We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are ...previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).
Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe ...than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran‐related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.
While overall gastrointestinal bleeding (GIB) rates have been extensively compared between warfarin and direct oral anticoagulants (DOACs), it is still unclear whether upper and lower GIB rates ...differ between these types of drugs. This study aimed to compare upper and lower GIB rates between warfarin and DOACs in a nationwide cohort.
Data on all patients in Iceland who received a prescription for oral anticoagulation from 2014 to 2019 were collected and their personal identification numbers linked to the electronic medical record system of the National University Hospital of Iceland and the 4 regional hospitals in Iceland. Inverse probability weighting was used to yield balanced study groups and rates of overall, major, upper, and lower GIB were compared using Cox regression. All GIB events were manually confirmed by chart review.
Warfarin was associated with higher rates of upper GIB (1.7 events per 100 person-years vs 0.8 events per 100 person-years; hazard ratio HR, 2.12; 95% confidence interval CI, 1.26-3.59) but similar rates of lower GIB compared with DOACs. Specifically, warfarin was associated with higher rates of upper GIB compared with apixaban (HR, 2.63; 95% CI, 1.35-5.13), dabigatran (5.47; 95% CI, 1.87-16.05), and rivaroxaban (HR, 1.74; 95% CI, 1.00-3.05). Warfarin was associated with higher rates of major GIB compared with apixaban (2.3 events per 100 person-years vs 1.5 events per 100 person-years; HR, 1.79; 95% CI, 1.06-3.05), but otherwise overall and major GIB rates were similar in warfarin and DOAC users.
Warfarin was associated with higher rates of upper but not overall or lower GIB compared with DOACs. Warfarin was associated with higher rates of major GIB compared with apixaban.
Background
Therapeutic phlebotomy is the standard treatment of hereditary hemochromatosis (HH), the most common genetic disease in people of Northern European descent. Red cell concentrates from HH ...donors have been reported safe for transfusion, but little data is available on the storage properties of platelet concentrates from HH donors.
Study Design and Methods
Whole blood was collected from 10 healthy individuals and 10 newly diagnosed HH patients with elevated serum ferritin. Platelet‐rich plasma (PRP) was prepared and split into four 20‐mL units. Platelet quality tests were performed on days 0, 1, 3, 5, and 7 of storage, including platelet aggregation (ADP, arachidonic acid, collagen, and epinephrine agonists), blood gas analysis, flow cytometry (CD41, CD42b, and CD62P expression), and ELISA (sCD40L and sCD62p in supernatant).
Results
Mean serum ferritin levels were higher in HH patients than in controls (847.5 vs 45.8 ng/mL, P < .001). Overall, no difference in quality test results was observed between the two study groups over 7‐day storage (P > .05), including blood gas analysis, platelet aggregation, and expression of surface (CD62p and CD42b) and secreted (sCD62P and sCD40L) activation markers. Expected alterations in metabolic (CO2 and glucose decrease, O2 and lactate increase, P < .001) and platelet activation markers (CD42b decrease, CD62P increase, P < .05) over time were observed in both groups.
Conclusion
Although these findings indicate that platelets of individuals with HH are comparable to platelets from healthy donors, more extensive studies are needed before definite conclusions can be drawn.
Abstract
The antithrombotic effect of vitamin K antagonists (VKA) depends on controlled lowering of the activity of factors (F) II and X whereas reductions in FVII and FIX play little role. PT-INR ...based monitoring, however, is highly influenced by FVII, which has the shortest half-life of vitamin K-dependent coagulation factors. Hence, variability in the anticoagulant effect of VKA may be partly secondary to an inherent flaw of the traditional monitoring test itself. The Fiix prothrombin time (Fiix-PT) is a novel test that is only sensitive to reductions in FII and FX and is intended to stabilize the VKA effect. Two clinical studies have now demonstrated that when warfarin is monitored with the Fiix-PT based normalized ratio (Fiix-NR) instead of PT-INR, anticoagulation is stabilized and less testing and fewer dose adjustments are needed. Furthermore, the relative risk of thromboembolism was reduced by 50–56% in these studies without an increase in major bleeding.
The new Fiix prothrombin time (Fiix-PT) and its derived Fiix-normalized ratio (Fiix-NR) is affected only by reductions in coagulation factors (F) II and X, the two factors responsible for the ...antithrombotic effect of vitamin K antagonists (VKA). Due to insensitivity to reductions in the short half-life FVII, the Fiix-NR rises later than standard PT-INR during warfarin initiation. To describe a warfarin initiation nomogram adapted for monitoring with Fiix-NR, anticoagulation development was assessed during use of standard PT-INR based initiation nomogram and after adapting the initiation nomogram for Fiix-NR monitoring. Normalized ratios were retrospectively assessed in consecutive warfarin naïve patients during their first 60 days of warfarin intake for one year prior to (PT-INR period) and for one year after replacing the PT-INR with the Fiix-NR (Fiix-NR period). The INR target was NR 2.0–3.0. We evaluated 160 patients monitored with PT-INR and dosed with the PT-nomogram, 57 monitored with Fiix-INR but dosed with PT-nomogram, and 163 Fiix-NR monitored patients dosed using a new Fiix nomogram. Mean PT-INR over 2.0 was reached on day 7 during the PT-period and remained around 2.5 thereafter. When the PT-nomogram continued in use during Fiix-monitoring significantly more patients became overanticoagulated during days 11–29. After the nomogram was modified to respond to rising Fiix-NR with larger initial dose reduction, the mean Fiix-NR reached over 2 on day 8–9 and remained around 2.5 thereafter. When warfarin is monitored with Fiix-NR, an adjusted dosing nomogram should be used during initiation to prevent early overanticoagulation.
Background
Although epistaxis is one of the most common side effects of oral anticoagulation, it is unclear whether epistaxis rates vary between different oral anticoagulants (OAC).
Objective
To ...compare rates of clinically relevant epistaxis between OAC.
Methods
Epistaxis event rates were compared between new users of apixaban, dabigatran, rivaroxaban, and warfarin in a nationwide population‐based cohort study over a 5‐year study period, 2014–2019. Data was collected from the Icelandic Medicine Registry and the five major hospitals in Iceland. Inverse probability weighting (IPW) was used to yield balanced baseline characteristics, and epistaxis rates were compared using Kaplan–Meier survival estimates and Cox regression.
Results
During the study period, 2098 patients received apixaban, 474 dabigatran, 3106 rivaroxaban, and 1403 warfarin. In total, 93 patients presented with clinically relevant epistaxis, including 11 (12%) major epistaxis events and one fatal epistaxis episode. Furthermore, seven patients (9%) with non‐major epistaxis later presented with major bleeding during the follow‐up period. Warfarin use was associated with higher rates of epistaxis compared to apixaban (2.2 events per 100‐person years (events/100‐py) vs. 0.6 events/100‐py, hazard ratio HR 4.22, 95% confidence interval CI 2.08–8.59, p < 0.001), rivaroxaban (2.2 events/100‐py vs. 1.0 events/100‐py, HR 2.26, 95% CI 1.28–4.01, p = 0.005), and dabigatran (2.2 events/100‐py vs. no events, HR n/a, p < 0.001).
Conclusion
Warfarin treatment was associated with higher rates of clinically relevant epistaxis compared to direct oral anticoagulants.
Introduction
Platelet function tests are used to screen and diagnose patients with possible inherited platelet function defects (IPFD). Some acquired platelet dysfunction may be caused by certain ...drugs or comorbidities, which need to be excluded before testing.
Aims
To identify current practice among centres performing platelet function tests in Northern Europe.
Methods
A total of 14 clinical centres from Sweden (six), Finland (two), Denmark (two), Norway (one), Estonia (two) and Iceland (one) completed the survey questionnaire, the population capture area of about 29.5 million.
Results
Six of the 14 (42.8%) centres providing platelet function assessment represent comprehensive treatment centres (EUHANET status). A Bleeding score (BS) or ISTH bleeding assessment tool (ISTH BAT score) is evaluated in 11/14 (78.6%) centres and family history in all. Five/14 centres (35.7%) use structured preanalytical patient instructions, and 10/14 (71.4%) recorded questionnaire on the preassessment of avoidance of any drugs or natural products affecting platelet functions. Preliminary investigations of screening tests of coagulation are performed in 10/14 (71.4%), while in 4/14 (28.6%), the diagnostic work‐up of IPFD and von Willebrand disease (VWD) is performed simultaneously. The work‐up of IPFD includes peripheral blood smear in 10/14 (71.4%), platelet aggregometry in all, flow cytometry in 10/14 (71.4%) and Platelet Function Analysis (PFA) in 3/11 (28.6%). Molecular genetic diagnosis is available in 7/14 (50%) centres.
Conclusions
The considerable variability in the current practice illustrates the need for harmonization between the Northern European centres according to the international registers (i.e. EUHASS) and IPFD guidelines (ISTH, EHA).
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