Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system

Summary

Patients with type 3 von Willebrand disease (VWD-3) have no measurable levels of VW factor (VWF) and usually require treatment with VWF-FVIII concentrate to prevent and/or stop bleeding. Even though the patients are treated prophylactically, they may experience bleeding symptoms. The aim of this study was to evaluate the effect of VWF-FVIII concentrate treatment in VWD-3 patients with the Total Thrombus Analysis System (T-TAS®), which measures thrombus formation under flow conditions. Coagulation profiles of 10 VWD-3 patients were analysed using T-TAS before and 30 minutes after VWF-FVIII concentrate (Haemate®) injection. Results were compared to VWF- and FVIII activity in plasma, and results with thromboelastometry and ris-tocetin-activated platelet impedance aggregometry (Multiplate®) in whole blood. For comparison, 10 healthy controls were also analysed with T-TAS. A median dose of 27 (range 15–35) IU/kg of VWF-FVIII concentrate increased VWF- and FVIII activity as expected. T-TAS thrombus formation was enhanced when a tissue factor/collagen-coated flow chamber was used at low shear, but treatment effects at high shear using a collagen-coated flow chamber were minimal. Whole blood coagulation assessed by thromboelastometry was normal and did not change (p > 0.05) but ristocetin-induced platelet aggregation improved (p < 0.001). In conclusion, T-TAS detects effects of VWF-FVIII concentrate treatment on coagulation-dependent thrombus formation at low shear, but minor effects are observed on platelet-dependent thrombus formation at high shear. The poor prediction of bleeding by conventional laboratory monitoring in VWD-3 patients might be related to insufficient restoration of platelet-dependent thrombus formation.

Keywords

Coagulation tests - flow chamber system - thromboelastography - von Willebrand disease - von Willebrand factor

• References

• 1 Favaloro EJ. Diagnosing von Willebrand disease: a short history of laboratory milestones and innovations, plus current status, challenges, and solutions. Semin Thromb Hemost 2014; 40: 551-570.
• 2 De Jong A, Eikenboom J. Developments in the diagnostic procedures for von Willebrand disease. J Thromb Haemost 2016; 14: 449-460.
• 3 Sadler JE, Budde U, Eikenboom JC. et al. Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 04: 2103-2114.
• 4 Keeney S, Collins P, Cumming A. et al. Diagnosis and management of von Willebrand disease in the United Kingdom. Semin Thromb Hemost 2011; 37: 488-494.
• 5 Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood 2015; 125: 2029-2037.
• 6 Franchini M, Mannucci PM. Gastrointestinal angiodysplasia and bleeding in von Willebrand disease. Thromb Haemost 2014; 112: 427-431.
• 7 Nogami K, Ogiwara K, Yada Y. et al. Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow chamber system. J Thromb Haemost 2016; 201: 667-674.
• 8 Hosokawa K, Ohnishi T, Kondo T. et al. A novel automated microchip flow-chamber system to quantitatively evaluate thrombus formation and antithrombotic agents under blood flow conditions. J Thromb Haemost 2011; 09: 2029-2037.
• 9 Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Haematol 2014; 89: 228-232.
• 10 Hosokawa K, Ohnishi T, Sameshima H. et al. Analysing responses to aspirin and clopidogrel by measuring platelet thrombus formation under arterial flow conditions. Thromb Haemost 2013; 109: 102-111.
• 11 Rodeghiero F, Tosetto A, Abshire T. et al. ISTH/SSC joint VWF and Perinatal/ Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 08: 2063-2065.
• 12 Ogiwara K, Nogami K, Hosokawa K. et al. Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system. Haemophilia 2015; 21: 71-80.
• 13 Meskal A, Vertessen F, Van der Planken M. et al. The platelet function analyzer (PFA-100) may not be suitable for monitoring the therapeutic efficiency of von Willebrand concentrate in type III von Willebrand disease. Ann Haematol 1999; 78: 426-430.
• 14 Sporn LA, Chavin SI, Marder VJ. et al. Biosynthesis of von Willebrand protein by human megakaryocytes. J Clin Invest 1985; 76: 1102-1106.
• 15 Kragh T, Napoleone M, Fallah MA. et al. High shear dependent von Willebrand factor selfassembly fostered by platelet interaction and controlled by ADAMTS13. Thromb Res 2014; 133: 1079-1087.
• 16 Castillo R, Monteagudo J, Escolar G. et al. Hemostatic effect of normal platelet transfusion in severe von Willebrand disease patients. Blood 1991; 77: 1901-1905.
• 17 Berntorp E. Prophylaxis and treatment of bleeding complications in von Wille-brand disease type 3. Semin Thromb Hemost 2006; 32: 621-625.
• 18 Hunt H, Stanworth S, Curry N. et al. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. Cochrane Database Syst Rev 2015; 02: CD010438.
• 19 Takeyama M, Kasuda S, Sakurai Y. et al. Factor VIII-mediated global hemostasis in the absence of von Willebrand factor. Int J Haematol 2007; 85: 397-402.
• 20 Valarche V, Desconclois C, Boutekedjiret T. et al. Multiplate whole blood impedance aggregometry: a new tool for von Willebrand disease. Thromb Haemost 2011; 09: 1645-1647.