Characterizing coagulation responses in humans and nonhuman primates following kidney xenotransplantation-A narrative review.

The recent report of the first pig kidney transplant in a living human brings hope to thousands of people with end-stage kidney failure. The scientific community views this early success with caution as kidney xenotransplantation exhibits many challenges and barriers. One of these is coagulation dysregulation. This includes (i) pig von Willebrand Factor (vWF) interaction with human platelets, which can induce abnormal clotting responses, heightening the risk of graft failure, (ii) the inefficiency of pig thrombomodulin in activating human protein C, which emphasizes the species-specific variations that aggravate coagulation challenges, and (iii) the development of thrombotic microangiopathy in the pig grafts and the occurrence of systemic consumptive coagulopathy in the recipients. Indeed, coagulation dysregulation largely results from differences in endothelial cell response and incompatibilities between pig and human coagulation-anticoagulation pathways. These barriers can be resolved by modifications to pig vWF and the expression of human thrombomodulin and endothelial protein C receptors in pig cells, serving as strategic interventions to align the coagulation systems of the two species more closely. These coagulation challenges have clinical implications in how they affect graft survival and patient outcome. Genetic engineering of the organ-source pig and the administration of various drugs have assisted in correcting this coagulation dysregulation. Hence, comprehending and controlling coagulation dysregulation is crucial for progress in xenotransplantation as a viable option for treating patients with terminal kidney disease.

Platelet-Type von Willebrand Disease: Complex Pathophysiology and Insights on Novel Therapeutic and Diagnostic Strategies.

von Willebrand disease (VWD) is the most common well-studied genetic bleeding disorder worldwide. Much less is known about platelet-type VWD (PT-VWD), a rare platelet function defect, and a "nonidentical" twin bleeding phenotype to type 2B VWD (2B-VWD). Rather than a defect in the von Willebrand factor (VWF) gene, PT-VWD is caused by a platelet GP1BA mutation leading to a hyperaffinity of the glycoprotein Ibα (GPIbα) platelet surface receptor for VWF, and thus increased platelet clearing and high-molecular-weight VWF multimer elimination. Nine GP1BA gene mutations are known. It is historically believed that this enhanced binding was enabled by the ß-switch region of GPIbα adopting an extended ß-hairpin form. Recent evidence suggests the pathological conformation that destabilizes the compact triangular form of the R-loop-the GPIbα protein's region for VWF binding. PT-VWD is often misdiagnosed as 2B-VWD, even the though distinction between the two is crucial for proper treatment, as the former requires platelet transfusions, while the latter requires VWF/FVIII concentrate administration. Nevertheless, these PT-VWD treatments remain unsatisfactory, owing to their high cost, low availability, risk of alloimmunity, and the need to carefully balance platelet administration. Antibodies such as 6B4 remain undependable as an alternative therapy due to their questionable efficacy and high costs for this purpose. On the other hand, synthetic peptide therapeutics developed with In-Silico Protein Synthesizer to disrupt the association between GPIbα and VWF show preliminary promise as a therapy based on in vitro experiments. Such peptides could serve as an effective diagnostic technology for discriminating between 2B-VWD and PT-VWD, or potentially all forms of VWD, based on their high specificity. This field is rapidly growing and the current review sheds light on the complex pathology and some novel potential therapeutic and diagnostic strategies.

Management of Venous and Arterial Thrombosis.

A thrombus is a hemostatic plug localized in a blood vessel [...].

Report of the ISTH registry on pregnancy and COVID-19-associated coagulopathy (COV-PREG-COAG).

Background: Concerns about COVID-19-associated coagulopathy (CAC) in pregnant individuals were raised in early pandemic. Methods: An ISTH-sponsored COVID-19 coagulopathy in pregnancy (COV-PREG-COAG) international registry was developed to describe incidence of coagulopathy, VTE, and anticoagulation in this group. Results: All pregnant patients with COVID-19 from participating centers were entered, providing 430 pregnancies for the first pandemic wave. Isolated abnormal coagulation parameters were seen in 20%; more often with moderate/severe disease than asymptomatic/mild disease (49% vs 15%; p < 0.0001). No one met the ISTH criteria for disseminated intravascular coagulopathy (DIC), though 5/21 (24%) met the pregnancy DIC score. There was no difference in antepartum hemorrhage (APH) with asymptomatic/mild disease versus moderate/severe disease (3.4% vs 7.7%; p = 0.135). More individuals with moderate/severe disease experienced postpartum hemorrhage (PPH) (22.4% vs 9.3%; p = 0.006). There were no arterial thrombotic events. Only one COVID-associated venous thromboembolism (VTE) was reported. Conclusions: Low rates of coagulopathy, bleeding, and thrombosis were observed among pregnant people in the first pandemic wave.

Machine Learning as a Diagnostic and Prognostic Tool for Predicting Thrombosis in Cancer Patients: A Systematic Review.

Khorana score (KS) is an established risk assessment model for predicting cancer-associated thrombosis. However, it ignores several risk factors and has poor predictability in some cancer types. Machine learning (ML) is a novel technique used for the diagnosis and prognosis of several diseases, including cancer-associated thrombosis, when trained on specific diagnostic modalities. Consolidating the literature on the use of ML for the prediction of cancer-associated thrombosis is necessary to understand its diagnostic and prognostic abilities relative to KS. This systematic review aims to evaluate the current use and performance of ML algorithms to predict thrombosis in cancer patients. This study was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Databases Medline, EMBASE, Cochrane, and ClinicalTrials.gov, were searched from inception to September 15, 2023, for studies evaluating the use of ML models for the prediction of thrombosis in cancer patients. Search terms "machine learning," "artificial intelligence," "thrombosis," and "cancer" were used. Studies that examined adult cancer patients using any ML model were included. Two independent reviewers conducted study selection and data extraction. Three hundred citations were screened, of which 29 studies underwent a full-text review, and ultimately, 8 studies with 22,893 patients were included. Sample sizes ranged from 348 to 16,407 patients. Thrombosis was characterized as venous thromboembolism (n = 6) or peripherally inserted central catheter thrombosis (n = 2). The types of cancer included breast, gastric, colorectal, bladder, lung, esophageal, pancreatic, biliary, prostate, ovarian, genitourinary, head-neck, and sarcoma. All studies reported outcomes on the ML's predictive capacity. The extreme gradient boosting appears to be the best-performing model, and several models outperform KS in their respective datasets.

Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH.

In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.

Assessing hypercoagulability and VTE risk using thromboelastography and Khorana score in women with cancers receiving chemotherapy.

Venous thromboembolism (VTE) is a common occurrence in cancer and chemotherapy increases thrombosis risk. Current risk assessment models such as the Khorana score (KS) and its modifications have limitations in female cancers. We assessed the coagulation profile of a group of women cancer patients under chemotherapy using thromboelastography (TEG) to determine if this can inform VTE risk assessment. Cancer patients who planned to receive chemotherapy were recruited. Baseline demographics, cancer data, BMI, Khorana Score (KS), and VTE risk factors were recorded and patients were followed for 6 months, for any thrombotic events. A total of 36 patients aged 35-85 (18 breast, 11 endometrial, 7 ovarian cancer) were evaluated. Hypercoagulability was detected in 63% of patients post-chemo cycle 1 and 75% post-cycle 2, with a significant increase in MA (maximum amplitude) and CI (clotting index), reduction in R (reaction time), K (clot kinetics), and LY30 (lysis time after 30 min of MA). KS showed only 7% of patients were high risk, 23% were low, and 70% were intermediate risk. MA and CI significantly increased in patients with intermediate and high-risk KS when compared with the low-risk patients and MA was positively correlated with KS. Five patients developed actual VTE; 100% of the tested ones were hypercoagulable either post-cycle 1 or 2 and 80% were KS intermediate risk. TEG is a hypercoagulability marker and TEG-MA and CI can potentially assess VTE risk. Larger studies are needed to assess the utility of TEG as an adjuvant to KS to better predict VTE in specific female cancers.

Hematologic characteristics and coagulopathy in pregnancy with COVID-19 succeeding the first wave: a multicenter retrospective cross-sectional study.

Background: Early reports have demonstrated an association of COVID-19 infection during pregnancy and postpartum period with coagulopathy and bleeding complications and indicated that pregnant people with COVID-19 are more likely to experience coagulopathy and venous thromboembolism. A recent report concerning such complications during the first wave of the pandemic was reassuring; however, no publications have evaluated these issues in the context of increased illness severity with the emergence of SARS-CoV-2 variants of concern. Objectives: We performed a retrospective, multinational cohort study in Canada, Romania, and the United Kingdom, aiming to provide a comprehensive analysis of the hematologic test characteristics of pregnancies affected by COVID-19 after the first wave of the pandemic. Results: Three-hundred-seventy patients were evaluated. Markers of inflammation and endothelial dysfunction were significantly elevated, in keeping with observations in the nonpregnant population. Reassuringly, despite more severe disease noted in succeeding waves of the pandemic, there was no significant evidence of COVID-19-associated coagulopathy, and overall, no association was demonstrated between isolated coagulation abnormalities and bleeding risk. Notably, fibrinogen below 2g/L was again linked with the risk of postpartum hemorrhage. Finally, venous thromboembolism risk was low but noted more frequently in those with severe illness despite thromboprophylaxis. Conclusion: Our findings add valuable insights into the nature of hematologic test characteristics, bleeding, and thrombotic complications for those affected with COVID-19 in pregnancy, reassuring readers of the low incidence of bleeding and thrombotic complications but inviting further debate as to the degree of thromboprophylaxis that may benefit the subgroup with severe disease.

Incidence and risk factors of venous and arterial thromboembolic events among patients with ovarian cancer- data from a large Canadian database.

OBJECTIVES: To determine the incidence of thromboembolic events (TEEs) in ovarian cancer patients and to identify risk factors that are significantly associated with the development of venous thromboembolism (VTE), arterial thromboembolism (ATE), or overall TEEs in this population. METHODS: This is a retrospective cohort study of 4491 patients with epithelial ovarian cancer identified in the British Columbia cancer registry between 1996 and 2017. The presence of TEEs and risk factors were identified in administrative health records from fee-for-service provider visits and hospital data using ICD-9-CM and ICD-10-CM billing codes. Statistical analysis was performed using Chi-squared test and Fischer's exact test. RESULTS: Of 4491 patients with epithelial ovarian cancer included in this study, 1.74% experienced ATE and (9.44%) experienced VTE. There was a significant association found between the occurrence of TEEs and all-cause mortality. Sepsis was significantly associated with both venous and arterial thromboembolism. The top three risk factors for arterial thromboembolism included peripheral vascular disease (PVD), open wound, and aneurysm. CONCLUSIONS: Risk factors predictive of thrombosis in ovarian cancer patients are not consistent between ATE and VTE, thus thrombotic events should not be combined for analysis. Differential thrombosis risk assessment is needed to improve prevention strategies and guide thromboprophylaxis for these patients.

ABO Blood Group and the Risk of Thrombosis in Cancer Patients: A Mini-Review.

Cancer-associated thrombosis (CT), especially venous thromboembolism (VTE), is a common occurrence with several factors contributing to a wide diversity in thrombosis risk. The association between ABO blood groups and the risk for CT has been examined in various studies, with non-O blood type associated with an increased thrombosis risk; however, these studies have reported varying results with recognized limitations. ABO blood groups are known to be implicated in hemostasis, in an association mediated through von Willebrand factor (VWF). In this narrative review, we aim to summarize the current knowledge surrounding the role of ABO blood groups in VTE, with a particular focus on the role of VWF and other contributing risk factors on VTE occurrence. We found evidence from literature for the impact of ABO blood groups in determining the risk of VTE in healthy populations, with a limited number of studies examining this effect in cancer patients. Additionally, research on the impact of ABO on different cancer types lacks rigor, particularly in regard to other risk factors. Overall, most studies showed strong association of increased risk of VTE amongst cancer patients with non-O blood groups and increased VWF levels. This association was weaker in a few studies. Further research is needed before a solid conclusion can be made about the ABO or ABO-VWF-mediated hypercoagulability and VTE risk in various cancers. These studies will help determine if ABO typing can be an added biomarker to improve VTE risk assessment models in cancer patients.

Assessing the risk of venous thromboembolism in patients with haematological cancers using three prediction models.

PURPOSE: Assessment of individual VTE risk in cancer patients prior to chemotherapy is critical for determining necessity of interventions. Risk assessment models (RAM) are available but have not been validated for haematological malignancy. We aimed to assess the validity of the Vienna Cancer and Thrombosis Study (V-CATS) score in prediction of VTE in a variety of haematological malignancies. METHODS: This is a prospective cohort study conducted on 81 newly diagnosed cancer patients undergoing chemotherapy. Demographic, clinical and cancer related data were collected, patients were followed up for 6 months, and VTE events were recorded. Khorana score (KS) was calculated. Plasma D-dimer and sP-selectin were measured, and then, V-CATS score was calculated. Receiver operator curve (ROC) was used to assess the sensitivity and specificity of RAMs. A modified V-CATS was generated and subsequently assessed by using new cut-off levels of d-dimer and sP-selectin based on ROC curve of the patients' results and compared the probability of VTE occurrence using all three RAMs. RESULTS: Among the 81 patients included in this study, a total of 2.7% were diagnosed with advanced metastatic cancer. The most frequent cancer was non-Hodgkin lymphoma (39.5%), and 8 patients (9.8%) developed VTE events. The calculated probability of VTE occurrence using KS, V-CATS and modified V-CATS scores at cut-off levels ≥ 3 was 87.5%, 87.5% and 100%, respectively. The AUC in ROC curve of modified Vienna CATS score showed significant difference when compared to that of V-CATS and KS (P = 0.047 and 0.029, respectively). CONCLUSION: The findings of our study highlight the value of three VTE risk assessment models in haematological malignancies. The modified V-CATS score demonstrated higher specificity compared to both V-CATS and KS, while all three scores exhibited similar sensitivity. We encourage the implementation of RAMs in haematological cancers for an appropriate use of thromboprophylaxis.

Tissue factor positive microparticles as a biomarker for increased risk of breast cancer-associated thrombosis: a mini review.

PURPOSE OF REVIEW: Cancer-associated thrombosis (CAT), such as venous thromboembolism (VTE), is a frequent complication in cancer patients, resulting in poor prognosis. Breast cancer is not highly thrombogenic but is highly prevalent, resulting in increased VTE cases. Many cancers express tissue factor (TF), a glycoprotein that triggers coagulation. The cancer cells were shown to express and release substantial amounts of TF-positive microparticles (MPTF), associated with a prothrombotic state. This narrative review evaluated the current use of the procoagulant MPTF as a biomarker for thrombosis risk in breast cancer. RECENT FINDINGS: Tumors of epithelial origin with elevated TF expression have been associated with increased VTE incidence. Thus, studies have affirmed the use of MPTF biomarkers for VTE risk in many cancers. Patients with metastatic breast cancer and CAT were found to exhibit elevated procoagulant microparticles in vitro, due to TF expression. The silencing of TF was associated with decreased microparticle release in breast carcinoma cell lines, associated with decreased coagulation. SUMMARY: CAT is a multifactorial condition, with several various underlying diseases. It is proposed that MPTF may be an effective biomarker for thrombosis risk in breast cancer patients but requires a more systemic evaluation utilizing standardized quantification methods.

Comparison of Composite Resin (Duo-Shade) Shade Guide with Vita Ceramic Shades Before and After Chemical and Autoclave Sterilization.

BACKGROUND This study aimed to compare a composite resin (Duo-Shade) shade guide with Vita ceramic shades before/after chemical and autoclave sterilization. MATERIAL AND METHODS Color values (L*a*b*) were recorded directly from shade tabs of prefabricated composite resin (Brilliant NG Universal Duo-Shade) and ceramic (Vita classic) shade guide with a calibrated spectrophotometer (Vita Easy Shade Advance 4.0). Seventy-two composite resin disk samples with 6 different shades (A1/B1, A2/B2, A3/D3, A3.5/B3, A4/C4, and C2/C3) (n=12 each) were divided into 2 groups (Gp) - Gp A (Autoclave) and Gp C (Chemical) (15 cycles) - to assess their influence on respective shades. Mean values calculated the color differences (ΔE) while differences in color values (L*a*b*) were graded on the National Bureau of Standards (NBS) 6-grade scale and assessed for Clinical Acceptance/Perceptible Threshold (CAT), (CPT). All differences were considered significant if the color difference ΔE was ≥3.3. RESULTS Only 2 out of 12 Shade tabs (C2C3, A4C4) of composite resin matched to Vita shade tab C2 and C4 (ΔE ≤3.3). Both groups showed notable color differences after respective sterilization protocols, with color differences in Gp A significantly higher than Gp C (DE ³3.3). Within groups, all shades in Gp A showed remarkably different color changes, with shade C2C3 and A1B1 being denoted as clinically unacceptable. CONCLUSIONS Manufacturer-provided shade guides do not match ceramic shades as claimed and chemical sterilization using 10% Deconex was associated with less color changes than with autoclave sterilization.

Corrigendum to 'The Hemophilia Joint Health Score version 2.1 Validation in Adult Patients Study: A multicenter international study' [Research and Practice in Thrombosis and Haemostasis, 6/2, (2022) e12690].

[This corrects the article DOI: 10.1002/rth2.12690.].

Laboratory Testing of Hemostasis in Pregnancy: A Brief Overview.

Normal pregnancy is associated with significant physiological changes in the coagulation and fibrinolytic systems with an inclination toward a hypercoagulable state. This includes an increase in plasma levels of most clotting factors, a decrease in endogenous anticoagulants, and inhibition of fibrinolysis. Although these changes are critical in maintaining placental function and reducing postpartum hemorrhage, they may contribute to an increased risk of thromboembolism, particularly toward the end of pregnancy and during puerperium. Hemostasis parameters and the non-pregnant population reference ranges cannot be used in the assessment of bleeding or thrombotic complication risk during pregnancy, and pregnancy-specific information and reference ranges are not always available to support the interpretation of laboratory tests. This review aims to summarize the use of relevant hemostasis tests to promote evidence-based interpretation of laboratory test results as well as discuss challenges associated with testing during pregnancy.

Evaluating the hemostatic effects of tranexamic acid in women with pre-eclampsia.

OBJECTIVE: To evaluate the hemostatic effects of tranexamic acid (TXA) ex vivo in women with pre-eclampsia. METHODS: This was an ex vivo study involving 45 normal pregnant women and 45 women with pre-eclampsia (nine with mild and 36 with severe features) matched for age, gestational age, and body mass index. Blood samples were collected and divided into two parts. The first served as the pre-TXA sample, while the second was spiked with TXA and served as the post-TXA sample. Plasma levels of D-dimer and plasmin-antiplasmin complex (PAP) were determined using enzyme-linked immunosorbent assay. RESULTS: The mean D-dimer and PAP values in the pre-TXA samples differed significantly between groups. Following spiking with TXA, the mean D-dimer and PAP levels did not differ significantly in the pre-TXA and post-TXA samples (P = 0.560 and P = 0.500, respectively) in the pre-eclampsia cohort. In normal pregnancy, the mean D-dimer and PAP levels in the post-TXA samples did not differ significantly (P = 0.070 and P = 0.050, respectively) from the pre-TXA samples following TXA spiking. CONCLUSION: TXA did not significantly affect D-dimer and PAP levels in pre-eclampsia, suggesting that TXA may not increase the thrombotic risks in patients with pre-eclampsia.

Hormonal contraception and thrombosis: Identifying the gaps in knowledge among females in post-secondary education.

Objective: To determine the current level of knowledge about hormonal contraception among young women so they may be better informed about the risks and various choices available to them regarding hormonal contraception (HC). Methods: In an online survey-based study, data was analyzed from the anonymous responses of 675 female participants aged 18-30 years in various academic programs at two post-secondary institutions in Kingston, Ontario. Surveys explored demographics, use/type/duration of hormonal contraception, and knowledge of HC and thrombosis. Kruskal Wallis test and Spearman Correlation were used to determine differences in knowledge level about contraceptives across age groups, education levels, as well as use/type/duration of HC. Results: 476 participants were users of HC (264 > 1 year) and 199 were non-HC users. 370 participants have a high school diploma. The knowledge level of HC risks was associated with duration of use and overall knowledge of thrombosis and HC. The knowledge level of thrombosis was correlated with duration of use, education level, and age. Participants with higher level of education or those that have been using HC for 5 years or longer had an increased knowledge surrounding thrombosis. Participants aged 24 and older had a higher knowledge of thrombosis than that of participants younger than 24. Overall, the data was used to generate a simple infographic to further educate women in this regard. Conclusion: Misconceptions remain among young women concerning benefits and risks of HC which can be addressed by formal education.