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.

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.

Enhancement of fibrinolysis in vitro by ultrasound.

The effect of ultrasound on the rate of fibrinolysis has been investigated using an in vitro system. Plasma or blood clots containing a trace label of 125I fibrin were suspended in plasma containing plasminogen activator and intermittently exposed to continuous wave 1-MHz ultrasound at intensities up to 8 W/cm2. Plasma clot lysis at 1 h with 1 microgram/ml recombinant tissue plasminogen activator (rt-PA) was 12.8 +/- 1.2% without ultrasound and was significantly (P = 0.0001) increased by exposure to ultrasound with greater lysis at 1 W/cm2 (18.0 +/- 1.4%), 2 W/cm2 (19.3 +/- 0.7%), 4 W/cm2 (22.8 +/- 1.8%), and 8 W/cm2 (58.7 +/- 7.1%). Significant increases in lysis were also seen with urokinase at ultrasound intensities of 2 W/cm2 and above. Exposure of clots to ultrasound in the absence of plasminogen activator did not increase lysis. Ultrasound exposure resulted in a marked reduction in the rt-PA concentration required to achieve an equivalent degree of lysis to that seen without ultrasound. For example, 15% lysis occurred in 1 h at 1 microgram/ml rt-PA without ultrasound or with 0.2 microgram/ml with ultrasound, a five-fold reduction in concentration. Ultrasound at 1 W/cm2 and above also potentiated lysis of retracted whole blood clots mediated by rt-PA or urokinase. The maximum temperature increase of plasma clots exposed to 4 W/cm2 ultrasound was only 1.7 degrees C, which could not explain the enhancement of fibrinolysis. Ultrasound exposure did not cause mechanical fragmentation of the clot into sedimentable fragments, nor did it alter the sizes of plasmic derivatives as demonstrated by SDS polyacrylamide gel electrophoresis. We conclude that ultrasound at 1 MHz potentiates enzymatic fibrinolysis by a nonthermal mechanism at energies that can potentially be applied and tolerated in vivo to accelerate therapeutic fibrinolysis.

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.

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.

Response to plasma exchange and splenectomy in thrombotic thrombocytopenic purpura. A 10-year experience at a single institution.

BACKGROUND: This study was designed to assess the response of patients with thrombotic thrombocytopenic purpura to plasma exchange and to evaluate the role of splenectomy after relapse. METHODS: The records of all patients with thrombotic thrombocytopenic purpura who had plasma exchange as primary treatment at a single center during a 10-year period were retrospectively reviewed. Response to the initial course of plasma exchange was determined, and the clinical outcome was evaluated in patients whose conditions were either refractory to exchange, responded without relapse, or relapsed after initial response. The outcome of patients treated during relapse with splenectomy was evaluated. A literature review was conducted to determine the clinical outcome in patients treated similarly. RESULTS: Twenty-seven patients for whom data could be evaluated had been treated in the 10-year period. Twenty-one (78%) responded to the plasma exchange, but the conditions of six (22%) were refractory and these patients died. Eight patients (30%) had one or multiple relapses after initial response but had prolonged remissions after additional plasma exchange alone (two patients) or splenectomy (six patients). A review of 19 reports, including 224 patients with thrombotic thrombocytopenic purpura initially treated with plasma exchange, revealed similar findings, with initial response in 81%, refractoriness in 19%, and relapse after initial response in 27% of patients. CONCLUSION: Response to plasma exchange in thrombotic thrombocytopenic purpura is associated with an excellent prognosis, and most deaths occur in patients whose conditions are refractory. Relapses after initial response are frequent but can be managed successfully with additional plasma exchange or with splenectomy, which often induces long-term remissions.

Plasminogen depletion during streptokinase treatment or two-chain urokinase incubation correlates with decreased clot lysability ex vivo and in vitro.

The relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/l. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 +/- 8% after 5 min to 21 +/- 8% at 10 min and was significantly lower (8 +/- 9%, p < 0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p < 0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.

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.

Acute thoracic inlet obstruction in achalasia with adenoid cystic and squamous cell carcinoma.

Respiratory symptoms due to compression of the trachea by the dilated esophagus in achalasia are extremely rare. A patient is presented whose respiratory manifestations included engorged neck veins and a neck swelling that fluctuated with respiration. He also had two malignant tumors in his dilated esophagus, a squamous cell carcinoma and an adenoid cystic carcinoma.

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.