| 21. |
- Berntorp, Erik, et al.
(författare)
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Standardization and clinical utility of thrombin-generation assays.
- 2008
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Ingår i: Seminars in Thrombosis and Hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 34:7, s. 670-682
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Tidskriftsartikel (refereegranskat)abstract
- Thrombin generation is a key process that determines the extent of a hemostatic plug or a thrombotic process. The ensuing thrombin burst is crucial for the formation of a stable fibrin clot. During its active life, thrombin exerts a multitude of highly regulated actions on the blood and the vessel wall, including the clotting of fibrinogen. The inappropriate generation of thrombin may lead to pathologic processes, foremost of which are hemorrhagic or thrombotic diseases. The coagulation system is usually investigated by means of two in vitro classic clotting tests, the activated partial thromboplastin time (APTT) and prothrombin time (PT), which assess only time to initiation of clot formation and do not entirely reflect global hemostatic balance. The APTT and PT permit identification of connectivity between the component activities identified as required for plasma coagulation and define the concept of intrinsic and extrinsic coagulation pathways, which converge at the point of formation of the prothrombinase complex. However, the mechanisms established by in vitro tests are not always mirrored in the human pathologies associated with bleeding or thrombosis. The recent development of newer tests based on the continuous registration of thrombin generation under in vitro conditions that mimic more closely what occurs in vivo prompt a reinvestigation of the balance between procoagulants and anticoagulants in patients with various hemostatic disorders. Thrombin-generation assays not only provide an overall assessment of hemostasis but also target potential extrahemostatic effects of the generated thrombin, a potent agonist of a multitude of cellular activation pathways. Moreover, estimation of an individual's thrombin-generation potential may correlate more closely with a hypercoagulable or hypocoagulable phenotype when compared with traditional coagulation tests. In this review, we discuss to what extent thrombin generation can be expected to reflect the clotting function of blood, the development and use of different thrombin-generation assay systems suitable for detecting changes in the kinetics of thrombin generation, and the clinical utility of thrombin generation.
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| 22. |
- Berntorp, Erik, et al.
(författare)
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The next generation of hemophilia treatment specialists
- 2006
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Ingår i: Seminars in Thrombosis and Hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 32, s. 39-42
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Tidskriftsartikel (refereegranskat)abstract
- We currently are witnessing a serious attrition of physicians specializing in hemophilia treatment in Europe and the United States while most physicians who complete training in hematology-oncology choose oncology practice as their career. Nevertheless, recent therapeutic developments, including advances in prophylaxis and inhibitor management, have renewed the demand for experts in hemophilia and related disorders. To meet this demand, several specialty training programs have been developed in the United States and Europe, specifically the International Course in Hemophilia in Malmo, Sweden, the Children's Hospital of Los Angeles International Pediatric Hemostasis and Thrombosis Program, and the Baxter/National Hemophilia Foundation Fellowship Programs. The purpose of these programs is to enhance the clinical expertise and further the professional development of individuals dedicated to treating patients with coagulation disorders.
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| 23. |
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| 24. |
- Berntorp, Erik, et al.
(författare)
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The von Willebrand Disease Prophylaxis Network (vWD PN): Exploring a treatment concept.
- 2006
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Ingår i: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 18, s. 19-22
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Tidskriftsartikel (refereegranskat)abstract
- The von Willebrand Disease Prophylactic Network (vWD PN) has been initiated to study the natural history of vWD bleeding, and to prospectively study the role of von Willebrand Factor (vWF) concentrate prophylaxis in vWD. Patients with all types of vWD in need of treatment with vWF concentrate will be enrolled into the study. Quality of life will be measured and safety and efficacy will be monitored at pre-determined intervals. Between February 2005 and July 18, 2005, 62 investigators from Europe and North America were participating in the vWD PN, and 61 have submitted census data. A total 5343 patients have been identified for enrolment, and of these, 991 patients were treated with plasma-derived products in the preceding 12 months, and 99 patients have received prophylaxis, predominantly for joint-related bleeds. The vWD PN aims to further elucidate the role of vWF concentrate prophylaxis in vWD and to identify patients most Likely to benefit from prophylaxis.
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| 25. |
- Berntorp, Erik, et al.
(författare)
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Treatment and prevention of acute bleedings in von Willebrand disease--efficacy and safety of Wilate, a new generation von Willebrand factor/factor VIII concentrate.
- 2009
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 15:1, s. 122-130
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Tidskriftsartikel (refereegranskat)abstract
- For many patients with von Willebrand disease (VWD), the replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is the treatment of choice. To evaluate clinical efficacy, safety and tolerability of Wilate, an albumin-free VWF/FVIII concentrate with a ratio of the two haemostatic moieties of approximately 1 to 1, a prospective clinical programme has been designed. The dataset on the treatment and prevention of bleedings is derived from 44 patients (20 males and 24 females) of all VWD types. Thousand and ninety five bleeding episodes were treated with an overall efficacy rating of excellent or good in 96%. The median dose per treatment day was 26 IU FVIII:C per kg. Eighty-one per cent of bleeds were stopped within 1 or 2 days. Gastrointestinal (GI) bleeds needed higher doses (mean 44 IU kg(-1)) and longer treatment (mean 4 days). Efficacy and dosing data from eight children of 12 or less years of age did not differ significantly from the overall study population. Nineteen patients, including six children, were treated prophylactically for more than 3 months (mean 14.8, range 3-46) with a mean prophylactic dose of 27.4 IU kg(-1) and a mean frequency of 1.9 infusions per week. A drop of bleeding frequency from a mean of 4.5 to 1.4 bleeds per month was observed. The overall tolerability was very good. Adverse drug reactions were rare and were mild or moderate in their intensity. The large prospective clinical dataset shows that Wilate is efficacious and safe in the treatment and prevention of haemorrhages in all VWD types in both adult and paediatric patients.
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| 26. |
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| 27. |
- Berntorp, Erik
(författare)
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VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice.
- 2007
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 13 Suppl 5, s. 69-72
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Tidskriftsartikel (refereegranskat)abstract
- We and others have previously shown that inhibitor containing plasma from patients with congenital haemophilia A sometimes reacts less with von Willebrand factor (VWF) containing concentrates compared with highly purified plasma-derived or recombinant factor VIII (FVIII) concentrates. To further substantiate the haemostatic role of a variation in inhibitor reactivity with different FVIII concentrates, we compared the inhibitor titres from 11 plasma samples against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested: Fandhi (Grifols) which contains VWF with a final ratio of approximately 1 (VWF IU per IU FVIII:C); Haemate (CSL Behring) with a ratio of 2.5 and Haemofil M (Baxter), a monoclonal antibody-purified concentrate containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer (Bayer) containing no VWF was included in the panel. A statistically significant difference in measured titres against the four concentrates was found. The inhibitor titre needed to inhibit 50% maximum thrombin generation was lowest for Kogenate Bayer and highest and similar for Fandhi and Haemate. This study confirms the results from previous research regarding variation of inhibitor reactivity against different concentrates and further shows that the VWF containing concentrates Fandhi and Haemate added to FVIII-deficient plasma with the presence of inhibitor generate more thrombin than do the purified concentrates Haemofil M and Kogenate Bayer. A further interesting aspect could be that bypass therapy may have an increased efficacy when infused together with FVIII concentrates containing VWF. However, the clinical implications of all these findings in vitro need to be established.
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| 28. |
- Björkman, Sven E., et al.
(författare)
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In vivo recovery of factor VIII and factor IX : intra- and interindividual variance in a clinical setting
- 2007
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 13:1, s. 2-8
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Tidskriftsartikel (refereegranskat)abstract
- In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL−1 per U kg−1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5–67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13–69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.
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| 29. |
- Bolton-Maggs, P H B, et al.
(författare)
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von Willebrand disease update: diagnostic and treatment dilemmas
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14:s3, s. 56-61
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Tidskriftsartikel (refereegranskat)abstract
- Although von Willebrand disease (VWD) is now well-described, many facets of diagnosis and management continue to be debated. The diagnosis of type 1 disease can be difficult but recent genetic analyses help to distinguish many factors which can influence von Willebrand factor (VWF) levels and bleeding phenotype. Type 2 disease (functional abnormalities) includes a particularly interesting group of disorders with faulty binding between VWF and FVIIIC (Normandy) where treatment methods need careful consideration. Type 3 VWD is the most severe form of VWD and a new international study is underway to examine the use of prophylaxis.
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| 30. |
- Borel-Derlon, A., et al.
(författare)
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Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin (R)): a prospective study of 50 patients
- 2007
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 5:6, s. 1115-1124
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: A plasma-derived von Willebrand factor (VWF) concentrate with low factor VIII (FVIII) content was specifically developed to treat von Willebrand disease (VWD). Efficacy and safety were investigated by merging the results of two comparable protocols conducted prospectively in 5 European and 12 French centers. Methods and results: Fifty patients with clinically severe VWD (72% had VWF ristocetin cofactor activity less than 10 IU dL(-1) and 46% had FVIII < 20 IU dL(-1)) were treated with the concentrate as the only therapy, except for clinical situations requiring a priming dose of FVIII to rapidly correct an intrinsic coagulation defect. A total of 139 spontaneous bleeding episodes were treated; only 53 (38%) needed a concomitant FVIII dose. Outcome was excellent or good in 89% of the episodes. Forty-four patients underwent 108 surgical or invasive procedures. Outcome was excellent or good in 95 scheduled procedures (only VWF was infused) and 13 emergency procedures (a priming FVIII dose was co-administered with the first VWF infusion). There were no thrombotic complications and none of the 18 patients with type 3 VWD developed anti-VWF or anti-FVIII antibodies. Conclusions. This concentrate safely and effectively provides hemostasis in patients with clinically severe VWD.
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