von Willebrand factor/ADAMTS‐13 interactions at birth: implications for thrombosis in the neonatal period
2018; Elsevier BV; Volume: 17; Issue: 3 Linguagem: Inglês
10.1111/jth.14374
ISSN1538-7933
AutoresUpendra Katneni, Juan C. Ibla, Ryan Hunt, Tal Schiller, Chava Kimchi‐Sarfaty,
Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoSummaryvon Willebrand factor (VWF) and its cleaving protease ADAMTS‐13 (A Disintegrin and Metalloproteinase with Thrombospondin type 1 motif, member 13) are essential components to hemostasis. These plasma proteins have also been implicated in a number of disease states, including those affecting children. The best described abnormality is the congenital form of thrombotic thrombocytopenic purpura (TTP) resulting from germline mutations in the ADAMTS‐13 gene. The VWF/ADAMTS‐13 interaction has more recently emerged as a causative risk factor in the pathogenesis of pediatric stroke and secondary microangiopathies. There is now increasing interest and need to measure these coagulation factors during the neonatal period and throughout childhood. Methods adopted from a multitude of technically diverging studies have been used to understand their role during this period. To date, studies of VWF/ADAMTS‐13 in this group of patients have reported conflicting results, which makes interpreting values in the clinical setting especially challenging. In this review we describe the historical evolution of the methodology used to measure VWF/ADAMTS‐13 and how it may influence the results obtained during the first days of life. We review the individual assays used to analyze VWF/ADAMTS‐13 as well as published reference values. Finally, we bring attention to the potential pathophysiologic role of VWF/ADAMTS‐13 in neonatal thrombosis. This has significant implications because the pathologic processes that explain thrombosis in neonates remain poorly characterized and thromboembolism remains a significant source of morbidity and mortality, particularly in sick children. von Willebrand factor (VWF) and its cleaving protease ADAMTS‐13 (A Disintegrin and Metalloproteinase with Thrombospondin type 1 motif, member 13) are essential components to hemostasis. These plasma proteins have also been implicated in a number of disease states, including those affecting children. The best described abnormality is the congenital form of thrombotic thrombocytopenic purpura (TTP) resulting from germline mutations in the ADAMTS‐13 gene. The VWF/ADAMTS‐13 interaction has more recently emerged as a causative risk factor in the pathogenesis of pediatric stroke and secondary microangiopathies. There is now increasing interest and need to measure these coagulation factors during the neonatal period and throughout childhood. Methods adopted from a multitude of technically diverging studies have been used to understand their role during this period. To date, studies of VWF/ADAMTS‐13 in this group of patients have reported conflicting results, which makes interpreting values in the clinical setting especially challenging. In this review we describe the historical evolution of the methodology used to measure VWF/ADAMTS‐13 and how it may influence the results obtained during the first days of life. We review the individual assays used to analyze VWF/ADAMTS‐13 as well as published reference values. Finally, we bring attention to the potential pathophysiologic role of VWF/ADAMTS‐13 in neonatal thrombosis. This has significant implications because the pathologic processes that explain thrombosis in neonates remain poorly characterized and thromboembolism remains a significant source of morbidity and mortality, particularly in sick children. Spontaneous or unprovoked thrombotic events, such as deep venous thrombosis, pulmonary embolism and stroke, in healthy neonates are rare 1.Chalmers E.A. Neonatal thrombosis.J Clin Pathol. 2000; 53: 419-23Crossref PubMed Scopus (47) Google Scholar. However, several risk factors for neonatal thromboembolisms are generally recognized, including indwelling vascular catheters, inherited thrombophilia, sepsis, perinatal hypoxia, systemic viral infections, congenital heart disease, polycythemia and low cardiac output. Maternal factors such as diabetes and systemic diseases are also linked to neonatal thromboembolism 2.Veldman A. Nold M.F. Michel‐Behnke I. Thrombosis in the critically ill neonate: incidence, diagnosis, and management.Vasc Health Risk Manag. 2008; 4: 1337-48Crossref PubMed Google Scholar. Neonatal thromboembolism most commonly occurs secondary to indwelling vascular catheters (up to 90%), rendering severe illness and concurrent indwelling vascular catheters important risk factors 1.Chalmers E.A. Neonatal thrombosis.J Clin Pathol. 2000; 53: 419-23Crossref PubMed Scopus (47) Google Scholar, 2.Veldman A. Nold M.F. Michel‐Behnke I. Thrombosis in the critically ill neonate: incidence, diagnosis, and management.Vasc Health Risk Manag. 2008; 4: 1337-48Crossref PubMed Google Scholar, 3.Massicotte M.P. Dix D. Monagle P. Adams M. Andrew M. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications.J Pediatr. 1998; 133: 770-6Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar, 4.Schmidt B. Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry.Pediatrics. 1995; 96: 939-43Crossref PubMed Google Scholar. A 2‐year nationwide questionnaire‐based study in Germany found the incidence of symptomatic neonatal thromboembolism to be 5.1 per 100 000 births 5.Nowak‐Gottl U. von Kries R. Gobel U. Neonatal symptomatic thromboembolism in Germany: two year survey.Arch Dis Child Fetal Neonatal Ed. 1997; 76: F163-7Crossref PubMed Scopus (351) Google Scholar. Thromboembolism among neonates admitted to neonatal intensive care units has a reported incidence of 2.4 per 1000 admissions 4.Schmidt B. Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry.Pediatrics. 1995; 96: 939-43Crossref PubMed Google Scholar. Since the publication of these studies in the 1990s, rates of neonatal thromboembolism have probably increased as a result of increased awareness, better detection methods and improved survival following serious neonatal diseases 2.Veldman A. Nold M.F. Michel‐Behnke I. Thrombosis in the critically ill neonate: incidence, diagnosis, and management.Vasc Health Risk Manag. 2008; 4: 1337-48Crossref PubMed Google Scholar. Diagnosis and treatment of neonatal thrombosis is guided by the clinical context (e.g. location, extent and age of thrombus, and severity of clinical symptoms) and may include anticoagulation, thrombolytic therapy and surgical thrombectomy. High quality data backing treatment decisions are lacking in the neonatal population. Here, we discuss the biology of two plasma proteins central to hemostasis: von Willebrand Factor (VWF) and ADAMTS‐13, the VWF‐cleaving protease. The significance of VWF/ADAMTS‐13 abnormal interactions in neonatal thrombosis is vastly unknown, however likely to play a critical role. The potential implications of genetic, secretory and functional influences upon VWF/ADAMTS‐13 interactions in neonates are fertile grounds for future research investigating the etiology of thrombosis in this age group. With this review we highlight the technical limitations of assays used to measure VWF/ADAMTS‐13 and provide the frame work for reporting data in neonates. Circulation through the microvasculature is maintained by a complex interaction of pro‐ and anticoagulant factors 6.Palta S. Saroa R. Palta A. Overview of the coagulation system.Indian J Anaesth. 2014; 58: 515-23Crossref PubMed Scopus (401) Google Scholar. Among these interactions, VWF/ADAMTS‐13 is critically involved in preserving capillary flow by means of production and degradation of prothrombotic high‐molecular‐weight (HMW) VWF polymers 7.Fujikawa K. Suzuki H. McMullen B. Chung D. Purification of human von Willebrand factor‐cleaving protease and its identification as a new member of the metalloproteinase family.Blood. 2001; 98: 1662-6Crossref PubMed Scopus (513) Google Scholar, 8.Gerritsen H.E. Robles R. Lammle B. Furlan M. Partial amino acid sequence of purified von Willebrand factor‐cleaving protease.Blood. 2001; 98: 1654-61Crossref PubMed Scopus (316) Google Scholar, 9.Levy G.G. Nichols W.C. Lian E.C. Foroud T. McClintick J.N. McGee B.M. Yang A.Y. Siemieniak D.R. Stark K.R. Gruppo R. Sarode R. Shurin S.B. Chandrasekaran V. Stabler S.P. Sabio H. Bouhassira E.E. Upshaw Jr, J.D. Ginsburg D. Tsai H.M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Nature. 2001; 413: 488-94Crossref PubMed Scopus (1436) Google Scholar, 10.Zheng X. Chung D. Takayama T.K. Majerus E.M. Sadler J.E. Fujikawa K. Structure of von Willebrand factor‐cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.J Biol Chem. 2001; 276: 41059-63Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar. The biologic activity of VWF (i.e. interaction with subendothelial collagen and platelets) is regulated by its molecular weight. Under conditions of high shear stress, VWF undergoes mechanical unraveling that exposes a cryptic cleavage in the A2 domain, allowing for ADAMTS‐13 catalytic degradation 11.Dong J.F. Moake J.L. Nolasco L. Bernardo A. Arceneaux W. Shrimpton C.N. Schade A.J. McIntire L.V. Fujikawa K. Lopez J.A. ADAMTS‐13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.Blood. 2002; 100: 4033-9Crossref PubMed Scopus (710) Google Scholar. The low‐molecular‐weight VWF monomers resulting from protease activity of ADAMTS‐13 are less thrombotic and are cleared from the circulation, facilitating unrestricted flow to capillaries 12.Tsai H.M. von Willebrand factor, shear stress, and ADAMTS13 in hemostasis and thrombosis.ASAIO J. 2012; 58: 163-9Crossref PubMed Scopus (24) Google Scholar. This mechanism of continuous production of VWF by endothelial cells and degradation by plasmatic ADAMTS‐13 is necessary for uninterrupted tissue perfusion 12.Tsai H.M. von Willebrand factor, shear stress, and ADAMTS13 in hemostasis and thrombosis.ASAIO J. 2012; 58: 163-9Crossref PubMed Scopus (24) Google Scholar. Deficiency of plasmatic ADAMTS‐13 results in unopposed accumulation of HMW VWF multimers, leading to microvascular thrombosis and consumptive thrombocytopenia, clinically termed thrombotic thrombocytopenic purpura (TTP) 13.Tsai H.M. Thrombotic thrombocytopenic purpura: a thrombotic disorder caused by ADAMTS13 deficiency.Hematol Oncol Clin North Am. 2007; 21: 609-32Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar. TTP can occur as a result of congenital deficiency of ADAMTS‐13 or following the development of anti‐ADAMTS‐13 antibodies, which inhibit the enzyme or promote its clearance 9.Levy G.G. Nichols W.C. Lian E.C. Foroud T. McClintick J.N. McGee B.M. Yang A.Y. Siemieniak D.R. Stark K.R. Gruppo R. Sarode R. Shurin S.B. Chandrasekaran V. Stabler S.P. Sabio H. Bouhassira E.E. Upshaw Jr, J.D. Ginsburg D. Tsai H.M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Nature. 2001; 413: 488-94Crossref PubMed Scopus (1436) Google Scholar, 14.Tsai H.M. Lian E.C. Antibodies to von Willebrand factor‐cleaving protease in acute thrombotic thrombocytopenic purpura.N Engl J Med. 1998; 339: 1585-94Crossref PubMed Scopus (1481) Google Scholar. Since its molecular identification and positive association with TTP, measuring ADAMTS‐13 activity in plasma has become the standard for diagnosis and as means to evaluate the effective treatment for TTP 15.Blombery P. Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives.J Blood Med. 2014; 5: 15-23PubMed Google Scholar. A recombinant version of ADAMTS‐13 has been tested for replacement therapy in a small group of young adults and adult patients with TTP with promising results 16.Scully M. Knöbl P. Kentouche K. Rice L. Windyga J. Schneppenheim R. Hovinga J.A.K. Kajiwara M. Fujimura Y. Maggiore C. Doralt J. Hibbard C. Martell L. Ewenstein B. Recombinant ADAMTS‐13: first‐in‐human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura.Blood. 2017; 130: 2055-63Crossref PubMed Scopus (139) Google Scholar. Increasing novel therapies for TTP require the accurate measurement of VWF/ADAMTS‐13 and this includes children of different age groups. In addition to TTP, ADAMTS‐13 was reported to play a role in several pathophysiological conditions associated with increased thrombosis in pediatric and young adult populations. Abnormal ADAMTS‐13 plasmatic levels have been described to be associated with the etiology of primary vascular diseases 17.Bongers T.N. de Bruijne E.L.E. Dippel D.W.J. de Jong A.J. Deckers J.W. Poldermans D. de Maat M.P.M. Leebeek F.W.G. Lower levels of ADAMTS13 are associated with cardiovascular disease in young patients.Atherosclerosis. 2009; 207: 250-4Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar and development of stroke in the pediatric population 18.Lambers M. Goldenberg N.A. Kenet G. Kirkham F.J. Manner D. Bernard T. Mesters R.M. Junker R. Stoll M. Nowak‐Gottl U. Role of reduced ADAMTS13 in arterial ischemic stroke: a pediatric cohort study.Ann Neurol. 2013; 73: 58-64Crossref PubMed Scopus (41) Google Scholar. Growing evidence suggests that abnormal VWF/ADAMTS‐13 interactions play a role in pathologic clot formation present in other common diseases, including sickle cell disease 19.Schnog J.‐.J.B. Hovinga J.A.K. Krieg S. Akin Ş. Lämmle B. Brandjes D.P.M. Gillavry M.R.M. Muskiet F.D. Duits A.J. ADAMTS13 activity in sickle cell disease.Am J Hematol. 2006; 81: 492-8Crossref PubMed Scopus (45) Google Scholar, sepsis 20.Nguyen T.C. Liu A. Liu L. Ball C. Choi H. May W.S. Aboulfatova K. Bergeron A.L. Dong J.‐.F. Acquired ADAMTS‐13 deficiency in pediatric patients with severe sepsis.Haematologica. 2007; 92: 121-4Crossref PubMed Scopus (117) Google Scholar and cancer 21.Mannucci P. Karimi M. Mosalaei A. Canciani M. Peyvandi F. Patients with localized and disseminated tumors have reduced but measurable levels of ADAMTS‐13 (von Willebrand factor cleaving protease).Haematologica. 2003; 88: 454-8PubMed Google Scholar, specifically in the pediatric population, with no data on neonates. The first report of von Willebrand disease (VWD) was published in 1926 by a Finnish physician, Eric von Willebrand, in a family with inherited bleeding disorder that affected both male and female members 22.Willebrand E.A.V. Hereditary pseudohaemophilia.Haemophilia. 1999; 5: 223-31Crossref PubMed Google Scholar, 23.Sadler J.E. Biochemistry and genetics of von Willebrand factor.Annu Rev Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1132) Google Scholar. Eric von Willebrand differentiated the condition from classical hemophilia based on inheritance pattern and referred to it as pseudo hemophilia 23.Sadler J.E. Biochemistry and genetics of von Willebrand factor.Annu Rev Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1132) Google Scholar. However, the lack of specific and reliable diagnostic tests and reports of concurrent decrease of FVIII resulted in diagnostic confusion between these conditions. In the 1950s, it was shown that plasma from severe hemophilia patients could correct VWD, leading to the distinction between these two diseases 23.Sadler J.E. Biochemistry and genetics of von Willebrand factor.Annu Rev Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1132) Google Scholar. In the following decades, significant progress was made in the immunological distinction between VWF and FVIII, purification of VWF and sequencing of VWF gene, leading to our current understanding of VWF and molecular mechanisms underlying VWD 23.Sadler J.E. Biochemistry and genetics of von Willebrand factor.Annu Rev Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1132) Google Scholar, 24.Verweij C.L. Diergaarde P.J. Hart M. Pannekoek H. Full‐length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit.EMBO J. 1986; 5: 1839-47Crossref PubMed Scopus (187) Google Scholar, 25.Zimmerman T.S. Ratnoff O.D. Powell A.E. Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand's dissase, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor.J Clin Invest. 1971; 50: 244-54Crossref PubMed Scopus (345) Google Scholar. VWD is currently classified into three categories based on quantitative and qualitative deficiencies of VWF 23.Sadler J.E. Biochemistry and genetics of von Willebrand factor.Annu Rev Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1132) Google Scholar (Table 1).Table 1von Willebrand disease (VWD) classification and characteristicsVWD typeCharacteristicsType 1Partial quantitative deficiency of VWF. The majority of VWD cases (~ 70%) fall into this category. Patients show normal multimeric pattern but all multimeric forms are reduced uniformly.Type 2 SubtypesQualitative defects of VWF. About 25% of all VWD cases fall into this category.2AAbsence of high‐molecular‐weight (HMW) VWF forms. Multiple mechanisms including impaired dimerization or multimerization, rapid clearance from circulation and intracellular retention can lead to this condition.2BIncreased affinity of VWF to the platelet GPIb receptor. HMW VWF–platelet complexes are rapidly cleared in vivo leaving low‐molecular‐weight (LMV) VWF forms that are hemostatically inactive.2MBinding of VWF to platelets or connective tissue is impaired.2NBinding of VWF to FVIII is impaired; this condition often resembles mild hemophilia A.Type 3Severe quantitative deficiency of VWF with antigen levels of < 5 IU dL−1 in most cases. Less than 5% of all VWD cases belong to this category. Open table in a new tab Multiple assays were developed over a period of time for quantitative and qualitative evaluation of VWF 26.Favaloro E.J. Pasalic L. Curnow J. Laboratory tests used to help diagnose von Willebrand disease: an update.Pathology. 2016; 48: 303-18Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 27.Flood V.H. Perils, problems, and progress in laboratory diagnosis of von Willebrand disease.Semin Thromb Hemost. 2014; 40: 41-8PubMed Google Scholar (Table 2). Assays developed to measure VWF antigen (VWF:Ag) in the early 1970s employed complex principles of immune‐electrophoresis 25.Zimmerman T.S. Ratnoff O.D. Powell A.E. Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand's dissase, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor.J Clin Invest. 1971; 50: 244-54Crossref PubMed Scopus (345) Google Scholar and radio‐immunoassay 28.Hoyer L.W. Immunologic studies of antihemophilic factor (AHF, factor VIII). IV. Radioimmunoassay of AHF antigen.J Lab Clin Med. 1972; 80: 822-33PubMed Google Scholar, and were cumbersome to perform. Subsequently, ELISA (1976) 29.Bartlett A. Dormandy K.M. Hawkey C.M. Stableforth P. Voller A. Factor‐VIII‐related antigen: measurement by enzyme immunoassay.Br Med J. 1976; 1: 994-6Crossref PubMed Scopus (76) Google Scholar and latex agglutination assays were developed to detect the VWF:Ag. Of these, latex agglutination‐based immunoassays are commonly used today 30.Chandler W.L. Peerschke E.I. Castellone D.D. Meijer P. NASCOLA Proficiency Testing CommitteeVon Willebrand factor assay proficiency testing. The North American Specialized Coagulation Laboratory Association experience.Am J Clin Pathol. 2011; 135: 862-9Crossref PubMed Scopus (61) Google Scholar. The VWF ristocetin cofactor activity (VWF:RCo) assay, a commonly used assay to measure VWF activity, was developed in 1973 31.Weiss H.J. Hoyer L.W. Rickles F.R. Varma A. Rogers J. Quantitative assay of a plasma factor deficient in von Willebrand's disease that is necessary for platelet aggregation. Relationship to factor VIII procoagulant activity and antigen content.J Clin Invest. 1973; 52: 2708-16Crossref PubMed Scopus (327) Google Scholar. This assay measures the interaction of VWF with the GPIb receptor of platelets in the presence of ristocetin, an antibiotic that facilitates binding of VWF to the GPIb receptor of platelets in the absence of shear stress conditions 27.Flood V.H. Perils, problems, and progress in laboratory diagnosis of von Willebrand disease.Semin Thromb Hemost. 2014; 40: 41-8PubMed Google Scholar. To overcome some of the intrinsic limitations encountered in this assay, VWF:GPIb assays that employ recombinant GPIb (rGPIb) instead of platelets were developed recently 26.Favaloro E.J. Pasalic L. Curnow J. Laboratory tests used to help diagnose von Willebrand disease: an update.Pathology. 2016; 48: 303-18Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 32.Vanhoorelbeke K. Cauwenberghs N. Vauterin S. Schlammadinger A. Mazurier C. Deckmyn H. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor.Thromb Haemost. 2000; 83: 107-13Crossref PubMed Scopus (107) Google Scholar, 33.Flood V.H. Gill J.C. Morateck P.A. Christopherson P.A. Friedman K.D. Haberichter S.L. Hoffmann R.G. Montgomery R.R. Gain‐of‐function GPIb ELISA assay for VWF activity in the Zimmerman program for the molecular and clinical biology of VWD.Blood. 2011; 117: e67-74Crossref PubMed Scopus (82) Google Scholar. VWF:GPIb assays are further classified as; (i) VWF:GPIbR assay (2000), which employs rGPIb and ristocetin 32.Vanhoorelbeke K. Cauwenberghs N. Vauterin S. Schlammadinger A. Mazurier C. Deckmyn H. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor.Thromb Haemost. 2000; 83: 107-13Crossref PubMed Scopus (107) Google Scholar and (ii) VWF:GPIbM assay (2011), which employs a gain of function mutant of GPIb (GPIbM) that readily binds to VWF in the absence of ristocetin 33.Flood V.H. Gill J.C. Morateck P.A. Christopherson P.A. Friedman K.D. Haberichter S.L. Hoffmann R.G. Montgomery R.R. Gain‐of‐function GPIb ELISA assay for VWF activity in the Zimmerman program for the molecular and clinical biology of VWD.Blood. 2011; 117: e67-74Crossref PubMed Scopus (82) Google Scholar.Table 2Laboratory assays for von Willebrand factor (VWF)AssayDescription of assayYear developedReferenceVWF:AgVWF:antigen assay – measures VWF protein levels197125.Zimmerman T.S. Ratnoff O.D. Powell A.E. Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand's dissase, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor.J Clin Invest. 1971; 50: 244-54Crossref PubMed Scopus (345) Google ScholarVWF:RCoVWF:ristocetin cofactor assay – measures the interaction of VWF with the GPIb receptor of platelets in the presence of ristocetin197331.Weiss H.J. Hoyer L.W. Rickles F.R. Varma A. Rogers J. Quantitative assay of a plasma factor deficient in von Willebrand's disease that is necessary for platelet aggregation. Relationship to factor VIII procoagulant activity and antigen content.J Clin Invest. 1973; 52: 2708-16Crossref PubMed Scopus (327) Google ScholarVWF:GPIbVWF:GPIb binding assay – measures the binding of VWF to GPIb fragment200032.Vanhoorelbeke K. Cauwenberghs N. Vauterin S. Schlammadinger A. Mazurier C. Deckmyn H. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor.Thromb Haemost. 2000; 83: 107-13Crossref PubMed Scopus (107) Google Scholar, 33.Flood V.H. Gill J.C. Morateck P.A. Christopherson P.A. Friedman K.D. Haberichter S.L. Hoffmann R.G. Montgomery R.R. Gain‐of‐function GPIb ELISA assay for VWF activity in the Zimmerman program for the molecular and clinical biology of VWD.Blood. 2011; 117: e67-74Crossref PubMed Scopus (82) Google ScholarRIPARistocetin induced platelet aggregation assay – measures aggregation of platelets by VWF at a very low concentration of ristocetin198034.Ruggeri Z.M. Pareti F.I. Mannucci P.M. Ciavarella N. Zimmerman T.S. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease.N Engl J Med. 1980; 302: 1047-51Crossref PubMed Scopus (271) Google ScholarVWF multimer analysisStudies multimer distribution of VWF198035.Hoyer L. Shainoff J. Factor VIII‐related protein circulates in normal human plasma as high molecular weight multimers.Blood. 1980; 55: 1056-9Crossref PubMed Google ScholarVWF:CBVWF:collagen binding assay – measures the collagen binding capacity of VWF198637.Brown J.E. Bosak J.O. An elisa test for the binding of von willebrand antigen to collagen.Thromb Res. 1986; 43: 303-11Abstract Full Text PDF PubMed Scopus (147) Google ScholarVWF:FVIIIVWF: FVIII binding assay – measures the binding of VWF to FVIII198938.Nishino M. Girma J. Rothschild C. Fressinaud E. Meyer D. New variant of von Willebrand disease with defective binding to factor VIII.Blood. 1989; 74: 1591-9Crossref PubMed Google Scholar Open table in a new tab By 1980, two assays that aid in the differential diagnosis of VWD, the ristocetin‐induced platelet aggregation assay (RIPA) 34.Ruggeri Z.M. Pareti F.I. Mannucci P.M. Ciavarella N. Zimmerman T.S. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease.N Engl J Med. 1980; 302: 1047-51Crossref PubMed Scopus (271) Google Scholar and VWF multimer analysis 35.Hoyer L. Shainoff J. Factor VIII‐related protein circulates in normal human plasma as high molecular weight multimers.Blood. 1980; 55: 1056-9Crossref PubMed Google Scholar, were established. RIPA measures aggregation of platelets by VWF at varying concentrations of ristocetin. VWF multimer analysis studies the multimeric distribution of VWF by molecular weight in an electrophoretic assay. Identification of binding of VWF to collagen in the early 1980s 36.Scott D.M. Griffin B. Pepper D.S. Barnes M.J. The binding of purified factor VIII/von Willebrand factor to collagens of differing type and form.Thromb Res. 1981; 24: 467-72Abstract Full Text PDF PubMed Scopus (34) Google Scholar led to introduction of an ELISA‐based VWF collagen binding assay (VWF:CB) in 1986 37.Brown J.E. Bosak J.O. An elisa test for the binding of von willebrand antigen to collagen.Thromb Res. 1986; 43: 303-11Abstract Full Text PDF PubMed Scopus (147) Google Scholar. VWF:CB measures the collagen binding activity of HMW:VWF multimers to collagen. FVIII binding assay (VWF:FVIII) 38.Nishino M. Girma J. Rothschild C. Fressinaud E. Meyer D. New variant of von Willebrand disease with defective binding to factor VIII.Blood. 1989; 74: 1591-9Crossref PubMed Google Scholar was introduced in 1989 and measures the binding of VWF to FVIII. This assay helps in the identification of type 2N VWD. Additional assays, including monoclonal antibody‐based assays (VWF:Ab), VWF propeptide assay (VWFpp) and VWF platelet binding assay (VWF:PB), were developed to aid in diagnosis of VWD. These assays have all been improved over a period of time for increased sensitivity and less variability and have been automated for higher accuracy and high‐throughput testing 26.Favaloro E.J. Pasalic L. Curnow J. Laboratory tests used to help diagnose von Willebrand disease: an update.Pathology. 2016; 48: 303-18Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar. VWF assays have some limitations. The ELISA and LIA‐based assays employed for quantitation of VWF antigen are generally sensitive, reliable and reproducible but, for LIA‐based methods, interference from rheumatoid factor and heterophile antibodies results in overestimation of VWF:Ag 26.Favaloro E.J. Pasalic L. Curnow J. Laboratory tests used to help diagnose von Willebrand disease: an update.Pathology. 2016; 48: 303-18Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 39.Favaloro E.J. Aboud M. Arthur C. Possibility of potential VWD misdiagnosis or misclassification using LIA technology and due to presence of rheumatoid factor.Am J Hematol. 2001; 66: 53-6Crossref PubMed Scopus (24) Google Scholar. The VWF:RCo assay, the most frequently used assay for measuring VWF activity, also has several limitations. Ristocetin, used in this assay to facilitate the binding of VWF to the GPIb receptor of platelets, is a non‐physiological modulator. Among the frequently used VWF assays, the VWF:RCo assay has low sensitivity and showed the highest variation in multiple studies, leading to diagnostic errors 30.Chandler W.L. Peerschke E.I. Castellone D.D. Meijer P. NASCOLA Proficiency Testing CommitteeVon Willebrand factor assay proficiency testing. The North American Specialized Coagulation Laboratory Association experience.Am J Clin Pathol. 2011; 135: 862-9Crossref PubMed Scopus (61) Google Scholar, 40.Meijer P. Haverkate F. An external quality assessment program for von Willebrand factor laboratory analysis: an overview from the European concerted action on thrombosis and disabilities foundation.Semin Thromb Hemost. 2006; 32: 485-91Crossref PubMed Scopus (88) Google Scholar. Further, p.D1472H and p.P1467S VWF polymorphisms interfere with VWF–ristocetin interactions, resulting in low VWF:Rco activity and false type 1 VWD diagnosis 41.Flood V.H. Gill J.C. Morateck P.A. Christopherson P.A. Friedman K.D. Haberichter S.L. Branchford B.R. Hoffmann R.G. Abshire T.C. Di Paola J.A. Hoots W.K. Leissinger C. Lusher J.M. Ragni M.V. Shapiro A.D. Montgomery R.R. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor.Blood. 2010; 116: 280-6Crossref PubMed Scopus (121) Google Scholar. Because of these limitations, increasingly VWF:RCo assay is either replaced or supplemented with VWF:GPIb and VWF:CB assays 26.Favaloro E.J. Pasalic L.
Referência(s)