Risk Factors, Treatment and Prevention of Venous Thromboembolism During Pregnancy and Postpartum

The naturally hypercoagulable state occurring during pregnancy and anatomical changes and changes in the plasma volume are the main reasons for the increased risk of venous thromboembolism (VTE) during pregnancy and puerperium. This risk is particularly enhanced in the presence of thrombophilia and a previous history of VTE. The cornerstone for treating and preventing VTE is low molecular weight heparin (LMWH). There is currently no consensus on the dosing and the need for monitoring treatment with LMWH, and varying protocols are used in different clinics. The risk models used to stratify the risk for recurrence are based on the presence of factors such as previous VTE, familial history and thrombophilia and lead to decisions on the dosing and the duration of thromboprophylaxis. Treatment with LMWH is considered safe and effective, with low incidence of adverse effects (bleeding, osteoporosis, etc.) and recurrence of VTE. The use of direct oral anticoagulants is currently not recommended in this setting, but case series have not indicated increased embryopathy. The lack of international guidelines and large studies underlines the need for collaboration in order to further improve outcomes and patient safety

Acquired Haemophilia A in four north European countries : survey of 181 patients

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5-99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.Peer reviewe

Phosphatidylserine positive microparticles improve hemostasis in in-vitro hemophilia A plasma models

Circulating microparticles (MPs) are procoagulant due to the surface containing phosphatidylserine (PS), which facilitates coagulation. We investigated if MPs improve hemostasis in HA plasma models. MPs isolated from pooled normal human plasma were added to severe, moderate and mild HA plasma models (0%, 2.5%, 20% FVIII). The MPs' effect on hemostasis was evaluated by calibrated automated thrombogram (CAT) and overall hemostasis potential (OHP) assays, while fibrin structure was imaged by standard confocal, stimulated emission depletion (STED) microscopy and scanning electron microscopy (SEM). MPs partially restored thrombin generation and fibrin formation in all HA plasma models. The procoagulant effect of MPs requires PS exposure, to a less extent of contact pathway activation, but not tissue factor exposure or in vitro stimulation of MPs. MPs partially normalized the fibrin structure, and using super-resolution STED, MPs attached to fibrin were clearly resolved. In summary, our results demonstrate that PS positive MPs could improve hemostasis in HA plasma models

Risk Factors and Risk Stratification of Thromboembolic Risk in Patients with Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy characterized by a high risk for thrombotic episodes, mainly venous thromboembolism (VTE). This risk is accentuated by cancer treatments such as immunomodulatory drugs (IMiDs). Cancer-associated thrombosis is one of the leading causes of mortality and morbidity, and the prevention of thrombosis is, therefore, of paramount significance. To this day, it is unclear which type of thromboprophylaxis is the most effective. This is partly due to the multifactorial etiology behind thrombosis since the compound of patient-, disease- and treatment-associated factors characterizing each patient with MM is unique. Additionally, the established risk scores are not reliable in patients with MM. The scope of this review is to summarize the factors contributing to increased thrombosis risk in MM, as well as the risk scores and thromboprophylaxis regimes available

Thrombin generation in different cohorts : Evaluation of the haemostatic potential

The aim of this thesis is to evaluate thrombin generation in patients with thrombophilia (Paper I), in patients with venous thromboembolism (Paper II), in healthy women during the menstrual cycle (Paper III), in patients with liver disease (Paper IV) and in patients with mild deficiency of factor VII (Paper V). For this purpose, thrombin generation was measured in platelet poor plasma by the calibrated automated thrombogram (CAT®) assay. Thrombin generation expresses the overall haemostatic potential, in contrast to the more traditional coagulation tests, which concentrate on individual factors or coagulation pathways. The thrombin generation markers that were measured and studied were: lagtime (clotting time), endogenous thrombin potential (ETP, total thrombin concentration), peak (maximum thrombin concentration) and time to peak (ttpeak). The cohorts for Papers I and II are part of a larger cohort (The LInköping Study on Thrombosis, LIST), which included 516 consecutive patients who presented at the Emergency Department of Linköping University Hospital, Sweden with the clinical suspicion of venous thrombosis. In Paper I thrombin generation was measured in the absence of thrombomodulin in patients with thrombophilia (factor V Leiden, n=98 and prothrombin G20210A mutation, n=15) and in an equal number of age- and gendermatched controls. The results were associated with the presence of thrombosis, as well as gender and age. It was shown that thrombin generation did not differ significantly among patients and controls. Patients with and patients without thrombophilia who had suffered a thrombosis upon inclusion had longer lagtime compared with their counterparts without thrombosis. Neither age nor gender had any effect on the results. In Paper II, thrombin generation at the time of an acute thromboembolic episode was studied as a potential early marker for recurrence during a 7-year follow-up in 115 patients with venous thrombosis upon inclusion. It was shown that patients with recurrences during follow-up had longer lagtime and ttpeak at the time of the acute thrombosis, whereas those without recurrences had higher ETP and peak. Those results were particularly evident in the group of patients with an unprovoked thrombosis upon inclusion. In Paper III, thrombin generation was measured in the follicular and luteal phase of a normal menstrual cycle in 102 healthy women not taking oral contraceptives. The results were associated with haemostatic parameters (fibrinogen, antithrombin, D-dimer, plasminogen activator inhibitor-1, factors VII, VIII, X and von Willebrand) as well as the physiological concentrations of oestradiol, progesterone, antimüllerian hormone and sex hormone-binding globulin and the number of pregnancies and deliveries for these women. ETP was significantly higher during the luteal phase. However, this could not be explained by the elevation of other procoagulant factors during the same phase. Progesterone was found to exert a more significant effect on haemostasis than oestradiol during both phases (multiple regression analysis). In Paper IV, thrombin generation was measured in the presence and absence of thrombomodulin in 47 patients with portal vein thrombosis, PVT (11 with cirrhotic PVT and 36 with non-cirrhotic PVT), 15 patients with Budd-Chiari syndrome and 24 patients with cirrhosis, as well as 21 healthy controls. Since 15 patients with PVT (2 with cirrhotic PVT and 13 with non-cirrhotic PVT) and 10 patients with Budd-Chiari syndrome were treated with warfarin at the time of the blood sampling, an equal number of patients matched for age, gender and prothrombin time-international normalized ratio with atrial fibrillation and no hepatic diseases were used as controls. It was shown that hypercoagulability, expressed as total and maximum concentration of generated thrombin as well as thrombomodulin resistance [thrombin generation markers measured in the presence]/[thrombin generation markers measured in the absence of thrombomodulin] was pronounced in the groups of patients with cirrhosis, regardless of the presence of splanchnic thrombosis. In Paper V, thrombin generation in the presence of human and different concentrations of rabbit thromboplastin was measured in 10 patients with mild deficiency of factor VII and in 12 controls. In these patients, the levels of factor VII varied slightly depending on the origin of the thromboplastin used in the reagent. Nine out of 10 patients had a mutation in common (Arg353Gln), which was, however, not associated with the diversity in the factor VII measurements due to the origin of thromboplastin. ETP in patients with mild factor VII deficiency was about 86% of the ETP in the control group. The expected thrombin generation patterns with increasing concentrations of thromboplastin did not differ depending on the origin of thromboplastin in the patient group

Thrombin generation in different cohorts : Evaluation of the haemostatic potential

The aim of this thesis is to evaluate thrombin generation in patients with thrombophilia (Paper I), in patients with venous thromboembolism (Paper II), in healthy women during the menstrual cycle (Paper III), in patients with liver disease (Paper IV) and in patients with mild deficiency of factor VII (Paper V). For this purpose, thrombin generation was measured in platelet poor plasma by the calibrated automated thrombogram (CAT®) assay. Thrombin generation expresses the overall haemostatic potential, in contrast to the more traditional coagulation tests, which concentrate on individual factors or coagulation pathways. The thrombin generation markers that were measured and studied were: lagtime (clotting time), endogenous thrombin potential (ETP, total thrombin concentration), peak (maximum thrombin concentration) and time to peak (ttpeak). The cohorts for Papers I and II are part of a larger cohort (The LInköping Study on Thrombosis, LIST), which included 516 consecutive patients who presented at the Emergency Department of Linköping University Hospital, Sweden with the clinical suspicion of venous thrombosis. In Paper I thrombin generation was measured in the absence of thrombomodulin in patients with thrombophilia (factor V Leiden, n=98 and prothrombin G20210A mutation, n=15) and in an equal number of age- and gendermatched controls. The results were associated with the presence of thrombosis, as well as gender and age. It was shown that thrombin generation did not differ significantly among patients and controls. Patients with and patients without thrombophilia who had suffered a thrombosis upon inclusion had longer lagtime compared with their counterparts without thrombosis. Neither age nor gender had any effect on the results. In Paper II, thrombin generation at the time of an acute thromboembolic episode was studied as a potential early marker for recurrence during a 7-year follow-up in 115 patients with venous thrombosis upon inclusion. It was shown that patients with recurrences during follow-up had longer lagtime and ttpeak at the time of the acute thrombosis, whereas those without recurrences had higher ETP and peak. Those results were particularly evident in the group of patients with an unprovoked thrombosis upon inclusion. In Paper III, thrombin generation was measured in the follicular and luteal phase of a normal menstrual cycle in 102 healthy women not taking oral contraceptives. The results were associated with haemostatic parameters (fibrinogen, antithrombin, D-dimer, plasminogen activator inhibitor-1, factors VII, VIII, X and von Willebrand) as well as the physiological concentrations of oestradiol, progesterone, antimüllerian hormone and sex hormone-binding globulin and the number of pregnancies and deliveries for these women. ETP was significantly higher during the luteal phase. However, this could not be explained by the elevation of other procoagulant factors during the same phase. Progesterone was found to exert a more significant effect on haemostasis than oestradiol during both phases (multiple regression analysis). In Paper IV, thrombin generation was measured in the presence and absence of thrombomodulin in 47 patients with portal vein thrombosis, PVT (11 with cirrhotic PVT and 36 with non-cirrhotic PVT), 15 patients with Budd-Chiari syndrome and 24 patients with cirrhosis, as well as 21 healthy controls. Since 15 patients with PVT (2 with cirrhotic PVT and 13 with non-cirrhotic PVT) and 10 patients with Budd-Chiari syndrome were treated with warfarin at the time of the blood sampling, an equal number of patients matched for age, gender and prothrombin time-international normalized ratio with atrial fibrillation and no hepatic diseases were used as controls. It was shown that hypercoagulability, expressed as total and maximum concentration of generated thrombin as well as thrombomodulin resistance [thrombin generation markers measured in the presence]/[thrombin generation markers measured in the absence of thrombomodulin] was pronounced in the groups of patients with cirrhosis, regardless of the presence of splanchnic thrombosis. In Paper V, thrombin generation in the presence of human and different concentrations of rabbit thromboplastin was measured in 10 patients with mild deficiency of factor VII and in 12 controls. In these patients, the levels of factor VII varied slightly depending on the origin of the thromboplastin used in the reagent. Nine out of 10 patients had a mutation in common (Arg353Gln), which was, however, not associated with the diversity in the factor VII measurements due to the origin of thromboplastin. ETP in patients with mild factor VII deficiency was about 86% of the ETP in the control group. The expected thrombin generation patterns with increasing concentrations of thromboplastin did not differ depending on the origin of thromboplastin in the patient group

Risk Factors and Risk Stratification of Thromboembolic Risk in Patients with Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy characterized by a high risk for thrombotic episodes, mainly venous thromboembolism (VTE). This risk is accentuated by cancer treatments such as immunomodulatory drugs (IMiDs). Cancer-associated thrombosis is one of the leading causes of mortality and morbidity, and the prevention of thrombosis is, therefore, of paramount significance. To this day, it is unclear which type of thromboprophylaxis is the most effective. This is partly due to the multifactorial etiology behind thrombosis since the compound of patient-, disease- and treatment-associated factors characterizing each patient with MM is unique. Additionally, the established risk scores are not reliable in patients with MM. The scope of this review is to summarize the factors contributing to increased thrombosis risk in MM, as well as the risk scores and thromboprophylaxis regimes available

in different cohorts Evaluation of the haemostatic potential

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Is thrombin generation at the time of an acute thromboembolic episode a predictor of recurrence? The LInkoping Study on Thrombosis (LIST) - A 7-year follow-up

Introduction: Venous thromboembolism(VTE) is considered a chronic disease, since a high percentage of patients experience recurrences. Oral anticoagulants are effective in preventing recurrences at a price of potential bleeding complications, which underlines the importance of finding reliable markers for estimating the individual recurrence risk. In this report we evaluate thrombin generation markers at the time of an acute VTE as predictive markers for recurrence risk. Gender, presence of factor V Leiden and acquired provocative factors were taken into consideration. Additionally, we study the correlation between thrombin generation at the time of an acute VTE and thrombin generation measured four to eight weeks after discontinuation of anticoagulants. less thanbrgreater than less thanbrgreater thanMaterials and Methods: Themain cohort consisted of 115 patients with a confirmed thromboembolic event at inclusion. The follow-up period was seven years. less thanbrgreater than less thanbrgreater thanResults: Patients with an initial unprovoked VTE and at least one recurrence had significantly prolonged thrombin generation, whereas those without recurrences had higher maximum and total thrombin concentration. In contrast, when thrombin generation was measured one to two months after discontinuation of anticoagulant treatment, it was shown that the patients who experienced recurrences had higher maximum thrombin concentration. less thanbrgreater than less thanbrgreater thanConclusions: Our study shows that thrombin generation profiles at the time of a VTE correlate to the clinical course after the acute episode. The great over-lap in thrombin generation between patients with and without recurrences though, makes the use of thrombin generation profiles for advice on length of oral anticoagulation for an individual patient doubtful at the present stage of knowledge.Funding Agencies|County Council of Ostergotland||Research Funds of the University Hospital, Linkoping, Sweden||</p