Wysokiński, Waldemar E.

Abstract Background: While Factor V Leiden is associated with an increased risk of thrombosis, the magnitude of that risk among homozygous carriers is uncertain. Methods: In a cross-sectional study of Mayo Clinic patients referred to the Special Coagulation Laboratory for a thrombophilia profile (n=379) over the 18-year period, 1996-2013, the prevalence of venous and arterial thrombosis was estimated for patients found to be Factor V Leiden carriers based on leukocyte genomic DNA genotyping. T tests and chi-square tests were used for continuous and categorical variables, respectively. Results: Among homozygous (n=111) and heterozygous (n=268) carriers, the mean age at testing (50.3 and 50.5 years, respectively; p=0.9) and the proportion of females (50% and 54%, respectively; p=0.5) did not differ significantly. Of 29 asymptomatic carriers at the time of testing, 14 were homozygotes. Of the remaining 350 carriers, the mean age at first venous or arterial thrombosis (42 vs 43.8 years; p=0.5) among homozygous and heterozygous carriers, respectively, did not differ significantly. Thirty-five (33%) and 83 (31%) homozygous and heterozygous carriers, respectively, had at least one recurrent venous or arterial thrombosis (p=0.72). The prevalence of deep venous thrombosis (DVT) was 61% and 46% in homozygous and heterozygous carriers, respectively (p=0.008); the prevalence of pulmonary embolism was 18% and 20%, respectively (p=0.69). The prevalence of arterial thrombosis (mainly stroke and/or TIA) was higher in heterozygous (23%) compared to homozygous carriers (8%). Conclusion: In the largest sample of homozygous Factor V Leiden carriers reported to date, thrombosis penetrance and phenotype did not appear to differ among homozygous vs. heterozygous carriers with the exception of a higher prevalence of DVT among homozygous carriers. These data should be interpreted with caution due to the potential for referral bias. Disclosures No relevant conflicts of interest to declare.

Abstract To provide direct comparison between apixaban and rivaroxaban in patients with acute cancer‐associated venous thromboembolism (Ca‐VTE), consecutive patients treated with apixaban, rivaroxaban, or enoxaparin at Mayo Thrombophilia Clinic (March 1, 2013 to January 31, 2018)) were followed prospectively. The primary effectiveness outcome was venous thromboembolism (VTE) recurrence, and the secondary was mortality. The primary safety outcome was major bleeding, the secondary clinically relevant safety outcome was non‐major bleeding (CRNMB), and the third a composite of major and CRNMB. There were 750 patients treated for acute Ca‐VTE with apixaban (n = 224), rivaroxaban (n = 163), and enoxaparin (n = 363) within 14 days of diagnosis and for at least 3 months, or until study event. Recurrent VTE was diagnosed in 11 receiving apixaban, 7 receiving rivaroxaban (apixaban vs rivaroxaban hazard ratio (HR) 1.31, 95% confidence interval (95% CI) 0.51‐3.36) and 17 in the enoxaparin receiving group (apixaban vs enoxaparin HR 1.14, 95% CI: 0.54, 2.42 and rivaroxaban vs enoxaparin HR 0.85, 95% Cl: 0.36, 2.06). There were 82 deaths in apixaban, 74 rivaroxaban (apixaban vs rivaroxaban HR 1.67, 95% Cl: 1.20, 2.33) and 171 in enoxaparin group (rivaroxaban vs enoxaparin HR 0.73, 95% Cl: 0.56, 0.96). Major bleeding occurred in 11 apixaban, 12 rivaroxaban (apixaban vs rivaroxaban HR 0.73, 95% Cl: 0.32, 1.66) and 21 enoxaparin group (apixaban vs enoxaparin HR 0.89, 95% Cl: 0.43, 1.84 and rivaroxaban vs enoxaparin HR 1.23, 95% Cl: 0.61, 2.50). The CRNMB rate was higher in rivaroxaban compared to apixaban ( P = .03) and LMWH ( P = .01) groups. Recurrence of VTE and major bleeding were similar in apixaban, rivaroxaban, and enoxaparin groups. Rivaroxaban was associated with higher CRNMB but lower mortality compared to apixaban and enoxaparin.

e23156 Background: A direct meta-analysis was performed to explore the efficacy and safety of direct oral factor Xa inhibitors with dalteparin in patients with cancer associated acute venous thromboembolism (VTE). Also, the comparative efficacy and safety of apixaban, rivaroxaban, and edoxaban was assessed with a network meta-analysis. Methods: MEDLINE, CENTRAL, and EMBASE were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer associated acute VTE. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence, major and clinically relevant non-major bleeding (CRNMB). Results: Three randomized control trials, at low risk of bias, enrolled 1,739 patients with cancer associated VTE. Direct comparison showed a lower rate of VTE recurrence in DOAC compared to dalteparin groups (odds Ratio [OR]:0.48, 95% Confidence interval [CI]:0.24-0.96; I2:46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared to dalteparin (OR: 0.10; 95% CI: 0.01–0.82), but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared to dalteparin (OR: 1.70; 95% CI: 1.04–2.78). CRNMB did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding whereas estimates in urothelial cancer were imprecise. Conclusions: DOACs appear to lower the risk of VTE recurrence compared to daltaparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared to the other DOACs.

SummaryReversibility in vivo of acute platelet thrombosis in response to specific anticoagulants is analyzed with thrombi that develop in segments (1 cm) of porcine carotid arteries externally crushed with a hemostat. Most thrombi fill the lumens of the injured segments (ca. 1 cm × 3 mm, 1 × w) within 30 min and comprise masses of platelets interpenetrated with neutrophil-lined seepage channels of blood. Continuous quantitative assay of thrombus mass is provided by a gamma detector placed over the injured segments to collect counts from 111In-labeled platelets. Thrombi established 30 min after injury, otherwise stable for 6 h, clear during 30-60 min of continuous infusion of either hirudin, tick anticoagulant or activated porcine protein C, or intermittent activation of endogenous protein C with a latent thrombin reagent. Anticoagulant dose-dependence of thrombus clearance is established for hirudin between 0.01 and 1.0 mg/kg/min. Thrombi become progressively refractory to hirudin between 0.5 and 6 h after injury. Neither heparin nor low-molecular-weight heparin in full (clinical) anticoagulant doses yield significant dethrombosis. It is concluded that, within time limits, controlled thrombin generation in platelet thrombi maintains platelet cohesion without catalyzing irreversible platelet aggregation or clotting of fibrinogen.

AbstractBackgroundLow molecular weight heparin (LMWH) is the guideline‐endorsed treatment for cancer‐associated venous thromboembolism (cVTE). Study objectives were to compare the efficacy and safety of rivaroxaban and enoxaparin in cVTE.MethodsUsing a cohort study design, consecutive patients with cVTE (3/1/2013‐7/31/2016), enrolled in the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry, were compared to contemporary cancer patients receiving enoxaparin. The cumulative incidence of venous thromboembolism (VTE) recurrence, major and clinically relevant non‐major bleeding, and survival were assessed at 3 and 12 months.ResultsNinety‐eight patients received rivaroxaban (51% female, mean age 63 ± 12 years) and 168 enoxaparin (34.5% female, mean age 62 ± 15 years). The most common cancers included gastrointestinal/pancreatic, genitourinary and hematologic cancers. More than half of patients had pulmonary emboli at presentation. More than half had metastases, and two‐thirds were receiving chemotherapy. At 3 months, there were no differences in VTE recurrence (rivaroxaban 1.0% vs enoxaparin 4.2%; P = .15), major bleeding (rivaroxaban 5.1% vs enoxaparin 3.6%; P = .55), or all‐cause mortality (rivaroxaban 4.1% vs enoxaparin 8.9%; P = .14). At 12 months, these outcomes did not differ by treatment strategy.ConclusionThe results of this “real‐world” experience with cVTE suggest that rivaroxaban may offer a safe and effective alternative to LMWH.

Millions of patients in the United States use anticoagulation for a variety of indications, such as the prevention of stroke in those with atrial fibrillation (AF) and the treatment and prevention of venous thrombosis. For over six decades warfarin was the only available oral anticoagulant, but now several DOACs are available and their use has become more prevalent in recent years. In spite of this increased use, many physicians remain reluctant to prescribe DOACs due to concerns about bleeding and reversibility.

AbstractIntroductionReticulated platelet (RP) content is increased in nonvalvular atrial fibrillation (NVAF). The purpose of this study was to determine if platelet content, morphology, and RP proportion are modulated by platelet genes.Methods and resultsExpression of six platelet‐predominate genes impacting platelet formation and release, platelet count, and RP content was assessed in NVAF patients before and 3–4 months after pulmonary veins isolation (PVI) and compared to normal sinus rhythm (NSR) controls. RNA from isolated platelets was reverse‐transcribed assayed against selected genes utilizing real‐time qPCR, and expressed as mean cycle threshold (ΔCt) using beta‐2‐microglobulin as endogenous control. RP content was assessed by flow cytometry. A fourfold lower expression of CFL1 gene coding for nonmuscle cofilin (7.8 ± 0.9 vs. 5.7 ± 1.6, P < 0.001) and twofold lower expression of four other genes were associated with similar platelet counts but fourfold higher (28.7+7.0 vs. 6.7+5.4, P < 0.001) RP content (%) in 97 NVAF cases compared to 51 NSR controls. Three to 4 months after PVI, RP decreased by 28%, while CFL1 gene expression increased over twofold but TUBA4A gene expression decreased almost twofold; NFE2 and MYL6 gene expression remained unchanged.ConclusionsNVAF is associated with notable downregulation of genes directing platelet production and size but increased RP content. PVI impacts the expression of many of these genes, implying a direct relationship between atrial fibrillation and platelet biogenesis.