Fifth Åland Island conference on von Willebrand disease.

The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016-90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis and VWF inhibitors.

During warfarin induction, the Fiix-prothrombin time reflects the anticoagulation level better than the standard prothrombin time.

Essentials Fiix-prothrombin time (PT) monitoring of warfarin measuring factor (F) II and X, is effective. Plasma obtained during warfarin induction and stable phase in Fiix-trial was assayed. Fiix-PT stabilized anticoagulation earlier than monitoring with traditional PT-INR. FVII had little effect on thrombin generation that was mainly determined by FII and FX. SUMMARY: Background The prothrombin time (PT) is equally prolonged by reduction of each of the vitamin K-dependent (VKD) factors (F) II, VII and X. The Fiix-PT is only affected by FII and FX, the main contributors to thrombin generation (TG). Objective To test the hypothesis that variability in warfarin anticoagulation is reduced early during monitoring with the normalized PT-ratio calculated from Fiix-PT (Fiix-International Normalized Ratio [INR]) compared with traditional PT-INR monitoring. Also, that because of its insensitivity to FVII, Fiix-PT more accurately reflects TG when Fiix-INR and PT-INR are discrepant. Methods Samples from Fiix-trial participants monitored with either Fiix-PT or PT were used. VKD coagulation factors and TG were measured in samples from 40 patients during stable anticoagulation and in serial samples obtained from 26 patients during warfarin induction. TG was assessed in relation to selective reduction in single VKD factors. Results During Fiix-warfarin induction full anticoagulation measured as FII or FX activity was achieved at a similar rate to that with PT-warfarin but subsequently stabilized better. Fiix-INR but not PT-INR mirrored total TG during initiation. During induction, FII (R2 = 0.66) and FX (R2 = 0.52) correlated better with TG and with a steeper slope than did FIX (R2 = 0.37) and in particular FVII (R2 = 0.21). In vitro, FII and FX were the main determinants of TG at concentrations observed during VKA anticoagulation, whereas FVII and FIX had little influence. Conclusions Fiix-PT monitoring reduces anticoagulation variability, suggesting that monitoring FVII has a limited role during VKA management. TG is better reflected by Fiix-PT.

Fiix-prothrombin time monitoring improves warfarin anticoagulation outcome in atrial fibrillation: a systematic review of randomized trials comparing Fiix-warfarin or direct oral anticoagulants to standard PT-warfarin.

BACKGROUND: Monitoring warfarin with Fiix-prothrombin time (Fiix-PT), which is only affected by coagulation factors II and X, stabilizes anticoagulation and reduces thromboembolism compared to PT/INR monitoring. We compared outcome in nonvalvular atrial fibrillation (NVAF) patients treated with Fiix-warfarin, direct oral anticoagulants (DOACs), or PT-warfarin. METHODS: A systematic efficacy and safety assessment by retrieving data from the Fiix trial and the four major phase III DOAC trials in NVAF. Prespecified outcomes included stroke and systemic embolism (SSE), SSE and myocardial infarction (MI), major bleeding (MB), composite major vascular events (SSEMI and MB; CMVE), and deaths. We calculated relative risk, 95% CI, and 95% confidence limits (CL) for each outcome and performed meta-analysis using fixed- and random-effects modeling. RESULTS: There were 613 and 628 observation years with Fiix-warfarin and PT-warfarin in the Fiix trial, and 70 628 and 57 962 with DOACs and PT-warfarin in DOAC trials. Populations were comparable although death rates were lower in the Fiix trial. Compared to pooled PT-warfarin, Fiix-warfarin reduced SSE (RR 0.54;95% CI 0.26-1.10/95% CL <1.00), SSEMI (0.51;0.26-0.99/<0.90), MB (RR 0.63;0.37-1.07/<0.99), and CMVE (RR 0.66;0.43-1.00/<0.94). Vascular death was lower (RR 0.13;0.04-0.47/<0.42). Compared to pooled DOACs, Fiix-warfarin consistently had lower point estimates for the RR for efficacy and safety, but only significant for lower death rates (vascular death RR 0.14;0.04-0.49/<0.43). Meta-analysis comparing Fiix-warfarin and DOACs with PT-warfarin consistently found Fiix-warfarin to have the lowest point estimates for efficacy. CONCLUSION: Monitoring warfarin with Fiix-PT reduces risk of vascular events in NVAF patients as much as DOACs. Warfarin monitored with Fiix-PT is an improved anticoagulant.

A single test to assay warfarin, dabigatran, rivaroxaban, apixaban, unfractionated heparin, and enoxaparin in plasma.

UNLABELLED: Essentials Simple and fast assaying of different anticoagulants (ACs) is useful in emergent situations. We used highly diluted prothrombin time (dPT) or highly diluted Fiix-PT (dFiix-PT) to assay ACs. Both tests could quantify target specific anticoagulants and warfarin anticoagulation. Improved results were consistently observed with the dFiix-PT compared with the dPT. SUMMARY: Background Assaying anticoagulants is useful in emergency situations or before surgery. Different specific assays are currently needed depending on the anticoagulant. Objectives We hypothesized that levels of warfarin, dabigatran, rivaroxaban, apixaban, and heparins could be measured with use of the diluted prothrombin time (dPT) and diluted Fiix-PT (dFiix-PT), using highly diluted thromboplastin (TP). The latter test is affected only by reduced levels of active factors II and X but corrects test plasma for other deficiencies Methods Increasing TP dilutions were used to identify suitable dilutions to measure dabigatran, rivaroxaban, apixaban, unfractionated heparin (UFH), and enoxaparin. Calibrators containing known amounts of direct oral anticoagulants (DOACs) were used to make standard curves. Citrated plasma samples were obtained from patients taking warfarin or DOACs with known drug concentrations as determined by specific assays. Results The dFiix-PT at a TP dilution of 1:1156 could be used to measure all of the drugs tested at therapeutic concentrations except for fondaparinux. The dPT achieved the same but required two TP dilutions (1:750 and 1:300). The warfarin effect could be assessed by using dFiix-PT at 1:1156 with a PT ratio identical to the international normalized ratio. Six different TPs yielded similar results, but two were less sensitive. Dabigatran, rivaroxaban, and apixaban could be accurately measured in patient samples using both dilute PT assays, but a better correlation was consistently observed between the dFiix-PT and specific assays than with the dPT. Conclusion The dFiix-PT using a single dilution of TP may be suitable to assess the anticoagulant effects of warfarin, dabigatran, rivaroxaban, apixaban, heparin, and enoxaparin.

Prediction of survival in patients suspected of disseminated intravascular coagulation.

BACKGROUND: Although antithrombin (AT), protein C (PC), and antiplasmin (AP) are consumed during disseminated intravascular coagulation (DIC), their association with mortality in patients initially suspected of acute DIC is unknown. We examined how these proteins associate with mortality in consecutive patients initially suspected of DIC, fulfilling or not fulfilling overt DIC criteria. METHODS: All consecutive patients clinically suspected of acute DIC during 5 years at a tertiary referral hospital were scored according to overt International Society of Thrombosis and Haemostasis (ISTH) DIC criteria. The influence of ISTH DIC score and measurements of AT, PC, and AP measured in all on mortality was assessed. RESULTS: During 1825 occurrences in 1814 patients, 91 fulfilled ISTH criteria for overt DIC (score ≥ 5). Both 28-day and 1-year mortality increased progressively as AT and in particular PC decreased. AT and PC correlated inversely with ISTH score (AT: R(2 ) = 0.14, P < 0.001, PC: R(2 ) = 0.21, P < 0.001). AP decreased when ISTH score of > 3 was reached. The 28-day mortality was 3%, 11%, 16%, 23%, 35%, and 52% and 1-year mortality 5%, 18%, 24%, 36%, 54%, and 63%, respectively for patients with an ISTH score of 0, 1, 2, 3, 4, and ≥5 (P < 0.001 for all). CONCLUSIONS: Lowered AT and in particular PC activity was predictive of mortality risk upfront in critically ill patients suspected of acute DIC. Mortality in patients suspected of acute DIC increased progressively across the spectrum of the overt ISTH score and not only in those fulfilling overt DIC criteria.

Recombinant factor VIIa as last-resort treatment of desperate haemorrhage.

INTRODUCTION: Studies are inconclusive regarding clinical outcomes after administration of recombinant activated coagulation factor VII (rFVIIa) during severe haemorrhage. The circumstances encountered during desperate haemorrhage make it difficult to include the most critically ill patients that could possibly benefit the most from such treatment into randomized controlled trials. We report our experience with rFVIIa as last-resort treatment of desperate haemorrhage when all standard treatment has failed. MATERIALS AND METHODS: Hospital charts of all consecutive patients treated with rFVIIa for desperate non-haemophilic bleeding over a 10-year period at the single institution administering rFVIIa were surveyed for treatment indications, clinical outcome, transfusion need and coagulation profiles. RESULTS: Fifty-five rFVIIa treatment occasions of desperate bleeding were identified in 54 patients (median age 54 years). A single rFVIIa dose was used in 86%, and haemorrhage was considered effectively contained by immediate clinical response on 81% of occasions. Overall, 38 patients (71%) survived for over 30 days. Two thromboembolic events occurred (3.6%). The 24-h mortality in 45 rFVIIa immediate clinical responders and 10 non-responders was 2% and 50%, respectively (P = 0.0004), and the 30-day mortality was 25% and 60%, respectively (P = 0.05). Blood product use decreased with rFVIIa (P < 0.01) as did the prothrombin time (20.0-13.3 s, P < 0.0001). CONCLUSIONS: The majority of unselected consecutive patients receiving rFVIIa as last-resort treatment for desperate haemorrhage were considered to have immediate clinical response as well as reduced transfusion requirements and correction of coagulation parameters. An immediate clinical response to rFVIIa may possibly be predictive of survival.

Effects of fibrinogen concentrate administration during severe hemorrhage.

BACKGROUND: Fibrinogen concentrate has been shown to improve coagulation in dilutional coagulopathy in experimental studies, but clinical experience is still scarce. The aim of this study was to evaluate laboratory data and the clinical outcome of fibrinogen administration in patients suffering from severe hemorrhage. MATERIALS AND METHODS: A retrospective study over a 3-year observation period of consecutive patients who received a single dose of fibrinogen concentrate but not recombinant factor VIIa as part of their treatment of severe hemorrhage, defined as >6 U of packed red blood cells (PRBCs). RESULTS: Thirty-seven patients were included, most of them suffering from severe hemorrhage following open heart surgery (68%). After a median fibrinogen dose of 2 g (range 1-6 g), an absolute increase in the plasma fibrinogen concentration of 0.6 g/l was observed (P<0.001). The activated partial thromboplastin time (APTT) decreased significantly (P<0.001), from 52 to 43 s and the prothrombin time (PT) decreased from 20 to 17 s, respectively. The transfusion requirement for PRBCs decreased from 6 to 3 U (P<0.01) in the 24 h after fibrinogen administration, but fresh-frozen plasma and platelet concentrate transfusions did not change significantly. Eight patients (22%) died in intensive care unit and the pre-operative fibrinogen concentration was not significantly different in these patients. CONCLUSION: Administration of fibrinogen for severe hemorrhage was associated with an increased fibrinogen concentration and a significant decrease in APTT, PT and the requirement for PRBCs.

Warfarin anticoagulation intensity in specialist-based and in computer-assisted dosing practice.

The efficacy and safety of oral anticoagulation (OA) with vitamin K antagonists depends on maintaining anticoagulation intensity, measured as international normalized ratio (INR), within defined target ranges. We assessed the quality of our current software-assisted warfarin dosing in the year 2006 in 941 unselected consecutive patients on stable OA with atrial fibrillation (AF), venous thromboembolism (VTE) and prosthetic heart valves (PHV) by comparing it to our previous cardiologist-based dosing practice in 1992 when a study was carried out on 241 comparable patients. Over 14 years, the time within target range increased in all three anticoagulated groups, i.e. in AF patients from 46% to 81%, in VTE patients from 62% to 84% and in patients with PHV from 40% to 64%. Only 1% of the treatment time is now spent at INR < 1.5 compared to 7% previously (P < 0.0001) and 0.4% of the treatment time at INR > 4.0 presently compared to 2.8% in the past (P < 0.0001). INR-targets are better achieved with the current software-assisted dosing practice and extreme low and high values are less common than previously. The results provide indirect evidence suggesting that both efficacy and safety has improved with the current practice.

Risk of excessive bleeding associated with marginally low von Willebrand factor and mild platelet dysfunction.

BACKGROUND: Bleeding symptoms are so commonly reported that it is not known whether they associate causally or coincidentally with mild but measurable primary hemostatic defects. OBJECTIVES/PATIENTS/METHODS: In order to evaluate if the mild primary hemostatic defects are truly causative of increased bleeding symptoms, we surveyed a population of healthy teenagers for bleeding symptoms. Using a case-control approach, we then estimated the risk of excessive bleeding associated with low von Willebrand factor (defined as VWF below the 5th percentile of a normal reference population), and with mild platelet dysfunction [PD, defined as concurrent reduced platelet aggregation responses to two agonists (adenosine diphosphate and epinephrine)]. RESULTS: Excessive bleeding was present in 63 out of 809 teenagers (7.8%). Among the 49 cases who were tested for VWF, low values by three measures were more commonly present than in 166 controls, specifically, ristocetin cofactor (RCo) activity [20.4% vs. 5.4%, odds ratio (OR) 4.5], collagen binding (14.3% vs. 4.2%, OR 3.8), and antigen level (20.4% vs. 6.0%, OR 4.0). The low RCo values ranged from 35 to 45 U dL(-1) except for a single case with 26 U dL(-1). Of the 47 teenagers with excessive bleeding who underwent platelet aggregation studies, reduced responses were more common than in controls (12.8% vs. 4.4%, OR 3.2). Twenty-nine per cent of cases with excessive bleeding had either low RCo or PD. CONCLUSION: Almost one in three teenagers who report excessive bleeding is likely to have a measurable hemostatic disturbance manifested either by marginally low VWF (by three measures) or by mild PD.

The contraceptive vaginal ring (NuvaRing) and hemostasis: a comparative study.

This open-label, nonrandomized study compared changes in hemostatic variables during NuvaRing and oral levonorgestrel 150 microg/ethinylestradiol 30 microg (LNG/EE) use for six cycles. Eighty-seven women started the study, 44 with NuvaRing and 43 with the LNG/EE oral contraceptive. For most procoagulation variables, there was no difference between NuvaRing and oral LNG/EE; only Factor VII levels increased in the NuvaRing group and decreased in the LNG/EE group. The majority of assessed variables show that anticoagulation and fibrinolytic activity was comparable between the NuvaRing and oral LNG/EE groups. Antithrombin activity and protein C activity both tended to be higher with NuvaRing. Levels of tissue plasminogen activator decreased in both groups but the reduction was smaller with NuvaRing. There were no significant differences in fibrin turnover between the treatment groups. The data show that both NuvaRing and oral LNG/EE are associated with a minimal effect on hemostatic variables.

Activated and total coagulation factor VII, and fibrinogen in coronary artery disease.

Fibrinogen (FBG) and total coagulation factor VII (FVIIc) concentrations are higher in those patients with coronary artery disease who are at increased future risk of acute ischemic events. The relationship between activated factor VII (FVIIa) and cardiovascular events, however, has not been intensively studied. Data were collected from 401 consecutive patients who underwent coronary angiography because of suspected coronary artery disease. Conventional risk factors FVIIc, FVIIa and FBG were assessed in relation to the severity of coronary artery disease, left ventricular ejection fraction, and previous clinical events. A strong positive correlation was found between FVIIa and FVIIc (p < 0.001), but neither FVIIa nor FVIIc correlated with FBG. No correlation was found between FVIIa, FVIIc or FBG levels and stenosis score for the severity of coronary artery disease, and all were similar in patients with stable or unstable angina pectoris. Multivariate regression analysis showed FVIIc to be higher in women (p = 0.004), and positively related to triglycerides (p = 0.001) and HDL cholesterol (p = 0.006), but not to a previous myocardial infarction or total cholesterol. FVIIa, on the other hand, was lower in patients with a previous myocardial infarction (p = 0.004), higher in women (p = 0.001) and those that previously had undergone percutaneous transluminal coronary angioplasty (p = 0.039), and positively related to total cholesterol (p = 0.011), duration of coronary artery disease (p = 0.032), and smoking (p = 0.008). FBG was positively associated with a previous myocardial infarction (p = 0.013), hypertension (p = 0.016), smoking (p = 0.005), and the thrombocyte count (p < 0.001). Finally, stepwise logistic regression analysis verified a previous myocardial infarction to be negatively associated with FVIIa (p = 0.03), and positively with FBG (p = 0.03), total cholesterol (p = 0.02), and the severity of coronary artery disease (p < 0.001). In conclusion, in patients suspected of coronary artery disease undergoing cardiac catheterization, FVIIa was decreased and FBG increased in those who had a previous myocardial infarction. FVIIa, FVIIc, or FBG levels were not, however, related to the severity of coronary artery disease, and they were similar in patients with stable or unstable angina pectoris.

[A prospective study of oral anticoagulation therapy monitored with the P&P-test.].

OBJECTIVE: To analyze the outcome of patients on oral anticoagulation therapy who are monitored with the prothrombin proconvertin time (P&P-test, PP). MATERIAL AND METHODS: The prothrombin-proconvertin time was used to adjust anticoagulant intensity in a prospective study of 326 patients treated with oral anticoagulants for a study period of 121 patient years. The goal intensity INR was 2.0-3.0 for all patients. The main indications were: artificial heart valves 26%, venousthromboembolism 25%, atrial fibrillation 23%, atherosclerotic disease 14% and systemic arterial embolism of uncertain etiology 7%. RESULTS: INR calculated directly from the PP correlated well with INR calculated from the PT. The mean time adjusted anticoagulant intensity was 2.3 and did not differ significantly according to indication. Six major bleedings, including one fatal, occurred in five patients during the study period. The INR was 1.8 in one patient who bled from a duodenal ulcer, but 6.8,7.9,8.6,11.6 (died) and 15.5 at five other events. The INR was <4.5 during 97% of the treatment time of the whole group and 1% of treat notment time were at an INR>6.0. The bleeders had a different pattern with 18% of the treatment time at INR>6.0. The risk of bleeding was one for every 73 days at that intensity or an almost 600 fold risk increase compared to an INR<4.5. One patient anticoagulated for systemic embolism had cerebral infarction with an event related INR of 2.0. Two patients with atrial fibrillation died from acute myocardial infarction but event related INR's were not available. One patient anticoagulated for venous thromboembolism died suddenly but was not autopsied. No embolic events occurred in patients with artificial heart valves in spite of the low intensity anticoagulation. CONCLUSION: Despite a relatively low intensity in all patient groups in this study thromboembolic events were rare. The risk of bleeding increased markedly at INR>6.0. The mortality rate of the ariticoagulated population was comparable to the expected age adjusted Icelandic mortality rate.

Performance of prothrombin-proconvertin time as a monitoring test of oral anticoagulation therapy.

Outcome and anticoagulation intensity was evaluated during 121 patient years of oral anticoagulant therapy monitored with the prothrombin-proconvertin clotting time (PP, also known as P&P). The PP-based international normalized ratio (INR; PP-INR) correlated well with the INR calculated from the prothrombin clotting time (PT; r = 0.92), and results were almost identical over a wide range after linear conversion (1/INR). When the PP-INR was 4.5 or less, the risk of major bleeding was 1 for every 118 treatment years, but it was 1 for every 73 days when the INR was 6 or more. The 1/PP-INR correlated better with factor II coagulant activity (r = 0.85) than did the 1/PT-INR (r = 0.78). The 1/PP-INR also correlated better with the native prothrombin antigen (r = 0.76) than did the 1/PT-INR (r = 0.68). The PP and PT results correlated better with factor II coagulant activity than with native prothrombin antigen. Thus, the PP clotting time results can be accurately converted to INR. The results also suggest that the PP may have advantages over the PT as an indicator of anticoagulation intensity during oral anticoagulation.

[Factor VQ50f) and prothrombin 20210 A mutations in an Icelandic apparently healthy population and patients suffering from venous thrombosis.].

INTRODUCTION: Inherited and aquired factors are important in the pathogenesis of thrombosis. Recent studies have demonstrated that mutations in the genes encoding coagulation factor V (FVQ506 or FVLeiden) and prothrombin (PT 20210 A) predispose to a markedly increased risk of venous thrombosis. FVQ506 is considered to be the most frequent cause of inherited venous thrombosis in Europeans and the allele frequency has been shown to be high. The aim of this study was to determine the allele frequency of the two mutations in an apparently healthy Icelandic population and patients suffering from venous thrombosis. MATERIAL AND METHODS: An apparently healthy Icelandic population and patients suffering from venous thrombosis were genotyped for the presence or absence of the FVQ506 and PT 20210 A mutations using PCR and restrictions fragment length polymorphisms. RESULTS: The allele frequency of FVQ506 was 0.0315 in the healthy population (n=159; 10 heterozygotes found). Fifteen of 99 patients with venous thrombosis were found to be heterozygous for FVQ506 (15.2%; allele frequency 0.071), significantly more when compared to controls (p<0.01). One apparently healthy individual (0.9%; n=108) and one of the patients (0.95%; n=99) were found to be heterozygous for PT 20210 A. CONCLUSION: The results demonstrate high prevalence of FVQ506 in the Icelandic population compared with many other European populations and that FVQ506 is commonly associated with venous thrombosis.