Differential Effects of Clopidogrel With or Without Aspirin on Platelet Reactivity and Coagulation Activation: A Randomized Trial in Healthy Volunteers.

Dual antiplatelet therapy (DAPT) is standard in acute coronary syndrome but confers a bleeding risk. To compare effects of clopidogrel single antiplatelet therapy (SAPT) with clopidogrel-based DAPT on hemostatic system activation we conducted a randomized clinical trial in 44 volunteers (clopidogrel (d1: 600 mg, d2-6: 150 mg) ± aspirin (100 mg)). Multiple electrode aggregometry-adenosine diphosphate (MEA-ADP) and MEA-arachidonic acid (MEA-AA) triggered aggregometry, vasodilator-stimulated phosphoprotein (VASP), beta thromboglobulin, p-selectin, thromboxane B2 , d-Dimer, prothrombin fragment 1.2 (f1.2), and a phospholipid-dependent clotting time were measured in venous blood. Changes are described by mean differences (Δmean (95% confidence interval (CI)) or geometric mean ratios (95% CI)). DAPT and SAPT comparably and significantly decreased MEA-ADP at 2 hours (-60% vs. -63%; P = 0.35, Δmean -4.9, 95% CI -15.4 to 5.5). At 24 hours (-59% vs. -47%, P = 0.04, Δmean -11.1, 95% CI -21.7 to -0.4]) and 8 days (-61% vs. -53%, P = 0.04, Δmean -11.3, 95% CI -22.0 to -0.6). Both treatments significantly reduced VASP and MEA-AA after 2 hours and 8 days. DAPT inhibited MEA-AA significantly stronger at 2 hours (-77% vs. -30%; P < 0.0001, Δmean -39.6, 95% CI -54.2 to -25.0), at 24 hours (-80% vs. -27%, P < 0.0001, Δmean -47.8, 95% CI -62.3 to -33.3), and 8 days (-79% vs. -27%, P < 0.0001, Δmean -48.9, 95% CI -62.5 to -35.4). Neither treatment significantly influenced beta thromboglobulin or p-selectin. DAPT abolished and SAPT reduced thromboxane B2 after 24 hours and 8 days. The d-Dimer was reduced by DAPT (0.94, 95% CI 0.89-1.00, P = 0.04) at 2 hours but not after 24 hours and 8 days. SAPT did not decrease d-Dimer. Neither treatment affected f1.2. DAPT and SAPT comparably affect platelet and coagulation activation in venous blood.

Data Rich, Information Poor: Can We Use Electronic Health Records to Create a Learning Healthcare System for Pharmaceuticals?

Judicious use of real-world data (RWD) is expected to make all steps in the development and use of pharmaceuticals more effective and efficient, including research and development, regulatory decision making, health technology assessment, pricing, and reimbursement decisions and treatment. A "learning healthcare system" based on electronic health records and other routinely collected data will be required to harness the full potential of RWD to complement evidence based on randomized controlled trials. We describe and illustrate with examples the growing demand for a learning healthcare system; we contrast the exigencies of an efficient pharmaceutical ecosystem in the future with current deficiencies highlighted in recently published Organisation for Economic Co-operation and Development (OECD) reports; and we reflect on the steps necessary to enable the transition from healthcare data to actionable information. A coordinated effort from all stakeholders and international cooperation will be required to increase the speed of implementation of the learning healthcare system, to everybody's benefit.

The effect of a dual or a triple antithrombotic therapy with apixaban on thrombus formation in vivo and in an ex vivo perfusion chamber model: An open-label, controlled, sequential study.

BACKGROUND: There is a need to optimize pharmacological treatment in patients with acute coronary syndrome and concomitant atrial fibrillation, in particular with newer antithrombotic medicines. We have therefore studied if dual or triple combination of antithrombotic agents exert similar effects on coagulation activation in an in vivo model in the skin microvasculature and in an ex vivo perfusion chamber. METHODS AND RESULTS: Shed blood platelet activation (ß-thromboglobulin [ß-TG]), thrombin generation (thrombin-antithrombin complex [TAT]) and volume as well as markers of thrombus size (D-dimer) and its platelet content (P-selectin) in a perfusion chamber were studied in a sequential, open-label, parallel group trial in 40 healthy male volunteers (n = 20 per group). Subjects received ticagrelor and apixaban without or with acetylsalicylic acid (ASA). Outcome parameters were assessed at 3 hours after therapy dosing, and at steady-state trough and peak conditions.A triple or dual therapy induced a comparable decrease in shed blood ß-TG at 3 hours after therapy dosing but was more pronounced at steady-state conditions with the more intense treatment combination. During both antithrombotic regimens a similarly sustained inhibition in thrombin generation was observed which was accompanied by comparable increases in shed blood volume. In contrast, no treatment effect could be observed in the perfusion chamber experiment. CONCLUSION: Ticagrelor and apixaban with or without ASA inhibit platelet activation and thrombin formation in vivo in healthy subjects. Platelet inhibition was greater at steady-state conditions after triple therapy administration.

Dabigatran: patient management in specific clinical settings.

Dabigatran, a direct thrombin inhibitor, is licensed for the prevention of venous thromboembolism after knee and hip replacement, the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the treatment of acute venous thromboembolism. As dabigatran has a favourable benefit-risk profile, it is being increasingly used. Dabigatran differs from vitamin K antagonists as regards its pharmacological characteristics and its impact on certain laboratory tests, and also in the lack of a direct antagonist that can reverse dabigatran-induced anticoagulation. In emergency settings such as acute bleeding, emergency surgery, acute coronary syndrome, thrombolysis for ischaemic stroke or overdosing, specific strategies are required. A working group of experts from various disciplines has developed strategies for the management of dabigatran-treated patients in emergency settings.

Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials.

BACKGROUND: Surgical intervention may pose significant risk of life-threatening bleeding in patients with von Willebrand's disease; prophylactic treatment with von Willebrand factor/factor VIII concentrate is generally indicated for von Willebrand's disease characterized by moderate to severe qualitative and quantitative deficiencies of Willebrand factor to raise and maintain both Willebrand factor and FVIII at haemostatic levels for surgical prophylaxis. MATERIALS AND METHODS: Since prospective clinical data in such situations were lacking, two recent, prospective, multicentre studies evaluated the prophylactic perioperative use of the on Willebrand factor/ factor VIII concentrates, Humate-P® and Haemate P. Despite some differences in the two studies, one conducted in the USA (n =35) and one in the European Union (n =27), the designs were similar enough to allow for a limited pooled analysis of data. In both studies, preoperative loading doses and subsequent maintenance doses were calculated using individual subject-derived incremental in vivo recovery values, although von Willebrand factor:ristocetin cofactor and FVIII:coagulation activity target levels differed between the protocols. Efficacy was rated daily by the investigator as excellent, good, moderate, or poor. RESULTS: Overall haemostatic efficacy (rating of excellent/good), assessed 24 hours after the last infusion (USA) or taken as the worst rating between surgery and day 14 (EU), was achieved in 95% of the pooled population of 62 adults and children. Efficacy did not appear to be affected by dosing variations. The rate of possibly related adverse events was low (8 subjects; 13%); one of these events was considered serious (pulmonary embolism). DISCUSSION: This pooled analysis of a relatively large number of patients for a rare disease confirms the feasibility of pharmacokinetically guided dosing of von Willebrand factor/factor VIII concentrate and highlights its efficacy and safety in the prevention of excessive perioperative bleeding.

Tissue factor exposing microparticles in inflammatory bowel disease.

BACKGROUND: Circulating procoagulant microparticles (MPs) are thought to be involved in the pathogenesis of venous thromboembolism in patients with inflammatory bowel disease (IBD). However, the exposure of tissue factor, the primary initiator of coagulation activation, on microparticles (TF(+)MPs) and its association with hemostasis activation has not yet been studied in IBD patients. METHODS: In this case-control study 49 IBD patients (28 Crohn's disease, 21 ulcerative colitis) and 49 sex- and age-matched, healthy controls were included. Clinical disease activity (Crohn's Disease Activity Index and Clinical Activity Index, respectively) was assessed and IBD-related data were determined by chart review. Numbers, cellular origin and procoagulant activity of TF(+)MPs in plasma were determined using flow cytometry and a chromogenic activity assay. D-dimer and high-sensitive C-reactive protein (CRP) served as markers for coagulation activation and inflammation, respectively. The primary endpoint was the number of TF(+)MPs in IBD patients compared to controls. RESULTS: Median number (interquartile range) of TF(+)MPs was higher in IBD patients than in controls (14.0 (11.9-22.8)×10(3)/mL vs. 11.9 (11.9-19.1)×10(3)/mL plasma, P=0.029). This finding was due to generally higher plasma levels of MPs from platelets and leukocytes in IBD patients. However, the number of TF(+)MPs was neither correlated with their procoagulant activity and D-dimer nor with disease activity and CRP. CONCLUSIONS: Increased numbers of circulating TF(+)MPs represent a new facet of hemostatic abnormalities in IBD. However, the lack of association with activation of the coagulation system and disease activity questions their pathogenetic role for venous thromboembolism in this patient group.

The influence of thrombophilia on the long-term survival of patients with a history of venous thromboembolism.

Data on the long-term survival following venous thromboembolism (VTE) are rare, and the influence of thrombophilia has not been evaluated thus far. Our aim was to assess thrombophilia-parameters as predictors for long-term survival of patients with VTE. Overall, 1,905 out-patients (99 with antithrombin-, protein C or protein S deficiency, 517 with factor V Leiden, 381 with elevated factor VIII and 160 with elevated homocysteine levels, of these 202 had a combination and 961 had none of these risk factors) were included in the study between September 1, 1994 and December 31, 2007. Retrospective survival analysis showed that a total of 78 patients (4.1%) had died during the analysis period, among those four of definite or possible pulmonary embolism and four of bleeding. In multivariable analysis including age and sex an association with increased mortality was found for hyperhomocysteinemia (hazard ratio 2.0 [1.1.-3.5]) whereas this was not the case for all other investigated parameters. We conclude that the classical hereditary thrombophilia risk factors did not have an impact on the long-term survival of patients with a history of VTE. Thus our study supports the current concept that thrombophilia should not be a determinant for decision on long term anticoagulation. However, hyperhomocysteinaemia, known as a risk factor for recurrent VTE and arterial disease, might impact survival.

Long-term survival of patients with a history of venous thromboembolism.

Limited data are available regarding long-term survival following venous thromboembolism (VTE). The objectives of this study are to evaluate long-term survival by retrospective survival analysis in patients with a history of VTE and to compare their survival with that of the general population. Patients with a history of VTE (min. 3 months after VTE) without cancer, who were referred to our department between 1994 and 2007, were included in the analysis. Information concerning mortality was available through the Austrian Central Death Register. The survival of patients was compared with that of the age- and gender-matched general Austrian population. Three thousand two hundred-nine patients (mean age, 46.2; range, 14-89 years) were included. Median time interval between the first VTE and inclusion was 14 months; median observation period was 6.6 years. During the considered time period, 169 patients (5.3%) died. The cumulative survival in patients was 0.97 and 0.87 after 5 and 10 years; men had a higher death rate than women; patients with idiopathic VTE had a less favourable survival than those with a triggering event. When patients were compared to the general population, the cumulative relative survival was 1.02 (95% CI 1.00-1.03). In none of the analysed subgroups (different sites of VTE; idiopathic vs. secondary VTE) was a reduced cumulative relative survival found. The relative survival of male patients was even slightly better, whereas that of women equalled that of the normal population. Our results indicate that after the initial phase, VTE does not seem to impair long-term survival of patients with a history of VTE without cancer.

Risk assessment for recurrent venous thrombosis.

Venous thrombosis is a common disease that frequently recurs. Recurrence can be prevented by anticoagulants, albeit at the cost of bleeding. Thus, assessment of the risk of recurrence is important to balance the risks and benefits of anticoagulation treatment. Many clinical and laboratory risk factors for recurrent venous thrombosis have been established. Nevertheless, prediction of recurrence in an individual patient remains a challenge. Detection of some laboratory markers is associated with only a moderate risk of recurrence, and the relevance of others is not known. Many patients have several risk factors and the effect of combined defects is obscure. Routine screening for these laboratory markers should therefore be abandoned. Risk assessment can be improved by measurement of global markers that encompass the effects of clotting and fibrinolytic disorders. Analysis of preliminary data suggests that risk assessment can also be refined through integration of prothrombotic coagulation changes and clinical risk factors.

The course of severe autoimmune thrombocytopenia in patients not undergoing splenectomy.

BACKGROUND AND OBJECTIVES: Splenectomy is the most effective treatment for patients with severe autoimmune thrombocytopenia (AITP) who do not have a spontaneous or drug- induced remission. However, this treatment has some short and long term risks. There is no consensus on the indications and optimal timing of splenectomy, since it is unknown up to which time from onset of symptoms a remission can be expected without splenectomy. DESIGN AND METHODS: We studied the incidence of complete or partial remissions in a cohort of 114 adult patients (68 women, 46 men, median age 49.8 years, interquartile range 28.3-68.4) with severe AITP (platelet count < 20x10(9)/L at diagnosis) using Kaplan Meier analysis. Patients who underwent splenectomy during the observation period were censored at the time of splenectomy. RESULTS: The probability of a complete remission was 61% and that of at least a partial remission was 86% at 5 years. The incidence of complete remission was highest within the first 6 months (30%), but increased up to 53% between 6 months and 3 years after diagnosis. The probability of a remission was not related to age, gender, or the presence or absence of platelet antibodies, but was higher in patients with an acute onset of symptoms in comparison to those with an insidious onset (p = 0.0003). The chance of a late remission was higher in patients with an insidious onset of disease. INTERPRETATION AND CONCLUSIONS: These data indicate that splenectomy may be delayed for up to 3 years, in particular in those patients whose AITP has had an insidious onset.

Family history for venous thromboembolism and the risk for recurrence.

PURPOSE: The relevance of a family history for venous thromboembolism with regard to the likelihood for recurrence is unknown. SUBJECTS AND METHODS: We studied 826 patients for an average of 36 months after a first unprovoked venous thromboembolism and withdrawal of oral anticoagulation. Patients with cancer, lupus anticoagulant, or deficiency of antithrombin, protein C, or protein S were excluded. The study endpoint was objective evidence of recurrent symptomatic venous thromboembolism. RESULTS: Recurrence for venous thromboembolism was recorded in 23 of 190 patients (12.1%) with a family history (at least one affected first-degree family member) and in 79 of 636 patients (12.4%) without familial thrombosis (relative risk for recurrence 1.0; 95% confidence interval, 0.7-1.6; P=.9). At 5 years, the likelihood for recurrence was 20% among patients with a family history for venous thromboembolism and 18% among those without a family history for venous thromboembolism (P=.9). Risk determinants for venous thromboembolism including factor V Leiden, factor II G20210A, and high factor VIII were not statistically different between the 2 groups. CONCLUSION: A family history for venous thromboembolism does not segregate patients into high- or low-risk categories and is not suitable to identify patients at increased risk for recurrent venous thromboembolism.

The optimal duration of secondary thromboprophylaxis in patients with venous thromboembolism. The importance of thrombophilia screening.

Venous thromboembolism is a chronic disease with an annual incidence of recurrence of 5 to 10%. Patients with venous thrombosis should be treated with anticoagulants for at least 3 months. The optimal duration of anticoagulation entails balancing the risk of recurrence against the risk of treatment-associated bleeding. Candidates for extended anticoagulation are patients with a high risk of recurrence. The risk of recurrence is increased in patients with antithrombin deficiency, the lupus anticoagulant, homozygous F V Leiden, combined defects, high F VIII, high F IX, high TAFI, hyperhomocysteinemia or more than one episode of thrombosis. The risk of recurrence is low in patients with venous thrombosis secondary to surgery or trauma. Routine thrombophilia screening is aimed at identifying patients who could benefit from extended anticoagulation. This population consists of patients with venous thrombosis at a young age, an unprovoked episode of venous thrombosis, patients with a strong positive family history or patients with recurrent venous thrombosis. Screening should comprise antithrombin determination and the search for the lupus anticoagulant. Patients harbouring one of these defects are at high risk of recurrence and most likely will profit from prolonged anticoagulation. The clinical relevance of new treatment strategies such as extended low-intensity warfarin or administration of the direct thrombin inhibitor (xi-)melagatran is at present unclear.

Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism.

BACKGROUND: In patients with a first symptomatic pulmonary embolism (PE), the risk of recurrence is unknown. We therefore investigated the risk of recurrence among patients with spontaneous symptomatic PE and among those with deep vein thrombosis (DVT) without symptoms of PE. METHODS: After discontinuation of secondary thromboprophylaxis for a first venous thromboembolism (VTE), we prospectively observed 436 patients for an average of 30 months. Patients with secondary VTE, natural inhibitor deficiencies, lupus anticoagulant, cancer, long-term antithrombotic therapy, vena cava filters, or pregnancy were excluded. The study outcome was objectively documented recurrent symptomatic VTE. RESULTS: Recurrent VTE was seen among 28 (17.3%) of 162 patients with symptomatic PE and among 26 (9.5%) of 274 patients with DVT without symptoms of PE. Compared with patients with DVT, the relative risk of recurrent VTE among patients with symptomatic PE was 2.2 (95% confidence interval, 1.3-3.7; P =.005). The relative risk was not affected by age, sex, presence of factor V Leiden or prothrombin G20210A, hyperhomocysteinemia, or high factor VIII levels. Compared with patients with DVT without symptoms of PE, patients with symptomatic PE had an adjusted relative risk of PE at recurrence of 4.0 (95% confidence interval, 1.3-12.3; P =.03). CONCLUSION: Patients with a first symptomatic PE not only have a higher risk of recurrent VTE than those with DVT without symptoms of PE, but are also at high risk of symptomatic PE at recurrence.

Mortality in severe, non aggressively treated adult autoimmune thrombocytopenia.

A total of 130 consecutive patients with severe autoimmune thrombocytopenia (AITP) who were diagnosed and treated in our institution between 1991 and 2001 were followed up. The patients were almost exclusively treated with prednisolone, immunoglobulin and/or splenectomy. The aim of the treatment was to keep the platelet count at least above 10,000 microL. None of the patients died from bleeding, two patients died from infection and seven from other unrelated causes. These data show that AITP is a relatively benign disease that does not require aggressive treatment. Bleeding can be prevented if the platelet count can be kept above 10,000 microL.

The risk of recurrent venous thromboembolism: the Austrian Study on Recurrent Venous Thromboembolism.

Venous thromboembolism (VTE) is a chronic disease. After withdrawal of oral anticoagulation at least a third of patients will experience a subsequent episode of venous thrombosis. Of these patients, approximately 5% will die from pulmonary embolism. The Austrian Study on Recurrent Venous Thromboembolism (AUREC) is a prospective cohort study aiming to investigate the overall rate of recurrent VTE, the predictive value of laboratory assays, the importance of acquired or congenital risk factors for thrombosis and the impact of extended or modified secondary thromboprophylaxis on the risk of recurrence among high-risk patients. So far, the AUREC investigators have identified subgroups of patients with a particular high risk of recurrence: patients with a history of venous thrombosis, elevated levels of coagulation factors VIII, IX and XI, pulmonary embolism or superficial venous thrombosis and a history of venous thrombosis and hyperhomocysteinemia. Patients with a history of venous thrombosis and mutations in genes encoding for coagulation factors (factor V Leiden, factor II, G20210A) do not have an enhanced risk of recurrence and, thus, do not qualify for extended secondary thromboprophylaxis. At present, interventional trials are in progress in patients with high factor VIII or hyperhomocysteinemia in order to investigate if these patient groups might benefit from extended oral anticoagulation or vitamin supplementation, respectively.

Unilateral chronic thromboembolic pulmonary disease associated with combined inherited thrombophilia.

Chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be an extreme variant of pulmonary thromboembolism. The underlying mechanisms for the failure of thrombus resolution are still unclear. In looking for inherited thrombophilia, an association with a lupus anticoagulant has been described repeatedly, and single cases of anticoagulant deficiencies (ie, antithrombin [AT], protein C, and protein S) have been reported. We describe a young patient with type I AT deficiency, the heterozygous prothrombin G20210A mutation, and unilateral chronic thromboembolic pulmonary disease presenting after a single thrombotic event. Pulmonary vascular patency was restored successfully by surgical pulmonary thromboendarterectomy. This case is unique because unilateral CTEPH is extremely uncommon, and it illustrates the severe clinical sequelae of the cosegregation of inherited thrombophilic defects.