), D-dimer and endogenous thrombin potential (ETP). All participants underwent conventional coronary angiography. CAD was defined as having any degree of atherosclerosis.ResultsOut of the 106 patients enrolled, 70 were found to have CAD. Mean exercise duration was 10:06 ± 4:11 min, with no significant differences between the groups. A significant increase from baseline to after exercise testing was observed in all measured markers in the total population (p ≤ 0.002 for all). In patients with angiographically verified CAD, total TFPI was significantly lower at baseline compared to patients without CAD (median value 67.4 and 76.6 ng/ml respectively, p = 0.027). However, no significant differences in changes of any of the measured markers during exercise were observed between the two groups.ConclusionPro-coagulant activity increased during short-term strenuous exercise testing in patients with symptoms suggestive of CAD. However the hypercoagulable state observed, was not more pronounced in patients with angiographically verified CAD compared to patients without CAD. NCT01495091.

Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma

BackgroundCirrhotic patients with hepatocellular carcinoma (HCC) exhibit hypercoagulability. AimWe investigated whether thromboelastometry can detect hypercoagulability in these patients and the association with portal vein thrombosis (PVT). MethodsAt baseline, cirrhotic patients with and without HCC underwent thromboelastometry. PVT onset was recorded over a 12-month follow-up period. ResultsSeventy-six patients (41 with and 35 without HCC) were included. Vital tumor volume (VTV) was >5cm3 in 18 patients. Fibrinogen was higher in HCC patients with VTV>5cm3 as compared to those with VTV≤5cm3 and those without HCC. Mean platelet count was significantly increased in HCC patients compared with non-HCC. At baseline thromboelastometry, HCC patients showed shorter CTF and higher MCF than non-HCC. PVT incidence was 24,4% and 11.4% in patients with (10/41) and without (4/35) HCC, respectively. Among HCC, 50% of PVT occurred in Child A patients. In HCC, FIBTEM MCF>25mm was associated with a 5-fold increased PVT risk [RR: 4.8 (2–11.3); p=0.0001]. Cox multivariate analysis confirmed HCC and increased MCF (FIBTEM) to be independently associated with increased PVT risk. ConclusionsHypercoagulability in HCC which can be detected by thromboelastometry is associated with increased risk of PVT even in Child A patients. The clinical implication of these findings deserves further investigation.

Hemorrhagic, Hemostatic, and Thromboelastometric Disorders in 35 Dogs with a Clinical Diagnosis of Leptospirosis: A Prospective Study.

BackgroundLeptospirosis in dogs is occasionally associated with a hemorrhagic syndrome, the pathophysiology of which is not fully understood.Hypothesis/ObjectivesTo characterize hematologic, hemostatic, and thromboelastometric abnormalities in dogs with leptospirosis and to study their association with hemorrhagic diatheses and outcomes.AnimalsThirty‐five client‐owned dogs.MethodsA prospective observational single cohort study was conducted. Results from the CBC, coagulation tests (prothrombin, activated partial thromboplastin and thrombin times, fibrinogen, fibrin(ogen) degradation products, and D‐dimer concentrations), rotational thromboelastometry (TEM), signalment, hemorrhagic diatheses, occurrence of disseminated intravascular coagulation (DIC) at admission, and survival to discharge were recorded.ResultsThe most common hematologic and hemostatic abnormalities were anemia (30/35), thrombocytopenia (21/35), and hyperfibrinogenemia (15/35). Eight dogs were diagnosed with DIC. A normal TEM profile was found in 14 dogs, a hypercoagulable profile in 14 dogs, and a hypocoagulable profile in 7 dogs. The 8 dogs with hemorrhagic diatheses at admission had significantly decreased platelet counts (P = .037) and increased D‐dimer concentrations (P = .015) compared with other dogs. Dogs with a hypocoagulable profile exhibited more hemorrhagic diatheses compared with the dogs that had normal and hypercoagulable profiles (P = .049). The mortality rate was lower in dogs with a hypercoagulable profile than in those with a hypocoagulable profile (21% vs 57%; P = .043). Disseminated intravascular coagulation was not a significant prognostic factor.Conclusions and Clinical ImportanceThromboelastometric parameters were altered in dogs with both hypercoagulable and hypocoagulable profiles. A hypocoagulable profile was significantly correlated with hemorrhagic diathesis and higher mortality rate.

Haemostasis in Immune Trombocytopenia Patients Responders to Agonists of Thrombopoietin Receptor

Introduction: The goal of treatment of patients with immune thrombocytopaenia (ITP) is to raise platelet count to a level that will minimize or stop bleeding. One of the therapeutic strategies employed is to augment platelet production with agonists of the thrombopoietin receptor (TPOR-A). Clinical trials for TPOR-A comparing their effects with placebo showed a reduction in proportion of patients reporting bleeding (Tarantino et al, Blood Coag Fibrinolysis, 2013, 24:284-296). This effect might rely on the increase in platelet count, but other factors known to compensate bleeding risk in thrombocytopenic ITP patients might be regulated by TPOR-A.Objective: We aimed to compare haemostasis in ITP patients untreated with any pharmacologic agent (UT-ITPp) and treated with TPOR-A (TPOA-Rp) using the coagulation global assays thromboelastrometry (ROTEM®) and Calibrated Automated Thrombogram (CAT).Methods: Thirty chronic UT-ITPp [platelet count: (86±60)x109 platelets/L], twenty six responders to TPOR-A [16 with Romiplostim® and 10 with Revolade®, platelet count: (132±46)x109 platelets/L] and fifty healthy controls were included. Citrated blood was centrifuged at 152 g 10 min at 23°C for obtaining platelet rich plasma (PRP) and at 1,500 g for 15 min at 23°C for platelet-poor plasma (PPP). Aliquots were stored at -80ºC until analysis.Non-activated ROTEM was performed on PRP adjusted to a platelet count of 25 x 109/L. Clotting time (CT, time from start of measurement until initiation of clotting [in seconds], alpha angle, which reflects the rate of fibrin polymerisation (tangent to the curve at 2-mm amplitude [in degrees]), maximum clot firmness, which reflects the maximum tensile strength of the thrombus (MCF, [in mm]) and LI60, which describes the percentage of maximum clot strength present at 60 min (in %), were recorded.Plasma thrombin generation was measured in PPP using the CAT test at a final concentration of 1 pM tissue factor and 4 microM phospholipids. We evaluated the endogenous thrombin potential (ETP, the total amount of thrombin generated over time); the lag time (the time to the beginning of the explosive burst of thrombin generation); the peak height of the curve (the maximum thrombin concentration produced); and the time to the peak.Platelet activation was determined by flow cytometry through PAC1-FITC binding after stimulation with 100 micromol/L thrombin receptor-activating peptide 6 (TRAP). Fibrinolytic proteins were tested in PPP using commercialized kits.Comparisons of quantitative variables were made with SPSS.22 software. Values of p≤0.05 were considered statistically significant.Results: Platelets from all patients with ITP had a defect in their ability to be activated, as shown by the lower PAC1 binding (p<0.001).No differences were observed among groups for thrombin generation except for an increase in ETP in both groups of ITP patients [control: 1240±320 nMxmin, UT-ITPp: 1464±443 nMxmin (p<0.05), TPOA-Rp: 1533±390 nMxmin (p<0.05)].In ROTEM experiments, PRP from UT-ITPp and TPOA-Rp showed a prolonged CT [control: 550± 95 sec, UT-ITPp: 1090±75 sec (p<0.05), TPOA-Rp: 859±209 sec (p<0.05)]. Only UT-ITPp presented a diminished alpha angle [control: 60.3±7.5, UT-ITPp: 49.3±7.3 (p<0.05), TPOA-Rp: 55.8±5.58]. On the other hand, TPOA-Rp had an increased MCF (control: 46.5±2.1 mm, UT-ITPp: 50.2±5.6 mm, TPOA-Rp: 57.9±4.4 mm, p<0.05) and LI60 (control: 91.8±3.1 %, UT-ITPp: 94.1±3.1 %, TPOA-Rp: 97.6±1.1 %, p<0.05).To evaluate whether increased LI60 values were due to an imbalance in fibrinolysis related proteins, tPA, uPA, TAFI and PAI-1 plasma levels were measured. No differences were observed among the two groups of patients and healthy controls except for PAI-1 which level was increased in TPOA-Rp (control: 12.9±12.3 ng/ml, UT-ITPp: 17.3±12.5 ng/ml, TPOA-Rp: 46.8±20.8, ng/ml p<0.05).Conclusions: As we previously described, TPOR-A treatment increased platelet count but did not ameliorate their function (Álvarez Román et al, Thromb Haemost. 2014, 112:65-72). Nevertheless, ITP patients responders to TPOR-A showed a haemostasis unbalanced on a hypercoagulable profile due, at least in part, to a hipofibrinolytic pattern mainly caused by an increase in PAI-1 plasma level. This fact, together with the increment in platelet count caused by TPOR-A, might help to protect these patients from bleeding.This work was supported by a grant from the FIS-FEDER PI15/01457 DisclosuresNo relevant conflicts of interest to declare.

Routine Hemostasis and Hemogram Parameters: Valuable Assessments for Coagulation Disorder and Chemotherapy in Cancer Patients.

Background:The clotting system abnormalities are the common complication in cancer patients. The aim of this retrospective study was to evaluate the coagulation state, clinical features, and treatment in cancer patients by routine tests.Methods:A total of 2328 patients with different types of cancer were classified as the positive group (n = 1419, including 53 patients with thrombosis) and the negative group (n = 909) based on D-dimer (DD) value. Of the 2328 cases, 354 were admitted for chemotherapy. Hemostasis test and complete blood count (CBC) were performed during treatment or following-up.Results:This study showed that the hypercoagulable state was affected not only by clinical staging (P < 0.0001) but also by metastasis site (P < 0.0001 for bone vs. lung). Compared to negative DD group, the higher fibrinogen level, the extended activated partial thromboplastin time, and prothrombin time interacted markedly with disease clinical stage (P < 0.05) in the positive group. Between positive DD groups with and without thrombus, the significantly statistic difference in white blood cell (WBC) and DD (P < 0.05) rather than in red blood cell (RBC) and platelet count was observed. However, the higher DD level was not correlated with WBC, RBC, and platelet count in the positive DD group. Furthermore, the hypercoagulable plasma profile in cancer patients was moderated 2–3 weeks after chemotherapy (P < 0.05 for first six cycles).Conclusions:The routine hemostatic parameters and CBC are valuable to assessment for thrombosis and chemotherapy even for disease prognosis.