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Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: To determine frequency of hypercoagulability testing and hypercoagulable states in patients with central retinal vein occlusion (CRVO) younger than 50 years., Design: Retrospective cohort study., Participants: Deidentified patients younger than 50 years with newly diagnosed CRVO from a national insurance claims database., Methods: The de-identified Clinformatics Data Mart Database (Optum) containing medical claims from a commercial and Medicare Advantage insurance database was used. All outpatient medical claims (office visits, associated diagnoses, and laboratory testing) and demographic data for each beneficiary during their enrollment were accessible., Main Outcome Measures: Prevalence of (1) laboratory hypercoagulable workup within 90 days of CRVO diagnosis, (2) new diagnosis of a hypercoagulable state within 1 year of CRVO diagnosis, and (3) diagnosis of hypertension, diabetes mellitus (DM), and hyperlipidemia., Results: One thousand one hundred eighty-one patients met inclusion criteria. Six hundred seventy-one patients (56.8%) were men, 450 patients (38.1%) had undergone hypercoagulable testing within 90 days, and 136 patients (11.5%) were diagnosed with a hypercoagulable state within 1 year after CRVO diagnosis. This proportion was similar between those patients with DM, hypertension, or hyperlipidemia (10.5% [65/620]) and those without (12.7% [71/561]; P = 0.28). Of the 136 patients diagnosed with a hypercoagulability state, 68.4% (93/136) had undergone testing within 90 days of CRVO diagnosis and 31.6% (43/136) did not. Of those who had not undergone hypercoagulability testing, 5.9% (43/731) were diagnosed with a hypercoagulable state within 1 year compared with 20.7% (93/450) in those who were tested (P < 0.001)., Conclusions: The prevalence of a hypercoagulable state within 1 year of CRVO diagnosis in patients younger than 50 years was 11.5%, and the prevalence was similar between patients with atherosclerotic risk factors and those without. Rate of testing was only 38.1%. Future research should examine the usefulness of uniform hypercoagulable testing in young CRVO patients., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: The association between coronavirus disease 2019 (COVID-19) and hypercoagulability has been extensively described, and pulmonary embolism is a recognized complication of COVID-19. Currently, the need for computed tomography pulmonary angiogram (CTPA) relies on the Wells score and serum D-dimer levels. However, because COVID-19 patients have a different thrombotic and inflammatory milieu, the usefulness of the Wells score deserves further exploration for this patient population. We aimed to explore the ability of the Wells score to predict pulmonary embolism in patients with COVID-19., Methods: In this retrospective study, patients found to have a CTPA and a COVID-19 diagnosis during the same admission were selected for analysis. Age and sex, CTPA results, and associated D-dimer levels were entered in a database. The Wells score sensitivity and specificity were calculated at different values, and the area under the curve of the receiver operating characteristic curve measured., Results: Of 459 patients with COVID-19, 64 had a CTPA and 12 (19%) had evidence of pulmonary embolism. Previous or current evidence of deep vein thrombosis, a Wells score above 4 points, and serum D-dimer levels 5 times above age-adjusted upper normal values were associated with pulmonary embolism. However, only 33% of patients with pulmonary embolism had a Wells score of 4 points or higher. The area under the curve of the receiver operating characteristic showed non-discriminating values (0.54) CONCLUSIONS: Although a Wells score of 4 or more points predicted pulmonary embolism in our cohort, the outcome can be present even with lower scores., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: S.S. reports grants from Boehringer-Ingelheim and Octapharma, personal fees from Boehringer-Ingelheim, Bayer, Daiichi, Alnylam, Sanofi, Bristol-Myers Squibb, and Pfizer, outside the submitted work.S.K. reports grants and personal fees from Bayer AG, grants and personal fees from Daiichi Sankyo, personal fees from Pfizer-Bristol-Mayers Squibb, grants and personal fees from BTG - Boston Scientific Group, grants from Boehringer-Ingelheim, personal fees from MSD, grants and personal fees from Actelion - Janssen, grants from Servier, outside the submitted work.

Prognostic factors for venous thromboembolism (VTE) recurrence following provoked VTE are largely unknown. Using the Clot Formation and Lysis (CloFAL) assay, single institutional research has shown overall improvement in acute hypercoagulability during the first 3 months postpediatric VTE, yet a rise in plasma coagulability in a subgroup of patients. We sought to define the incidence of rise in coagulability during the first 3 months post-provoked VTE, to investigate its relationship with elevated D-dimer, and to test the hypothesis that a marked rise in coagulability is independently prognostic of VTE recurrence. CloFAL and D-dimer assays were performed on plasma at 4 to 6 weeks and 3 months post-VTE in the Johns Hopkins pediatric VTE cohort and National Institutes of Health-sponsored Kids-DOTT trial. Associations of VTE recurrence with D-dimer and CloFAL assay measures were evaluated via logistic regression. Eighty-seven patients were included. Median follow-up was 1 year. Complete veno-occlusion was determined in 12% at 6 weeks. During the first 3 months post-VTE, a marked rise in coagulability was observed by CloFAL assay in 17% of patients, while D-dimer was elevated in 21%. Recurrent VTE occurred in 10% of patients. CloFAL assay, but not D-dimer, was associated with recurrence (odds ratio [OR] 5.87, 95% confidence interval [95% CI], 1.34-25.8]). After adjustment for veno-occlusion, patients with a marked rise in coagulability by CloFAL assay had a 10-fold increased risk of recurrent VTE (OR 10.33 [95% CI, 1.83-58.19]). Future work should seek to elucidate the mechanisms underlying a rise in plasma coagulability following provoked VTE and to substantiate its prognostic utility for recurrent VTE., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Obesity is linked to hypercoagulability with an increased risk of venous thromboembolic events (VTE) in the uninjured population. Therefore, we hypothesize that obesity (body mass index [BMI] ≥30 kg/m [BMI30]) is associated with a hypercoagulable state postinjury characterized by increased clot strength and resistance to fibrinolysis., Methods: Our prospective Trauma Activation Protocol database includes all trauma activations patients for whom a rapid thrombelastography is obtained within 60 minutes postinjury prior to any transfusions. The data set was then stratified by BMI and subjects with BMI30 were compared with those with BMI less than 30 kg/m). The following thrombelastography measurements were obtained: activated clotting time, clot formation rate (angle), maximum clot strength (MA), and % clot lysis 30 minutes after MA (LY30, %). Fibrinolysis shutdown (SD) was defined as LY30 < 0.6% and hyperfibrinolysis (HF) as LY30 greater than 7.6%. Continuous variables are expressed as median (interquartile range)., Results: Overall, 687 patients were included of whom 161 (23%) had BMI30. The BMI30 group was older, had a lower proportion of males and of blunt trauma, and was less severely injured. After adjustment for confounders, BMI30 was independently associated with lower odds of MA less than 55 mm (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.13-0.60) and of HF (OR, 0.31; 95% CI, 0.10-0.97) and higher odds of SD (OR, 1.82; 95% CI, 1.09-3.05). No independent association was observed with angle less than 65° (OR 0.57 95% CI 0.30-1.05). While VTEs were more frequent among BMI30 patients (5.0 vs. 3.3%), this did not reach significance after confounding adjustment (p = 0.11)., Conclusion: Obesity was protective against diminished clot strength and hyperfibrinolysis, and obesity was associated with an increased risk of fibrinolytic SD in severely injured patients. These findings suggest a relative hypercoagulability. Although no difference in VTEs was noted in this study, these findings may explain the higher rate of VTEs reported in other studies., Level of Evidence: Prognostic and Epidemiological, level III.

Background: Thrombelastography (TEG) maximal amplitude (mA) has also been shown to reflect hypercoagulability and increased venous thromboembolism (VTE) risk in adult trauma patients. Based on these previous works, we sought to identify when children become adults with respect to TEG mA values and whether this correlated with VTE risk., Methods: We evaluated all trauma patients admitted from January 2010 to December 2013 who were highest-level activations. Age was evaluated as a continuous variable, followed by a categorical evaluation. TEG mA values were evaluated as continuous and dichotomous (hypercoagulable, mA ≥ 65 mm). Logistic regression was then constructed controlling for age categories, sex, and injury severity to assess the association with TEG mA values and VTE risk., Results: A total of 7,194 Level 1 trauma patients were admitted during this time frame (819 were <18 years of age). The likelihood of mA equal to or greater than 65 mm remained at 35% to 37% through age 30 years with significant increases observed at ages 31 years to 35 years (45%) and 46 years to 50 years (49%), both p < 0.01. When controlling for injury severity, race, and sex, logistic regression demonstrated that every 5-year increase in age (after age 30 years) was associated with a 16% increased likelihood of hypercoagulability at admission. Beginning with age 1 year, VTE risk remained at 1.5% or less until age 13 years where it increased to 2.3%, increasing again at age 15 years to 5.1%. Two additional significant increases were identified between ages 31 years and 35 years (5.5%) as well as 46 years and 50 years (7.6%), both p < 0.001. Logistic regression demonstrated a 3.4-fold increased risk for VTE among those aged 31 years to 50 years compared with those who are younger than 30 years. The same model noted a 2.3-fold increased risk compared with those who are older than 50 years., Conclusion: Beginning at age 13 years, children transition toward adult hypercoagulability, as evidenced by elevated TEG mA values and VTE risk. However, the greatest VTE risk (and highest likelihood of hypercoagulable mA) is among those adults 31 years to 50 years of age., Level of Evidence: Prognostic and epidemiologic study, level III.

Stroke is a leading cause of disability worldwide. Cryptogenic strokes (CS) account for almost a quarter of ischemic strokes despite modern diagnostic evaluation. A working definition of CS based on stroke classification systems is essential for accurate conceptualization of this common entity. Mechanistic categories (potential paradoxical embolism; atherosclerotic disease of the aorta or supra-aortic vasculature; and occult arrhythmia) should aide in parsing the often heterogeneous mix of conditions included in the CS subtype. Despite efforts to unravel mechanisms of CS, specific or targeted recurrent stroke prevention strategies are lacking. For example, recent trials have shown no clear benefit of patent foramen ovale closure in stroke prevention after CS. There are promising ongoing clinical trials that will address appropriate diagnostic evaluations in CS as well as novel therapeutic interventions. Overall, a standardized approach must be framed to diagnose and manage patients with CS and guide clinical practice and future research.

MTHFR polymorphism testing is frequently ordered by physicians as part of the clinical evaluation for thrombophilia. It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous t-hromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as a part of a routine evaluation for thrombophilia.

Context: Hereditary and acquired deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. Proper diagnosis requires high-quality assays for these proteins., Objective: To determine the accuracy and interlaboratory precision of AT, PC, and PS assays used by laboratories participating in the United States College of American Pathologists proficiency testing program in thrombophilia and to grade the performance of laboratories., Design: Standardized normal plasma with assigned analyte values was sent in 2 separate challenges to participating laboratories. Participants measured AT, PC, and PS levels using local methods., Results: When compared with the assigned values for the international standard, the order of assay accuracy from highest to lowest was AT activity, PC antigen, AT antigen, total PS antigen, PC activity, PS activity, and free PS antigen (range of assay bias, 2.6%-8.8%). The order of assay precision from highest to lowest was PC activity, AT activity, AT antigen, total PS antigen, PS activity, free PS antigen, and PC antigen (range of assay coefficient of variation, 6.1%-20.0%). Most testing events (87.8%) could be graded as pass or fail using a target range of ±3 standard deviations from the method-specific mean. The pass rate was 98.2% for all AT, PC, and PS testing events combined., Conclusions: Accuracy and precision were higher for AT assays and lower for PC and PS assays. It was feasible to grade individual laboratory performance.

Thrombophilia is a tendency for venous thromboembolism (VTE) and it can be acquired or hereditary. Knowledge about hereditary thrombophilia (HT) has increased in the last two decades and this has lead to widespread testing of HT in patients with VTE. A comprehensive evaluation of HT can be complex. This article reviews the currently established hereditary thrombophilic disorders and discusses the potential usefulness and implications of testing for thrombophilia.

Objective: To examine how practicing obstetricians evaluate and manage thrombophilias in selected clinical situations., Methods: A questionnaire investigating knowledge and practice patterns pertaining to thrombophilia was mailed to 300 randomly selected American College of Obstetricians and Gynecologists Fellows and Junior Fellows in February 2005., Results: Approximately 50% (151) of questionnaires were returned. Statistical analysis focused on the 104 responding obstetricians. The majority (greater than 70%) know which thrombophilias are inherited and which are acquired. More than 50% send an inherited thrombophilia panel and antiphospholipid antibodies on patients with a history of fetal demise, intrauterine growth restriction (less than 5th percentile), abruption, and severe preeclampsia. Ninety-two percent test patients with recurrent miscarriages for antiphospholipid antibodies. Despite no clear evidence, 80% also test these patients for inherited thrombophilias. The majority intervene with either thromboprophylaxis or low-dose aspirin when managing patients at risk for thromboembolism. Seventy percent use low-molecular-weight (fractionated) heparin for patients requiring therapeutic anticoagulation, while 62% also use it for prophylactic anticoagulation. Thirty-eight percent of physicians using low-molecular-weight (fractionated) heparin monitor anti-factor Xa levels. The majority (56%) felt their residency training with regard to thrombophilia was barely adequate. Only 8% felt their training was comprehensive, while 36% felt it was adequate., Conclusion: Most responding obstetricians do not manage thrombophilia patients according to expert opinion. Despite the fact that often there is no clear evidence for treatment, many physicians are inclined to intervene in patients at risk for thromboembolism. Educational endeavors are needed to guide obstetricians caring for patients at risk for thromboembolism., Level of Evidence: III.

Objective: To investigate the effect of structured didactic lectures by leaders in the field of Maternal-Fetal Medicine on reported clinical decision-making., Methods: An interactive survey of obstetric management was performed as part of a postgraduate course at the 2004 Annual Meeting of the Society for Maternal-Fetal Medicine. Seven controversial topics were addressed, including tocolytic therapy, progesterone supplementation for the prevention of preterm birth, screening for inherited thrombophilia, cervical cerclage for a shortened cervix, the management of preterm premature rupture of membranes, magnesium sulfate seizure prophylaxis, and dexamethasone therapy for hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. The survey was carried out before and after a series of structured didactic lectures, thereby allowing for analysis of the effect of the lectures on reported clinical decision-making., Results: A total of 298 obstetric care providers attended the postgraduate course. By report, the majority of attendees were Maternal-Fetal Medicine specialists (60.7%), less than 10 years out from specialty training (56.3%), and practicing in a university-based setting (52.9%). An average of 233 practitioners (range 157-298) answered each question. Comparison of responses to the survey given before and after the lectures demonstrated significant differences, especially in the areas of tocolytic therapy and inherited thrombophilias., Conclusions: Postgraduate lectures by leaders in the field of Maternal-Fetal Medicine have significant immediate impact on reported clinical decision-making.