sign in sign up
<<
Home , Factor XII

commentaries

ar factor-kappaB blockade in multiple myeloma: leads to MAPK pathway activation through a PI3K- 2007. Role of autophagy in cancer. Nat. Rev. Cancer. therapeutic applications. Blood. 99:4079–4086. dependent feedback loop in human cancer. J. Clin. 7:961–967. 12. Kinkade, C.W., et al. 2008. Targeting AKT/mTOR Invest. 118:3065–3074. 18. Kaarbo, M., Klokk, T.I., and Saatcioglu, F. 2007. and ERK MAPK signaling inhibits hormone-refrac- 15. She, Q.B., et al. 2005. The BAD integrates Androgen signaling and its interactions with other tory prostate cancer in a preclinical mouse model. survival signaling by EGFR/MAPK and PI3K/Akt signaling pathways in prostate cancer. Bioessays. J. Clin. Invest. 118:3051–3064. kinase pathways in PTEN-deficient tumor cells. 29:1227–1238. 13. Ley, R., et al. 2004. Extracellular signal-regulated Cancer Cell. 8:287–297. 19. Shen, M.M., and Abate-Shen, C. 2007. Pten inac- kinases 1/2 are serum-stimulated “Bim(EL) kinas- 16. Qi, X.J., Wildey, G.M., and Howe, P.H. 2006. Evi- tivation and the emergence of androgen-indepen- es” that bind to the BH3-only protein Bim(EL) dence that Ser87 of BimEL is phosphorylated by dent prostate cancer. Cancer Res. 67:6535–6538. causing its phosphorylation and turnover. J. Biol. Akt and regulates BimEL apoptotic function. 20. Datta, S.R., Brunet, A., and Greenberg, M.E. 1999. Chem. 279:8837–8847. J. Biol. Chem. 281:813–823. Cellular survival: a play in three Akts. Dev. 14. Carracedo, A., et al. 2008. Inhibition of mTORC1 17. Mathew, R., Karantza-Wadsworth, V., and White, E. 13:2905–2927. The elusive physiologic role of Factor XII Alvin H. Schmaier

Division of Hematology and Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA.

Physiologic hemostasis upon injury involves many plasma in a can reciprocally activate more FXII and well-regulated cascade of proteolytic reactions to form a clot. Deficiency of liberate from high-molecular- blood Factors VIII, IX, or XI is associated with hemophilia. Fac- weight (HK). Bradykinin is a tor XII (FXII) autoactivates by contact with a variety of artificial or biologic mediator of vasodilatation and increased negatively charged surfaces (contact activation), resulting in blood coagula- vascular permeability (4). α-FXIIa when tion and activation of the inflammatory -kinin and complement cleaved by forms Factor systems. However, surprisingly, individuals deficient in FXII rarely suffer βXIIa (β-FXIIa), which then activates the from bleeding disorders. Most biologic surfaces that activate FXII become macromolecular complex of the first com- expressed in disease states. Investigators have long searched for physiologic ponent of complement, resulting in clas- activators of FXII and its role in vivo. In this issue of the JCI, Maas et al. show sic activation; plasma that misfolded protein aggregates produced during systemic amyloidosis kallikrein also directly activates comple- allow for plasma FXIIa and activation and increased forma- ment components C3 and C5 (5, 6). Thus, tion of kallikrein–C1 inhibitor complexes, without Factor XIa activation the activation of FXII results in coagula- and coagulation (see the related article beginning on page 3208). This study tion and complement activation with bra- describes a novel biologic surface for FXII activation and activity, which ini- dykinin liberation (Figure 1). tiates inflammatory events independent of hemostasis. Contact activation of Factor XII In the early 1950s, Oscar Ratnoff and Joan FXI that, when activated to become FXIa, Since FXII-deficient patients, along with Colopy observed a patient, John Hageman, leads to the formation of Factor IXa — a PK- and HK-deficient patients, do not whose blood, upon routine preoperative key intermediary in the intrinsic pathway have a bleeding disorder, the relevance of screening, was found to have prolonged of coagulation. These seminal studies the waterfall cascade hypothesis for blood clotting times in glass test tubes, even contributed to the presentation of their coagulation hemostasis initiated by acti- though Hageman had no history or symp- waterfall cascade hypothesis for the blood vated FXII has been questioned. Contact toms of a bleeding disorder (1). The obser- coagulation system; a similar hypothesis activation describes the unique property vation that something was missing in his was proposed that same year by Robert of FXII to undergo autoactivation and a blood, and that this factor changed upon MacFarlane (2, 3). Ratnoff and his collab- change in shape when exposed to negative- exposure to glass, ushered in the notion orators went on to show that FXII, which ly charged artificial or biologic surfaces. that blood clotting factors circulate as alters its physical properties during activa- Formation of FXIIa leads to PK activation inactive precursors that can be activated. tion, induces vasodilatation and vascular in the presence of HK, hence the name con- Ratnoff, in collaboration with Earl Davie, permeability. These studies encapsulate tact activation system. However, the molecu- identified that, in the disorder that became the major known properties of FXII (Fig- lar basis for the formation of activated known as Hageman trait, a plasma serine ure 1), a protein that autoactivates upon FXII remains unknown (7, 8). Over the last later called Factor XII (FXII) was exposure to negatively charged surfaces to 4 decades, a growing list of “physiologic” missing. Absence of FXII prevents the acti- become the Factor XIIa (α-FXIIa), negatively charged surfaces upon which vation of the blood coagulation which then activates FXI, prekallikrein FXII autoactivates have been recognized. (PK), and C1 esterase (a subunit of the In addition to nonphysiologic agents such Nonstandard abbreviations used: FXII, Factor XII; complement cascade). The consequence as glass, polyethylene, and silicone rubber, FXIIa, activated FXII; HK, high-molecular-weight of FXI activation by α-FXIIa is the ini- FXII autoactivation occurs upon expo- kininogen; PK, prekallikrein. tiation of a series of proteolytic reactions sure to articular cartilage, skin, fatty acids, Conflict of interest: The author has declared that no conflict of interest exists. resulting in generation, which endotoxin, amyloid protein, and heparins, Citation for this article: J. Clin. Invest. 118:3006–3009 precedes clot formation. α-FXIIa activa- among others (9). It is in this context of (2008). doi:10.1172/JCI36617. tion of PK forms plasma kallikrein that identifying a biologic surface that sup-

3006 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 9 September 2008 commentaries

deposition of misfolded amyloid proteins in organs and/or tissues, the authors observed significantly elevated levels of activated FXII compared with controls, as assessed by one commercially available assay (10). The authors go on to show that contact activation initiated by FXII in reaction to these misfolded proteins is associated with elevated levels of plasma kallikrein–C1 inhibitor complexes, but not FXIa–C1 inhibitor complexes, both in vitro and in patients with systemic amy- loidosis (10). This latter finding suggests that PK activation (and consequent activa- tion of the inflammatory kallikrein-kinin and complement systems) triggered by FXII autoactivation in reaction to mis- folded or amorphous protein aggregates Figure 1 can proceed independently of the intrinsic Mechanisms for FXII activation. There are two pathways for FXII (Hageman factor) activation: coagulation pathway (Figure 1). autoactivation upon exposure to negatively charged surfaces and proteolytic activation on cell Do the results of the Maas et al. (10) membranes. FXII autoactivates (K = 2.4 M) on an artificial or biologic surface such as kaolin m μ study reveal a major new pathway for FXII or a to activate FXII to α-FXIIa. α-FXIIa then activates FXI to FXIa to initiate hemo- stasis and activates PK to form plasma kallikrein (KAL). KAL cleaves HK to liberate bradykinin, autoactivation and provide insight regard- which induces vasodilatation and vascular permeability. KAL also activates the complement ing a physiologic activity for FXII? What is system by directly activating complement components C3 and C5 and cleaving α-FXIIa to form intriguing about the current investigation β-FXIIa (a soluble light chain enzymatic form [Hageman factor fragment]), which then activates is that it demonstrates constitutive FXII the macromolecular C1qr,s complex to enzymatically active C1r and C1s. The results of the contact activation in the disease state of study by Maas et al. in this issue of the JCI (10) suggest that a second FXII autoactivation systemic amyloidosis. The data also sug- mechanism occurs upon exposure of FXII to aggregates of misfolded proteins and that this gest that FXII autoactivation in reaction to activation results in PK activation without FXI activation — showing that the kallikrein-kinin misfolded protein initiates an inflamma- system can be activated separately from the coagulation cascade by FXII. A second pathway for FXII activation occurs on endothelial cells. PK bound to HK on endothelial cells is activated tory response in reaction to these abnor- to plasma KAL by the prolylcarboxypeptidase (PRCP) (Km = 9 nM). KAL then mal protein deposits. Activation of the activates FXII to α-FXIIa (Km = 11 μM). FXII also binds to endothelial cells in the presence of so-called contact system proteins has been zinc ions and when bound stimulates ERK1/2 phosphorylation. CK1, cytokeratin 1; gC1qR, recognized in other pathologic states, such gC1q receptor; uPAR, receptor. as acute attacks of hereditary , sepsis, diabetic retinopathy, induced arte- rial , and acute myocardial ports FXII autoactivation that the study by coagulation cascade has left researchers infarction. However, the authors suggest Maas et al. in this issue of the JCI should be puzzling as to the physiological role of FXII that in systemic amyloidosis, there is PK viewed (10). Although many biologic sub- and how it is activated in vivo. The present activation without FXI activation (10). stances allow for FXII autoactivation, their report by Maas et al. (10) provides insight This contact activation–mediated disease exposure to this zymogen usually does not into a novel activity for FXII, i.e., its abil- phenotype also has been recognized in occur constitutively in the intravascular ity to initiate an inflammatory response acute attacks of , compartment in non-disease states. An in the presence of aggregates of abnormal, where PK activation and bradykinin for- alternative hypothesis, which bypasses any misfolded proteins in vivo. mation occur without FXI activation. role for FXII in physiologic blood coagula- There are some methodological ques- tion, was proposed by Gailani and Broze, Factor XII autoactivation initiated tions pertaining to the current study that who showed that, in vitro, in the presence by misfolded or aggregated proteins should be raised (10). Since the second- of dextran sulfate and HK, thrombin acti- In the study in this issue by Maas et al. order rate constants of plasma kallikrein vates FXI (11). Although questions have (10), the authors show that FXII auto- and FXIa inhibition by C1 inhibitor are arisen as to whether thrombin activation of activation occurs in vitro in reaction to similar, but the plasma concentration FXI can actually occur in plasma due to its misfolded or amorphous protein aggre- of PK is 18-fold higher than that of FXI, high concentration (thrombin gates of transthyretin (a homotetrameric many more subjects would have had to be proteolyzes fibrinogen and FXI with the protein in plasma and CSF), Bence-Jones studied in the FXI group to conclusively same affinity, but fibrinogen is 2 orders protein (a monoclonal globulin protein show that FXI was not activated signifi- of magnitude more abundant than FXI in found in blood or urine), glycated albu- cantly in systemic amyloidosis. Further, plasma), the hemostasis community has min, glycated hemoglobin, or the angio- the higher coefficient of variation of the adopted this latter mechanism to explain static drug endostatin (10). In individuals controls in the FXIa–C1 inhibitor assay the hemostatic activity of FXI but not FXII diagnosed with systemic amyloidosis, a also may have contributed to the lack of (12–14). This revised model of the blood condition characterized by the abnormal differences seen in these patient samples.

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 9 September 2008 3007 commentaries

The mechanism(s) by which PK, but not produces kinetically favorable PK activa- Acknowledgments FXI, activation occurs in response to FXII tion (Km = 9 nM) versus PK activation by The author wishes to acknowledge the dis- autoactivation in reaction to misfolded α-FXIIa on negatively charged surfaces coverer of Factor XII, Oscar D. Ratnoff, who proteins has not been elucidated in the (Km = 2.4 μM) (Figure 1) (19, 20). Formed died on May 20, 2008. This work is support- current report (10). In future studies, it plasma kallikrein then leads to favorable ed by grants HL052779-13, HL055709-05, would be helpful to determine whether FXII activation (Km = 11 μM). FXII activa- and HL070766 from the National Heart, misfolded protein–triggered autoactiva- tion by plasma kallikrein on cells occurs Lung, and Blood Institute. tion of purified FXII results in reduced or at a faster rate than autoactivation (20). absent activation of purified FXI compared FXII is a multidomain protein with a sur- Address correspondence to: Alvin H. with PK. Do misfolded proteins only bind face cell-binding region that has an EGF- Schmaier, Case Western Reserve University, HK and PK and not FXI? Finally, why do like growth factor region and a catalytic Department of Medicine, Division of Hema- only aggregated proteins and not fibrillar domain. It is structurally similar to EGF, tology and Oncology, 10900 Euclid Avenue, proteins trigger FXII autoactivation? single chain urokinase, and tissue plas- WRB2-130, Cleveland, Ohio 44106-7284, FXII autoactivation in reaction to mis- minogen activator. In the intravascular USA. Phone: (216) 368-1172; Fax: (216) folded or amorphous protein aggregates compartment, FXII binds to endothelial 368-3014; E-mail: [email protected]. in vivo, although a nonphysiologic event, cell urokinase plasminogen activator 1. Ratnoff, O.D., and Colopy, J.E. 1955. A familial may in fact constitute a type of detection receptor, cytokeratin 1, and the comple- hemorrhagic trait associated with a deficiency of or defense response to these structurally ment receptor gC1qR (21) (Figure 1). a clot promoting fraction of plasma. J. Clin. Invest. abnormal proteins. This pathway may FXII binding to endothelial membranes 34:602–613. 2. Davie, E.W., and Ratnoff, O.D. 1964. Waterfall constitute a means to regulate comple- is highly regulated by the plasma concen- sequence for intrinsic blood coagulation. Science. ment and inflammatory systems that tration of HK and Zn2+ (21). FXII, when 145:1310–1320. involve coagulation , thrombo- bound to cells, stimulates ERK1/2 phos- 3. Macfarlane, R.G. 1964. An enzyme cascade in the 3 blood clotting mechanism, and its function as a modulin, and thrombin itself. Other bio- phorylation and [ H]thymidine uptake biochemical amplifier. Nature. 202:498–499. logic substances that have been reported (22) (Figure 1). 4. Rocha, E. Silva, M., Beraldo, W.T., and Rosenfeld, to support FXII autoactivation and arise Epidemiological studies in humans show G. 1949. Bradykinin, a hypotensive and smooth in disease states include RNA and sulfa- that a polymorphism in FXII associated muscle stimulating factor released from plasma globulin by snake and by . Am. J. tides released after cell disruption and with lowered plasma FXII levels correlates Physiol. 156:261–273. polysomes present on a develop- with increased risk for myocardial infrac- 5. Ghebrehiwet, B., Silverberg, M., and Kaplan, A.P. ing thrombus (15, 16). Unlike the present tion (23). These human clinical data do not 1981. Activation of the classic pathway of comple- ment by Hageman factor fragment. J. Exp. Med. report (10), the previous two studies sug- correlate with the findings in FXII-defi- 153:665–676. gested that FXII autoactivation in reac- cient mice, which have shown reduced arte- 6. DiScipio, R.G. 1982. The activation of the alterna- tion to a developing thrombus leads to rial thrombosis risk in several provocative tive pathway C3 convertase by human plasma kal- likrein. Immunology. 45:587–595. FXI activation and thrombin formation mouse models (24). It has been proposed 7. Samuel, M., Pixley, R.A., Villanueva, M.A., and (15, 16). The Maas et al. report suggests that the plasma kallikrein-kinin system Colman, R.W. 1992. Human factor XII (Hage- that certain biologic surfaces that trigger influences thrombosis risk independent of man factor) autoactivation by dextran sulfate: circular dichroism, fluorescence, and ultraviolet FXII autoactivation may lead to differen- hemostasis. Results from studies of both difference spectroscopic studies. J. Biol. Chem. tial FXI or PK activation (10). Pathological the kininogen- and bradykinin B2 recep- 267:19691–19697. contact activation in vivo is mostly asso- tor–knockout mice, in which the develop- 8. Chen, X., et al. 2006. Ordered adsorption of coagu- ciated with artificial substances interact- ment of arterial thrombosis is delayed, sup- lation factor XII on negatively charged polymer surfaces probed by sum frequency generation ing with the intravascular compartment. port that assessment (25, 26). vibrational spectroscopy. Anal. Bioanal. Chem. An extreme instance of this was reported In conclusion, the results of the pres- 388:65–72. recently: the infusion of unfractionated ent report by Maas et al. (10) indicate the 9. Schmaier, A.H. 1994. Contact activation. In Thrombo- sis and hemorrhage. J. Loscalzo and A.I. Schafer, editors. heparin adulterated with oversulfated existence of a pathway of FXII autoacti- Blackwell Publishing. Boston, Massachusetts, chondroitin sulfate caused constitutional vation upon its exposure to misfolded or USA. 87–105. symptoms of nausea, dyspnea, and vomit- aggregated proteins in the intravascular 10. Maas, C., et al. 2008. Misfolded proteins activate Factor XII in humans, leading to kallikrein forma- ing and 81 deaths from hypotension (17, compartment or in tissues and that this tion without initiating coagulation. J. Clin. Invest. 18). Oversulfated chondroitin sulfate, pathway stimulates inflammatory sys- 118:3208–3218. which in some heparin preparations was tems without hemostasis activation. This 11. Gailani, D., and Broze, G.J. 1991. Factor XI activa- tion in a revised model of blood coagulation. Science. as high as 30% wt/wt, was associated with pathway is not unlike that activated in 253:909–912. FXII autoactivation, plasma kallikrein acute attacks of hereditary angioedema, in 12. Scott, C.F., and Colman, R.W. 1992. Fibrinogen formation, bradykinin liberation, and which the absence of C1 inhibitor leads to blocks the autoactivation and thrombin-mediated activation of factor XI on dextran sulfate. Proc. Natl. C3a and C5a formation, without evidence increased contact system activation with- Acad. Sci. U. S. A. 89:11189–11193. of FXI activation (18). out hemostasis initiation. Alternatively, on 13. Brunnee, T., et al. 1993. Activation of factor XI in a developing thrombus, FXII contributes plasma is dependent on factor XII. Blood. 81:580–586. Physiologic activation and to the size and strength of the occlusion. 14. Pedicord, D.L., Seiffert, D., and Blat, Y. 2007. Feed- back activation of factor XI by thrombin does activities of FXII and PK Additional studies are needed to better not occur in plasma. Proc. Natl. Acad. Sci. U. S. A. An alternative to the contact activation understand how there can be unique mech- 104:12855–12860. hypothesis for FXII activation has been anisms of FXII autoactivation resulting in 15. Kannemeier, C., et al. 2007. Extracellular RNA constitutes a natural procoagulant in proposed. On cultured endothelial cells, the formation of α-FXIIa that differentially blood coagulation. Proc. Natl. Acad. Sci. U. S. A. the serine protease prolylcarboxypeptidase activates its various substrates. 104:6388–6393.

3008 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 9 September 2008 commentaries

16. Smith, S.A., et al. 2006. Polyphosphate modulates and Schmaier, A.H. 1998. Factor XII does not ini- 46C>T polymorphism with risk of coronary heart blood coagulation and . Proc. Natl. Acad. tiate prekallikrein activation on endothelial cells. disease in the WOSCOPS study. Atherosclerosis. Sci. U. S. A. 103:903–908. Thromb. Haemost. 80:74–81. 165:153–158. 17. Guerrini, M., et al. 2008. Oversulfated chondroitin 21. Mahdi, F., Shariat-Madar, Z., Figueroa, C.D., and 24. Renne, T., et al. 2005. Defective thrombus forma- sulfate is a contaminant in heparin associated with Schmaier, A.H. 2002. Factor XII interacts with the tion in mice lacking coagulation factor XII. J. Exp. adverse clinical events. Nat. Biotechnol. 26:669–675. multiprotein assembly of urokinase plasminogen Med. 202:271–281. 18. Kishimoto, T.K., et al. 2008. Contaminated hepa- activator, gC1qR, and cytokeratin 1 on endothelial 25. Merkulov, S., et al. 2008. Deletion of murine rin associated with adverse clinical events and cell membranes. Blood. 99:3585–3596. kininogen 1 (mKng1) causes loss of plas- activation of the contact system. N. Engl. J. Med. 22. Gordon, E.M., et al. 1996. Factor XII-induced ma kininogen and delays thrombosis. Blood. 358:2457–2467. mitogenesis is mediated via a distinct signal 111:1274–1281. 19. Shariat-Madar, Z., Mahdi, F., and Schmaier, A.H. transduction pathway that activates a mitogen- 26. Shariat-Madar, Z., et al. 2006. Bradykinin B2 recep- 2004. Recombinant prolylcarboxpeptidase acti- activated protein kinase. Proc. Natl. Acad. Sci. U. S. A. tor knockout mice are protected from thrombosis vates plasma prekallikrein. Blood. 103:4554–4561. 93:2174–2179. by increased nitric oxide and prostacyclin. Blood. 20. Rojkjaer, R., Hasan, A.A.K., Motta, G., Schousboe, I., 23. Zito, F., et al. 2002. Association of the factor XII 108:192–199. Platelet adhesion: a game of catch and release Robert K. Andrews1 and Michael C. Berndt2

1Department of Immunology, Alfred Medical Research & Education Precinct (AMREP), Monash University, Melbourne, Victoria, Australia. 2College of Medicine and Health, University College Cork, Cork, Republic of Ireland.

The interaction of circulating with the vessel wall involves a process To date, little is understood about the of cell catch and release, regulating cell rolling, skipping, or firm adhesion mechanical properties of individual GPIbα/ and leading to thrombus formation in flowing blood. In this regard, the vWF molecular bonds, or how congeni- interaction of platelet glycoprotein Ibα (GPIbα) with its adhesive ligand, tal point mutations affecting GPIbα-vWF vWF, is activated by shear force and critical for platelet adhesion to the vessel binding affinity determine the physical wall. In this issue of the JCI, Yago and colleagues show how gain-of-function interaction. In their study in this issue of the mutations in the GPIbα-binding vWF A1 domain disrupt intramolecular JCI, Yago et al. use atomic force microscopy interactions within WT vWF A1 that regulate binding to GPIbα and flow- (AFM) and molecular dynamics simulations enhanced platelet rolling and adhesion (see the related article beginning on to show how orientation of the GPIb-bind- page 3195). Together, these studies reveal molecular mechanisms regulating ing A1 domain of vWF with GPIbα, involv- GPIbα-vWF bond formation and platelet adhesion under shear stress. ing alignment of specific resi- dues, may regulate catch/slip bonding and One of nature’s mightiest forces is reptil- ated cell adhesion, in particular cell attach- release of GPIbα as shear force increases (8). ian in origin. The gecko’s foothold has a ment under hydrodynamic shear flow in force of approximately 10 N/cm2, allowing the bloodstream (2–8). In the case of blood vWF the gecko to more than support its own platelets, this involves the reversible inter- vWF is a multifunctional adhesive glycopro- weight under the force of gravity (1). The action between platelet glycoprotein Ibα tein stored in platelet α-granules and Wei- biomechanics of this superb adaptation (GPIbα; the major ligand-binding subunit bel-Palade bodies of endothelial cells. In its for reversible weight-bearing attachment of the GPIb–IX-V complex) and vWF asso- mature form, it consists of disulfide-linked, to smooth surfaces involves hair-like struc- ciated with an injured or diseased vessel approximately 275-kDa subunits forming tures (seta) on the footpad that end in mul- wall. Fluid shear rates in flowing blood multimers of at least 20,000 kDa (Figure tiple spatula-shaped projections capable may be minimal at the center of the ves- 1). Each subunit is composed of conserved of bearing approximately 20 μN per seta. sel, but become increasingly pronounced domains: D′-D3-A1-A2-A3-D4-B1-B2-B3- Altering the 3D orientation of the seta with approaching the vessel wall as a result of C1-C2 (12). The A1 domain encompass- the surface (related to uncurling and peel- drag (9). Shear stress on an adherent cell ing the disulfide bond at C1272–C1458 ing movements of the toe) can increase or (force per unit area) depends on cell size, (C509–C695 in the mature sequence) con- decrease detachment forces (1). fluid viscosity, and proximity to the wall. tains the for GPIbα, heparin, No less remarkable in the mammalian At the cellular level, this has profound and other binding partners. The vWF A3 world are structural adaptations at the effects on initial contact, translocation, domain binds collagen, while C1 contains molecular level controlling receptor-medi- and firm adhesion of platelets under shear an Arg-Gly-Asp (RGD) sequence that binds conditions. As shear rates increase from the platelet integrin αIIbβ3. The GPIb-bind- low physiological rates (less than 600 s–1) ing site on vWF A1 is cryptic under static Nonstandard abbreviations used: ADAMTS- 13, a disintegrin and metalloproteinase with a to high physiological rates (up to about conditions, but becomes competent to bind thrombospondin type 1 motif–13; AFM, atomic force 1,500 s–1) to pathological rates (up to about receptor when matrix associated, exposed microscopy; GP, glycoprotein; vWD, von Willebrand 10,000 s–1, such as in a stenotic artery), con- to shear force, or activated by nonphysi- disease. tact adhesion of platelets is increasingly ological modulators such as the bacterial Conflict of interest: The authors have declared that no conflict of interest exists. dependent on GPIbα/vWF, and elongated glycopeptide ristocetin or the snake toxin Citation for this article: J. Clin. Invest. 118:3009–3011 tether-like structures may form parallel to botrocetin (12, 13). Ultralarge vWF multim- (2008). doi:10.1172/JCI36883. the direction of flow (10, 11). ers expressed on activated endothelial cells

The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 9 September 2008 3009