Interactions of von Willebrand factor and ADAMTS13 in von Willebrand disease and thrombotic thrombocytopenic purpura

Summary

The function of von Willebrand factor (VWF), a huge multimeric protein and a key factor in platelet dependent primary haemostasis, is regulated by its specific protease ADAMTS13. The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so-called triplet structure of individual VWF oligomers by multimer analysis. Lack of VWF high molecular weight multimers (VWF-HMWM) or their pathologically enhanced degradation under - lies a particular type of von Willebrand disease, VWD type 2A with a significant bleeding tendency, and may also be observed in acquired von Willebrand syndrome due to cardiovascular disease. In these conditions multimer analysis is an obligatory and powerful tool for diagnosis of VWD. The opposite condition, the persistence of ultralarge VWF (UL-VWF) multimers may cause the microangiopathic life-threatening disorder thrombotic thrombocytopenic purpura (TTP). During the course of active TTP, UL-VWF is consumed in the hyaline thrombi formed in the microvasculature which will ultimately result in the loss of UL-VWF and VWF-HMWM. Therefore, VWF multimer analysis is not a valid tool to diagnose TTP in the active phase of disease but may be helpful for the diagnosis of TTP patients in remission.

Zusammenfassung

Der von-Willebrand-Faktors (VWF), ein riesiges multimeres Protein ist ein Schlüsselfaktor für die Thrombozyten-abhängige primäre Hämostase und wird über seine spezifische Protease ADAMTS13 reguliert. Die ADAMTS13-abhängige Degradierung des VWF in seine proteolytischen Fragmente zeigt sich als charakteristische so genannte Triplet-Struktur der einzelnen VWF-Oligomere in der Multimer-Analyse. Das Fehlen hochmolekularer VWF-Multimere oder deren pathologisch verstärkte Degradierung charakterisiert einen besonderen Typ des VWS, den Typ 2A mit einer signifikanten Blutungsneigung, die auch bei einer erworbenen Form im Rahmen kardiovaskulärer Erkrankungen beobachtet wird. In diesen Fällen ist die VWFMultimeranalyse ein notwendiges und diagnostisch hilfreiches Mittel. Die gegensätz - liche Situation, die Persistenz von „ultragroßen” VWF-(UL-VWF-)Multimeren kann zu der mikroangiopathischen und lebensbedrohenden thrombotisch-thrombozytopenischen Purpura (TTP) führen. Während einer aktiven TTP wird jedoch der besonders aktive hochmolekulare VWF in den entstehenden hyalinen Mikrothromben verbraucht. Dies führt schließlich zum Verlust der UL- und der hochmolekularen VWF-Multimere. Daher ist in der aktiven Phase einer TTP die VWF-Multimeranalyse in der Regel nicht weiterführend, kann aber hilfreich sein bei TTP-Patienten in Remission.

Keywords

Triplet pattern - phenotype-genotype relation - animal models

Schlüsselwörter

Triplet-Struktur - Phänotyp-Genotyp- Beziehung - Tiermodelle

• References

• 1 Sadler JE, Mannucci PM, Berntorp E. et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-174.
• 2 Wang JW, Valentijn JA, Valentijn KM. et al. Formation of platelet-binding von Willebrand factor strings on non-endothelial cells. J Thromb Haemost 2012; 10: 2168-2178.
• 3 Arya M, Anvari B, Romo GM. et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 2002; 99: 3971-3977.
• 4 Dent JA, Berkowitz SD, Ware J. et al. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87: 6306-6310.
• 5 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.
• 6 Furlan M, Robles R, Solenthaler M, Lämmle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1997; 91: 3097-3103.
• 7 Tsai HM. Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87: 4235-4244.
• 8 Sadler JE, Budde U, Eickenboom JC. et al. The 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.
• 9 Schneppenheim R, Budde U. Von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein. J Thromb Haemost 2011; 09 (Suppl. 01) 209-215.
• 10 Bonthron DT, Handin RI, Kaufman RJ. et al. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-273.
• 11 Schneppenheim R, Budde U, Obser T. et al. Expression and characterization of von Willebrand dimerization defects in different types of von Willebrand disease. Blood 2001; 97: 2059-2066.
• 12 Gaucher D, Dieval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 1994; 84: 1024-1030.
• 13 Ledford M, Rabinowtz I, Sadler JE. et al. New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami. Blood 1993; 82: 169-175.
• 14 Schneppenheim R, Obser T, Drewke E. et al. The first mutations in von Willebrand disease type IIC Miami. Thromb Haemost. 2001 Suppl: P1805.
• 15 Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID and IIE). J Clin Invest 1086; 77: 947-951.
• 16 Schneppenheim R, Michiels JJ, Obser T. et al. A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood 2010; 115: 4894-4901.
• 17 Tiede A, Priesack J, Werwitzke S. et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008; 06: 569-576.
• 18 Casonato A, Pontara E, Sartorello F. et al. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 2002; 99: 180-184.
• 19 Castaman G, Tosetto A, Eikenboom JC, Rodeghiero F. Blood group significantly influences von Willebrand factor increase and half-life after desmopressin in von Willebrand disease Vicenza. J Thromb Haemost 2010; 08: 2078-2080.
• 20 Budde U, Schneppenheim R, Eikenboom J. et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). J Thromb Haemost 2008; 06: 762-771.
• 21 Geszi A, Budde U, Deak I. et al. Accelerated clearance alone explains ultra-large multimers in von Willebrand disease. J Thromb Haemost 2010; 08: 1273-1280.
• 22 Ganderton T, Wong JWH, Schroeder C, Hogg PJ. Lateral self-association of VWF involves the Cys2431-2453 disulfide/dithiol in The C2 domain. Blood 2011; 118: 5312-5318.
• 23 Hassenpflug QD, Budde U, Obser T. et al. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood 2006; 107: 2339-2345.
• 24 Lyons SE, Bruck ME, Bowie EJW, Ginsburg D. Impaired intracellular transport produced by a subset of type-IIA von Willebrand disease mutations. J Biol Chem 1992; 267: 4424-4430.
• 25 Holmberg L, Dent JA, Schneppenheim R. et al. Von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest 1993; 91: 2169-2177.
• 26 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease 2B: a cohort study of 67 patients. Blood 2009; 113: 526-534.
• 27 Gill JC, Wilson AD, Endres-Brooks J, Montgomery RR. Loss of the largest von Willebrand factor multimers from plasma of patients with congenital cardiac defects. Blood 1986; 67: 758-761.
• 28 Vincentelli A, Susen S, Le Touneau T. et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003; 349: 343-349.
• 29 Meyer AL, Mahlesa D, Bara C. et al. Acquired von Willebrand syndrome in patients with an axial flow left ventricular assist device. Circ Heart Fail 2010; 03: 675-681.
• 30 Budde U, Schäfer G, Müller N. et al. Acquired von Willebrand’s disease in the myeloproliferative syndrome. Blood 1984; 64: 981-985.
• 31 Budde U, Dent JA, Berkowitz SD, Ruggeri ZM, Zimmerman TS. Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome. Blood 1986; 68: 1213-1217.
• 32 Budde U, Scharf RE, Franke P. et al. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma. Blood 1993; 82: 749-757.
• 33 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435.
• 34 Turner N, Nolasco L, Moake J. Generation and break down of soluble ultralarge von Willebrand factor multimers. Semin Thromb Hemost 2012; 30: 38-46.
• 35 Turner NA, Nolasco L, Ruggeri ZM, Moake JL. Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 2009; 114: 5102-5111.
• 36 Baldauf C, Schneppenheim R, Stacklies W. et al. Shear-induced unfolding activates von Willebrand factor A2 domain for proteolysis. J Thromb Haemost 2009; 07: 2096-2105.
• 37 Zheng XL. Structure-function and regulation of ADAMTS-13 protease. J Thromb Haemost. 2013 Suppl 1: 11-23.
• 38 De Meyer SF, Budde U, Deckmyn H, Vanhorelbeke K. In vivo von Willebrand factor size heterogeneity in spite of the clinical deficiency of ADAMTS-13. J Thromb Haemost 2011; 09: 2506-2508.
• 39 Raife TJ, Cao WJ, Atkinson BS. et al. Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. Blood 2009; 114: 1666-1674.
• 40 Thompson EA, Howard MA. Proteolytic cleavage of human von Willebrand factor induced by enzyme(s) released from polymorphonuclear cells. Blood 1986; 67: 1281-1285.
• 41 Feys HB, Root J, Vandenputte N. et al. Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in baboon (Papio ursinus). Blood 2012; 116: 2005-2010.
• 42 Kokame K, Matsumoto M, Soejima K. et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 99 2002; 11902-11907.
• 43 Schneppenheim R, Budde U, Oyen F. et al. Von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 2003; 101: 1845-1850.
• 44 Lotta LA, Wu HW, Mackie IJ. et al. Residual plasmatic activity of ADAMTS13 is correlated with the phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood 120 2012; 440-448.
• 45 Schneppenheim R, Kremer JAHovinga, Becker T. et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost 96 2006; 3-6.
• 46 Ferrari S, Knöbl P, Kolovratova V. et al. Inverse correlation of free and immune complex-sequestered anti-ADAMTS13 antibodies in a patient with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2012; 10: 156-158.
• 47 Bockmeyer C, Claus RA, Budde U. et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultralarge von Willebrand factor. Haematologica 2008; 93: 137-140.
• 48 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for Diagnosis and Management of Type 1 von Willebrand disease (MCMDM-1VWD). Blood 2007; 109: 112-121.