Histidine-rich glycoprotein inhibits contact activation of blood coagulation

THROMBOSIS RESEARCH 60; 385396,199O 0049-3848/90 $3.00 + .OO Printed in the USA. Copyright (c) 1990 Pergamon Press pk. All rights reserved.

i%tridB.V-,

1,-F.-,

staffan~+and!DaKbenHalki~* Departmentof MolecularBiology and Plant Physiology Universityof Aa?hus, DK-8000Aarhus C, Denmark

(Received

30.8.1990;

accepted

in revised form 24.9.1990

by Editor H. Prydz)

Histidine-richglycoproteinhas been purified from bovine plasma employihg two different purificationprocedures.The firstprocedure was one-step ion-exchangechrmatography using phosphocellue involved fractionation using lose, while the secord procedur polyethyleneglycol6000 follmed by calm chromatcgraphyemploy!the effect of purified ing a+Sepharose and heparin-w. bovine histidine-richglycoproteinon the contact activation of blood coagulationwas studied in hman plasma by using as activating surface either an ellagicacid-phospholipid suspension (C!ephotest) or sulfatide.Contactactivationwas nmitored by the generation of amidolytic activity tmamls a synthetic chromogenicsubstrate (S-2302) for factor XIIa and plasma kallikrein. Bovine histidine-richglycoproteininhibitsthe contact activationinduced bybothoftheseactivatingsurfaces.

In 1972 histidine-richglycoproteinwas purified for the first time, from human plasma, and characterizedas a histidine-rich3.8S-e2~lycoprotein without Imown function (1,2). Since then, histidine-richglycoproteinhas been purified by other means; it has been characterizedboth as a plasma protein with affinity for the lysine-bindingsite of let-ingle 1 in plamincqen (3) and also as ~lautorosette inhibition faclm? (4). Histidine-rich glycoproteinbinds to heparin (1) and neutralizesits anticoagulanteffects (5-10).In addition,histidine-richglycoproteinbirds heme (11) and certain Key words: Histidine-richglycoprotein,intrinsiccoagulation,inhibition

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divalent

cations (Zn2+ among others) (12). The amino-acid sequeme of human histidine-richglywprotein has been deduced frcm the cDNA sequence (13). The polypeptidechain consists of 507 amino-acidresiduesandcontains~i~sharinghcplrologywithotherplasM proteins.Inthis context,itismstintere&ingtonotethatthehistidinerichregionishcmolcgoustothehistidine-richregion inhigh-molecular-mss kininogen (HK). Contact activationof the blood coagulationsystem and activationof the plasm kalli)arein-kinin system both result frcanthe same cmplex series of proteolytic reactions involving factor XII, plasm prekallikrein,HK and an activating surface (14). The exact initiation me&a&m is still to be elucidated,but the interactionof factor XII, plasma prelmllikreinand HK with an activating surface leads to the formationof factorXIIa and plasma kalli.Weinthroughlimikdmkualproteolysis. Inthisreaction,HKactsasa non-enzymatic cofactor (15). Upon activation, factor XII, proteolytically activates factor XT to factor XI, in another HK-dependentstep (16), thus leadingtoapropagationof intrinsiccoagulation.whenplasmakallikreinhas been formed, it can cleave HK, thereby releasing the vasoactivenonapeptide bradykinin. Different kinds of surfaces have been used for contact activation & vitro and among these are kaolin (17), ellagic acid (18), dextran sulfate (19), sulfatide (20),ard phosphatidyl-serine(21),but the surfacesparticipating in contact activation in vivo are still poorly characterized.Factor XII binds directly to negativelycharyed surfaces (22),while plasma prelmllikreinbir&tonegatively&ary~surfacesviaHK, withwhich it ciraAates in plasma in a 1:l stoi&im&ric ccwplex (16). The binding of bovine HK to kaolinismediatedbytheaforemnt' loned histidine-richregion (23). Fkgulation of contact activationthrough formationof cmplexes between the active serine proteinases anl_uleir correspomling serine proteinase inhibitorsiswell established,and Cl-inhibitorseems to be themstimportant inhibitorof factor XII, (24) and plasma kallikrein (25),while factor XIa is mainly tier the control of al-proteinaseinhibitor (26) and to a lesser extent antithrcmbin III (27). l?ecmtly, a different mechanism for contact activation inhibition was described (28), presumably involving cmpetitive neutralisationby l32-glycqmtein I of the negativecharges on the actiMtingsurface;B2_glycaproteinIisaplasmaKoteinwithnoother~lldoammked biological function. We have shown previously that the free bchain released from plasma factor XIII on activationwith thrombin inhibits contact activation of blood coagulation in the same way (29). The hcanology between the histidine-richregions in histidine-richglycmproteinand HK (13) suggests thathistidine-rich glycoproteincould have a similar effect on the contact activation.

.

Ma.kmAs.

C@otest

(batch 180) was obtained frcanNycomed (Oslo, Norway), H-D-Pro-Phe-Zq-p-nitroanilide(S-2302) was frcm Kabi Diagnostica (Stockholm,Sweden). F?ms#locellulc5e(Pll) was frml wasakkigift frcmDr. T. E. Whatman (Maidstone,UK), ardheparin-Sephame frcxnPhamacia (UppPetersen (thislaboratory).cM-sepharosewas~ FRG), F?BF was frcm Aldrich sala, Sweden). ME was frm Merck (Dam&x&, (Steinheim,FRG), ardbenzamidine,bovineserma~tibovinebrain sulfatides were frcm Sigma (St. Umis, m, USA). e was frcnn Boehrixqer (Mannheim,FRG), human plasminogen was a kind gift frcunDr. L. andthechrcanogeniC

substrate

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sottrup-J~(thislaboratory),andPrI(bovine pancreatictrypsin inhibitor) was a kind gift frcanDr. L. lhim (NOVC-N~sk, Hagsmrd, Denmark). Column material for mversed pbaseHPLCwasSpherisorb5sODS2(PhaseSeparatiohs, Deeside,UK). ReagentsamI solventsfor sequencingwerefromPathbum (Walkerbmn, Peebleshire, Scotlar~I)except Quadrolwhich was frcm Pierce (Rockford,IL, USA). All other chemicalskere of analytical grade. Nomal humanplasMwasfnanoneofus(TH)andpreparedfram50mlblooddrawninto 0.8 ml 0.25 M d&odium-~+ihydrate, pJi7.5. Fresh bovine blood was collectsd at the local slaughter-housein 10 litre polyethylenecontainersusing 1.25 liter 97 nMtrisodiumcitrate containing8 aMbenmmidine asanticoagula&. . . Eavine plasma histidineFmificatialofbistmm+bgl~ rich glycoproteinwas purified by two different methods. All purification stepsinbothmthodswerecamiedoutat4 T. Thefirstmethodwastheprocedur e of Hylatt et al. (4) except that all Imffers used during the purificationcontained 1 nM benmmidine amI 0.11&I PMSFandthatMXwasomittedfrrmthesamelmffers. !lhesecond method cxmbinedpurificationsteps taken from other published procedures (1,30,31).To 3.5 litres of fresh bovine plasm me added PMSF and PIT to final concentrationsof 1nMandlO ng/lrespectively, and these concentrationswere maintained in all buffers used durm the purification. pTI was included as it has been shown that histidine-rich+ycoprotein is addition of very sensitive to plasmin-catalyseddegradation (32,33).After 50% PEG 6000 to a final concentrationof 11% and stirring for 1 h, the precipitatewas remvedbycentrifugation. The supernatantwasdilutedwith2 volumes of cold Millipore-filtered water, and the pH was adjustedto 6 with 1 MCH3a30Hbefore addition of llitre of CM-Sphamse. Following.stirri~~~ for 1 h, the CM-Sepharosewas collectedand washed with 4 litres of cold Millipore-filteredwater on a sintered glass filter before being packed in a mlmn. The column was washed with Millipore-filtered water until the effluent reached baseline level and was then eluted with a gradient of NH4HOB3 (0 --> 0.167 M, 1 1 + 1 1). Fractions containinghistidine-richglycoprotein,as assessed by SDS-PAGE, were pooled, come&rated in an Amicon cell using a FMlO filter, and dialysed against 20 nM NaP, 0.4 M NaCl, pH 6.3 before affinity chrmatography on heparin-Sepharosein the same buffer. The column was washed with 20 nM Nap, 0.4 M NaCl, pH 6.3 until the effluent reached baseline. level and then eluted with 20 nM Nap, 1 M NaCl, pH 6.3. mxIx!scrl~inhibiticnof ocntact activaticm.Contact activation of blood coagulationwas achievedby using either Cephotestor sulfatide. Accordingtothemam.facturers axmnexcially available Cephotest is a suspension of animal-braincephalins containing 15 p ellagic acid (1 ml Cephotest stock SolUtiOn contains cephalihs fromlmg dried brain). A fourfold dilution of the stock solutionof Cephotestwith 50 nM Tris-HCl, 100 I@¶ NaCl, pH 7.5 was used as contact activator. In a total volume of 600 ~1 various ~~ofCephotestwerepre_incubatedwithvarious amuntsofbovine histidine-richglycoproteinfor 5 min at 37 T. After addition of 100 pl five-folddiluted EDT&plasma, contact activationtook place for 2 min at 37 T. Tlheamidolyticactivity was assayed by adding 75 ~1 4 nM S-2302 to the activationmixture. After 1 min the reactionwas stopped by adding 50 ~1 50% aceticacid. Twenty-fiverq of bovine brain sulfatidewere dissolved in 15.5 ml a-1~1~: CH3CH (l:l,v/v), disfribtted in 500 ~1 aliqouts and frozen at -20 OC. After evaporationof the organic solvent,the sulfatidesuspensi~~preparedby adding 200 1.r1 50 r@lTris-HCl,100 @+INaCl, pH 7.5 at 60 OC to an aliquot,and vortexingfor 5 lni.n follcwedby sonicationfor 5 min. The resultingsuspension (4 q/ml, 5 ItM)was used directly as stock solution.When sulfatidewas used

388

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as

contact activator 200 ~1 25 pM sulfatidewas pre-incubatedwith various amunts of bovine histidim-rich glyccproteinfor 30 min on ice in a total Contact activationwas initiatedby adding 200 ~1 undiluted volm of 400 /.41. plasma,andtheinczlbationwascontirnred~ice.Every30secuptoatotal activationtimeof atleastlomin, 20~laligmtswereassayedforamidolytic activity by addirq them to 200 ~1 0.4 I&¶ S-2302 in 50 mM Tris-HCl, 100 rrM NaCl, pH 7.5 at 37 OC. After 45 set the reactionwas stopped by adding 50 ~1 50% acetic acid. S-2302 is a substrate for both factor XII, ard plasm kallikrein (34) and the releaseofpnitroanili.newas shmntobelinearundesthegiven conditions.F&agent blank was deby adding acetic acid to the mixhxe before addition of plasma. The absorptionof p-nitroanilinewas masmed at 405 nm and the amidolytic activity was calculated as j.nmlp-nitroaniline released per second of incubationper litre of undilutedplasma in one litre assaymixtureperminuteofactivation,usir~~ e=9800~~~1forp-nitroaniline (35). Ihe amidolytic activity is expressed as @ZatlD1minW1 unless othms&esta~. l@Zat= ljnmlp-nitroanilinepersec.Allresultsshown havebeendetemined at least induplicate. . . m seprenz analysis. The amino-terminalsequexe of purified histidine-richglycoproteinwas detemined using a ESzkman89OCseqmcerand the PIH-aminoacids were identifiedby reversedphaseHPJ=

A Ala-Val-Z+sn-Pr&Ihr-

Bovine

HRG:

Buman

BEG:

Bovine

HE:

Gly-Xaa-Asp-Ala-Val-

Hlm-arl

BRG:

Asp-Cys-Ser-Ala-Val-

Bovine

BEG:

Glu-Pm-Val-Ala-Val-

HmEln

HRG:

Glu-ProSlu-AlaSlu-

Val-Sex-Mc

6OkDa 43kDa

26kDa IL kDa

~~~lA:Amirmterminalsequenoeofbovineandhumanhistidinerich Panel B: SDS-PAGE (lo%-20% gradient gel) (36) of purified bovine his&me-rich glycqrotein (1.7 w/lane) in the p=s==e~~ of ME. Lane 1: Histidine-richglycopmtein in the abeence of m; lane 2: Histidine-richglycopmte ininthe pmsence of MZ; lane 3: Molecularweight &ar&rdswiththeirweighti.&i~ted i.nkDa.

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Purificationof bovine histidine-richglympmtein was carried out by two both yieldinghighlypurifiedhistidine-richglycaprotein asjudgedbyamino-terminalamino-acid sequencing,revealingasingleseqence. This sequencedetermination(Fig. 1, panel A) revealedthat bovine histidine-rich glycoprotein contains an additional N-terminal alanine residue ccq+red with human histidine-richglyqmkein . It is possible that this alanine residue correspor& to the alanine residue fcund as thelastaminoacid residue in the signal peptide frm human histidine-richglymprotein (13). Tkyptic peptides coveringmrethan one-thirdof bovinehistidine-rich gly~r~inhavebeensequenced,andeverypeptidesequenced canbefoundto match a hmologous &ret& in humnhistidine-rich glycqrotein, confirming theidentityofthemolearle (resultsnot shorn))). In non-reducing as well as reducing SDS-PAGE bovine histidine-rich glycoproteinmigrates as a closely-spaceddoublet (Fig. 1, panel B). I-hm-an histidine-richglycoproteinprepared frcxnone of us (TH) migrates slightly fasterthanbovimhistidine-ri&glycoproteinbySDS-PAGE, ardhas anaminoterminalamino-acidsequenceidenticalto that previouslydetemined (31). The first purification procedure us& was the one-step ion-exchange chromata$qhy using phosphocellulose describedby Rylatt et al. (4).Hmever, in our hands this method results inverydifferentoverallyields of purified

different methods,

-2 ._ E x

8 16

16

‘2m 14 Y t 12 >

.E >

.a t;

1

16

14

_-14

12

-. 12

10

10

'. 10

8

8

--8

6

6

--6

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4

-'4

m .o 0g P 2

2

--2

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100 200 300400 500600 Cephotest

(PI/assay)

10 20 30 40 50 60 70 80 HRG

(pglassay)

Figure2. Panel A: Contact activationof humanplasmawith incr~ing amunts of Cephotestpre-incubat& for 5 min inthe aksence (m) and in the presence of 32.5 ~19 add& bovine histidine-rid?glymprotein per assay (0). The amidolytic activities were corrected for reagent blank. Panel B: Contact activationof human plasma with a constantamxntof cephatest (500 pl) prei_nmbaM for 5 min in the presence of increasingalmuntsofaddedbovi.ne histidine-richglycqmtein. The amidolytic activities mre correct& for reagent blank.

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histidine-richglycoprotein,depeMingonthebatchof@os@mcellulose,in spite of identical treatment of the pho@mcellulose in the critical precycling step. The yields varied bekween 5 q and 145 mg frcan1 litre of plasma. In additiontothis, thephosphocellulosecanonly beusedtwiceand theprocedurerequireslaryeamunts of bovine serum albumin in the precyclingstep.Inordertocircurmrenttheseproblenrs,~haveccpnbinedsteps taken frcanotber pxification pmcedmes (1,30,31)and obtained a reliable purification pmc&ure which in 4 days results in purified histidine-rich glycoproteininan overall yield of z 25% assming anaverageplasmaconcentration of 100 &/ml. The inhibitingeffect on the contact activationof blood coagulationby bovinehistidine-richglyccproteinwas investigatedinnormalhmanplasma using either Cephotest or sulfatide as activating surface. The reason for using a heterologous system is thatbovineplasmaisless susceptibleto contact activationthan human plasma (29). ?Lhecapacity of Cephotestto activate the contact system depends onthe amount of Cephotestand the addition of histidine-richglycoprotein (Fig. 2, panelA).Ascanbeseen,thepresence of addfzdhistidine-richglycoprotein inhibits Gem iMuc!ed contact activation.Thedose-response curve (Fig. 2,panelB) indicatesthatthepresmce of less than 0.4 ~(9histidine-rich glycoproteinin the activationmixture inhibits the action of Cephotest in humanplasma. In Fig. 3, panel A shows hm the amidolyticactivity inducedby Cephotest develops as a function of contact activation time with and without added bovine histidine-richglycopmtein. It can be seeen clearly that the rateof

3

6

. 5

30

5

12

t

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Q

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.g

20

-g

15 ._ i

6

.g

10

-2

4

8

5

2 8 ._

2

E

L .=

E

E

-----------__

t 8 t

I---0

I

1 Activation

time

(min)

2

Preincubation

3

4 time

5 (mid

Figure 3. Panel A: Rate of ax&act activationof humanplasma activatedwith aphotest (300 pl) pre-inalbatedfor 5 min in the absence (m) and in the presence of 32.5 jq added bovine histidine-richglycqrotein per assay (0). Panel B: Contact activationof human plasma activatedwith @hotest (300 ~1) of 32,5 /q added bovine pre-ina&kedforbetwefzn0and5mininthepresence histidine-richglyccproteinperassay. Thebrokenline iMic&esthelevelof . amidolyticactivity inthe ab6enceofbovinehistidine-richglympmtem . The amidolyticactivitieswere correctedfor reagent blank.

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contact activation was lower in the presence of 32.5 ~(9 histidine-rich glycoproteinper assaY* Al~apre-incubationtimeof5minwasusedinthe~imentson the inhibitionby bovine histidine-richglycoproteinof the contactactivation i&uced by CqMtest, a significant inhibitory effect was also oberved withoutpre-inabtiontime andwithpre-incubation timesshorterthan5min (Fig. 3, panel B). It should be mentioned that histidine-richglycoprotein purified ineitherofthewaysdescriked inhibitsthecontactactivation. When sulfatidewas used as activatiq surface, amore ccanplexpattem of inhibitionwas not&L Fig. 4 shows how the amidolyticactivity induced by sulfatidedevelops as a functionof contact activationtime with and without added bovine histidine-richglycoprotein (Fig. 4, panel A). It can be seen that intact bovine histidine-richglycopmtein hardly affects the contact activation rate whereas plasmin-degradedbovine h&t&line-rich glycoprotein does. None the less, intact lmvine his&line-rich glycoprotein seems to inhibit the total anmunt of amidolyticactivity generatedwhen sulfatide is usedas activatingsurface.InFig.4,panelBshowshowincreasingarmxntsof plasmin-degradedbovine histidine-rich glycoprotein affects the rate of sulfatide-induced contact activation.

B

A

50 40 30 20 10 2

4

6

8

2

10

Activation

time

4

6

8

10

(mid

F'iv 4. Rate of contact activationof human plasma activatedwith sulfatide pre-incubatedfor 30 min with or withouta&led bovine his&line-rich glyccprol&n. The concentrationof sulfatide in the activationmixture was 8.3 @4. Panel A: Activationof human plasma with sulfatidein the absence (.)I ard in the presence (0) of 240 1(9added intactbovinehi+idine-rich glycoproteinper assay, and inthe pmsenceof 24Oj.~gaddedpl~bovinehistidinerich glycoproteinper assay (m). Panel B: Rate of contact activation of human plasma activatedwith sulfatidepre-incubatedfor 30 min with or without addedplasmin-deqxkd bovine histidine-richglycopmtein. The amcentration of sulfatide in the activation mixtme was 8.3 j&L The amcuntsofadded plasmin-deq&edbovinehistidine-richgl ycopmtein per assay were 0 (m), 290 w (.)I 435 1-14 (O), 580 & (o), and 870 ~(9(A).

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lke dose-responsecurve (Fig. 5) shows that the presence of less than 145 /Ag plamikkgmded histidine-rich glycoprotein in the activation mixture inhibitsthe sulfatide-induced contact activation.

300

600

900

HRG ()lg/activation

mixture)

Figure 5. Contact activation of humnplasmawithsulfatidepreincubatedfor30mininthepr~0f j_lneasing amounts of addedplasmindegraded bovine histidine-rich glycopmtein. The concentrationof sulfatidein the activationmixtures were 8.3 /.M.

Histidine-richglycoprotein is a multifunctionalplasma protein, to which severalfunctionshavebeenascribedonthebasisof~iments invitro. We here report the observation of a previously mmcognized property of histidine-richglycoprotein. Histidine-richglyccproteincontains a region hcmologous to the histidine-rich region in HK (13,37).This region in HK is known to be essential for the coagulationcofactoractivityof HK due to its kaolin-bindingprqxrties (23). For this reason, we investigatedwhetherhistidine-richglycopm tein could inhibit contact activationof blood coagulation. Theresultspresen&d (Fig. 2-5) indicate that bovine histidine-rich glycoproteinhas the abilityto inhibit contact activationof factorXI1 and plasma prekallikreininduced by Cephotestand sulfatide in humn plasma. It is possible that this inhibition results frcm binding of histidine-rich glycoproteinto the negative &ax-gee on the activating&ace. In order to substantiatethis proposal, we are currently studying the binding of histidine-rich glycoprotein to sulfatide and negatively charyed.phospholipd vesicles using 90° light-scattering (38). It is, however, mporkmt to emphasize that the rate of sulfatide-iMuced contact activationis unchanged by the preseme of intact bovine histidine-richglycoprotein,although the presence of plamin-degrad& histidine-richglycoproteinlouers it significantly. The reason for inkstigating the effect of plasmin-degradedhistidinerich glycoprotein on the sulfatide-inducedcontact activation was that

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hi&&dine-rich glycoproteinis very sensitive to plamnin-catalyzeddegradation (32,33). It &mild be added that in patients undergoing thrmbolytic therapy the levels in plasma of undegraded hi&&dine-rich glyccproteinare very law, although the levels of total histidine-richglycoprotein are unchangedasactivatihgsurface Aninterestingpointtonoteisthatwith@phote& the amount of histidine-richglycoproteihrequired to detect inhibitionof contact activationwas fcnmd to be less than 0.5 w, which&well belowthe amount of histidine-richglycoproteincontainedinthe plasma in the activation mixture. With sulfatide as activatirq surface, the lowest amcunt of plasmin-degradedhistidine-richglycoproteinwe have used to detect contact activation inhibition is approximately5 times higher than the amount of histidine-richglycoproteinin the plasm in the activationmixture;however, it is likely that smiler amountsof plasnin-degradedhistidine-richglycoprotein will be able to inhibitcontact activation. Assessment of the biologicalsignificanceof the obeerved inhibitionof contact~activationby histidine-richglycoproteinis not easy, because the surfaces involved in contact activation &) Y&o are not yet well characterized and because the precise physiolcgicalrole of the contact activation system is still uncertain.

interestofDr. Ingerschausboeinthisprojectisgreatfullya~ledged.'Ihis'kEOIJC~a~SuppOrtedfinanciallybygrantsto~frcwtheDanish Cancer Society and the NOVD Foundation.

Thekind

1.

HAUPT,H. & HEIMBUGER, N. ~roteine mithaher affinitatzu carboxymethylcellulose, I. Home-Sevler's Z. Phvsiol.Chem. 353, 11251132, 1972.

2.

B, N., HADFT, H., KRANZ, T. & HAULER, S. vroteine mithoher affinitat au carboxymethylcellulose, II. Home-Sevler's Z. Phvsiol. Chem. 353, 1133-1140,1972.

3.

LLsfJEN,H. R., HOYLAEU'S,M. & COLLEN, D. Isolationand characterization of a humn plasma protein with affinity for the lysine binding sites in plasminogen.J. Biol. Chem. 255, 10214-10222,1980.

4.

RYLUT, D. B., SIA, D. Y., MUNDY, J. P. & PARISH, C. R. Autorosette inhibition factor. Isolation and properties of the human plasma protein. Eur. J. Biochem.119, 641-646,1981.

5.

m, H. R., KXIAERE,M.&~LUN,D.Heparinbixlingproperties of human histidine-richglycoprotein.J. Biol. Chem. 258, 3803-3808, 1983.

6.

LL7NEN, H. R., HDYIAERTS,M. & UXLEN, D. Neutralizationof heparin

activitybybindingtoh~histidine-richglycoprotein. 29, 443-446, 1983.

lbromb. Res.

394

7.

8.

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LKJNIN, H. R., VAN HOEF, B. & CXI-, D. Histidine-richglyccprotein mdulates the anticoagulant activity of heparin in hman plw. mrcmb.Haemstas. 51, 266-268,1984. LANE,

D. A.,

PFSLEt,

G.,

FLYNN,

A.

M.,

m,

E. A.

& LTiMXHL,

U.

Neutralization of heparin-related saccharides by histidine-rich glycoprotein and platelet factor 4. J. Biol. Chem. 261, 3980-3986, 1986. 9.

m, C. B., m, W. T. 61 UCKBURN, M. N. Histidine-rich glyccpmtein modulation of the anticoagulantactivity of heparin. JBiol. Chem. 262, 7567-7574,1987.

10.

BURCH, M. K., =CKBURN, M. N. & MXGAN W. T. Further characterization of the interaction of histidine-rich glycoprotein with heparin: Evidence for thebinding of twomolecules of histidine-ri&glycoprotein by high molecular weight heparin and for the involvement of hktidine residues in heparin binding. Biochemistrv 26, 7477-7482, 1987.

11.

MXGAN, W. T. Human serumhistidine-richglycoprotein.I. Interaction With-, n&alionsardoqanic ligamk Biochim.Biorhvs.Acta 533, 319-333, 1978.

12.

&QRGAN, W. T. Interactionofthehistidine-richglycoprotein of serum With metals. Bicxzhemistrv 20, 1054-1061,1981.

13.

KOIDE, T., l?Xl?ER, D., Ym, S. & DAVIE, E. W. &n.inoacid sequence of human histidine-rich glycoprotein derived frcan the mcleotide sequenceof its cDNA. Biochemistrv25, 2220-2225,1986.

14.

KAPLAN, A. P. & SILmEw;, M. The coagulation-kininpathwayof human plasm. Blood 70, 1-15, 1987.

15.

GRIF'F'IN, J. H. & CXHRANE, C. G. Mechanisms for the involvementof high molecular weight kinimgen in surfareactions of Hagemax.factor.Prcc. Natl. Acad. Sci. USA 73, 2554-2558,1976.

16.

WIGGINS,

17.

MARGOIJS,

J. H. Role of R. C., BOUMA, B. N., UXHRANE, C. G. & (;RIFFIN, high-molecular-weightkininogenin surface binding and activaticmof coagulation factor XI and prekallikrein.Proc. Natl. Acad. Sci. USA 74, 4636-4640,1977. J. The kaolin clotting time. J. Clin. Pathol. 11, 406-409,

1958. 18.

RXIXOFF, 0. D. & CRUM, J. D. Activationof Hageman factor by solutions of ellagic acid. J. Lab. Clin. Med. 63, 359-377,1964.

19.

~,C.Determinationofprekalli)areininh~plasma:optimal conditionsfor activatingprekallikrein.J. I&. Clin. Med. 91, 83-95, 1978.

20.

-,

K., HElMARK,R. L., KURXHI, K. & DAVIE, E. W. Activationof kuvine factor XII (Hagernan factor) byplasmakallikrein. Biochemistxy 2, 1322-1330,1980.

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G. L. Possible basis for the M. A., FWIXAWA,K.&B, apparent surface selectivityof the contact activationof human blood coagulationfactors.Biochemistrv25, 6688-6694,1986.

21.

GRIEL?,

22.

C. G. The relationshipof stmdure and REVAK,S.D.&CXHRANE, functionin human Hageman factor.J. Clin. Invest. 57, 852-860, 1976.

23.

MARI, N., SUGO, T., FWII, S., KATD, H. & IWANAGA, S. The role of bovine high-mlexlar-weight (HMW) kininogen in contact-mediated activation of bovine factor XII: Interactionof HMW kininogen with kaolin and plasma prekallikrein.J. Biochem. (Tokvol 89, 1699-1709, 1981.

24.

PIXLEX, R. A., SCHAPIRA, M. & COLMAN, R. W. 'l&eregulationof human factor XII, by plasma proteinaseinhibitors.J. Biol. Chem. 260, 17231729, 1985. HARPEL, P. c., LlmIN,_M. F. & KAPIAN, A. P. Distrikutionof plasma kallikrein between Cl inactivator ard a2-macrcglolxilin in plasma utilizing a new assy for cr2-macroglokulin-kallikrein ccqdexes. JBiol. them. 260, 4257-4263,1985.

26.

SCSYIT,C. F., SCHAPIRA,M. A., JAMES, H. L., CDHIN, A. B. & COUQN, R. W. Inactivationof factor XI, by plasma prutease inhibitors.J. Clin. Invest. 69, 844-852,1982.

27.

H. C. Inhibition SOONS, H., JANSSEN-CLAESSm, T., TANS, G. & w, of factor XI, by antithrombinIII. Biochemistry26, 4624-4629,1987.

28.

SCHOUSBOE, I. J32-Glycqmtein I: Aplasm inhibitor of the contact activationof the intrinsicblood coagulationpathway. Blood 66, 10861091, 1985.

29.

HALKIEEt, T. & MAGNUSSON,S. Contactactivationof blood coagulationis

inhibited by plasma factor XIII b-chain. Tbrcanb.Res. 51, 313-324, 1988. 30.

LEUNG, L. L. K., NACHMAN, R. L. & HARP=, P. C. Ccanplexformationof platelet thm&xpo&in with histidine-richglycoprotein.J. Clin. Invest. 73, 5-12, 1984.

31.

KOIDE, T., ODANI, S. & ONO, T. Human histidine-richglycoprotein: Simultaneouspurificationwith antithrmbin III ard characterization of its gross structme. J. Biochem. fTokvo198, 1191-1200,1985.

32.

LIJNEN, H. R., RYLATT, D. B. 61 COLLUV, D. Physicmchemical,inmunochemical and functionalcomparisonof human histidine-richglycaprotein and aUtOmsette inhibitionfactOr. Biochim. Bitivs. Acta 742, 109-115,1983.

33.

-, A., NUIRY, I. & l+SXZAN,W. T. Proteolysisof histidine-rich glycoproteininplasMandinpatientsundeqoing thrmbolytictherapy. womb. Res. 40, 653-661,1985.

34.

SIL-ERG, M., DUNN, J. T., GARDE, L. & KAPLAN, A. P. Autcactivation Of human Hageman factor.J. Biol. C&m. 255, 7281-7286,1980.

396

lNHlBlTlON

Vol. 60, No. 5

OF CONTACT ACTIVATION

35.

FluE@Em,P.&mmgenicpeptide sub6tratee.aLeirueefortheassay Offa~inthefitninolyticand~plasMkalliluein-kininsystem. Scar& J. Clin. Lab. Invest. 42, Sqql. 162, 25-32, 1982.

36.

I&lLI, U. K. CleaMge of skru&wal~duringtheassemblyof the head of bacteriophage T4. Nature 227, 680-685, 1970.

37.

TMAGAKI, Y., IQDMJRA, N. & NAKANISHI, S. Clonilqardsequmce analysis of CD?& for hunan high molecular weight and law molecular weightpdcidmgens. J. Biol. Chem. 260, 8601-8609, 1985.

38.

~,G.L.&I;IM,T.K.QuilibriainvolvedinprothrcPnbin-ard blood-clottirq factor X-membmne binding. Bio&emistnr 1977.

16, 4164-4171,