Von Willebrand Factor and von Willebrand s Disease: A Complex Protein and a Complex Disease

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1 ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 19, No. 3 Copyright 1989, Institute for Clinical Science, Inc. Von Willebrand Factor and von Willebrand s Disease: A Complex Protein and a Complex Disease ROBERT D. BONA, M.D. Department of Medicine, Section Hematology-Oncology, Saint Francis Hospital and Medical Center, Hartford, CT ABSTRACT Von W illebrand factor is a complex protein which is im portant in several ways for normal hemostasis. Von W illebrand s disease results when there is either a quantitative or qualitative disorder of von W illebrand factor. In this review, the structure and function of von W illebrand factor are discussed. Additionally, the current laboratory and clinical classification of von W illebrand s disease and closely related variants are outlined. Von W illebrand s disease (vwd) is a com m on, com plex, usually m ild, congenital bleeding disorder characterized by qualitative and/or quantitative abnorm alities of the von W illebrand factor molecule. There is wide variability in the clinical manifestations of the disease as well as m arked biochem ical heterogeneity. The purpose of this review will be twofold. First, the function of von W illebrand factor (vwf) will be described, and, secondly, the way in which von W illebrand disease subtypes are recognized and categorized will be reviewed. Von W illebrand factor is a glycoprotein synthesized by endothelial cells17,31 a n d m e g a k a ry o c y te s. 29 I t is e ith e r secreted constitutively or stored in Weibel Palade bodies or alpha granules of endothelial cells or platelets, resp ectively. T he g en e for vw F has b e e n cloned by several groups11,20,27,30 and codes for an initial translation product w ith a m olecular w eight of approxim ately 300,000 daltons. This p ro te in 184 exists in a p re-p ro form th at quickly dim erizes in the endoplasm ic reticu lum 32 after cleavage of the pre-peptide off the amino term inal end of the molecule. Subsequent cleavage of the prop eptide results in the production of a m atu re m o lecu le, w ith a m olecular w eight of 220,000 daltons. T he final plasma product is formed as dimers are assem bled into m ultim ers by head to head interaction involving the amino te r minus. This final product circulates in the plasm a as a complex of m ultim ers ranging in molecular weight from one to 20 million daltons. 16 Glycosylation, sulfation, and interchain disulfide bond form ation also are im portant post translational events req u ired for the proper synthesis of the protein.32,33 The cleaved pro-peptide is secreted into the plasma as a distinct protein and has been designated as von W illebrand antigen II.7,22 T he protein serves a variety of functions and through epitope m apping, utilizing m onoclonal antibodies and lim ited /89/ $09.00 Institute for Clinical Science, Inc.

2 VON WILLEBRAND FACTOR AND VON WILLEBRAND'S DISEASE 185 proteolysis, m ultiple functional domains have been id en tified on th e p rotein. Binding sites for heparin, collagen, factor VIII, and the platelet glycoproteins lb and the IIb,IIIa complex have been id e n tifie d. 2,6 1 0 F u jim u ra e t al10 have used vw F tryptic digests and dem onstrated that the binding site for platelet glycoprotein lb lies on the amino term i nus. F u rth erm o re, they w ere able to dem onstrate binding despite reduction and alkylation of the peptide, suggesting that the native conformation of vw F was not critical for binding of glycoprotein lb. Utilizing the Staphylococcus aureus V8 protease followed by tryptic digests, F o ster and colleagues8 have recen tly dem onstrated that a m ajor factor VIII binding site resides w ithin the aminoterm inal 272 amino acid residues of the m o lecu le. T hey also o b se rv e d th a t reduction of this 35,000 dalton fragment elim inated its ability to bind purified factor VIII. Thus, unlike the binding site for g ly co p ro tein lb, in ta c t disulfide bonds appear to be im portant for the ability of vw F to support binding of factor VIII. Factor V III circulates in the plasma non-covalently complexed with von Willebrand factor and appears to be stabilized by this in teractio n. 36 The other major function of von W illebrand factor is its ability to m ediate the adhesion of platelets to the subendothelium. Von W illebrand factor binds to the exposed subendothelium presum ably via binding sites on the molecule for subendothelial collagen18 or o th e r vessel wall com ponents and to the platelet, via glycoprotein lb. 4 P la te le t vw F is also im p o rta n t in m ediating the adhesion of platelets to collagen9 and p latelet vw F may have greater specific activity than its plasma counterpart13 w hen ristocetin cofactor activity is used as a m easure of the functional activity of the protein. The relative effects of plasm a and p late le t vw F on supporting platelet adhesion to collagen is not known, but their effects appear to be additive.9 The importance of platelet vw F is further em phasized by noting th a t p a tien ts w ith abnorm al p late le t vw F, b u t norm al plasm a vw F, have clinical findings of a bleeding disorder (see following). Von W illebrand factor also interacts w ith glycoprotein IIb,IIIa on activated platelets, but the role of this interaction in prim ary hemostasis is not known. 6 Von W illebrand s disease is a common and generally m ild bleeding disorder that is characterized by a quantitative and/or qualitative abnorm ality of von W illebrand factor leading to a decreased circulating von W illebrand factor antigen, prolonged bleeding time, abnormal ristocetin cofactor activity, a prolonged partial throm boplastin tim e (PTT), and a depressed factor VIII level. In patients w ith m ild disease, th e laboratory diagnosis of th e disorder can be difficult. This is generally felt to be due to the g reat v a ria b ility in c irc u la tin g vw F levels and, thus, variation in laboratory tests in a given p a tie n t over a given period of tim e. 1 The widespread use of m ultim er analysis has led to an expanded classification of von W illebrand s disease. Ruggeri, et al, have proposed an interim classification based on plasma m ultim er analysis and p latelet resp o n siveness to low doses of risto c e tin 26 (table I). Patients who have solely a quantitative disorder of vw F have norm al plasm a vw F m ultim er patterns and generally have mild clinical bleeding syndromes. This group of patients com prises the majority of patients with von W illebrand disease and usually responds to intravenous infusions of l-desam ino-8 -D-argin in e v a s o p r e s s in (D D A V P ) w ith increases in plasma vwf. 5 A second group of patients are characterized by qualitative and quantitative ab n orm alities of vw F. T he risto cetin

3 186 BONA T A B L E I Classification of von Wllebrand's Disease VWD RCo Mai timers RIPA Response to DDAVP I. Quantitative L N N or L Good DDAVP abnormality 11. Qualitative Very HMW forms L Poor Cryo abnormality low absent III.Heightened Very HMW forms I Poor Cryo/ response to low absent plat ristocetin IV. Very low Very All forms L Poor Cryo low absent L = low N = normal I = increased RCo = Ristocetin RIPA = Ristocetin induced platelet aggregation DDAVP = l-desamino-8-d-arginine vasopressin HMW = High molecular weight Cryo = Cryoprecipitate Plat = Platelets cofactor activity is usually depressed to a g reater ex ten t than the vw F antigen suggesting this qualitative abnorm ality as well as a quantitative one. The qualitative abnormalities can usually be dem onstrated by plasm a m ultim er analysis where absence of the highest molecular weight m ultim ers is readily observed. 15 M ultim er analysis done with higher resolution separating systems have dem onstra te d absence of satellite bands or other abnorm alities of satellite bands.3 Taken together, these abnorm alities indicate either an abnormality in the basic protein subunit or an abnormality in the processing step(s) leading to dimerization and m ultimerization. Abnormalities of glycosylation and/or sulfation are also p o s s ib le, b u t n o t as o f y e t w e ll d escrib ed. 12 A qualitatively abnorm al vw D variant has been described and designated as the so called platelet discordant ty p e. 21 Plasm a vw F antigen and m ultim er analysis are normal, but p la te le t vw F functional activity and antigen level are depressed. The functional activity is depressed out of proportion to the protein level, suggesting a structural defect in the protein leading to depressed function. Generally, patients in this second group (those with qualitative as well as quantitative abnormalities) Rx do not show a substantial rise in their plasma (or platelet) vw F to infusions of DDAVP and may require cryoprecipitate infusions for b leeding or p ro p h y laxis. E n h a n c e d a g g re g a tio n of p a tie n t platelet rich plasma to low doses of ristocetin (0.5 mg per ml) is the hallmark of the th ird general group of von W illebrand disease patients. M ultim er analysis of plasma from these patients usually dem onstrates absence of the high m olecular w eight m ultim ers, and differentiation of this group from group num ber 2 by m u ltim e r analysis alo n e is n e a r impossible. H em ostatic disorders characterized by heightened aggregation to ristocetin and abnormal m ultim er analysis have been called type IIB von W illebrand s disease25 and pseudo or platelet type von W illebrand s disease35 (table II). Type IIB von W illebrand s disease is characterized by an abnormal von Willebrand factor which binds to platelets, causing the hyperresponsiveness to ristocetin. P latelet type von W illebrand disease is seen when there is a platelet abnormality (currently not defined on a molecular level) leading to binding of the high molecular weight vw F m ultimers to p latelets. This also resu lts in the hyperresponsiveness to ristocetin. In both disorders th ere is an absence of high m olecular weight m ultim ers from the plasma and platelet aggregation with C o m p a r i s o n o f T y p e C h a r a c t e r i s t i c T A B L E I I l i b vw D a n d P s e u d o - v W D Type lib VWD PseudovWD H e i g h t e n e d r e s p o n s e t o r i s t o c e t i n + + T h r o m b o c y t o p e n i a i n r e s p o n s e t o + + D D A V P A b s e n c e o f h i g h m o l e c u l a r w e i g h t + + p l a s m a m u l t i m e r s A b n o r m a l v o n W i l l e b r a n d f a c t o r + - A b n o r m a l p l a t e l e t s + D D A V P = l - d e s a m i n o D - a r g i n i n e v a s o p r e s s i n

4 VON WILLEBRAND FACTOR AND VON WILLEBRAND S DISEASE 187 a low dose of ristocetin is identified. There is, additionally, a variable amount o f throm bocytopenia seen in b o th disorders This is presum ably related to in vivo p late le t clum ping and su b sequent clearance by the reticuloendothelial system. In type IIB von W illebrand disease, the abnormality resides in the von W illebrand factor and, therefore, p a tie n t von W illebrand factor dem ons tra te s in cre ase d b in d in g to norm al platelets. In p latelet type von W illebrand s disease, the abnormality resides in the platelet and, therefore, patient von W illebrand factor does not show increased binding to norm al platelets. However, patient s platelets will dem onstrate increased binding to normal von W illebrand factor. 23 Throm bocytopenia can be seen to a variable ex ten t in both type IIB and p latelet type von W illebrand s disease and is freq u en tly aggravated by the administration of D DAVP. 14' 19 This latter observation has led m ost clinicians to advocate the use of cryoprecipitate in the treatm ent of patients with type IIB vw D ra th e r than DDAVP. C ryoprecipitate may aggravate the throm bocytopenia seen in platelet type vw D and the best approach to the m anagem ent of these patients may be concurrent transfusion o f platelets and cryoprecipitate. Thrombocytopenia during pregnancy has recently been described in several patients with either type IIB or platelet type von W illebrand d isease P re sumably, this relates to increases in von W illebrand factor during pregnancy with subsequent binding to platelets leading to reticuloendothelial cell clearance. T h e final g ro u p of p a tie n ts have severe von W illebrand s disease and are plagued by severe lifelong bleeding problem s and very low or unm easurable levels of vw F antigen.37 This group is seen rarely, and p a tie n ts are e ith e r homozygous for a genetic defect or double heterozygotes. 28 Von W illebrand factor is a large glycoprotein that plays a pivotal role in norm al hem ostasis by at least two m echanism s; stab ilizin g factor V III in th e circulation and m ediating platelet adhesion to the damaged subendothelium. In addition to stabilizing factor VIII, it concentrates it at the site of vascular dam age. This role of localizing the cofactor function m ay also be im portant. Von W illebrand disease is a relatively com m on, usually m ild b leed in g d iso rd er characterized by abnorm alities in the von W ille b ra n d factor m olecule. As m ore so p h istic a te d tech n iq u e s have been established to investigate these abnorm alities, it has becom e evident that this is an extremely heterogeneous disorder. F urther definitive classification should follow our increased understanding of this very complex disorder. Acknowledgments Thanks are extended to Drs. Dominick Pasquale and Leon Hoyer for their helpful comments. References 1. A b i l d g a a r d, C. F., S u z u k i, Z., H a r r i s o n, J., J e f c o a t, K., and Z i m m e r m a n, T. S.: Serial studies in von Willebrand s disease: Variability versus variants. Blood 56: , B o c k e n s t e d t, P., G r e e n b e r g, J. M., and H a n - d i n, R. I.: Structural Basis of von Willebrand Factor Binding to Platelet glycoprotein lb and collagen. J. Clin. Invest. 77: , C ia v a r ella, G., C ia v a r ella, N., A n t o n c e c - c h i, S., D e M attia, D., Ra n ie r i, P., D e n t, J., Z im m e r m a n, T. S., and R u g g e r i, Z. M.: High resolution analysis of von Willebrand factor multim eric composition defines a new variant of type I von W illebrand disease with aberrant structure but presence of all size multimers (type IC ). Blood 66: , C O L L E R, B. S., P E E R S C H K E, E. I., SCUDDER, L. E., and S u l l i v a n, C. A.: Studies w ith a murine monoclonal antibody that abolishes ristocetin induced binding of von Willebrand factor to platelets: Additional evidence in support of glycoprotein lb as a platelet receptor for von Willebrand factor. Blood 61:99 110, d e l a F u e n t e, B., K a s p e r, C. K., R i c k l e s, F. R., and H o y e r, L. W.: Response of patients with mild and moderate hemophilia A and von Willebrand s disease to treatm ent with desmopressin. Ann. Int. Med. J03:6-14, 1985.

5 188 BONA 6. D e M a r c o, L., G i r o l a m i, A., Z i m m e r m a n, T. S., and R u g g e r i, Z. M.: Von Willebrand factor interaction with the glycoprotein Ilb/IIIa complex. J. Clin. Invest. 77: , F a y, P. J., K a w a i, Y., W a g n e r, D. D., G i n s - b u r g, D., B o n t h r o n, D., O h l s s o n - W i l h e l m, B. M., C h a v i n, S. L., A b r a h a m, G. N., H a n - d i n, R. I., O r k i n, S. H., M o n t g o m e r y, R. R., and M a r d e r, V. J.: Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Science 232: , F o s t e r, P. A., F u l c h e r, C. A., M a r t i, T., T i t a n i, K., and Z i m m e r m a n, T. S. : A major factor VIII binding domain resides w ithin the amino-terminal 272 amino acid residues of von W illebrand factor. J. Biol. Chem. 262: , F r e s s i n a u d, E., B a r u c h, D., R o t h s c h i l d, C., B a u m g a r t n e r, H. R., and M e y e r, D.: Platelet von Willebrand factor: Evidence of its involvem ent in platelet adhesion to collagen. Blood 70: , F u jim u r a, Y., T it a n i, K., H o l l a n d, L. Z., R u s s e l l, S. R., R o b er ts, J. R., E ld e r, J. H., R u g g e r i, Z. M., and Z im m e r m a n, T. S.: Von Willebrand factor. J. Biol. Chem : , G i n s b u r g, D., H a n d i n, R. I., B o n t h r o n, D. T., D o n l o n, T. A., B r u n s, G. A. P., L a t t, S. A., and O r k i n, S. H.: Human von W illebrand factor (vwf): Isolation of complementary DNA (cdna) clones and chromosome localization. Science 228: , G r a l n i c k, H. R., C o l l e r, B. S., and S u l t a n, Y.: Carbohydrate deficiency of the factor VIII/ von Willebrand factor protein in von Willebrand disease variants. Science 192:56-59, G r a l n i c k, H. R., W i l l i a m s, S. B., M c K e o w n, L. P., K r i z e k, D. M., S h a f e r, B. C., and R i c k, M. E.: Platelet von Willebrand factor: Comparison with plasma von Willebrand factor. Thromb. R e s. 35: , G r a l n i c k, H. R., W i l l i a m s, S. B., M c K e o w n, L. P., and R i c k, M. E.: Von Willebrand s disease w ith spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor. J. Clin. Invest. 76: , H o y e r, L. W., R i z z a, C. R., T u d d e n h a m, E. G. D., C a r t a, C. A., A r m i t a g e, H., and ROTBLAT, F.: Von W illebrand factor multim er patterns in von W illebrand s disease. Brit. J. Haemat. 55: , H o y e r, L. W. and SH A IN O FF, J. R.: Factor VIII related protein circulates in normal hum an plasma as high molecular weight multimers. Blood 5 5 : , J a f f e, E. A., H o y e r, L. W. and N a c h m a n, R. L. : Synthesis of von Willebrand factor by cultured human endothelial cells. Proc. Natl. Acad. Sci. USA 7i:1906, K e s s l e r, C. M., F l o y d, C. M., R i c k, M. E., K r i z e k, D. M., L e e, S. L., and G r a l n i c k, H. R. : Collagen factor VUI/von Willebrand factor protein interaction. Blood 63:1291, H y r le, P. A., N ie ssn e r, H., D e n t, J., Pa n zer, S., B r e n n e r, B., Z im m e r m a n, T. S., and L e c h n e r, K.: IIB von W illebrand s disease: Pathogenetic and therapeutic studies. Brit. J. Haemat. 69:55-59, Ly n c h, D. C., Z im m e r m a n, T. S., C o l l in s, C. J., B r o w n, M., M o r in, M. J., L in g, E. H., and L iv in g s t o n, D. M.: Molecular cloning of cd N A for hum an von W illebran d factor: Authentication by a new method. Cell 41:49-56, M a n n u c c i, P. M., L o m b a r d i, R., Ba d e r, R., Via n e l l o, L., F e d e r ic i, A. B., So l in a s, S., M a zz u c c o n i, M. G., and M a r ia n i, G.: Heterogeneity of type I von Willebrand disease: Evidence for a subgroup with an abnormal von Willebrand factor. Blood 66: , M c C a r r o l l, D. R., L e v in, E. G., and M o n t gom ery, R. R.: Endothelial cell synthesis of von W illebrand antigen II, von W illebrand factor and von Willebrand factor/von Willebrand antigen II complex. J. Clin. Invest. 75: , M il l e r, J. L., K u p in s k i, J. M., C a stella, A., and R u g g e r i, Z. M.: Von W illebrand factor binds to platelets and induces aggregation in platelet-type but not type IIB von Willebrand disease. J. Clin. Invest. 72: , Ric k, M. E., W il l ia m s, S. B., Sa c h e r, R., and M c K e o w n, L. P.: Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrand s disease. Blood 69: , R u g g e r i, Z. M., Pa r e t i, F. I., M a n n u c c i, P. M., C ia v a rella, N., an d Z im m e r m a n, T. S.: H e ig h te n e d in teractio n b e tw e e n p la te le ts and factor V IH /von W ille b ra n d factor in a n ew subty p e o f von W ille b ra n d s disease. N ew E ngl. J. M ed. 302: , R u g g e r i, Z. M. and Z im m e r m a n, T. S.: von Willebrand factor and von Willebrand disease. Blood 70: , Sa d ler, J. E., Sh e l t o n -I n h o l e s, B. B., So r- a c e, J. M., H a r l a n, J. M., T it a n i, K., and D a v ie, W. W.: Cloning and characterization of two cdna s coding for human von Willebrand factor. Proc. Natl. Acad. Sci. USA $2: , Sh e l t o n -I n l o e s, B. B., C h e h a b, F. F., M a n n u c c i, P. M., F e d e r ic i, A. B., and Sa d l e r, J. E.: Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J. Clin. Invest. 79:1459, S po r n, L. A., C h a v in, S. I., M a r d er, V. J., and Wa g n er, D. D.: Biocynthesis of von Willebrand protein by hum an megakaryocytes. J. Clin. Invest. 76: , Ve r w e ij, C. L., d e V r ie s, C. J. M., D is t e l, B., van Z o n n e v e l d, A. J., van K e s s e l, A. G., van M ourik, J. A., and Pannek o ek, H.: Construction for cdna coding for human von Willebrand factor using antibody probes for colonyscreening and m apping of th e chromosomal gene. Nucleic Acids Res. 13:4699, Wa g n er, D. D. and M a r d e r, V. J.: Biosynthesis

6 VON WILLEBRAND FACTOR AND VON WILLEBRAND'S DISEASE 189 of von Willebrand protein by human endothelial cells. J. Biol. Chem. 258: , W a g n e r, D. D. and M a r d e r, V. J.: Biosynthesis of von Willebrand protein by human endothelial cells: Processing steps and their intracellular localization. J. Cell Biol. 99: , W a g n e r, D. D., M a y a d a s, T., and M a r d e r, V. J.: Initial glycosylation and acidic ph in the Golgi apparatus are required for multimerization of von Willebrand factor. J. Cell Biol. 102: , W e i n s t e i n, R., E d w a r d s, R., C a r t a, C., P a n e k, S., and R i c k l e s, F. R. : Thrombocytopenia associated with pregnancy in platelet-type von Willebrand disease. Blood (Suppl) 70:1236, W e i s s, H. J., M e y e r, D., R a b i n o w i t z, R., P i e t u, G., G i r m a, J. P., V i c i c, W. J., a n d R o g e r s, J.: P s e u d o - v o n W i l l e b r a n d s d i s e a s e. N e w E n g l. J. M e d. 306: , W e i s s, H. J., S u s s m a n, I. I., and H o y e r, L. W.: Stabilization of factor VIII in plasma by the von W illebrand factor. J. C lin Invest. 60: , Z i m m e r m a n, T. S., A b i l d g a a r d, C. F. a n d M e y e r, D.: T h e f a c t o r V III a b n o r m a l i t y i n s e v e r e v o n W i l l e b r a n d s d i s e a s e. N e w E n g l. J. M e d. 301:1307, 1979.