Disseminated intravascular coagulation: epidemiology, biomarkers, and management.

Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.

Viscoelastic testing in liver transplantation.

Despite the lack of large randomized clinical studies, viscoelastic tests (VETs) have been a critical armamentarium for hemostatic control in liver transplantation (LT) since the 1960s. Many transplant institutions have adopted VETs in their clinical practice. Several small-size randomized clinical trials on LT patients have suggested that VET-guided hemostatic treatment algorithms have led to decreased indications for and amounts of transfused blood products, especially fresh-frozen plasma, compared to standard laboratory-based hemostatic management. VETs have also been reported to offer insight into the diagnosis and prediction of LT patients' development of hypercoagulability-related morbidity and mortality. There is still a need for VET device-specific hemostatic algorithms in LT, and clinicians must take into account the tendency to underestimate the coagulation capacity of VETs in patients with end-stage liver disease where hemostasis is rebalanced.

Thrombin Inhibition: Preliminary Assessment of the Anticoagulant Potential of Turnera subulata (Passifloraceae).

Cardiovascular and thromboembolic disturbances are the main causes of disease-related deaths worldwide. Regardless of the etiological factors involved in thrombus formation, coagulation is mainly activated by thrombin, one of the most important blood clotting molecules. Thus, this study evaluated the Turnera subulata leaf crude extract, its ethyl acetate fraction effect on the coagulation cascade, and its possible side effects. Their phytocomposition indicated polyphenols, mainly flavonol-3-O-glycosylate and a flavone glycoside, without in vitro and in vivo toxicity. Regarding their potential anticoagulants, results displayed partial thromboplastin and prothrombin time activation, and Xa and IIa, and thrombin inhibition by heparin II cofactor, indicating significant anticoagulant activity, suggesting direct and indirect thrombin inhibition as the main mechanism of action. Therefore, T. subulata leaf active compounds exhibit therapeutic potential required to develop phytotherapeutic formulations to assist conventional anticoagulants in clinical treatments.

Pharmacy Technician Management of Stable, In-Range INRs Within a Clinical Pharmacy Anticoagulation Service.

BACKGROUND: There is increasing demand on pharmacist time within clinical pharmacy services, and pharmacy technicians are a crucial resource for expanding pharmacy practice. OBJECTIVE: To assess the safety and effectiveness of pharmacy technician management of stable, in-range international normalized ratio (INR) results compared with usual care. METHODS: This retrospective, longitudinal, noninferiority cohort study was conducted at an integrated health care delivery system with a centralized anticoagulation service. Adult patients receiving chronic warfarin therapy with therapeutic INR results over a 3-month period (i.e., 100% time in therapeutic range [TTR] during the 3 months before the index date) were eligible for referral to technician warfarin management between March 1, 2015, and December 31, 2015. Patients with similar INR control during the same period but not referred to technician management were included as comparators in the usual care group. A one-sided noninferiority margin for the technician management group was set to -2.5% for mean TTR. Propensity scoring was used in regression modeling via inverse probability of treatment weights to compare between-group differences to account for covariates that may have influenced assignment to the technician group. Finally, bleeding, thromboembolic, and mortality outcomes were compared. RESULTS: 1,840 and 1,116 patients were included in the technician and usual care groups, respectively. The mean age of included patients was 73.1 years, and the majority (77.9%) had received warfarin for > 3 years. TTR during follow-up was 83.3% and 77.7% in the technician and usual care groups, respectively (mean difference = 5.7%; 95% CI = 4.1%-7.2%). The risk of thromboembolism was similar between the technician and usual care groups (HR = 0.84; 95% CI = 0.17-4.22; P = 0.832); however, bleeding (HR = 0.60; 95% CI = 0.39-0.94; P = 0.026) and all-cause mortality (HR = 0.44; 95% CI = 0.25-0.77; P = 0.004) were lower in the technician group during follow-up. CONCLUSIONS: Technician management of stable patients receiving chronic warfarin therapy within an integrated health care delivery system's centralized anticoagulation service was associated with noninferior TTR results compared with usual care pharmacist management. DISCLOSURES: This study was internally funded by the Kaiser Permanente Pharmacy Department. The study sponsor had no role in the study design, analysis, or interpretation. The authors have no relevant financial conflicts of interest to disclose.

Rivaroxaban vs. warfarin on extended deep venous thromboembolism treatment: A cost analysis.

Background Standard treatment for deep venous thromboembolism involves parenteral anticoagulation overlapping with a vitamin K antagonist, an approach that is effective but associated with limitations including the need for frequent coagulation monitoring. The direct oral anticoagulant rivaroxaban is similarly effective to standard therapy as a single-drug treatment for venous thromboembolism and does not require routine coagulation monitoring. The aim of this analysis was to project the long-term costs and outcomes for rivaroxaban compared to standard of care (tinzaparin/warfarin). Methods A total of 184 patients who were under anticoagulant therapy with warfarin or rivaroxaban for extended deep venous thromboembolism were retrospectively evaluated; 59 received rivaroxaban and 125 received warfarin therapy. Assessments were made on age, gender, place of residence, the duration of anticoagulation, mean international normalized ratio value, the effective rate of international normalized ratio (time in the therapeutic range), bleeding-related complication rate, duration of hospitalization due to complications, the number of annual outpatient department admission, cost for drug, cost for hospitalization, cost for outpatient department admission and international normalized ratio measurements. Results The annual outpatient cost is higher in warfarin group (147.09 ± 78 vs. 62.32 ± 19.79 USD p < 0.001). But annual drug cost is higher in rivaroxaban group (362.6 vs. 71.55 ± 31.01 USD p < 0.001). Overall cost of rivaroxaban group is higher than warfarin group (476.25 ± 36.78 vs. 364.82 ± 174.44 USD). Warfarin is not cost-effective when non-drug costs (342.5 ± 174.44 vs. 113.65 ± 36.77) and hospital costs (173.85 ± 122.73 vs. 64.9 ± 23.55 USD) were analyzed. Conclusion This analysis suggests that rivaroxaban has lower costs than warfarin in terms of outpatient department admission and hospital costs due to complications; however, warfarin was more economic when all cost parameters were considered. Time in the therapeutic range was found as 56% for warfarin that should be taken into account while analyzing costs and benefits.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.

[Direct oral anticoagulants: what is the exact assessment of coagulation tests and plasma levels by laboratory tests in clinical practice?]. / Les anticoagulants oraux directs : quelle est la place de la biologie dans leur suivi et/ou leur utilisation ?

Direct oral anticoagulants (DAO), anti-IIa or anti-Xa, are intended to be widely used for the treatment and prevention of thrombotic disorders in venous thromboembolic disease and atrial fibrillation as an alternative of vitamin K antagonists (VKA). Despite predictable pharmacological properties, spontaneous or provoked hemorrhagic risks by DAO are major limitations. Thus, after few years of inconsistence concerning biological implication and in particular coagulation tests, it is now established that we need biology to evaluate hemorrhagic risk before surgery or in hemorrhagic cases.

Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

BACKGROUND: Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. METHODS AND RESULTS: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. CONCLUSIONS: GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Assessment of platelet function with light transmission aggregometry in 24 patients supported with a continuous-flow left ventricular assist device: a single-center experience.

OBJECTIVES: This study evaluated platelet function for an extended period of time in patients with a HeartMate II continuous-flow left ventricular assist device (Thoratec Corporation, Pleasanton, Calif) with light transmission aggregometry and investigated the potential role of this test in clinical management. METHODS: Twenty-four patients were studied prospectively after implantation. Mean duration of support was 8.5 months. Platelet functions were assessed with light transmission aggregometry induced by thrombin receptor agonist peptide, ristocetin, or arachidonic acid. All patients received an aspirin regimen that was progressively increased until arachidonic acid-triggered platelet aggregation dropped lower than 20%. Plasma levels of von Willebrand factor were also determined when ristocetin-induced platelet agglutination was impaired. RESULTS: Intensity of platelet aggregation with thrombin receptor agonist peptide was little changed in patients with a HeartMate II relative to control subjects. Aspirin dose greater than 160 mg/d was progressively required in 46% of patients. Ristocetin-induced platelet agglutination was impaired in 4 patients in association with a lack of high molecular weight von Willebrand factor multimers. Three patients had thromboembolic events (12.5%) and 8 (33%) suffered from major bleeding complications. CONCLUSIONS: High platelet reactivity during treatment with aspirin is common in patients with a HeartMate II. Moreover, light transmission aggregometry may detect impaired ristocetin-induced platelet agglutination, enabling dosage of aspirin to be adjusted. Our strategy showed no major improvements in terms of thrombosis rate when compared with published data, although bleeding frequency was somewhat reduced. Benefits of light transmission aggregometry testing need to be assessed in a larger randomized study with a longer follow-up.

Cost-effectiveness of pharmacist-participated warfarin therapy management in Thailand.

INTRODUCTION: Although pharmacist-participated warfarin therapy management (PWTM) is well established, the economic evaluation of PWTM is still lacking particularly in Asia-Pacific region. The objective of this study was to estimate the cost-effectiveness of PWTM in Thailand using local data where available. METHODS: A Markov model was used to compare lifetime costs and quality-adjusted life years (QALYs) accrued to patients receiving warfarin therapy through PWTM or usual care (UC). The model was populated with relevant information from both health care system and societal perspectives. Input data were obtained from literatures and database analyses. Incremental cost-effectiveness ratios (ICERs) were presented as year 2012 values. A base-case analysis was performed for patients at age 45 years old. Sensitivity analyses including one-way and probabilistic sensitivity analyses were constructed to determine the robustness of the findings. RESULTS: From societal perspective, PWTM and UC results in 39.5 and 38.7 QALY, respectively. Thus, PWTM increase QALY by 0.79, and increase costs by 92,491 THB (3,083 USD) compared with UC (ICER 116,468 THB [3,882.3 USD] per QALY gained). While, from health care system perspective, PWTM also results in 0.79 QALY, and increase costs by 92,788 THB (3,093 USD) compared with UC (ICER 116,842 THB [3,894.7 USD] per QALY gained). Thus, PWTM was cost-effective compared with usual care, assuming willingness-to-pay (WTP) of 150,000 THB/QALY. Results were sensitive to the discount rate and cost of clinic set-up. CONCLUSION: Our finding suggests that PWTM is a cost-effective intervention. Policy-makers may consider our finding as part of information in their decision-making for implementing this strategy into healthcare benefit package. Further updates when additional data available are needed.

Current practices in preclinical drug development: gaps in hemostasis testing to assess risk of thromboembolic injury.

The Health and Environmental Sciences Institute Cardiac Biomarkers Working Group surveyed the pharmaceutical development community to investigate practices in assessing hemostasis, including detection of hypocoagulable and hypercoagulable states. Scientists involved in discovery, preclinical, and clinical research were queried on laboratory evaluation of endothelium, platelets, coagulation, and fibrinolysis during safety assessment studies. Results indicated that laboratory assessment of hemostasis is inconsistent among institutions and not harmonized between preclinical and clinical studies. Hemostasis testing in preclinical drug safety studies primarily focuses on the risk of bleeding, whereas the clinical complication of thrombosis is seldom assessed. Our results reveal the need for broader utilization of biomarkers to detect altered hemostasis (e.g., endothelial and platelet activation) to improve preclinical safety assessments early in the drug development process. Survey respondents indicated a critical lack of validated markers of hypercoagulability and subclinical thrombosis in animal testing. Additional obstacles included limited blood volume, lack of cross-reacting antibodies for hemostasis testing in laboratory species, restricted availability of specialized hemostasis analyzers, and few centers of expertise in animal hemostasis testing. Establishment of translatable biomarkers of prothrombotic states in multiple species and strategic implementation of testing on an industry-wide basis are needed to better avert untoward drug complications in patient populations.

Assessment of the standard pediatric unfractionated heparin dosing protocol.

Current dosing guidelines for unfractionated heparin therapy in pediatric patients are based on recommendations of only one study that evaluated a weight-based dosing nomogram. To test the hypothesis that adhering to a strict weight-based nomogram yields better therapeutic results in pediatric patients, we prospectively monitored 25 consecutive pediatric patients who received unfractionated heparin based on the nomogram, and compared them to control patients whose treatment did not follow the standard nomogram. The mean time needed to achieve the target activated partial thromboplastin time was significantly shorter in the study group than the control group (18.32 ± 9.98 vs. 43.8 ± 30 h). A higher proportion of the study group reached the target activated partial thromboplastin time at 12, 24, and 36 h, compared to controls: 44% vs. 6%, 72% vs. 28%, 100% vs. 58%, respectively. Within the study group, patients under 1 year of age needed more time to achieve the target activated partial thromboplastin time than those over 1-year old. The performance of the standard dosing nomogram was excellent with regard to early anticoagulation target achievement, without increasing the risk of bleeding. Further studies are warranted to refine this nomogram for pediatric patients who are less than 1-year old.

Cancer and coagulation.

Thromboembolism, including both venous and arterial events, occurs commonly amongst patients with cancer. The occurrence of thromboembolism has significant consequences for cancer patients, including direct and indirect associations with mortality, morbidity, requirement for long-term anticoagulant therapy and consumption of healthcare resources. Recent studies have resulted in a better understanding of clinical risk factors and biomarkers of cancer-associated thrombosis, and a risk assessment model incorporating both has now been validated in multiple settings. Thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparins (LMWHs) has been shown to be safe and effective in high-risk settings such as hospitalization for medical illness and the postsurgical period. Emerging new data from randomized studies have focused on outpatient prophylaxis, suggesting potential benefits in this setting as well. Treatment of cancer-associated thrombosis requires long-term anticoagulation with LMWH. Results from ongoing and planned trials of novel anticoagulants in the cancer setting are awaited.

Future of anticoagulant therapy.

Prophylaxis and treatment of thromboembolic diseases is one of the main targets in medicine. Side effects and the necessity of dose adjustment limit the administration of coumarins and unfractionated heparin. Coumarins are therefore underused specially in the elderly population. Low-molecular-weight heparins, heparinoids, and direct thrombin inhibitors have overcome some of the limitations but they all have to be administered systemically. Synthetic systemically indirect and orally to apply direct factor Xa inhibitors and direct thrombin inhibitors are under development. They all aim to improve the underuse and the benefit/risk ratio for anticoagulant therapy. This overview describes the results of the recent studies of these inhibitors of blood coagulation. The future of the new anticoagulants will depend on the demonstration of their safety, efficacy, and health cost savings compared to the conventional antithrombotics.

Assessment of thrombotic risk factors predisposing to thromboembolic complications in prosthetic orthopedic surgery.

BACKGROUND: Congenital thrombophilia is responsible for thromboembolic complications despite prolonged low-molecular-weight heparin (LMWH) prophylaxis following hip and knee endoprosthesis surgery. METHODS: A series of 86 patients with hip or knee endoprosthesis surgery were assessed 1 year after operation. Antithrombin III, protein C, and protein S were determined, and the activated protein C sensitivity ratio was measured. We screened for the presence of lupus anticoagulant, factor V Leiden mutation, and polymorphism of prothrombin G20210A. The lower limb venous circulation was monitored by color Doppler ultrasonography. Pulmonary embolism (PE) was diagnosed using ventilation and perfusion scintigraphy. RESULTS: In all, 33 patients had thromboembolic complications, 18 with thrombophilia (7 with combined form). Of the 53 patients without complications 12 had thrombophilia (2 with combined form). The differences were statistically significant. The risk score, the prevalence of FV Leiden and prothrombin G20210A mutations, and lupus anticoagulant were also significantly higher in the symptomatic group. Deep vein thrombosis (DVT) developed preoperatively in 15 patients; DVT and PE in 4 patients; thrombophilia was diagnosed in 53% and 75% of these cases. In all, 17 patients had postoperative thromboembolic complications: DVT developed in nine and PE in one patient (all with thrombophilia); DVT + PE developed in seven patients (all but one had thrombophilia). CONCLUSIONS: Significant differences were found in the incidence (P < or = 0.01) of thrombophilia and the risk score (P < or = 0.02) between symptomatic and asymptomatic patients. We recommend preoperative thrombophilia screening for patients with a history or familial prevalence of thromboembolism and/or with a high risk score (> or =15). In cases of thrombophilia, the form and duration of anticoagulant treatment must be decided individually.

Transcranial Doppler and acoustic pressure fluctuations for the assessment of cavitation and thromboembolism in patients with mechanical heart valves.

The formation and collapse of vapor-filled bubbles near a mechanical heart valve is called cavitation. Such microbubbles are suspected to have strong pro-coagulant effects. Therefore, cavitation may be a contributing factor to the pro-thrombotic effects of mechanical valves. Herein, we systematically review the available evidence linking cavitation and thrombosis. We also critically appraise the potential usefulness of transcranial Doppler and other new non-invasive diagnostic methods to study cavitation and cerebral embolism in mechanical valve patients. Experimental studies indicate that cavitation microbubbles cause platelet aggregation, complement-activation, fibrinolysis, release of tissue-factor, and endothelial damage. Administration of 100% oxygen to mechanical valve patients during transcranial Doppler examination can transiently decrease the counts of Doppler-detected cerebral microemboli compared with room air. This is associated with removal of most circulating gaseous emboli from cavitation. This method may therefore be applied to the study of cavitation and thromboembolism. Additionally, the analysis of high-frequency acoustic-pressure fluctuations detected from the implosion of cavitation bubbles is a promising method for assessment of cavitation in vivo; however, this requires further development. A better understanding of cavitation is important in order to adequately investigate its role in the overall pro-thrombotic effects in mechanical valve patients. Such studies may allow establishing guidelines for new valve designs.

The clinical significance of anti-prothrombin antibodies for risk assessment of thromboembolism in patients with lupus anticoagulant.

INTRODUCTION: Thromboembolism is a common manifestation of lupus anticoagulant (LA), however only a subgroup of LA-patients is affected by thrombosis. Study objective was to investigate whether anti-prothrombin antibodies can identify LA-patients at increased risk for thrombosis. MATERIALS AND METHODS: In total 79 patients, 50 with (42 men/8 women) and 29 without thrombosis (21 men/8 women), were investigated for their presence of anti-prothrombin IgG and IgM antibodies using assays from two different manufacturers (Aeskulisa=assay I, CoaChrom=assay II). RESULTS: The prevalence of elevated levels of anti-prothrombin IgG, IgM as well as IgG and/or IgM antibodies was 66% [assayI] (36% [assayII]), 38% (24%) and 72% (50%) in patients with thrombosis and 55% (24%), 28% (28%) and 66% (41%) in patients without thrombosis, respectively. Neither anti-prothrombin IgG or IgM nor IgG and/or IgM antibodies were found to indicate an increased risk for thrombosis. In the subgroup of patients with arterial or venous thrombosis there was also no association between anti-prothrombin antibodies and thrombosis. The comparison of median levels of IgG and IgM anti-prothrombin antibodies between patients with and without thrombosis yielded a borderline statistically significant difference only for anti-prothrombin IgG antibodies by using assay II (p=0.033), all other comparisons were not statistically significant. CONCLUSIONS: In conclusion, presence of anti-prothrombin antibodies was not associated with thromboembolism in LA-patients.