Recurrence after stopping anticoagulants in women with combined oral contraceptive-associated venous thromboembolism: A systematic review and meta-analysis.

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.

Identification of hypercoagulability with thrombelastography in patients with hip fracture receiving thromboprophylaxis.

Background: Venous thromboembolism (VTE) is the second most common complication after hip fracture surgery. We used thrombelastography (TEG), a whole-blood, point-of-care test that can provide an overview of the clotting process, to determine the duration of hypercoagulability after hip fracture surgery. Methods: In this prospective study, consecutive patients aged 51 years or more with hip fractures (trochanteric region or neck) amenable to surgical treatment who presented to the emergency department were eligible for enrolment. Thrombelastography, including calculation of the coagulation index (CI) (combination of 4 TEG parameters for an overall assessment of coagulation) was performed daily from admission until 5 days postoperatively, and at 2 and 6 weeks postoperatively. All patients received 28 days of thromboprophylaxis. We used single-sample t tests to compare mean maximal amplitude (MA) values (a measure of clot strength) to the hypercoagulable threshold of greater than 65 mm, a predictor of in-hospital VTE. Results: Of the 35 patients enrolled, 11 (31%) were hypercoagulable on admission based on an MA value greater than 65 mm, and 29 (83%) were hypercoagulable based on a CI value greater than 3.0; the corresponding values at 6 weeks were 23 (66%) and 34 (97%). All patients had an MA value greater than 65 mm at 2 weeks. Patients demonstrated normal coagulation on admission (mean MA value 62.2 mm [standard deviation (SD) 6.3 mm], p = 0.01) but became significantly hypercoagulable at 2 weeks (mean 71.6 mm [SD 2.6 mm], p < 0.001). There was a trend toward persistent hypercoagulability at 6 weeks (mean MA value 66.2 mm [SD 3.8 mm], p = 0.06). Conclusion: More than 50% of patients remained hypercoagulable 6 weeks after fracture despite thromboprophylaxis. Thrombelastography MA thresholds or a change in MA over time may help predict VTE risk; however, further study is needed.

Contexte: La thromboembolie veineuse (TEV) est la deuxième complication la plus courante après une chirurgie pour fracture de la hanche. Nous avons eu recours à la thromboélastographie, un test de sang total effectué au point d'intervention et donnant une idée du processus de coagulation, pour évaluer la durée de l'hypercoagulabilité à la suite d'une chirurgie pour fracture de la hanche. Méthodes: Cette étude prospective a été menée auprès de patients consécutifs admissibles de 51 ans et plus qui se sont présentés à l'urgence pour une fracture de la hanche (région trochantérienne ou col du fémur) pouvant faire l'objet d'un traitement chirurgical. Une thromboélastographie (TEG), qui comprenait le calcul de l'indice de coagulation (IC) [combinaison de 4 paramètres du TEG permettant une évaluation globale de la coagulation], a été réalisée chaque jour, de l'admission au cinquième jour postopératoire, de même qu'à 2 et à 6 semaines postopératoires. Tous les patients ont suivi une thromboprophylaxie de 28 jours. Nous avons réalisé des tests t pour échantillon unique afin de comparer l'amplitude maximale (AM) moyenne (une mesure de la résistance d'un caillot) au seuil d'hypercoagulabilité de plus de 65 mm, un prédicteur de TEV à l'hôpital. Résultats: Des 35 patients recrutés, 11 (31 %) présentaient une hypercoagulabilité à l'admission selon une AM supérieure à 65 mm, et 29 (83 %) présentaient une hypercoagulabilité selon un IC supérieur à 3,0; les valeurs correspondantes à 6 semaines étaient de 23 (66 %) et de 34 (97 %), respectivement. Tous les patients avaient une AM de plus de 65 mm à 2 semaines. Dans l'ensemble, les patients avaient une coagulation normale à l'admission (AM moyenne 62,2 mm [écart type (E.T.) 6,3 mm], p = 0,01), mais présentaient une hypercoagulabilité importante à 2 semaines (moyenne 71,6 mm [E.T. 2,6 mm], p < 0,001). L'hypercoagulabilité avait tendance à persister à 6 semaines (AM moyenne 66,2 mm [E.T. 3,8 mm], p = 0,06). Conclusion: Malgré la thromboprophylaxie, plus de 50 % des patients présentaient toujours une hypercoagulabilité 6 semaines après leur fracture. Les seuils d'AM à la thromboélastographie et les changements de l'AM au fil du temps pourraient aider à prédire le risque de TEV, mais d'autres études sur le sujet sont nécessaires.

Anticoagulating patients with high-risk acquired thrombophilias.

Antiphospholipid syndrome (APS), heparin-induced thrombocytopenia, and paroxysmal nocturnal hemoglobinuria are 3 acquired thrombophilias that carry a high risk of venous and arterial thromboembolism. Management of these conditions has largely included anticoagulation with a vitamin K antagonist after an initial period of a parenteral anticoagulant, for as long as the thrombotic risk is still present. The available evidence for the use of direct oral anticoagulants (DOACs) is limited and primarily consists of case series and cohort studies, which are summarized in this chapter. Randomized trials evaluating DOACs in patients with APS are reviewed. Further research is needed prior to widely adopting DOACs for use in these high-risk acquired thrombophilias; however, there may be selected low-risk subgroups where DOAC use is possible after careful consideration and patient discussion.

Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis.

We performed a meta-analysis to evaluate the risk of venous thromboembolism (VTE) in pregnant women with essential thrombocythemia. Twenty-one trials and 756 pregnancies met inclusion criteria. The absolute VTE risk in the antepartum period is not above a threshold where low-molecular-weight heparin (LMWH) prophylaxis is clearly indicated or below a threshold where LMWH should be withheld (2.5%; 95% CI, 1.3-4.3). Postpartum, the absolute VTE risk is above a threshold where postpartum LMWH prophylaxis should be considered (4.4%; 95% CI, 1.2-9.5).

The risk of cesarean delivery after labor induction among women with prior pregnancy complications: a subgroup analysis of the AFFIRM study.

BACKGROUND: To determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction). METHODS: The AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor. RESULTS: There were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35-1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17-0.84; p = 0.01). CONCLUSIONS: The risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.

A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia.

We performed a meta-analysis of randomized controlled trials comparing low-molecular-weight heparin (LMWH) vs no LMWH in women with inherited thrombophilia and prior late (≥10 weeks) or recurrent early (<10 weeks) pregnancy loss. Eight trials and 483 patients met our inclusion criteria. There was no significant difference in livebirth rates with the use of LMWH compared with no LMWH (relative risk, 0.81; 95% confidence interval, 0.55-1.19;P= .28), suggesting no benefit of LMWH in preventing recurrent pregnancy loss in women with inherited thrombophilia.

Are Anti-ß2 Glycoprotein 1 Antibodies Associated with Placenta-Mediated Pregnancy Complications? A Nested Case-Control Study.

BACKGROUND: While anti-ß2 glycoprotein 1 (anti-ß2GP1) antibody positivity is included in the diagnostic criteria for antiphospholipid syndrome (APS), the association between anti-ß2GP1 and the obstetrical complications of APS has been inconsistently reported and remains unclear. OBJECTIVE: We completed a case-control study nested within the Canadian Ottawa and Kingston (OaK) Birth Cohort to evaluate the association between anti-ß2GP1 antibody positivity and placenta-mediated pregnancy complications. STUDY DESIGN: Five hundred cases were randomly selected among pregnant women who experienced any of the following independently adjudicated placenta-mediated pregnancy complications: preeclampsia, placental abruption, late pregnancy loss (≥ 12 weeks' gestation), and birth of a small-for-gestational age (SGA) infant < 10th percentile. Five hundred pregnant women without any placenta-mediated pregnancy complications were selected as controls. Stored blood samples were analyzed for the presence of anti-ß2GP1 antibodies by enzyme-linked immunosorbent assay. RESULTS: Anti-ß2GP1 immunoglobulin G (IgG) and/or immunoglobulin M (IgM) antibodies in titers ≥ 20 G/M units (> 99th percentile) were present in 24 of 497 (4.8%) of controls and 33 of 503 (6.6%) of cases. There was no significant difference between cases and controls for the composite outcome of any placenta-mediated pregnancy complications (odds ratio, 1.38, 95% confidence interval [CI], 0.8-2.37, p = 0.25). CONCLUSION: Our results call into question the association between anti-ß2GP1 antibodies and placenta-mediated pregnancy complications, with further research needed.

Pulmonary Complications of Pregnancy: Venous Thromboembolism.

Unique considerations are needed when diagnosing and treating venous thromboembolism (VTE) in women who are pregnant or postpartum. What are the risks to the fetus, such as drug exposure or the risk of radiation with diagnostic imaging? How does the physiology of pregnancy affect imaging techniques and anticoagulation management? How should anticoagulation be managed around labor and delivery? These questions highlight some of the important considerations needed when managing a pregnant patient with suspected or confirmed VTE. This review outlines what is known about the epidemiology, pathophysiology, clinical risk factors, diagnosis, and therapeutic management of VTE in pregnancy. We also review our preferred diagnostic and treatment algorithm for a pregnant patient with suspected or confirmed VTE.

Racial and ethnic disparities in eligibility for postpartum venous thromboembolism prophylaxis in the United States.

BACKGROUND: Postpartum venous thromboembolism (VTE) incidence differs by race and ethnicity in the United States. However, it is unclear whether the eligibility criteria for postpartum VTE prophylaxis mirror this disparity. OBJECTIVE: To characterize the prevalence of risk factors and eligibility for postpartum VTE prophylaxis, among US Birthing people, stratified by race and ethnicity. METHODS: We analyzed the National Inpatient Sample from October 2015 to December 2019, using diagnosis and procedure codes to identify postpartum individuals and their VTE risk factors. We compared proportion of delivery hospitalizations meeting eligibility for thromboprophylaxis stratified by race or ethnicity, according to American College of Gynecology and Obstetrics, American College of Chest Physicians, Royal College of Obstetricians and Gynecologists (RCOG), and American Society for Hematology guidelines. RESULTS: Among a national estimate of 14 967 861 delivery hospitalizations in the United States, the proportion of individuals eligible for thromboprophylaxis using the RCOG, American College of Chest Physicians, American College of Gynecology and Obstetrics, and American Society for Hematology guidelines were 32.9%, 8.0%, 0.2%, and 0.2%, respectively. Using the RCOG criteria, non-Hispanic Black individuals had the highest proportion of thromboprophylaxis eligibility (39.7%), whereas it was lowest among Hispanic individuals (30.8%). Racial disparities in thromboprophylaxis eligibility were driven by differences in clinical risk factors (38.8% non-Hispanic Black population vs 30.5% Hispanic population) and cesarean section rates (35.9% vs 32.2%), rather than history of VTE (0.3% vs 0.1%), inherited thrombophilia (0.2% vs 0.2%), or sickle cell disease (0.4% vs <0.1%). CONCLUSION: Non-Hispanic Black individuals were most likely to qualify for postpartum thromboprophylaxis, attributable to clinical risk factors rather than inherited risk factors. An urgent need exists to better understand ethno-racial disparities in thromboprophylaxis use and to equitably address modifiable risk factors for postpartum VTE.

Diagnostic strategies in postpartum individuals with suspected venous thromboembolism: A scoping review.

BACKGROUND: The risk of venous thromboembolism (VTE) is increased postpartum and contributes to important morbidity and mortality. While there have been advances in evaluating diagnostic algorithms for suspected VTE during pregnancy, there is limited data for postpartum individuals. OBJECTIVE: We conducted a scoping review to describe and evaluate diagnostic strategies used to investigate suspected VTE in postpartum individuals. METHODS: A comprehensive search strategy was conducted in Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (January 1, 2000-September 30, 2022) to identify original articles that reported on diagnostic strategies in postpartum individuals with suspected VTE. We extracted demographics, clinical decision rules used, D-dimer and imaging completed, including test performance and VTE outcomes. RESULTS: A total of 13 studies conducted across 11 countries with separate postpartum data were included for 759 individuals with suspected PE (n = 634) or DVT (n = 125), including unpublished data (n = 251). Among those with suspected PE, computed tomography pulmonary angiography was conducted more commonly (n = 522) than ventilation-perfusion scans (n = 69), with PE positivity rates that ranged from 4 %-27.6 % and 0-50 % across studies, respectively. Among 131 postpartum individuals with suspected PE who had a D-dimer measured, only 4.6 % (6/131) had a negative D-dimer test. For postpartum individuals with suspected DVT, the most common diagnostic test was compression ultrasonography (positivity rate 12.2 %-18.6 %). There were limited retrospective data evaluating the clinical decision rules. CONCLUSIONS: There are heterogeneous approaches globally in the diagnosis of suspected postpartum VTE. Limited high-quality data available underscores the need for more robust evidence to inform clinical practice.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository ("Registry").

BACKGROUND: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. OBJECTIVES: To prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. PATIENTS/METHODS: Using an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. RESULTS: As of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). CONCLUSION: Fourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

Preeclampsia: Platelet procoagulant membrane dynamics and critical biomarkers.

A state-of-the-art lecture titled "Preeclampsia and Platelet Procoagulant Membrane Dynamics" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Platelet activation is involved in the pathophysiology of preeclampsia and contributes to the prothrombotic state of the disorder. Still, it remains unclear what mechanisms initiate and sustain platelet activation in preeclampsia and how platelets drive the thrombo-hemorrhagic abnormalities in preeclampsia. Here, we highlight our findings that platelets in preeclampsia are preactivated possibly by plasma procoagulant agonist(s) and overexpress facilitative glucose transporter-3 (GLUT3) in addition to GLUT1. Preeclampsia platelets are also partially degranulated, procoagulant, and proaggregatory and can circulate as microaggregates/microthrombi. However, in response to exposed subendothelial collagen, such as in injured vessels during cesarean sections, preeclampsia platelets are unable to mount a full procoagulant response, contributing to blood loss perioperatively. The overexpression of GLUT3 or GLUT1 may be monitored alone or in combination (GLUT1/GLUT3 ratio) as a biomarker for preeclampsia onset, phenotype, and progression. Studies to further understand the mediators of the platelet activation and procoagulant membrane dynamics in preeclampsia can reveal novel drug targets and suitable alternatives to aspirin for the management of prothrombotic tendencies in preeclampsia. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress.

Overexpression of facilitative glucose transporter-3 and membrane procoagulation in maternal platelets of preeclamptic pregnancy.

BACKGROUND: Preeclampsia (PE) is a hypertensive disorder during pregnancy that results in significant adverse maternal and neonatal outcomes. Platelet activation is present in PE and contributes to the thrombo-hemorrhagic states of the disorder. However, the mechanisms that initiate and/or sustain platelet activation in PE are ill-defined. OBJECTIVES: We aimed to characterise this mechanism and the procoagulant potentials of platelets in PE. METHODS: In this quantitative observational study, we analyzed platelet procoagulant membrane dynamics in patients with PE (n = 21) compared with age-matched normotensive pregnancies (n = 20), gestational hypertension (n = 10), and non-pregnant female controls (n = 19). We analyzed fluorescently labeled indicators of platelet activation, bioenergetics, and procoagulation (phosphatidylserine exposure and thrombin generation), coupled with high-resolution imaging and thrombelastography. We then validated our findings using flow cytometry, immunoassays, classical pharmacology, and convolutional neural network analysis. RESULTS: PE platelets showed significant ultra-structural remodeling, are more extensively preactivated than in healthy pregnancies and can circulate as microaggregates. Preactivated platelets of PE externalized phosphatidylserine and thrombin formed on the platelet membranes. Platelets' expression of facilitative glucose transporter-1 increased in all pregnant groups. However, PE platelets additionally overexpress glucose transporter-3 to enhance glucose uptake and sustain activation and secretion events. Although preeclampsia platelets exposed to subendothelial collagen showed incremental activation, the absolute hemostatic response to collagen was diminished, and likely contributed to greater blood loss perioperatively. CONCLUSIONS: We revealed 2 bioenergetic mediators in the mechanism of sustained platelet procoagulation in preeclampsia. Although glucose transporter-1 and glucose transporter-3 remain elusive antiprocoagulant targets, they may be sensitive monitors of PE onset and progression.

Preventing Postpartum Venous Thromboembolism in 2022: A Narrative Review.

The postpartum period represents the most critical time for pregnancy-associated venous thromboembolism (VTE), which is responsible for substantial morbidity and an important cause of maternal mortality. The estimated risk of postpartum VTE of about 1/1,000 deliveries can be modulated with the knowledge of maternal and obstetrical risk factors, although a precise estimate remains challenging in individuals. The use of postpartum low-dose low-molecular-weight heparins are tailored at intermediate and high-risk groups to reduce the thrombotic burden, despite the lack of dedicated randomized controlled trials. In this review, we will highlight the contemporary evidence on the risk of postpartum VTE, its stratification and its prevention. We will also discuss our knowledge on the values and preferences of women for postpartum thromboprophylaxis and their adherence to treatment.

Evaluation of patients' experience and related qualitative outcomes in venous thromboembolism: A scoping review.

BACKGROUND: Venous thromboembolism (VTE) is a prevalent disease with high morbidity and mortality. VTE has well-documented physical sequelae; however, the psychological and emotional impacts are seldom evaluated in randomized controlled trials. OBJECTIVE: We conducted a scoping review of published qualitative studies aiming to understand the physical, psychological, and emotional impact of VTE as reflected from patients' perspectives. This scoping review is part of a larger initiative to develop a core outcome set for VTE treatment studies. METHODS: A systematic literature search was conducted to identify qualitative studies assessing patient experience of VTE. Two authors independently screened titles and abstracts using Covidence systematic review software. Full-text reviews were conducted independently by 2 study team members. A modified method of "thematic synthesis" was used to collate themes upon reading and rereading of the publications. RESULTS: Our search strategy returned a total of 4944 citations; 28 were ultimately included in the analysis. The studies were conducted across 13 countries and representative of 436 participants including a spectrum of VTE subpopulations. There were seven major themes identified: Acute impacts: an unforeseen blow, Sustained psychological distress, Loss of self: life is changed, Challenges of thrombosis management, Balancing coping and control, Negative experience with the medical system, and VTE in the context of other conditions. CONCLUSIONS: The physical, psychological, and emotional impacts of VTE extend beyond objective outcomes typically evaluated in clinical trials. An improved understanding of the outcomes most important to patients will improve patient-centered care in VTE.