Mortality due to bleeding,myocardial infarction and stroke in dialysis patients

Essentials

• Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown.
• We compared death causes of 201 918 dialysis patients with the general population.
• Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis.
• Clinicians should be aware of the increased bleeding and thrombosis risks.

Summary

Background

Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death.

Objectives

To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population.

Methods

We included 201 918 patients from 11 countries providing data to the ERA‐EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age‐standardized and sex‐standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional‐hazards regression.

Results

As compared with the general population, the age‐standardized and sex‐standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9–13.7) for bleeding as a cause of death (6.2 per 1000 person‐years among dialysis patients versus 0.3 per 1000 person‐years in the general population), 13.4 (95% CI 13.0–13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person‐years), and 12.4 (95% CI 11.9–12.9) for stroke (14.3 versus 0.7 per 1000 person‐years).

Conclusion

Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions.

     

Comorbidity and the increased mortality after hospitalization for stroke: a population‐based cohort study

Essentials

• Comorbidity is prevalent in the stroke population and affects post‐stroke survival.

• A stroke patient cohort (n = 201 691) and a general population cohort were followed for survival.
• Cancer and advanced renal/liver disease substantially increased one‐year stroke mortality.
• Tailoring stroke interventions according to comorbidity may reduce excess mortality.

Summary

Background

Comorbidity is prevalent among stroke patients, affecting post‐stroke survival. It remains unknown whether comorbidity impacts post‐stroke mortality beyond the combined individual effects of stroke and comorbidity.

Methods

Using nationwide Danish databases, we performed a cohort study of 201 691 patients ≥ 18 years old with incident ischemic stroke, intracerebral or subarachnoid hemorrhage, or unspecified stroke during 1995–2012, and 992 942 adults from the general population, matched to stroke patients by birth year, sex and individual comorbidities in the Charlson Comorbidity Index. During up to 5 years of follow‐up, we computed standardized mortality rates (SMRs) to assess interaction contrasts as a measure of excess mortality not explained by the additive effects of stroke and comorbidity acting alone.

Results

Five‐year post‐stroke mortality was 48%, corresponding to an SMR of 187 deaths per 1000 person‐years. During the 30‐day peak post‐stroke mortality (SMR, 180 per 1000 person‐months), interaction with comorbidity represented 23%, 34% and 51% of post‐stroke mortality rates among patients with low (score = 1), moderate (score = 2–3) and high (score = 4+) comorbidity based on Charlson Comorbidity Index scores. The interaction accounted for 5% to 32% of subsequent 31–365‐day post‐stroke mortality rates, depending on comorbidity level. The interaction contrasts were most notable among comorbid patients with cancer, particularly with hematological or metastatic disease, followed by patients with moderate‐to‐severe liver or renal disease.

Conclusion

Comorbidity, notably cancer and advanced renal or liver disease, increased 1‐year mortality after stroke beyond the combined effects expected from either disease acting alone.

     

Efficacy,safety and pharmacokinetics of a new high‐purity factor X concentrate in women and girls with hereditary factor X deficiency

Essentials

• Plasma‐derived factor X concentrate (pdFX) is used to treat hereditary factor X deficiency.
• pdFX pharmacokinetics, safety and efficacy were assessed in factor X‐deficient women/girls.
• Treatment success rate was 98%; only 6 adverse events in 2 subjects were possibly pdFX related.
• On‐demand pdFX 25 IU kg^?1 was effective and safe in women/girls with factor X deficiency.

Summary

Background

A high‐purity, plasma‐derived factor X concentrate (pdFX) has been approved for the treatment of hereditary FX deficiency, an autosomal recessive disorder.

Objective

To perform post hoc assessments of pdFX pharmacokinetics, safety and efficacy in women and girls with hereditary FX deficiency.

Patients/Methods

Subjects aged ≥ 12 years with moderate/severe FX deficiency (plasma FX activity of < 5 IU dL^?1) received on‐demand or preventive pdFX (25 IU kg^?1) for ≤ 2 years.

Results

Of 16 enrolled subjects, 10 women and girls (aged 14–58 years [median, 25.5 years]) received 267 pdFX infusions. Mean monthly infusions per subject were higher among women and girls (2.48) than among men and boys (1.62). In women and girls, 132 assessable bleeding episodes (61 heavy menstrual bleeds, 47 joint bleeds, 15 muscle bleeds, and nine other bleeds) were treated with pdFX, with a 98% treatment success rate versus 100% in men and boys. Mean pdFX incremental recovery was similar in the two groups (2.05 IU dL^?1 versus 1.91 IU dL^?1 per IU kg^?1), as was the mean half‐life (29.3 h versus 29.5 h). Of 142 adverse events in women and girls, headache was the most common (12 events in six subjects). Six events (two infusion‐site erythema, two fatigue, one back pain, one infusion‐site pain) in two subjects were considered to be possibly pdFX‐related. Following the trial, pdFX was used to successfully maintain hemostasis in two subjects undergoing obstetric delivery.

Conclusions

pdFX was well tolerated and effective in women and girls with FX deficiency. Although women and girls had different bleeding symptoms and sites than men and boys, their pdFX pharmacokinetic profile was comparable.

     

Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant,in patients with severe hemophilia

Essentials

• Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII.
• A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia.
• MarzAA was safe and tolerated at intravenous doses up to 30 μg kg^?1
• Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX.

Summary

Background

Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia.

Objectives

To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non‐bleeding patients with congenital hemophilia A or B with or without inhibitors.

Methods

This international, phase 1, open‐label study (NCT01439971) enrolled males aged 18–64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single‐dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg^?1). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD.

Results

Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose‐limiting toxicity. No treatment‐emergent severe or serious adverse events occurred. MarzAA showed linear dose–response PK across the 4.5–30 μg kg^?1 dose range, with a terminal half‐life of ? 3.5 h. Dose‐dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses.

Conclusions

MarzAA was tolerated at doses up to 30 μg kg^?1. The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

     

Thrombocytopenia in high‐risk patients with antiphospholipid syndrome

Essentials

• The prevalence of thrombocytopenia in patients with antiphospholipid syndrome is not well defined.
• We studied triple positive patients with antiphospholipid syndrome and its catastrophic variant.
• Prevalence of thrombocytopenia was 6% and 100% in patients who developed the catastrophic form.
• In triple positive patients thrombocytopenia is low and platelets drop during the catastrophic form.

Summary

Background

Thrombocytopenia is the most common non‐criteria hematological feature in patients with antiphospholipid syndrome (APS). This condition is more common in patients with catastrophic APS (CAPS).

Objectives

To evaluate the prevalence of thrombocytopenia in a large series of high‐risk patients with APS, and to assess the behavior of the platelet count during CAPS.

Methods/Patients

This was a cross‐sectional study in which we analyzed the platelet counts of a homogeneous group of high‐risk APS patients (triple‐positive). Six of these patients developed a catastrophic phase of the disease, and the platelet count was recorded before the acute phase, during the acute phase, and at recovery.

Results

The mean platelet count in 119 high‐risk triple‐positive patients was 210 × 10⁹ L^?1. With a cut‐off value for thrombocytopenia of 100 × 10⁹ L^?1, the prevalence of thrombocytopenia was 6% (seven patients). No difference between primary APS and secondary APS was found. In patients who suffered from CAPS, a significant decrease from the basal count (212 ± 51 × 10⁹ L^?1) to that at the time of diagnosis (60 ± 33 × 10⁹ L^?1) was observed. The platelet count became normal again at the time of complete remission (220 ± 57 × 10⁹ L^?1). A decrease in platelet count always preceded the full clinical picture.

Conclusions

This study shows that, in high‐risk APS patients, the prevalence of thrombocytopenia is low. A decrease in platelet count was observed in all of the patients who developed the catastrophic form of the disease. A decrease in platelet count in high‐risk APS patients should be considered a warning signal for disease progression to CAPS.

     

Evaluation of a microfluidic flow assay to screen for von Willebrand disease and low von Willebrand factor levels

Essentials

• von Willebrand factor (VWF) function is shear stress dependent.
• Platelet accumulation in a microfluidic assay correlates with VWF levels.
• The microfluidic assay discriminates type 1 von Willebrand disease from healthy controls.
• The microfluidic flow assay detects responses to therapeutic intervention (DDAVP).

Summary

Background

von Willebrand disease (VWD) is a mucocutaneous bleeding disorder with a reported prevalence of 1 in 10 000. von Willebrand factor (VWF) function and platelet adhesion are regulated by hemodynamic forces that are not integrated into most current clinical assays.

Objective

We evaluated whether a custom microfluidic flow assay (MFA) can screen for deficiencies in VWF in patients presenting with mucocutaneous bleeding.

Methods

Whole blood from individuals with mucocutaneous bleeding was assayed in a custom MFA.

Results

Thirty‐two patients with type 1 VWD (10/32) or reported mucocutaneous bleeding were enrolled. The platelet adhesion velocity (r = 0.5978 for 750 s^?1 and 0.6895 for 1500 s^?1) and the maximum platelet surface area coverage (r = 0.5719 for 750 s^?1 and 0.6633 for 1500 s^?1) in the MFA correlated with VWF levels. Furthermore, the platelet adhesion velocity at 750 s^?1 (type 1 VWD, mean 0.0009761, 95% confidence interval [CI] 0.0003404–0.001612; control, mean 0.003587, 95% CI 0.002455–0.004719) and at 1500 s^?1 (type 1 VWD, mean 0.0003585, 95% CI 0.00003914–0.0006778; control, mean 0.003132, 95% CI 0.001565–0.004699) differentiated type 1 VWD from controls. Maximum platelet surface area coverage at 750 s^?1 (type 1 VWD, mean 0.1831, 95% CI 0.03816–0.3281; control, mean 0.6755, 95% CI 0.471–0.88) and at 1500 s^?1 (type 1 VWD, mean 0.07873, 95% CI 0.01689–0.1406; control, mean 0.6432, 95% CI 0.3607–0.9257) also differentiated type 1 VWD from controls. We also observed an improvement in platelet accumulation after 1‐desamino‐8‐d ‐arginine vasopressin (DDAVP) treatment at 1500 s^?1 (pre‐DDAVP, mean 0.4784, 95% CI 0.1777–0.7791; post‐DDAVP, mean 0.8444, 95% CI 0.7162–0.9726).

Conclusions

These data suggest that this approach can be used as a screening tool for VWD.

     

Effect of rosuvastatin on risk markers for venous thromboembolism in cancer

Essentials

• Statins lower venous thromboembolism risk in general but have not been studied in cancer patients.
• We completed a randomized trial of rosuvastatin vs. placebo among cancer patients on chemotherapy.
• Rosuvastatin did not significantly lower prothrombotic biomarkers including D‐dimer.
• The role of statins in venous thrombosis prevention in cancer patients remains unknown.

Summary

Background

Statin therapy is associated with lower risk of venous thromboembolism (VTE) but has not been prospectively evaluated in patients with advanced cancer.

Objectives

We determined if statin administration in this high‐risk population reduces the risk of VTE, based on established and emerging biomarkers.

Patients/Methods

This double‐blind, crossover, randomized controlled trial among patients with advanced cancer receiving systemic therapy allocated participants to rosuvastatin 20 mg daily or placebo for 3–4 weeks prior to crossover to the alternative therapy, with a 3–5‐week washout. D‐dimer, C‐reactive protein (CRP), soluble (s)P‐selectin, factor VIII (FVIII), thrombin generation and exploratory biomarkers focusing on endogenous thrombin potential, including tissue factor (TF), activated factor IX (FIXa) and activated factor XI (FXIa), were measured at the start and end of both treatment periods. The primary outcome was change in D‐dimer with rosuvastatin compared with placebo.

Results

Of 38 enrolled participants, 24 (63%) completed the study. Rosuvastatin did not cause statistically significant changes in D‐dimer levels or any other biomarker. CRP levels decreased by 40%; 4.3 mg L^?1 (95% confidence interval, ?11.0 to +2.5 mg L^?1) compared with placebo. In post‐hoc analysis, participants who received rosuvastatin initially during their first line of treatment had a 13% decrease in D‐dimer. Circulating TF, FIXa and FXIa were detected in 26%, 68% and 71% of cancer patients despite not being found in healthy individuals.

Conclusions

Rosuvastatin did not cause favorable changes in biomarkers of VTE risk in advanced cancer patients receiving chemotherapy. The role of statin therapy as thromboprophylaxis in the cancer population remains uncertain.

     

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Essentials

• Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers.
• We studied the association of CKD and venous thromboembolism (VTE) in a case‐cohort study.
• Factor VIII, D‐dimer and C‐reactive protein appeared to explain the association of CKD and VTE.
• Statin use was protective against VTE in those with and without CKD.

Summary

Background

Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown.

Objectives

To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients.

Methods

Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non‐cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow‐up. The hazard ratio (HR) of VTE per 10 mL min^?1 1.73 m^?2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD.

Results

The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02–1.25), and VTE risk was attenuated by 23% (95% CI 5–100) by D‐dimer, by 100% (95% CI 50–100) by factor VIII, and by 15% (95% CI 2–84) by C‐reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32–0.70), but not in those with CKD (HR 1.07, 95% CI 0.51–2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups.

Conclusions

Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.

     

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation,predicts the risk of venous thromboembolism in cancer patients

Essentials

• Neutrophil extracellular traps (NETs) might play a role in cancer‐related coagulopathy.
• We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE).
• We found a constant association with VTE for citrullinated histone H3.
• Biomarkers of NET formation could reflect a novel pathomechanism of cancer‐related VTE.

Summary

Background

Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients.

Objectives

To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell‐free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients.

Patients/Methods

Nine‐hundred and forty‐six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3‐month, 6‐month, 12‐month and 24‐month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively.

Results

Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2‐year risk of 14.5%) than patients with levels below this cut‐off (2‐year risk of 8.5%, n = 710). In a competing‐risk regression analysis, a 100 ng mL^?1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04–1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D‐dimer level, and soluble P‐selectin level (SHR 1.13, 95% CI 1.04–1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time‐dependent, with associations with a higher risk of VTE only during the first 3–6 months.

Conclusion

These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer‐associated thrombosis.

     

Factor XI promotes hemostasis in factor IX‐deficient mice

Essentials

• Mice lacking factor IX (FIX) or factor XI (FXI) were tested in a saphenous vein bleeding model.
• FIX‐deficient mice displayed a hemostatic defect and FXI‐deficient mice were similar to wild type mice.
• Infusion of FXI or over‐expression of FXI in FIX‐deficient mice improved hemostasis.
• FXI may affect the phenotype of FIX‐deficiency (hemophilia B).

Summary

Background

In humans, deficiency of coagulation factor XI may be associated with a bleeding disorder, but, until recently, FXI‐deficient mice did not appear to have a hemostatic abnormality. A recent study, however, indicated that FXI‐deficient mice show a moderate hemostatic defect in a saphenous vein bleeding (SVB) model.

Objectives

To study the effect of FXI on bleeding in mice with normal levels of the FXI substrate FIX and in mice lacking FIX (a murine model of hemophilia B).

Methods

Wild‐type mice and mice lacking either FIX (F9^?) or FXI (F11^?/?) were tested in the SVB model. The plasma levels of FXI in F11^?/? mice were manipulated by infusion of FXI or its active form FXIa, or by overexpressing FXI by the use of hydrodynamic tail vein injection.

Results

F9^? mice showed a significant defect in the SVB model, whereas F11^?/? mice and wild‐type mice were indistinguishable. Intravenous infusion of FXI or FXIa into, or overexpression of FXI in, F9^? mice improved hemostasis in the SVB model. Overexpression of a FXI variant lacking a FIX‐binding site also improved hemostasis in F9^? mice.

Conclusions

Although we were unable to demonstrate a hemostatic defect in F11^?/? mice in the SVB model, our results support the premise that supraphysiological levels of FXI improve hemostasis in F9^? mice through FIX‐independent pathways.

     

The fibrinogen prothrombin time‐derived method is not useful in patients anticoagulated with low molecular weight heparins or rivaroxaban

Essentials

• Fibrinogen prothrombin time‐derived (FIBPT‐d) behavior in anticoagulated patients is under studied.
• FIBPT‐d method overestimates fibrinogen in rivaroxaban and low molecular weight heparin samples.
• Unfractionated heparin and dabigatran samples showed similar bias to the control group.
• Rabbit brain and human recombinant thromboplastin behavior was different in rivaroxaban samples.

Summary

Background

The fibrinogen prothrombin time‐derived (FIBPT‐d) method with photo‐optical coagulometers is easy and economical. However, there are few reports on the behavior of this test on samples from patients anticoagulated with direct oral anticoagulants or low molecular weight heparin (LMWH).

Objective

To compare fibrinogen results obtained with the Clauss (FIB C) method and the FIBPT‐d method with two thromboplastins in anticoagulated patients.

Population

The study population comprised 295 consecutive anticoagulated patients: 99 treated with vitamin K antagonists (VKAs), 49 treated with unfractionated heparin (UFH), 47 treated with LMWH, 50 treated with rivaroxaban, 50 treated with dabigatran, and 100 normal controls (NCs).

Methods

Dabigatran samples were analyzed by the use of FIB C with HemosIL Fibrinogen C or 100 NHI thrombin units mL^?1 reagents; rabbit brain and human recombinant thromboplastins with HemosIL PTFibrinogen HS plus (HS) and Recombiplastin 2G (RP) were used for FIBPT‐d method. Heparin and rivaroxaban levels were assessed with HemosIL Liq antiXa with specific calibrators; dabigatran levels were determined with the HemosIL Direct Thrombin Inhibitor Assay. All assays were performed on the ACL TOP platform in two laboratories. Percentage biases for the FIBPT‐d method versus the FIB C method were calculated by the use of Bland–Altman plots.

Results

Positive biases of the FIBPT‐d method versus the FIB C method with both thromboplastins were seen in NC samples (13.7% and 18.9% for HS and RP, respectively), but biases with HS in rivaroxaban and VKA patient samples were higher than that in NC samples, at 31.9% and 34.0%, respectively. LMWH patient samples showed higher bias than NC samples: 26.5% and 29.3.0% with HS and RP, respectively. UFH and dabigatran patient samples showed similar bias as NC samples.

Conclusion

The FIBPT‐d method should not be used in anticoagulated patients, because the FIBPT‐d mathematical algorithm has been validated only in normal subjects, so overestimation could occur in these patients.

     

Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study

Essentials

• The association between chronic kidney disease and bleeding is unknown.
• We followed 10 347 subjects at high cardiovascular risk for bleeding events.
• Chronic kidney disease was associated with a 1.5‐fold increased bleeding risk.
• Especially albuminuria rather than decreased kidney function was associated with bleeding events.

Summary

Background

There are indications that patients with chronic kidney disease have an increased bleeding risk.

Objectives

To investigate the association between chronic kidney disease and bleeding in patients at high cardiovascular risk.

Methods

We included 10 347 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2015 for an outpatient visit with classic risk factors for arterial disease or with symptomatic arterial disease (Second Manifestation of Arterial disease [SMART] cohort). Patients were staged according to the KDIGO guidelines, on the basis of estimated glomerular filtration rate (eGFR) and albuminuria, and were followed for the occurrence of major hemorrhagic events until March 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding were calculated with Cox proportional hazards analyses.

Results

The incidence rate for bleeding in subjects with chronic kidney disease was 8.0 per 1000 person‐years and that for subjects without chronic kidney disease was 3.5 per 1000 person‐years. Patients with chronic kidney disease (n = 2443) had a 1.5‐fold (95% CI 1.2–1.9) increased risk of bleeding as compared with subjects without chronic kidney disease (n = 7904) after adjustment. Subjects with an eGFR of < 45 mL min^?1 1.73 m^–2 with albuminuria had a 3.5‐fold (95% CI 2.3–5.3) increased bleeding risk, whereas an eGFR of < 45 mL min^?1 1.73 m^–2 without albuminuria was not associated with an increased bleeding risk (HR 1.3, 95% CI 0.7–2.5).

Conclusion

Chronic kidney disease is a risk factor for bleeding in patients with classic risk factors for arterial disease or with symptomatic arterial disease, especially in the presence of albuminuria.

     

Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism

Essentials

• Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk.
• Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk.
• A greater 6‐year rise in N‐terminal natriuretic peptide is associated with increased VTE incidence.
• Volume overload or impending cardiac disease may contribute to VTE occurrence.

Summary

Background

We previously showed that participants in the population‐based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE).

Objective

We hypothesized that ARIC participants with larger 6‐year increases in the levels of three biomarkers – C‐reactive protein (CRP), N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), and troponin T – would also have an increased subsequent risk of VTE.

Methods

We measured changes in the levels of these biomarkers in 9844 participants from 1990–1992 to 1996–1998, and then identified VTEs through 2015.

Results

A greater 6‐year rise in the level of NT‐proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow‐up. After adjustment for other VTE risk factors, those whose NT‐proBNP level rose from < 100 pg mL^?1 to ≥ 100 pg mL^?1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15–1.80), as compared with the reference group with an NT‐proBNP level of < 100 pg mL^?1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19–2.31) during the first 10 years of follow‐up, but was attenuated (1.24, 95% CI 0.99–1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation.

Conclusions

The two most likely explanations for our results are that: (i) an increasing NT‐proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT‐proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

     

Dabigatran versus vitamin k antagonist: an observational across‐cohort comparison in acute coronary syndrome patients with atrial fibrillation

Essentials

• Acute coronary syndrome (ACS) with atrial fibrillation (AF) is a therapeutic challenge.
• Dual and triple antithrombotic therapy showed a similar thrombotic risk in ACS patients with AF.
• The omission of aspirin during the first month did not increase the rate of ischemic events.
• Replacement of vitamin K antagonist by dabigatran leads to an increased thrombotic risk.

Summary

Background

Dual antithrombotic therapy comprising a vitamin K antagonist (VKA) plus clopidogrel reduces the incidence of major bleeding compared with triple therapy (VKA + clopidogrel + aspirin) in acute coronary syndrome (ACS) patients with atrial fibrillation (AF), with a similar thrombotic risk. The oral thrombin inhibitor dabigatran (150 mg twice a day) showed superiority over VKA in non‐valvular AF, but data supporting its use in AF patients presenting with ACS are limited.

Objective

We sought to evaluate the efficacy of dabigatran vs. VKA in the management of AF patients undergoing percutaneous coronary intervention for an ACS.

Methods

In this open‐label study, 133 consecutive patients received dabigatran plus clopidogrel. Another cohort of 133 patients treated with VKA plus clopidogrel was used as the control group.

Results

After propensity score adjustment, the cumulative incidence of major adverse cardiovascular events over 24 months was higher with dabigatran vs. VKA (adjusted hazard ratio, 2.28; 95% confidence interval, 1.46–3.56). Similar rates of major bleeding were found (adjusted hazard ratio, 1.17; 95% confidence interval, 0.46–2.96).

Conclusions

In AF patients presenting with ACS, replacement of VKA by dabigatran concurrently with clopidogrel is associated with an increased thrombotic risk, without a reduction in major bleeding.

     

Polymorphism in dural arteriovenous fistula: matrix metalloproteinase‐2‐1306 C/T as a potential risk factor for sinus thrombosis

Essentials

• Sinus thrombosis may play a crucial role in development of dural arteriovenous fistula (DAVF).
• Little is known about the association between gene polymorphism and the development of DAVF.
• MMP‐2‐1306 C/T showed a higher prevalence rate in DAVF cases with sinus thrombosis.
• MMP‐2‐1306C/T polymorphism is likely a potential risk factor for sinus thrombosis in DAVF.

Summary

Background

Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying DAVF development.

Objectives

To investigate the associations of gene polymorphisms and DAVF.

Materials and Methods

By the use of real‐time PCR genotyping, seven single‐nucleotide polymorphisms (SNPs) of angiogenesis‐related genes were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were subgrouped on the basis of location (cavernous sinus versus lateral sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without).

Results

We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)‐2‐1306 C/T (rs243865) had a significantly increased risk of sinus thrombosis in DAVF (odds ratio 6.2; 95% confidence interval 1.7–22.9). There was a weak difference in associations of tissue inhibitor of metalloproteinase (TIMP)‐2 (rs2277698) gene polymorphism and DAVF patients subgrouped by CVR grading.

Conclusions

These preliminary results indicate that MMP‐2‐1306 C/T, but not MMP‐9, TIMP‐1, TIMP‐2, and vascular endothelial growth factor A SNP variants, is a risk factor for the development of sinus thrombosis in DAVF patients.

     

Risk stratification for the development of venous thromboembolism in hospitalized patients with cancer

Essentials

• The Khorana score is validated for risk of venous thromboembolism (VTE) in cancer outpatients.
• We conducted a multicenter analysis of medically hospitalized cancer patients.
• Patients with a higher Khorana score on admission were more likely to develop VTE.
• The Khorana score is predictive of in‐hospital, symptomatic VTE development.

Summary

Introduction

The Khorana score is a validated risk assessment score for estimating the risk of symptomatic venous thromboembolism (VTE) in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting the development of VTE in cancer patients during hospital admission.

Methods

We conducted an analysis of consecutive, adult cancer patients hospitalized for medical reasons between January and June 2010 in three academic medical centers. Information on objectively diagnosed, symptomatic VTE during hospitalization, use of anticoagulant thromboprophylaxis (TP) and Khorana score variables at the time of admission was collected.

Results

A total of 1398 patients were included. Mean age was 62 years, 51.2% were male, and mean BMI was 25.9 kg m^?2. The most frequent reasons for hospitalization were chemotherapy administration (22.3%), followed by pain control and palliation (21.4%). The overall incidence of VTE was 2.9% (95% CI, 2.0–3.8%), occurring in 5.4% (95% CI, 1.9–8.9%) of the high‐, 3.2% (95% CI, 2.0–4.4%) of the intermediate‐ and 1.4% (95% CI, 0.3–2.6%), of the low‐risk groups. High‐risk patients were more likely than low‐risk patients to have VTE (OR, 3.9; 95% CI, 1.4–11.2).

Conclusion

The Khorana score is predictive of in‐hospital, symptomatic VTE development in cancer patients who are hospitalized for medical reasons and may be a useful tool for tailoring inpatient anticoagulant thromboprophylaxis.

     

Preclinical pharmacokinetics and biodistribution of subcutaneously administered glycoPEGylated recombinant factor VIII (N8‐GP) and development of a human pharmacokinetic prediction model

Essentials

• N8‐GP is an extended half‐life recombinant factor VIII (FVIII) for the treatment of hemophilia A.
• Subcutaneous (SC) FVIII dosing might reduce the treatment burden of prophylaxis.
• SC N8‐GP has a favorable PK profile in animal models and disappears from skin injection sites.
• Combined animal (SC) and clinical (IV) data suggest that daily SC dosing may provide prophylaxis.

Summary

Background

N8‐GP is an extended half‐life recombinant factor VIII (FVIII) for the treatment of hemophilia A. Subcutaneous administration of FVIII may reduce the treatment burden of prophylaxis; however, standard FVIII products have low bioavailability after subcutaneous dosing in animals.

Objective

To evaluate the pharmacokinetics, effectiveness and local distribution of subcutaneously administered N8‐GP in preclinical models and predict the human pharmacokinetic (PK) profile.

Methods

The pharmacokinetics of subcutaneously administered N8‐GP were evaluated in FVIII knockout (F8‐KO) mice and cynomolgus monkeys; a human PK prediction model in hemophilia A patients was developed. The hemostatic effect was evaluated in a tail vein bleeding model in F8‐KO mice. The injection‐site distribution and absorption of subcutaneously administered N8‐GP were assessed in F8‐KO mice by the use of temporal fluorescence imaging and immunohistochemistry.

Results

Subcutaneously administered N8‐GP had a bioavailability, a first‐order absorption rate and a half‐life, respectively, of 24%, 0.094 h^?1 and 14 h in F8‐KO mice, and 26%, 0.33 h^?1 and 15 h in cynomolgus monkeys. A dose‐dependent effect of subcutaneously administered N8‐GP on blood loss was observed in mice. A minimal amount of N8‐GP was detected at the injection site 48–72 h after single or multiple dose(s) in F8‐KO mice. Subcutaneously administered N8‐GP was localized to the skin around the injection site, with time‐dependent disappearance from the depot. PK modeling predicted that subcutaneously administered N8‐GP at a daily dose of 12.5 IU kg^?1 will provide FVIII trough levels of 2.5–10% in 95% of patients with severe hemophilia A.

Conclusions

Subcutaneously administered N8‐GP may provide effective hemophilia A prophylaxis. A phase I clinical trial is underway to investigate this possibility.

     

Genes associated with venous thromboembolism in colorectal cancer patients

Essentials

• The underlying pathophysiological mechanisms behind cancer‐associated thrombosis are unknown.
• We compared expression profiles in tumor cells from patients with and without thrombosis.
• Tumors from patients with thrombosis showed significant differential gene expression profiles.
• Patients with thrombosis had a proinflammatory status and increased fibrin levels in the tumor.

Summary

Background

Venous thromboembolism (VTE) is a frequent complication in patients with cancer, and is associated with significant morbidity and mortality. However, the mechanisms behind cancer‐associated thrombosis are still incompletely understood.

Objectives

To identify novel genes that are associated with VTE in patients with colorectal cancer (CRC).

Methods

Twelve CRC patients with VTE were age‐matched and sex‐matched to 12 CRC patients without VTE. Tumor cells were isolated from surgical samples with laser capture microdissection approaches, and mRNA profiles were measured with next‐generation RNA sequencing.

Results

This approach led to the identification of new genes and pathways that might contribute to VTE in CRC patients. Application of ingenuity pathway analysis indicated significant links with inflammation, the methionine degradation pathway, and increased platelet function, which are all key processes in thrombus formation. Tumor samples of patients with VTE had a proinflammatory status and contained higher levels of fibrin and fibrin degradation products than samples of those without VTE.

Conclusion

This case–control study provides a proof‐of‐principle that tumor gene expression can discriminate between cancer patients with low and high risks of VTE. These findings may help to further unravel the pathogenesis of cancer‐related VTE. The identified genes could potentially be used as candidate biomarkers to select high‐risk CRC patients for thromboprophylaxis.

     

Alcohol consumption and the risk of incident pulmonary embolism in US women and men

Essentials

• The association of moderate alcohol consumption with pulmonary embolism (PE) risk remains unclear.
• In three large US cohorts, we evaluated the association of alcohol consumption with PE risk.
• We found no evidence of an association of alcohol consumption amount or frequency with PE risk.
• Secondary analyses of type and heavy episodic drinking also yielded null findings.

Summary

Background

Moderate alcohol consumption has been variably associated with hemostatic and fibrinolytic factor levels, but the association between alcohol consumption and the risk of incident pulmonary embolism (PE) remains uncertain.

Objective

To evaluate alcohol consumption amount and frequency in relation to PE risk.

Methods

Nurses’ Health Study (NHS), NHS II and Health Professionals Follow‐Up Study participants free of venous thromboembolism (VTE) at baseline (n = 217 442) reported alcohol consumption by type, quantity and frequency, every 2–4 years. Incident PE cases were identified by self‐report and confirmed for participants without cancer. In this cohort study, we used Cox proportional hazards models to estimate multivariable‐adjusted hazard ratios (HRs) for PE associated with alcohol consumption amount and, separately, frequency. Secondary analyses evaluated alcohol type and heavy episodic drinking in relation to PE risk, and amount and frequency in relation to medical record‐confirmed idiopathic PE and any self‐reported VTE risk. Cohort‐specific analyses were pooled using random‐effects meta‐analysis.

Results

During ≥ 20 years of follow‐up, we identified 1939 PE events. We found no strong evidence of an association between PE risk and alcohol consumption amount (pooled HR_adj for 5.0–14.9 g day^?1 vs. abstention = 0.97 [95% CI, 0.79, 1.20]) or frequency (pooled HR_adj for 5–7 drinking days per week vs. abstention = 1.04 [95% CI, 0.88, 1.23]). Secondary analyses of type, heavy episodic drinking, idiopathic PE and VTE also yielded null findings.

Conclusions

Among three large prospective cohorts of US men and women, we found no evidence of an association between the amount or frequency of alcohol consumption and PE risk.

     

In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents

Essentials

• Patients with hemophilia A and inhibitors receiving emicizumab experience breakthrough bleeding.
• Safety concerns may exist when combining emicizumab with bypassing agents.
• Combined bypassing agent and bispecific antibody increased thrombin generation up to 17‐fold.
• Thrombotic effects should be considered when combining emicizumab with plasma bypassing agent.

Summary

Background

Investigational non‐factor products such as emicizumab offer a treatment option for patients with hemophilia and inhibitors. However, their mechanism of action raises questions regarding safety when they are combined with treatments for breakthrough bleeding.

Objectives

To evaluate in vitro thrombin generation (TG) and clot formation for combinations of activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and a sequence‐identical analog of emicizumab (SIA).

Methods

Therapeutic concentrations of SIA (20–600 nm ) alone or with aPCC (0.05–1 U mL^?1), isolated aPCC components or rFVIIa (0.88–5.25 μg mL^?1) were tested for TG and compared with reference ranges for healthy donor plasma. Coagulation of FVIII‐inhibited blood was determined with a widely established method, i.e. rotational thromboelastometry (ROTEM), and confirmed with the Total Thrombus‐formation Analysis System.

Results and conclusions

SIA (600 nm ) or aPCC (0.5 U mL^?1) alone resulted in peak thrombin levels of 21.4 nm and 38.6 nm , respectively, both of which are lower than normal (83.7 ± 29.8 nm ). SIA plus aPCC (0.5 U mL^?1) increased the peak thrombin level 17‐fold over SIA alone, exceeding the reference plasma value by 4.2‐fold. This hypercoagulable effect occurred with 600 nm SIA combined with as little as 0.25 U mL^?1 aPCC, confirmed by ROTEM. FIX was the main driver for enhanced TG. SIA plus rFVIIa (1.75 μg mL^?1) induced a 1.8‐fold increase in the peak thrombin level in platelet‐rich plasma, but it did not reach the normal range. These in vitro experiments demonstrate excessive TG after administration of a combination of aPCC and SIA at clinically relevant doses. Careful judgement may be required when breakthrough bleeding is treated in patients receiving emicizumab.