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Highly elevated plasma level of von Willebrand factor accelerates the formation of platelet thrombus under high shear stress in plasma with deficient ADAMTS13 activity

      Highlights

      • Upshaw-Schulman syndrome (USS) is congenital TTP caused by deficiency of ADAMTS13.
      • The gravida with USS developed thrombocytopenia during the second or third trimesters.
      • The mechanism of first episode of TTP develops during this period is not yet elucidated.
      • Elevated level of VWF accelerated thrombus formation in the context of deficient ADAMTS13.
      • ADAMTS13 plays a major role in down-regulation of VWF function in thrombus formation.

      Abstract

      Upshaw-Schulman syndrome (USS) is a thrombo-hemorrhagic disease caused by congenital deficiency of ADAMTS13 due to ADAMTS13 gene mutations. USS is characterized by repeated episodes of thrombocytopenia and microangiopathic hemolytic anemia that respond dramatically to infusions of fresh frozen plasma. There are two phenotypic expressions of USS: one is the early-onset type and the other, the late-onset type, is asymptomatic during childhood with the first bout of thrombotic thrombocytopenic purpura (TTP) developing after adolescence or during adulthood. We found that gravida with the latter phenotype developed thrombocytopenia and hemolytic anemia during the second or third trimesters, often followed by thrombotic microangiopathies (TMAs). These phenomena suggest that elevated plasma von Willebrand Factor (VWF) might be crucial because plasma levels of VWF antigen usually increase by 200–500% during this period of gestation. Here, we performed platelet function assays using a mixture of anti-coagulated blood from normal volunteers, human VWF, anti-ADAMTS13 monoclonal antibody A10, and purified plasma-derived ADAMTS13 to investigate the effect of plasma VWF levels on platelet thrombus formation in the context of deficient ADAMTS13. In vitro studies showed that mural thrombus formation and platelet aggregation under high shear stress were markedly augmented by increasing the amounts of exogenously added VWF when ADAMTS13 activity was deficient, as may be the case in the in vivo circulation of gravida with USS. These results suggest that highly elevated plasma VWF might accelerate platelet thrombus formation not only in the circulation but also on the surface of vascular endothelial cells in the setting of ADAMTS13 deficiency in USS.

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      References

        • Ruggeri Z.M.
        Von Willebrand factor, platelets and endothelial cell interactions.
        J. Thromb. Haemost. 2003; 1: 1335-1342
        • Wagner D.D.
        The Weibel-Palade body: the storage granule for von Willebrand factor and P-selectin.
        Thromb. Haemost. 1993; 70: 105-110
        • Arya M.
        • Anvari B.
        • Romo G.M.
        • Cruz M.A.
        • Dong J.F.
        • McIntire L.V.
        • 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
        • Moake J.L.
        • Rudy C.K.
        • Troll J.H.
        • Weinstein M.J.
        • Colannino N.M.
        • Azocar J.
        • 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
        • Fujimura Y.
        • Matsumoto M.
        • Yagi H.
        • Yoshioka A.
        • Matsui T.
        • Titani K.
        Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome.
        Int. J. Hematol. 2002; 75: 25-34
        • Levy G.G.
        • Nichols W.C.
        • Lian E.C.
        • Foroud T.
        • McClintick J.N.
        • McGee B.M.
        • et al.
        Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.
        Nature. 2001; 413: 488-494
        • Kokame K.
        • Matsumoto M.
        • Soejima K.
        • Yagi H.
        • Ishizashi H.
        • Funato M.
        • et al.
        Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity.
        Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11902-11907
        • Furlan M.
        • Robles R.
        • Galbusera M.
        • Remuzzi G.
        • Kyrle P.A.
        • Brenner B.
        • et al.
        von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
        N. Engl. J. Med. 1998; 339: 1578-1584
        • Furlan M.
        • Lammle B.
        Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease.
        Best Pract. Res. Clin. Haematol. 2001; 14: 437-454
        • George J.N.
        The association of pregnancy with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
        Curr. Opin. Hematol. 2003; 10: 339-344
        • Stirling Y.
        • Woolf L.
        • North W.R.
        • Seghatchian M.J.
        • Meade T.W.
        Haemostasis in normal pregnancy.
        Thromb. Haemost. 1984; 52: 176-182
        • Fujimura Y.
        • Titani K.
        • Holland L.Z.
        • Russell S.R.
        • Roberts J.R.
        • Elder J.H.
        • et al.
        von Willebrand factor. A reduced and alkylated 52/48-kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein Ib.
        J. Biol. Chem. 1986; 261: 381-385
        • Fujimura Y.
        • Usami Y.
        • Titani K.
        • Niinomi K.
        • Nishio K.
        • Takase T.
        • et al.
        Studies on anti-von Willebrand factor (vWF) monoclonal antibody NMC-4, which inhibits both ristocetin- and botrocetin-induced vWF binding to platelet glycoprotein Ib.
        Blood. 1991; 77: 113-120
        • Hiura H.
        • Matsui T.
        • Matsumoto M.
        • Hori Y.
        • Isonishi A.
        • Kato S.
        • et al.
        Proteolytic fragmentation and sugar chains of plasma ADAMTS13 purified by a conformation-dependent monoclonal antibody.
        J. Biochem. 2010; 148: 403-411
        • Uemura M.
        • Tatsumi K.
        • Matsumoto M.
        • Fujimoto M.
        • Matsuyama T.
        • Ishikawa M.
        • et al.
        Localization of ADAMTS13 to the stellate cells of human liver.
        Blood. 2005; 106: 922-924
        • Sugimoto M.
        • Matsui H.
        • Mizuno T.
        • Tsuji S.
        • Miyata S.
        • Matsumoto M.
        • et al.
        Mural thrombus generation in type 2A and 2B von Willebrand disease under flow conditions.
        Blood. 2003; 101: 915-920
        • Ikeda Y.
        • Handa M.
        • Kawano K.
        • Kamata T.
        • Murata M.
        • Araki Y.
        • et al.
        The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress.
        J. Clin. Invest. 1991; 87: 1234-1240
        • Yagi H.
        • Konno M.
        • Kinoshita S.
        • Matsumoto M.
        • Ishizashi H.
        • Matsui T.
        • et al.
        Plasma of patients with Upshaw-Schulman syndrome, a congenital deficiency of von Willebrand factor-cleaving protease activity, enhances the aggregation of normal platelets under high shear stress.
        Br. J. Haematol. 2001; 115: 991-997
        • Houdijk W.P.
        • Sakariassen K.S.
        • Nievelstein P.F.
        • Sixma J.J.
        Role of factor VIII-von Willebrand factor and fibronectin in the interaction of platelets in flowing blood with monomeric and fibrillar human collagen types I and III.
        J. Clin. Invest. 1985; 75: 531-540
        • Tschopp T.B.
        • Weiss H.J.
        • Baumgartner H.R.
        Decreased adhesion of platelets to subendothelium in von Willebrand's disease.
        J. Lab. Clin. Med. 1974; 83: 296-300
        • Alevriadou B.R.
        • Moake J.L.
        • Turner N.A.
        • Ruggeri Z.M.
        • Folie B.J.
        • Phillips M.D.
        • et al.
        Real-time analysis of shear-dependent thrombus formation and its blockade by inhibitors of von Willebrand factor binding to platelets.
        Blood. 1993; 81: 1263-1276
        • Donadelli R.
        • Orje J.N.
        • Capoferri C.
        • Remuzzi G.
        • Ruggeri Z.M.
        Size regulation of von Willebrand factor-mediated platelet thrombi by ADAMTS13 in flowing blood.
        Blood. 2006; 107: 1943-1950
        • Motto D.G.
        • Chauhan A.K.
        • Zhu G.
        • Homeister J.
        • Lamb C.B.
        • Desch K.C.
        • et al.
        Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
        J. Clin. Invest. 2005; 115: 2752-2761
        • Chauhan A.K.
        • Walsh M.T.
        • Zhu G.
        • Ginsburg D.
        • Wagner D.D.
        • Motto D.G.
        The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis.
        Blood. 2008; 111: 3452-3457
        • Banno F.
        • Kokame K.
        • Okuda T.
        • Honda S.
        • Miyata S.
        • Kato H.
        • et al.
        Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura.
        Blood. 2006; 107: 3161-3166
        • Shida Y.
        • Nishio K.
        • Sugimoto M.
        • Mizuno T.
        • Hamada M.
        • Kato S.
        • et al.
        Functional imaging of shear-dependent activity of ADAMTS13 in regulating mural thrombus growth under whole blood flow conditions.
        Blood. 2008; 111: 1295-1298
        • Chauhan A.K.
        • Motto D.G.
        • Lamb C.B.
        • Bergmeier W.
        • Dockal M.
        • Plaimauer B.
        • et al.
        Systemic antithrombotic effects of ADAMTS13.
        J. Exp. Med. 2006; 203: 767-776