Margareta Holmström

Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months.

Summary.  Background: The influence of the duration of anticoagulant therapy after venous thromboembolism (VTE) on the long‐term morbidity and mortality is unclear. Aim: To investigate the long‐term sequelae of VTE in patients randomized to different duration of secondary prophylaxis. Methods: In a multicenter trial comparing secondary prophylaxis with vitamin K antagonists for 6 weeks or 6 months, we extended the originally planned 2 years follow‐up to 10 years. The patients had annual visits and at the last visit clinical assessment of the post‐thrombotic syndrome (PTS) was performed. Recurrent thromboembolism was adjudicated by a radiologist, blinded to treatment allocation. Causes of death were obtained from the Swedish Death Registry. Results: Of the 897 patients randomized, 545 could be evaluated at the 10 years follow‐up. The probability of developing severe PTS was 6% and any sign of PTS was seen in 56.3% of the evaluated patients. In multivariate analysis, old age and signs of impaired circulation at discharge from the hospital were independent risk factors at baseline for development of PTS after 10 years. Recurrent thromboembolism occurred in 29.1% of the patients with a higher rate among males, older patients, those with permanent triggering risk factor – especially with venous insufficiency at baseline – signs of impaired venous circulation at discharge, proximal deep vein thrombosis, or pulmonary embolism. Death occurred in 28.5%, which was a higher mortality than expected with a standardized incidence ratio (SIR) of 1.43 (95% CI 1.28–1.58), mainly because of a higher mortality than expected from cancer (SIR 1.83; 95% CI 1.44–2.23) or from myocardial infarction or stroke (SIR 1.28; 95% CI 1.00–1.56). The duration of anticoagulation did not have a statistically significant effect on any of the long‐term outcomes. Conclusion: The morbidity and mortality during 10 years after the first episode of VTE is high and not reduced by extension of secondary prophylaxis from 6 weeks to 6 months. A strategy to reduce recurrence of VTE as well as mortality from arterial disease is needed.

Optimal Timing of Resumption of Warfarin After Intracranial Hemorrhage

Background and Purpose— The optimum timing of resumption of anticoagulation after warfarin-related intracranial hemorrhage in patients with indication for continued anticoagulation is uncertain. We performed a large retrospective cohort study to obtain more precise risk estimates. Methods— We reviewed charts of 2869 consecutive patients with objectively verified intracranial hemorrhage over 6 years at 3 tertiary centers. We calculated the daily risk of intracranial hemorrhage or ischemic stroke with and without resumption of warfarin; we focused on patients who survived the first week and had cardiac indication for anticoagulation or previous stroke. Using a Cox model, we estimated rates for these 2 adverse events in relation to different time points of resumed anticoagulation. The combined risk of either a new intracranial hemorrhage or an ischemic stroke was calculated for a range of warfarin resumption times. Results— We identified warfarin-associated intracranial hemorrhage in 234 patients (8.2%), of whom 177 patients (76%) survived the first week and had follow-up information available; the median follow-up time was 69 weeks (interquartile range [IQR] 19–144). Fifty-nine patients resumed warfarin after a median of 5.6 weeks (IQR 2.6–17). The hazard ratio for recurrent intracranial hemorrhage with resumption of warfarin was 5.6 (95% CI, 1.8–17.2), and for ischemic stroke it was 0.11 (95% CI, 0.014–0.89). The combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir if warfarin was resumed after approximately 10 to 30 weeks. Conclusion— The optimal timing for resumption of warfarin therapy appears to be between 10 and 30 weeks after warfarin-related intracranial hemorrhage.

Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s

Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P < .01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P < .01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score >10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US

Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy

1000 for Swedish patients; (P < .01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.

Validation of a composite score for clinical severity of hemophilia

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis

BACKGROUND There is uncertainty regarding the efficacy and incidence of thromboembolic events in patients treated with prothrombin complex concentrates (PCC) for the emergency reversal of warfarin effect. METHODS During 2002 to 2010 we prospectively included 160 patients treated with PCC for emergency reversal of warfarin either for bleeding or because of the need of emergency surgery. A possible relationship to PCC was considered if objectively verified thromboembolism occurred within 7days of PCC administration. Efficacy was adjudicated as good if the bleeding was controlled promptly or if the surgeon did not report excessive perioperative bleeding. RESULTS We included 160 patients; 72% received PCC for bleeding. The median international normalized ratio (INR) before and after treatment with PCC was 3.5 (interquartile range [IQR] 2.6-5.4) and 1.4 (IQR 1.2-1.6). The mean dose of PCC was 1800IU (IQR 1200-2000). In addition to PCC, 74% of the patients received vitamin K and 34% received plasma. Six patients (3.8%; 95% confidence interval [CI], 1.4-8.0%) developed thromboembolic events (3 strokes, 1 myocardial infarction, 1 deep vein thrombosis, 1 splenic infarction), possibly related to PCC. The clinical efficacy was good in 146 (91%), moderate in 6 (4%), poor in 4 (2.5%) and non-evaluable in 4 patients. CONCLUSION The administration of PCC for the emergency reversal of warfarin may be associated with a low risk of thromboembolism. The contribution of an unmasked thrombotic process by cessation of anticoagulation or of activation of coagulation by the hemorrhagic event should also be considered.

Detection of elevated INR by thromboelastometry and thromboelastography in warfarin treated patients and healthy controls

Summary.  Introduction: Evaluation of modulators of the phenotypic expression of hemophilia may benefit from a scoring system that reflects several aspects of the clinical severity instead of only one dimension. Methods: We describe here how we constructed a composite Hemophilia Severity Score (HSS) and performed validation. The items in the HSS are annual incidence of joint bleeds, World Federation of Hemophilia Orthopedic joint score, and annual factor consumption. The latter two were adjusted for age at start of prophylaxis and body weight. Data for 100 adolescent or adult patients with hemophilia A or B in the mild, moderate or severe form without inhibitors were collected for the 1990–1999 period. We evaluated the reliability (multidimension property, test–retest) and validity (content, convergent, discriminant and known groups) of the score. Results: The HSS ranged from 0 to 0.94 and was higher in severe hemophilia A than severe hemophilia B (median 0.50 and 0.24; P = 0.031). The validation indicated that the HSS is reliable and reflective of the clinical severity of hemophilia. The presence of factor V G1691A or prothrombin G20210A polymorphisms was found in 13 patients. The clinical severity, measured as the HSS or each of the three components, appeared to be modified by prothrombin G20210A but not by FV G1691A. Conclusion: The HSS is a well‐defined tool that provides a comprehensive representation of the clinical severity of hemophilia in adults. It would be useful in larger studies on the assessment of modulators of the phenotypic expression of hemophilia.

Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes.

Summary.  Background: Prospective studies of the epidemiology and clinical significance of low plasminogen activator inhibitor type 1 (PAI‐1) activity are lacking. Objective: To evaluate the prevalence of low PAI‐1 activity in patients with a bleeding tendency in comparison with a normal population. Methods: In 586 consecutive patients, referred because of bleeding symptoms, we added analyses of PAI‐1 activity and tissue plasminogen activator complex with PAI‐1 (t‐PA–PAI‐1) to the routine investigation, consisting of platelet count, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, von Willebrand factor activity, and antigen. Controls were 100 blood donors and 100 age‐ and sex‐matched healthy individuals. The latter were also evaluated regarding the previous bleeding episodes. The bleeding history was classified as clinically significant or not, and the criteria were fulfilled in 75% of the patients and 18% of the healthy controls. Results: The routine laboratory investigation of the patients was negative in 57%. Low PAI‐1 activity, defined as <1.0 U mL−1, was found in 23% of the patients and in 13% and 10% of the blood donors and healthy controls, respectively (odds ratio and 95% CI, 2.04; 1.11–3.77 and 2.75; 1.39–5.42, respectively). The difference remained statistically significant after the adjustment for body mass index, use of estrogens, sex and age (odds ratio for patients vs. healthy controls 3.23; 95% CI, 1.22–8.56, P = 0.019). The distribution of the 4G/5G genotypes in the patients was not different from that of two control populations. No specific symptom predicted for low PAI‐1, which did not aggravate the clinical picture in association with the other hemostatic defects. Low tPA–PAI‐1 was not associated with the increased bleeding tendency. Conclusion: Low PAI‐1 activity is common in patients with a bleeding diathesis, but it is a risk factor of minor clinical importance and not associated with specific bleeding manifestations.

Thromboelastography (TEG®) compared to conventional coagulation tests in surgical patients – a laboratory evaluation

INTRODUCTION The diagnostic potential of whole blood viscoelastic tests thromboelastography (TEG®) and thromboelastometry (ROTEM®) to detect warfarin-induced INR elevation remains elusive. METHODS Viscoelastic tests were performed in 107 patients on warfarin and 89 healthy controls. Tests were activated by kaolin for TEG, and ellagic acid (INTEM) or tissue factor (EXTEM) for ROTEM. RESULTS Viscoelastic tests revealed significant differences in clotting profiles between controls and warfarin-treated patients. Compared with healthy controls, patients treated with warfarin had prolonged EXTEM clotting and TEG reaction time (p<0.001), both of which were also increased beyond the reference range. Increased INR values correlated with EXTEM CT (Spearman rho=0.87) and TEG R-time (rho=0.73). EXTEM CT had a sensitivity and specificity of 0.89 and 1.00, respectively, to detect elevated INR above 1.2 units, with a positive and negative predictive values (PPV and NPV) of 1.00 and 0.88, respectively. Similarly, TEG R-time had a sensitivity and specificity of 0.86 and 0.87, respectively, with a PPV of 0.89 and a NPV of 0.83. The corresponding receiver operator characteristic area under the curve was 0.99 (95% confidence interval [CI], 0.99 - 1.00) for EXTEM CT and 0.94 (95% CI, 0.91 - 0.97) for TEG R-time. CONCLUSIONS Tissue factor-activated viscoelastic testing (EXTEM) revealed individuals with warfarin-induced INR elevation accurately, while TEG - activated through the intrinsic pathway - still was of acceptable diagnostic value. Further studies are required to evaluate the diagnostic potential of viscoelastic tests in relation to standard laboratory tests in other mixed patient populations, where the PPV and NPV may be inferior.