The effect of micronized progesterone and medroxyprogesterone acetate in combination with transdermal estradiol on hemostatic biomarkers in postmenopausal women diagnosed with POI and early menopause: a randomized trial.

OBJECTIVE: To compare the impact of micronized progesterone (MP) or medroxyprogesterone acetate (MPA) in combination with transdermal estradiol (t-E2) on traditional coagulation factors and thrombin generation parameters in postmenopausal women diagnosed with premature ovarian insufficiency or early menopause. METHOD: Randomized prospective trial conducted in women diagnosed with premature ovarian insufficiency or early menopause and an intact uterus, recruited over 28 months. All participants were prescribed t-E2 and randomized to either cyclical MP or MPA using a web-based computer randomization software, Graph Pad. Thrombin generation parameters were measured at baseline and repeated after 3-months. Traditional hemostatic biomarkers were measured at baseline and repeated after 3, 6, and 12-months. Seventy-one participants were screened for the study, of whom 66 met the inclusion criteria. In total, 57 participants were randomized: 44 completed the thrombin generation assessment arm of the study, whilst 32 completed 12-months of the traditional coagulation factor screening component of the trial. RESULTS: Thrombin generation parameters did not significantly change from baseline after 3-months duration for either progestogen component when combined with t-E2, unlike the traditional coagulation factors. Protein C activity, free Protein S, and Antithrombin III levels decreased with time in both treatment arms. CONCLUSION: Fluctuations in traditional hemostatic biomarkers were not reproduced by parallel changes in thrombin generation parameters that remained neutral in both groups compared with baseline. The absence of statistically significant changes in thrombin generation for the first 3-months of hormone therapy use is reassuring and would suggest a neutral effect of both progestogens on the global coagulation assay.

Relationship between development of post-thrombotic syndrome and serial ultrasound, D-dimer, and factor VIII activity after a first deep venous thrombosis.

OBJECTIVE: The aim of this study was to evaluate the relationship of post-thrombotic syndrome (PTS) with residual vein thrombosis, deep venous reflux (DVT), D-dimer, and factor VIII (FVIII) after a first deep venous thrombosis (DVT). METHODS: There were 133 participants with objectively confirmed DVT, of whom 114 were observed for 6 months after completion of anticoagulation. Ultrasound, D-dimer, and FVIII evaluations were undertaken at 6 weeks after completion of anticoagulation and at the end of follow-up. PTS was considered present in those with a score of ≥5 on the Villalta scale at either assessment. RESULTS: The cumulative incidence of PTS was 51.8%, with median duration of follow-up of 11 months. Median D-dimer and FVIII in those with PTS were significantly higher at both time points compared with those without. Similarly, residual vein thrombosis and deep venous reflux were more prevalent in those with PTS at both study assessments. On multivariable analysis, only FVIII at end of study remained significantly associated with PTS with an odds ratio of 2.83 (95% confidence interval, 1.09-7.42; P = .034). Ultrasound markers and D-dimer were not significantly associated with PTS after adjustment for age, body mass index, Charlson Index ≥1, and proximal extent of DVT. CONCLUSIONS: FVIII activity at end of follow-up was independently associated with PTS, suggesting underlying activation of coagulation.

Presenting D-dimer and early symptom severity are independent predictors for post-thrombotic syndrome following a first deep vein thrombosis.

Post-thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT). Current preventative strategies are limited to the daily wear of graduated compression stockings (GCS). The aim of this study was to evaluate early predictors of PTS. One hundred and twenty-two consecutive patients with a first DVT were prospectively recruited from diagnosis and followed for up to 6 months post-end of anticoagulation. D-dimer was measured in 107 participants at presentation and Villalta scale was evaluated in 70 participants at a median of 2 weeks following diagnosis. PTS developed in 51·6% of participants. GCS were obtained by 78·1% of participants, with 33·7% reporting daily wear at the end of follow-up. Mean early Villalta scale was significantly higher in those with PTS (8·1 ± 3·7) compared to those without (2·6 ± 2·7, P < 0·001). Median D-dimer was significantly higher in those with PTS [3260 ng/ml, interquartile range (IQR) 820-8000 ng/ml] compared to those without (1540 ng/ml, IQR 810-2520 ng/ml, P < 0·001). The adjusted odds ratio for every one point increase in early Villalta scale was 1·78 [95% confidence interval (CI), 1·19-2·64; P = 0·005] and for D-dimer >1910 ng/ml it was 2·71 (95% CI, 1·05-7·03; P = 0·04). These markers could enable targeted counselling regarding GCS for those at high risk of PTS.

African-Caribbean ethnicity is associated with a hypercoagulable state as measured by thrombin generation.

African-Caribbean ethnicity is associated with an increased risk of both first and recurrent venous thromboembolism (VTE). The aim of this study was to evaluate thrombin generation in African-Caribbeans compared with whites in patients with deep vein thrombosis (DVT) and healthy volunteers. Thrombin generation was measured in a case-control study of 80 patients who had completed anticoagulation therapy for a first DVT (50 white and 30 African-Caribbean) and 66 controls. Peak thrombin with and without thrombomodulin was significantly higher in African-Caribbeans with DVT compared with whites with DVT (P < 0.001 for both comparisons) and African-Caribbean controls (P < 0.001, 0.003, respectively). Endogenous thrombin potential (ETP) with and without thrombomodulin was significantly higher in African-Caribbeans with DVT than whites with DVT (P ≤ 0.001 for both comparisons). Maximum velocity and ETP ratio were increased in African-Caribbeans with DVT compared with whites with DVT (P < 0.001 and 0.030, respectively) and African-Caribbean controls (P < 0.001 and 0.019, respectively). Within the control group, peak thrombin was significantly increased in African-Caribbeans compared with whites (P = 0.017). ETP, peak thrombin with thrombomodulin and maximum velocity were also increased in African-Caribbeans compared with white controls (P = 0.045 for all comparisons). African-Caribbeans with DVT had significantly higher factor VIII levels compared with whites with DVT and controls. African-Caribbean ethnicity confers a hypercoagulable state as measured by thrombin generation. This supports epidemiological findings of increased risk of first and recurrent VTE. Thrombin generation requires adjustment for ethnicity in studies undertaken in ethnically diverse populations.