Essentials
Pregnancy is a risk factor for thrombosis.
Management of thrombosis risk in pregnancy remains a challenge.
Prophylaxis needs to be personalized.
Our score may be a helpful tool for the ...management of pregnancies at high risk of thrombosis.
Summary
Background
Patients with thrombophilia and/or a history of venous thromboembolism (VTE) are at risk of thrombosis during pregnancy. A risk score for pregnancies with an increased risk of VTE was previously described by our group (Lyon VTE score).
Objectives
The aim of this prospective study was to assess the efficacy and safety of our score‐based prophylaxis strategy in 542 pregnancies managed between 2005 and 2015 in Lyon University Hospitals.
Patients/Methods
Of 445 patients included in the study, 36 had several pregnancies during the study period. Among these 445 patients, 279 had a personal history of VTE (62.7%), 299 patients (67.2%) had a thrombophilia marker, and 131 (29.4%) thrombophilic women had a personal history of VTE. During pregnancy, patients were assigned to one of three prophylaxis strategies according to the risk scoring system.
Results
In the antepartum period, low molecular weight heparin (LMWH) prophylaxis was prescribed to 64.5% of patients at high risk of VTE. Among them, 34.4% were treated in the third trimester only, and 30.1% were treated throughout pregnancy. During the postpartum period, all patients received LMWH for at least 6 weeks. Two antepartum‐related VTEs (0.37%; one with a score of < 3 and the other with a score of > 6) and four postpartum‐related VTEs (0.73%; three with scores of 3–5 and one with a score of > 6) occurred. No case of pulmonary embolism was observed during the study period. The rate of bleeding was 0.37%. No serious bleeding requiring transfusions or surgery occurred during the study period.
Conclusion
The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.
Patients with congenital afibrinogenemia suffer from spontaneous recurrent severe bleeding. While fibrinogen concentrates are known to effectively treat bleeding episodes, thrombotic complications ...often occur upon replacement therapy, rendering clinical management highly challenging.
We hereby report a case of combined afibrinogenemia and congenital antithrombin deficiency manifested by recurrent life-threatening bleeding, as well as spontaneous severe arterial occlusion, such as acute coronary syndrome and stroke, and venous thromboses like pulmonary embolism.Secondary fibrinogen prophylaxis is recommended following any initial life-threatening bleeding episode in patients with afibrinogenemia, yet the high associated risk of thrombosis illustrates the complexity of choosing the most effective prophylaxis strategy combining fibrinogen concentrate with antithrombotic agent for optimal protection against the risk of both severe bleeding and thrombosis. For our patient, the thrombin generation assay objectively confirmed her prothrombotic tendency.
This case may help us better understand the pathophysiology of arterial thrombosis in afibrinogenemia, while highlighting the difficulty of managing such complications.
Objective
Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in ...different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations.
Methods
We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded.
Results
To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug–drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute range 23–58 ml/minute) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml range 504–2,229 ng/ml versus 917 ng/ml range 208–3316 ng/ml) (P < 0.001).
Conclusion
We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.
Background: Human prothrombin complex concentrates (PCCs) are used for prevention and treatment of bleeding episodes in patients under warfarin therapy. PCCs contain human factor (F) II, FVII, FIX, ...FX, protein C and protein S. The concentrations of these coagulation factors contained in PCCs are variable and do not reflect entirely the capacity of these drugs to correct hemostasis. Furthermore, commercially available PCCs do not have exactly the same composition, though they are all labelled and prescribed in units per kg of FIX (10–40 IU of FIX/kg). As the final product generated by PCCs is thrombin, a thrombin generation (TG) test could theoretically be used for monitoring the hemostatic correction. Methods: TG was measured in platelet free plasma in the presence of tissue factor 5 pm and phospholipids 4 μm with a final concentration of PCC of 0–0.1–0.2–0.3–0.4–0.5–0.75–1 IU ml−1. The activity of vitamin K‐dependent coagulation factors (i.e. FII, FVII, FIX, FX, protein C and protein S) were determined for each concentration of two different PCCs available on the French market. Results and Discussion: Our results showed that the addition of two different PCCs dose‐dependently increased the TG capacity in patients with INR of 2–2.5–3–4 and >7 (n = 15 subjects) that reached the normal values. We also found a significant correlation between endogenous thrombin potential (ETP) and INR (Pearson test, P < 0.0001). The two PCCs improved the TG parameters differently with increasing concentrations. The difference in the correction of TG capacity observed between the two drugs could be explained by a variable increase in FX, FVII and protein C with similar doses. These results strongly suggest that TG assay could be used for monitoring the clinical efficacy of PCC and for optimizing the therapeutic regimen towards a more individualized therapy involving the type of the bleeding complications, the level of inhibition of the coagulation system and the molecule content of the PCC.
Objective
Data on sustained remission of granulomatosis with polyangiitis (GPA) after discontinuation of therapy (referred to as GPA with sustained remission off‐therapy SROT) are scarce. In the ...present study, SROT among GPA patients from the French Vasculitis Study Group Registry was evaluated to identify factors associated with its occurrence and durability.
Methods
For inclusion of patients in the study, the diagnosis of GPA had to meet the GPA classification criteria defined by the American College of Rheumatology and/or the revised Chapel Hill Consensus Conference nomenclature for vasculitis. SROT was defined as achievement of remission (a Birmingham Vasculitis Activity Score of 0) that was sustained for ≥6 consecutive months after having discontinued glucocorticoid (GC) and immunosuppressant treatments. The characteristics of the patients at baseline and treatments received were compared at 3, 5, and 10 years postdiagnosis according to whether or not SROT had been reached and maintained.
Results
Among 795 patients with GPA, 92 GPA patients with SROT at 3 years postdiagnosis were compared to 342 control subjects who had experienced disease relapse and/or were still receiving GCs or immunosuppressants. No baseline differences were found, but patients with SROT at 3 years postdiagnosis had more frequently received intravenous cyclophosphamide as induction therapy compared to control subjects (P = 0.01), with a higher median number of infusions (P = 0.05). At 5 years postdiagnosis, no baseline differences were observed between groups, but patients with SROT at 5 years postdiagnosis had received more cyclophosphamide infusions compared to control subjects (P = 0.03). More patients with SROT had received rituximab as maintenance therapy than control subjects at 3 years and 5 years postdiagnosis (P = 0.09 and P < 0.001, respectively). Of the 74 patients enrolled in the GPA Registry with 10‐year follow‐up data after having received conventional maintenance therapy, 15 (20%) had reached SROT at 3 years, and 5 (7%) maintained SROT at 10 years postdiagnosis.
Conclusion
After conventional therapies, 7% of GPA patients had reached SROT at 10 years postdiagnosis. No baseline vasculitis characteristics distinguished patients who achieved/maintained SROT from those who experienced disease relapse and/or those who continued to receive GCs or immunosuppressant therapy, but patients with SROT had received more intensive induction therapy and rituximab as maintenance therapy more frequently.
Background
Thirty percent of Covid‐19 patients admitted to intensive care units present with thrombotic complications despite thromboprophylaxis. Bed rest, obesity, hypoxia, coagulopathy, and acute ...excessive inflammation are potential mechanisms reported by previous studies. Better understanding of the underlying mechanisms leading to thrombosis is crucial for developing more appropriate prophylaxis and treatment strategies.
Objective
We aimed to assess fibrinolytic activity and thrombin generation in 78 Covid‐19 patients.
Patients and Methods
Forty‐eight patients admitted to the intensive care unit and 30 patients admitted to the internal medicine department were included in the study. All patients received thromboprophylaxis. We measured fibrinolytic parameters (tissue plasminogen activator, PAI‐1, thrombin activatable fibrinolysis inhibitor, alpha2 anti‐plasmin, and tissue plasminogen activator‐modified ROTEM device), thrombin generation, and other coagulation tests (D‐dimer, fibrinogen, factor VIII, antithrombin).
Results and Conclusions
We observed two key findings: a high thrombin generation capacity that remained within normal values despite heparin therapy and a hypofibrinolysis mainly associated with increased PAI‐1 levels. A modified ROTEM is able to detect both hypercoagulability and hypofibrinolysis simultaneously in Covid‐19 patients with thrombosis.
Abstract Adverse events associated with the administration of fondaparinux are mainly bleeding complications. Fondaparinux lacks specific antidotes and there is no routine laboratory assay for ...monitoring the efficacy of fondaparinux. Thrombin generation test measures the kinetic of thrombin formation over time which is a more complete characterisation of the individual coagulation capacity than classical clot based assays. In the present study the reversal effect of three procoagulant molecules was tested on the anticoagulant effect of fondaparinux. A complete correction of thrombin generating capacity was found with low doses of Feiba while rFVIIa was responsible for a partial correction of the coagulation capacity.
Objectives
Benefits of hydroxychloroquine (HCQ) use on physician reported outcomes are well documented in systemic lupus erythematosus (SLE). We assess for the first time the association and ...predictive value of blood HCQ levels towards health-related quality of life (HRQOL) in SLE.
Methods
Data from the PLUS study (a randomized, double-blind, placebo-controlled, multicentre study) were utilized. Blood HCQ levels were quantified by high-performance liquid chromatography along with HRQOL assessments (Medical Outcomes Study-SF-36) at baseline (V1) and month 7 (V2).
Results
166 SLE patients’ data were analysed. Mean (SD) age and disease duration were 44.4 (10.7) and 9.3 (6.8) years. Eighty-seven per cent were women. Mean (SD, median, IQR) HCQ concentrations in the blood at V1 were 660 (314, 615, 424) ng/ml and increased to 1020 (632, 906, 781) ng/ml at V2 (mean difference 366 units, 95% confidence interval −472 to −260, p < 0.001). No significant correlations between HCQ concentrations with HRQOL domains at V1 or V2 were noted. There were no differences in HRQOL stratified by HCQ concentrations. HCQ concentrations at V1 or changes in HCQ concentration (V2-V1) were not predictive of HRQOL at V2 or changes in HRQOL (V2-V1).
Conclusions
No association of HCQ concentrations with current or longitudinal HRQOL were found in SLE.
To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).
Randomised, placebo-controlled study in patients with SSc to ...assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).
Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).
The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.
NCT01295736.
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