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Journal: Journal of thrombosis and thrombolysis

146

Topical hemostatic agents are used intra-operatively to prevent uncontrolled bleeding. Gelfoam(®) Powder contains a hemostatic agent prepared from purified pork skin gelatin, the efficacy of which is increased when combined with thrombin. However, the effect of increasing concentrations of thrombin on resultant hemostasis is not known. This study sought to evaluate the ability of various concentrations of thrombin in combination with Gelfoam Powder to control bleeding using a swine liver lesion model. Ten pigs underwent a midline laparotomy. Circular lesions were created in the left medial, right medial, and left lateral lobes; six lesions per lobe. Gelfoam Powder was hydrated with Thrombin-JMI(®) diluted to 250, 375, and 770 IU/mL. Each concentration was applied to two lesion sites per lobe. Bleeding scores were measured at 3, 6, 9, and 12 min using a 6-point system; comparison of bleeding scores was performed using ANOVA with the post hoc Tukey test. The bleeding scores with thrombin concentrations at 770 IU/mL were significantly lower than at 250 and 375 IU/mL at all four time points. The percentage of biopsies with a clinically acceptable bleeding score rose from 37.9, 46.6, and 71.2 % at 3 min to 55.2, 69.0, and 88.1 % at 12 min in the 250, 375, and 770 IU/mL thrombin groups, respectively. The study showed that the hemostatic response to thrombin was dose-related: using higher concentrations of thrombin with Gelfoam Powder yielded improved hemostasis, as determined by lower bleeding scores.

Concepts: Hemostasis, Pork, Antihemorrhagic, Antihemorrhagics, Chitosan

27

Rivaroxaban is a direct factor Xa inhibitor, which is rapidly absorbed in the upper gastrointestinal (GI) tract. In large trials, it has been shown to be effective and safe in VTE treatment. However, in these trials patients with morbid obesity were not reported and it is unknown if the standard dosage of 20 mg rivaroxaban is sufficient for bariatric patients, especially after bariatric surgery, which may impact the resorption of rivaroxaban. We report the case of a bariatric patient with high venous thromboembolism risk and instable INR after recent bariatric surgery, who was switched from Vitamin-K antagonists to rivaroxaban. After intake of 20 mg rivaroxaban, plasma concentration were repeatedly measured until 3 h after the second dose using a commercially available chromogenic aXa-assay. Furthermore, INR and aPTT were measured. Peak concentrations of 224.22 ng/ml were observed. After 6 h, plasma concentration decreased to 86.9 ng/ml and remained stable until 12 h (86.32 ng/ml). After 24 h, a trough level of 35.54 ng/ml was observed. The patients INR did immediately increase and remained significantly elevated throughout the day with a slow decrease. Since peak values of rivaroxaban plasma concentrations were in the expected range of published data, we conclude that resorption of rivaroxaban was immediate and not significantly impaired by bariatric surgery of the upper GI tract. Consequently, no dose adjustments seem to be necessary in this high-risk population.

Concepts: Obesity, Overweight, Warfarin, Weight loss, Bariatric surgery, Digestion, Gastric bypass surgery, Bariatrics

26

Contrast induced nephropathy (CIN) is a common complication of coronary angiography/angioplasty. Prevention is the key to reduce the incidence of CIN and it begins with appropriate pre-procedural management. Statins have been shown to possess pleiotropic effects (anti-oxidant, anti-inflammatory and anti-thrombotic properties) and their effects on CIN were assessed in several studies with conflicting results. Aim of this meta-analysis is to evaluate the efficacy of short-term statins for the prevention of CIN in patients undergoing coronary angiography/percutaneous interventions. We performed formal searches of PubMed, EMBASE, Cochrane central register of controlled trials and major international scientific session abstracts from January 1990 to January 2014 of trials which compares short-term statins versus Placebo for the prevention of CIN in patients undergoing coronary angiography/angioplasty. Data regarding study design, statin dose, inclusion/exclusion criteria, number of patients, and clinical outcome was extracted by 2 investigators. Eight trials were included, with a total of 4734 patients. CIN occurred in 79/2,358 patients (3.3 %) treated with statins versus 153/2,376 patients (6.4 %) of the placebo group [OR 95 % CI 0.50 (0.38-0.66), p < 0.00001; p het = 0.39]. Benefits were both observed with high-dose short-term statins [OR 95 % CI 0.44 (0.30-0.65), p < 0.0001; p het = 0.16] and low-dose statins, [OR 95 % CI 0.58 (0.39-0.88), p = 0.010; p het = 0.90]. By meta-regression analysis, no significant relationship was observed between benefits from statin therapy and patient's risk profile (p = 0.26), LDL cholesterol (p = 0.4), contrast volume (p = 0.94) or diabetes rate (p = 0.38). This meta-analysis showed that among patients undergoing coronary angiography/percutaneous intervention the use of short-term statins reduces the incidence of CIN, and therefore is highly recommended even in patients with low LDL-cholesterol levels.

Concepts: Cholesterol, Myocardial infarction, Atherosclerosis, Randomized controlled trial, Low-density lipoprotein, Statin, Atheroma, Mevalonate pathway

25

Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.

Concepts: Present, Time, Warfarin, Anticoagulant, Dabigatran, Thrombin, Factor X, Direct thrombin inhibitor

24

Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or

Concepts: Stroke, Atrial fibrillation, Warfarin, Pre-clinical development, Anticoagulant, Heparin, Dabigatran, Vitamin K

23

The concept of resistance in blood coagulation has become important. In the past it was limited to the resistance shown by some patients to heparin, coumarin or aspirin. Subsequently, it was demonstrated that a mutation in a single clotting factor, FV, showed resistance to activated protein C. Since activated protein C is supposed to downregulate aFV and aFVIII, their persistence in the circulation gives origin to a hypercoagulable state. Recently antithrombin resistance has been defined. Several prothrombin abnormalities (dysprothrombinemias) have been shown to be resistant to the action of antithrombin. This is associated with the occurrence of a trombophilic state. Prothrombin may therefore be associated like FV with both a bleeding condition (prothrombin deficiency) and a thrombophilic state (some dysprothrombinemias). Finally, thrombomodulin resistance has been defined in liver cirrhosis. These patients often show an increased ratio between FVIII levels and protein C. This imbalance may be partly responsible for the frequent presence of portal vein thrombosis seen in these patients. All these studies have greatly increased the complexity of the clotting mechanisms and interactions. They have cast light on clinical events which had remained unknown or ill-defined.

Concepts: Blood, Coagulation, Platelet, Warfarin, Heparin, Protein C, Thrombin, Antithrombin

23

To determine incidence, risk factors, hematologic complications, and prognostic significance of thrombocytopenia in the general medicine population, we performed a single-institutional, retrospective study of all adult patients admitted to a general medical ward from January 1st, 2014 to December 31st, 2014 with hospital-acquired thrombocytopenia. Those with moderate thrombocytopenia, defined as a platelet count nadir of <100 × 10^9/L and/or a >50% relative decline, were compared to those with less severe thrombocytopenia. Of the 7420 patients admitted, 465 (6.3%) developed hospital-acquired thrombocytopenia. Infection and moderate thrombocytopenia were present in 56 and 23%, respectively. Severe sepsis and antibiotic use were both associated with moderate thrombocytopenia, and proton pump inhibitor use was statistically significant in both univariate and multivariate analysis. Hematologic complications were more frequent with moderate thrombocytopenia, including frequency of HIT testing and red blood cell transfusions. Outcome metrics including transfer to an intensive care unit (OR 6.78), death during admission (OR 6.85), and length of stay (10.6 vs. 5.1 days) were all associated with moderate thrombocytopenia. Thrombocytopenia is associated with poor prognosis, and the association between moderate thrombocytopenia and proton pump inhibitor use is relatively novel and should be validated in prospective studies.

Concepts: Medicine, Blood, Red blood cell, Intensive care medicine, Platelet, Multivariate statistics, Hematology, Blood transfusion

22

The influence of anemia on the long-term clinical outcomes has not been fully evaluated in patients with venous thromboembolism (VTE). We evaluated the influence of anemia among 3012 patients in the COMMAND VTE Registry with a median follow-up period of 1219 days. The outcomes measures were ISTH major bleeding, recurrent VTE and all-cause death. There were 1012 patients (34%) with moderate/severe anemia (Hb ≤ 10.9 g/dl), 615 patients (20%) with mild anemia (Hb 11.0-12.9 g/dl for men, and 11.0-11.9 g/dl for women), and 1385 patients (46%) without anemia. The cumulative 5-year incidence of major bleeding was significantly higher in patients with anemia (moderate/severe anemia: 17.6%, mild anemia: 12.1%, and no anemia: 8.7%, P < 0.001). After adjusting the confounders, the excess risk of mild and moderate/severe anemia, respectively, relative to no anemia for major bleeding remained significant (mild: adjusted HR 1.41: [95% CI 1.00-1.98], P = 0.048; moderate/severe: adjusted HR 1.91: [95% CI 1.42-2.58], P < 0.001, respectively). The excess risk of moderate/severe anemia relative to no anemia was also significant for mortality (adjusted HR 2.89: 95% CI 2.45-3.42, P < 0.001), but the risk was neutral for recurrent VTE (adjusted HR 1.05: 95% CI 0.76-1.45, P = 0.77). In conclusions, VTE patients with mild and moderate/severe anemia had higher risk for major bleeding events without significant excess risk for recurrent VTE events, and the risk for major bleeding events increased according to the severity of anemia. We should pay more attention to the optimal intensity and duration of anticoagulation in VTE patients with anemia.

18

The role of inferior vena cava filter (IVC) filters for prevention of pulmonary embolism (PE) is controversial. This study evaluated outcomes of IVC filter placement in a managed care population. This retrospective cohort study evaluated data for individuals with Humana healthcare coverage 2013-2014. The study population included 435 recipients of prophylactic IVC filters, 4376 recipients of therapeutic filters, and two control groups, each matched to filter recipients. Patients were followed for up to 2 years. Post-index anticoagulant use, mortality, filter removal, device-related complications, and all-cause utilization. Adjusted regression analyses showed a positive association between filter placement and anticoagulant use at 3 months: odds ratio (ORs) 3.403 (95% CI 1.912-6.059), prophylactic; OR, 1.356 (95% CI 1.164-1.58), therapeutic. Filters were removed in 15.67% of prophylactic and 5.69% of therapeutic filter cases. Complication rates were higher with prophylactic procedures than with therapeutic procedures and typically exceeded 2% in the prophylactic group. Each form of filter placement was associated with increases in all-cause hospitalization (regression coefficient 0.295 [95% CI 0.093-0.498], prophylactic; 0.673 [95% CI 0.547-0.798], therapeutic) and readmissions (OR 2.444 [95% CI 1.298-4.602], prophylactic; 2.074 [95% CI 1.644-2.616], therapeutic). IVC filter placement in this managed care population was associated with increased use of anticoagulants and greater healthcare utilization compared to controls, low rates of retrieval, and notable rates of device-related complications, with effects especially pronounced in assessments of prophylactic filters. These findings underscore the need for appropriate use of IVC filters.

Concepts: Health care, Regression analysis, Cohort study, Pulmonary embolism, Anticoagulant, Inferior vena cava, Deep vein thrombosis, Inferior vena cava filter

12

TV viewing is associated with risk of arterial vascular diseases, but has not been evaluated in relation to venous thromboembolism (VTE) risk in Western populations. In 1987-1989, the Atherosclerosis Risk in Communities Study obtained information on the frequency of TV viewing in participants aged 45-64 and followed them prospectively. In individuals free of prebaseline VTE (n = 15, 158), we used a Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident VTE according to frequency of TV viewing (“Never or seldom”, “Sometimes”, “Often” or “Very often”). During the 299,767 person-years of follow-up, we identified 691 VTE events. In a multivariable-adjusted model, the frequency of TV viewing showed a positive dose-response relation with VTE incidence (P for trend = 0.036), in which “very often” viewing TV carried 1.71 (95% CI 1.26-2.32) times the risk of VTE compared with “never or seldom” viewing TV. This association to some degree was mediated by obesity (25% mediation, 95% CI 10.7-27.5). Even among individuals who met a recommended level of physical activity, viewing TV “very often” carried 1.80 (1.04-3.09) times the risk of VTE, compared to viewing TV “never or seldom”. Greater frequency of TV viewing was independently associated with increased risk of VTE, partially mediated by obesity. Achieving a recommended physical activity level did not eliminate the increased VTE risk associated with frequent TV viewing. Avoiding frequent TV viewing as well as increasing physical activity and controlling body weight might be beneficial for VTE prevention.

Concepts: Blood, Atherosclerosis, Obesity, Artery, Vein, Hazard ratio, David Cox, Hazard