Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!

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Best Practice & Research Clinical Obstetrics and Gynaecology

%o&rnal ho'e(age) ***+else"ier+co',locate,b(obgyn

Coag&lation in (regnancy
Patric. /hornton0 B1#c0 1BBCh0 2C3RC#40 Clinical Research 2ello*0 5oanne $o&glas0 1$0 2RCPC0 Clinical Pro6essor 7
$e(art'ent o6 3nesthesia0 8ni"ersity o6 British Col&'bia0 BC 9o'en:s ;os(ital0 <anco&"er0 BC0 Canada

=ey*ords) coag&lation hae'ostasis >brinolysis (latelets thro'bocyto(aenia coag&lation 6actors 6actor de>ciencies (regnancy he(arin thro'bo(hilia ne&ra>ial anaesthesia ne&ra>ial hae'ato'a

/he coag&lation syste' &ndergoes signi>cant change d&ring (regnancy+ /he clinician caring 6or the (art&rient '&st &nderstand these changes0 (artic&larly *hen the (art&rient has a (re?e>isting hae'atological condition+ Beca&se 'any hae'atological condi? tions are rare0 there o6ten is li'ited in6or'ation to g&ide the obstetric and anaesthetic 'anage'ent o6 these (art&rients+ @ 2009 Alse"ier Btd+ 3ll rights reser"ed+

/o li'it blood loss a6ter tra&'a it is essential to seal bleeding "essels *itho&t a66ecting blood >o* (er'anently+ ;ae'ostasis0 de>ned as the arrest o6 bleeding0 co'es 6ro' the Gree. roots0 hae'e 'eaning blood and stasis 'eaning ca&sing to sto(+ /he (rocess o6 hae'ostasis is a dyna'ic and delicate eC&ilibri&' bet*een coag&lation and >brinolysis (2ig+ 1)+ Coag&lation res&lts 6ro' an inter? action a'ong "essel *alls0 (latelets and coag&lation 6actors+ 1 2ollo*ing endothelial da'age0 (latelets adhere to the s&bendotheli&' 6or'ing a (latelet (l&g *hich then beco'es (er'anent *ith >brin de(osition+1 Clot 6or'ation is li'ited by antithro'bin (3/) and (roteins C and #+ /he >brinolytic syste' 6&nctions to 'aintain the >&id state thro&gh the brea.do*n o6 >brin by (las'in+ Plas'in is generated 6ro' (las'inogen by the action o6 tiss&e (las'inogen acti"ator (t?P3)+

Physiological changes to coag&lation d&ring (regnancy Pregnancy is associated *ith changes in hae'ostasis0 incl&ding an increase in the 'a%ority o6 clotting 6actors0 a decrease in the C&antity o6 nat&ral anticoag&lants and a red&ction in >brinolytic
7 Corres(onding a&thor+ $e(art'ent o6 3nesthesia0 BC 9o'en:s ;os(ital0 Roo' 1D-20 4!00 Oa. #treet0 <E; 3F1 <anco&"er0 BC0 Canada+ /el+) G1 E04 H-! 21!HI 2a>) G1 E04 H-! 2-33+ A?'ail address) %do&glasJc*+bc+ca (5+ $o&glas)+

1!21?E934,K see 6ront 'atter @ 2009 Alse"ier Btd+ 3ll rights reser"ed+ doi)10+101E,%+b(obgyn+2009+11+010

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4F/R4F#4C Collagen AL/R4F#4C <44

CaMM

<44a L44

=alli.rein

Pre.alli.rein L44a M =ininogen

Bi(id

L4a /hro'bo(lastin
CaMM

L4 4La

4L

CaMM

La
CaMM <a P23

Prothro'bin (44) 2ibrinogen (4) 24BR4FOBN/4C #N#/A1 Barge 2rag'ents 2ibrin degradation (rod&cts #'all 6rag'ents L444a $o&ble chain &ro.inase4nsol&ble (oly'er =alli.rein2ibrin #ingle chain &ro.inase Plas'in Pro&ro.inasePlas'inogen acti"ator 2ibrin Plas'inogen

/hro'bin (44a)
CaMM

CO11OF P3/;93N

2ibrin 'ono'er

4nhibition

#ol&ble 6ibrin (oly'er

4nhibition
CaMM

2ig+ 1+ For'al coag&lation (ath*ay+

acti"ity+2 4 /hese changes res&lt in a state o6 hy(ercoag&lability0 204 are li.ely d&e to hor'onal changes! and increase the ris. o6 thro'boe'bolis'+ /he increase in clotting acti"ity is greatest at the ti'e o6 deli"ery *ith (lacental e>(&lsion0 releasing thro'bo(lastic s&bstances+2 /hese s&bstances sti'&late clot 6or'ation to sto( 'aternal blood loss+ 3s (lacental blood >o* is &( to -00 'l 'inO10 considerable hae'orrhage can occ&r i6 clotting 6ails+ Coag&lation and >brinolysis generally ret&rn to (re?(regnant le"els 3 4 *ee.s (ost(art&'+ 203

a+ Platelets /he (latelet co&nt decreases in nor'al (regnancy (ossibly d&e to increased destr&ction and hae? 'odil&tion *ith a 'a>i'al decrease in the third tri'ester+ E b+ Coag&lation 6actors 2actors <444 (2<444)0 "on 9illebrand 6actor ("96)0 ristocetin co6actor (RCo3) and 6actors L (2L) and L44 (2L44) increase d&ring (regnancy+204 Be"els o6 6actor <44 (2<44) increase grad&ally d&ring (regnancy and reach "ery high le"els (&( to 1000P) by ter'+20- 2ibrinogen also increases d&ring (regnancy *ith le"els at ter' 200P abo"e (re?(regnant le"els+2

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Other 6actors either re'ain at non?(regnant le"els or decrease d&ring (regnancy+ 2actor L444 (2L444)0 *hich is res(onsible 6or stabilising >brin0 increases in the >rst tri'ester b&t by ter' it is !0P o6 non? (regnant le"els+H 2actor < (2<) concentrations increase in early (regnancy then decrease and stabiliQe+ 2 2actor 44 (2440 (rothro'bin) le"els 'ay increase or not change in early (regnancy b&t are nor'al by ter'+2 /here is debate abo&t 6actor L4 (2L4) le"els *ith re(orts indicating increases or decreases+ 9010 #i'ilarly0 24L le"els are re(orted as increasing0 decreasing or re'aining stable thro&gho&t (regnancy+ 4n one st&dy0 !0P o6 carriers o6 24L de>ciency had 24L le"els !0 48 dl O1 at ter'+11 Protein C le"els re'ain the sa'e or are slightly increased d&ring (regnancy 12 *hile (rotein # decreases+ 3/ le"els re'ain nor'al d&ring (regnancy+ 204

c+ 2ibrinolysis 2ibrinolysis is red&ced in (regnancy d&e to decreases in t?P3 acti"ity0 *hich re'ains lo* &ntil 1?h (ost(art&' *hen acti"ity ret&rns to nor'al+4 /his red&ction is d&e to the grad&al0 e"ent&ally three6old0 increase in (las'inogen acti"ator inhibitor?1 (P34?1) and the increasing le"els o6 (las'inogen acti"ator inhibitor?2 (P34?2)+4 /he (lacenta (rod&ces P34?1 and is the (ri'ary so&rce o6 P34?2+ P34?2 le"els at ter' are 2! ti'es that o6 nor'al (las'a+13 Post(art&'0 t?P3 le"els C&ic.ly ret&rn to nor'al as P3?1 le"els decreaseI ho*e"er0 P3?2 le"els re'ain ele"ated 6or a 6e* days+ /hro'bin?acti"atable >brinolysis inhibitor (/324) (an anti>brinolytic *hich clea"es the C?ter'inal lysine in >brin to render it resistant to clea"age by (las'in) le"els are increased in the third tri'ester+ 14 $?$i'er le"els increase in (regnancy1!01E b&t are not tho&ght to indicate intra"asc&lar coag&lation as >brinolysis is de(ressed+ /hese $?$i'ers 'ay originate 6ro' the &ter&s+ 1-

/ests o6 coag&lation Obstetric anaesthetists are concerned that (ro"iding ne&ra>ial anaesthesia in (art&rients *ith coag&lation abnor'alities 'ay ca&se bleeding in the e(id&ral or s&barachnoid s(ace *ith ne&rological i'(air'ent (s(inal,e(id&ral,ne&ra>ial hae'ato'a)+ Fe&ra>ial hae'ato'as associated *ith ne&ra>ial bloc.s ha"e been re(orted rarely in (art&rients+ 1H 4n the non?(regnant (o(&lation0 s(inal hae'ato'as associated *ith ne&ra>ial bloc.s o6ten occ&r in (atients *ith an &nderlying coag&lo(athy+ 4deally0 there *o&ld be a test that *o&ld (redict the ris. o6 bleeding in the e(id&ral,s(inal s(ace+

3+ Platelet co&nt #o'e anaesthetists rely on (latelet co&nt as a screening test 6or coag&lation abnor'alities in healthy (art&rients (rior to ne&ra>ial bloc.+ ;o*e"er0 the 3'erican #ociety o6 3nesthesiologists Practice G&idelines 6or Obstetric 3nesthesia states that a (latelet co&nt is not essential (rior to ne&? ra>ial bloc. in a healthy (art&rient *ith no ris. 6actors 6or bleeding+ 19 3ltho&gh there are so'e rare conditions that res&lt in abnor'al (latelet 6&nction (e+g+0 1ay ;egglin ano'aly) a nor'al (latelet co&nt *ill (ro"ide reass&rance that coag&lation is nor'al in a healthy (art&rient+ 3 (latelet co&nt at ter' R-0 S 109 lO1 'ay indicate the (resence o6 ;ABBP (hae'olysis0 ele"ated li"er enQy'es0 lo* (latelets) syndro'e0 disse'inated intra"asc&lar coag&lation ($4C)0 i''&ne thro'bocyto(aenia and other rare conditions co?e>isting *ith (regnancy+ D&estions ha"e been raised abo&t (latelet 6&nction in (re?ecla'(sia020021 b&t as these st&dies &sed bleeding ti'e0 their res&lts are not considered de>niti"e+ ;o*e"er0 the concern re'ains and is not yet resol"ed+ 1H

B+ Prothro'bin ti'e 3s 'ost coag&lation 6actors increase in nor'al (regnancy0 the (rothro'bin ti'e (P/) and the acti"ated (artial thro'bo(lastin ti'e (3P//) are shortened+ /he P/ and its deri"ed 'eas&re0 inter? national nor'alised ratio (4FR)0 test 6or 6actors s&ch as 2440 2<0 2<440 2L and >brinogen+ #o'e n&tritional de>ciencies and,or li"er disease *ill decrease these 6actors (rolonging the P/+ 2&rther'ore0 P/ and

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3P// 'ay be arti>cially (rolonged d&e to the (resence o6 an anti(hos(holi(id antibody (3PB3)0 s&ch as l&(&s anticoag&lant+ 4n 6act0 (atients *ith 3PB3 are (rothro'botic+ C+ 3cti"ated (artial thro'bo(lastin ti'e /he 3P// is considered a good screening test 6or de>ciencies o6 2<4440 24L0 2L4 and 2L44+ /he 3P// 'ay be (rolonged by the (resence o6 an 3PB3 and,or &n6ractionated,standard he(arin (#;)+ /o di66erentiate bet*een the (resence o6 an 3PB3 and a 6actor de>ciency0 the (atient:s (las'a is 'i>ed !0)!0 *ith nor'al (las'a+ 46 the 3P// re'ains abnor'al an 3PB3 is (resent+

$+ Bleeding ti'e #ince its introd&ction0 bleeding ti'e *as &sed to assess (latelet 6&nction in (art&rients *ith thro'bocyto(aenia+ 3 (rolonged bleeding ti'e *as tho&ght to (redict the ris. o6 bleeding0 *hich theoretically co&ld increase the ris. o6 a ne&ra>ial hae'ato'a+ ;o*e"er0 bleeding ti'e is &sed rarely no* as it has a n&'ber o6 disad"antages) it is in"asi"e0 &nreliable0 highly o(erator de(endent and not s&itable to re(eated tests+ Bleeding ti'e also is insensiti"e0 es(ecially to 'ild (latelet de6ects0 and not a good (redictor o6 bleeding ris.+22023 Beca&se o6 these (roble's0 other tests are being st&died+

A+ /hro'bo?elastogra(hy /he thro'boelastogra(h (/AG) (ro"ides in6or'ation abo&t the "ario&s stages o6 coag&lation and >brinolysis+ /he 'a>i'&' a'(lit&de (13) is tho&ght to re(resent (latelet 6&nction+ /AG is &sed by so'e centres to (redict the ris. o6 bleeding 6ro' coag&lation abnor'alitiesI ho*e"er0 the sensiti"ity and s(eci>city o6 /AG in (regnancy re'ain &n(ro"en+ 2402! 3n abnor'al test has not been sho*n to be (redicti"e 6or de"elo('ent o6 a ne&ra>ial hae'ato'a0 b&t 'ost anaesthetists *ill not (ro"ide regional anaesthesia i6 the 13 is abnor'al+

2+ Platelet 6&nction analyserT (P23) /his test 'eas&res the s(eed o6 6or'ation o6 a (latelet (l&g in "itro0 e>(ressed as clos&re ti'e in seconds+ #t&dies in (art&rients s&ggest that it is an e66ecti"e bedside test o6 (latelet 6&nction 2EI ho*e"er0 e"idence is lac.ing to s&((ort its ro&tine &se+

$isorders that a66ect coag&lation /hro'bocyto(aenia /hro'bocyto(aenia a66ects E 10P o6 all (regnancies+ 2- 3 decrease in (latelet co&nt is nor'al in (regnancy altho&gh 'ost (latelet co&nts re'ain *ithin nor'al li'its (U1!0 S 10 9 lO1)+E02H 3 lo*er than (hysiological (latelet co&nt 'ay occ&r in (regnancy 6or 'any reasons0 ranging 6ro' the relati"ely benign0 gestational thro'bocyto(aenia to 'ore sinister conditions0 s&ch as ;ABBP syndro'e+ #o'e (re?e>isting conditions that 'ay ca&se thro'bocyto(aenia at ter' incl&de) ty(e 2b "on 9illebrand disease ("9$)0 idio(athic thro'bocyto(aenic (&r(&ra (4/P)0 l&(&s erythe'atos&s and bone 'arro* disease+ Pregnancy?related ca&ses o6 thro'bocyto(aenia incl&de gestational thro'bo? cyto(aenia0 (re?ecla'(sia incl&ding ;ABBP syndro'e0 ac&te 6atty li"er o6 (regnancy0 $4C and thro'? bocyto(aenic (&r(&ra+2- #e"ere se(sis0 so'e 'edications (e+g+0 #;) and "iral in6ections 'ay coincide *ith (regnancy (rod&cing thro'bocyto(aenia+2-

a+ Gestational thro'bocyto(aenia Gestational thro'bocyto(aenia is a benign condition that occ&rs d&ring the third tri'ester *ith a (latelet co&nt that is generally U90 S 109 lO1b&t 'ay be as lo* as -0 S 109 lO1+29 4n one st&dy0 the

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incidence o6 thro'bocyto(aenia *as -+3P0 o6 *hich H1P *ere gestational thro'bocyto(aenia+ 2H /he diagnosis is 'ade by e>cl&sion o6 other disorders+ Part&rients *ith gestational thro'bocyto(aenia are asy'(to'atic0 ha"e a nor'al (latelet co&nt in early (regnancy *ith no history o6 (re"io&s thro'? bocyto(aenia and no e"idence o6 (re?ecla'(sia+ /hese (atients are not at increased ris. o6 hae'or? rhage0 and there is no contraindication to ne&ra>ial anaesthesia+ 30

b+ 4dio(athic thro'bocyto(aenic (&r(&ra 4/P 'ay (resent 6or the >rst ti'e in (regnancy and is the 'ost co''on reason 6or isolated thro'? bocyto(aenia in the >rst tri'ester+2- 4/P is an a&toi''&ne disorder *hich is associated *ith the (rod&ction o6 anti?(latelet i''&noglob&lin (4gG)0 res&lting in (latelet destr&ction in the retic&lo?endo? thelial syste'+ ;o*e"er0 anti?(latelet 4gG is not al*ays (resent0 'a.ing the diagnosis (roble'atic+ 31 Baboratory >ndings incl&de an isolated thro'bocyto(aenia (resenting either (re?(regnancy or in early (regnancy *ith large0 *ell?gran&lated (latelets+ $es(ite lo* (latelet n&'bers0 hae'ostasis is o6ten nor'al+ /he British Co''ittee 6or #tandards in ;ae'atology g&idelines reco''end a (latelet co&nt o6 H0 S 109 lO1 6or e(id&ral anaesthesia+32 ;o*e"er0 'any anaesthetists0 s&ch as the a&thors0 *o&ld do a ne&ra>ial bloc. (es(ecially s(inal anaesthesia) in healthy0 asy'(to'atic 4/P (atients *ith (latelet co&nts U!0 S 109 lO1+ /his (ractice is based on the consideration that a (latelet co&nt U!0 S 109 lO1 is considered s&6>cient 6or caesarean deli"ery+ 32 /he .ey iss&e in 'anaging an 4/P (art&rient is *hether inter"ention is necessary to (re"ent hae? 'orrhage+ 4n (atients *ith "ery se"ere0 sy'(to'atic thro'bocyto(aenia ((latelet co&nt 10 S 109 lO1)0 treat'ent is &rgently reC&ired+ One gra' (er .ilogra' (er day o6 intra"eno&s ga'? 'aglob&lin (4<4g)0 ad'inistered o"er 2 days0 *ill raise the (latelet co&nt in a((ro>i'ately -!P o6 4/P (atients32 and the (latelet co&nt *ill re'ain ele"ated 6or 3 E *ee.s+ 2&rther 4<4g 'ay be reC&ired later in (regnancy+ 3nother o(tion is high?dose corticosteroids (e+g+0 (rednisone 1 'g .g O1 ((re?(regnancy *eight) daily)+32 /here are no trials co'(aring 4<4g to corticosteroids 6or e66ect+ 3d'inistration o6 4<4g and,or corticosteroids &s&ally *ill raise the (latelet co&nt to enable ne&ra>ial anaesthesia+ Occasion? ally0 a s(lenecto'y is reC&ired d&ring (regnancy and this 'ay be done la(arasco(ically in the second tri'ester+33 Platelet trans6&sion is generally contraindicated0 b&t0 in the setting o6 ac&te hae'orrhage and an e>tre'ely lo* (latelet co&nt0 it 'ay be li6e?sa"ing+ 32

3naesthetic i'(lications o6 thro'bocyto(aenia /here is considerable debate abo&t ad'inistering ne&ra>ial anaesthesia in (art&rients *ith thro'bocyto(aenia+ 3 (latelet co&nt 6ro' -0 S 109 lO1 to 100 S 109 lO1 in an other*ise healthy (art&rient sho&ld not contraindicate regional anaesthesia+ 1ost 3'erican anesthesiologists *o&ld insert an e(id&ral in a healthy (art&rient *ith a (latelet co&nt UH0 S 10 9 lO1+34 3 Canadian s&r"ey re(orted that 1E+2P o6 &ni"ersity?based anaesthetists *o&ld (lace an e(id&ral i6 the (latelet co&nt *as U!0 S 109 lO1 in an other*ise healthy (art&rient+3! /he sit&ation is 'ore contro"ersial in the setting o6 (re?ecla'(sia0 incl&ding ;ABBP syndro'e+ 4n this sit&ation0 'ost anaesthetists consider the (latelet co&nt0 the clinical (ict&re (i+e+0 hae'orrhage ris. and e"idence o6 coag&lo(athy) and *hether the thro'bocyto(aenia is stable or decreasing+ 4n one re(ort o6 ;ABBP syndro'e0 12 (art&rients *ith a (latelet co&nt R!0 S 10 9 lO1 recei"ed &ne"ent6&l e(id&ral anaesthesia+3E 4n so'e cases a (latelet trans6&sion *as gi"en i''ediately (rior to ne&ra>ial anaesthesia+ 4n contrast0 there is a re(ort o6 an e(id&ral hae'ato'a in t*o cases o6 ;ABBP syndro'e) one a6ter s(inal anaesthesia and the other a6ter e(id&ral catheter re'o"al+ 3- Both had signs o6 coa? g&lo(athy+ #t&dies &sing /AG in *o'en *ith (re?ecla'(sia s&ggest that coag&lation is nor'al *ith a (latelet co&nt V-! S 109 lO1+3H039

2actor de>ciencies /he 'ost co''on 6actor de>ciencies enco&ntered in (regnancy are "on 9illebrand disease and hae'o(hilia carrier states+

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a+ "on 9illebrand disease ("9$) "on 9illebrand disease is the 'ost 6reC&ent inherited bleeding disorder0 a66ecting 1P o6 the (o(? &lation+40 "9$ is d&e to C&antitati"e (ty(es 1 and 3) or C&alitati"e (ty(e 2) de6ects o6 "96 *ith a&toso'al do'inant trans'ission+ "96 (rotects circ&lating 2<444 6ro' (roteolysis and is reC&ired 6or nor'al (latelet adhesion to the in%&ry site+ 4n "9$ the 'ar.ed red&ction in 2<444 acti"ity (rod&ces the clinical syndro'e+ /here are three ty(es o6 "9$) ty(es 10 2 and 3 *ith s&bty(es in ty(e 2 (230 2B0 210 2F)+ /y(e 10 the 'ost 6reC&ent *ith an incidence o6 -!P0 is &s&ally 'ild and is characterised by a de>ciency o6 "96+ /y(e 2 and its s&bty(es in"ol"e abnor'alities o6 binding to glyco(roteins and 2<444 (C&alitati"e de6ect)+ /y(e 3 is characterised by the co'(lete absence o6 "96 and is &s&ally se"ere+ /hro'bocyto(aenia occ&rs *ith ty(e 2b+ /he diagnosis o6 "9$ is 'ade clinically and in the laboratory+ /he 'ost co''on sy'(to' o6 /y(e 1 "9$ in *o'en is 'enorrhagia040 b&t there 'ay be a history o6 br&ising0 e(ista>is or other '&cosal bleeding0 and bleeding a6ter dental e>tractions or s&rgery+ 41 Baboratory diagnosis in"ol"es 'eas&ring "960 RCo3 and 2<444 le"els+ 9o'en *ith "9$ ha"e reasonably good (regnancy o&tco'es+ /he increases in >brinogen0 2<440 2<4440 2L and "96 d&ring (regnancy are considered (rotecti"e+ Be"els o6 "960 RCo3 and 2<444 sho&ld be chec.ed in early (regnancy and in the third tri'ester to ens&re adeC&ate le"els 6or deli"ery+ 40 Pregnant (atients *ith ty(e 3 "9$0 ty(e 2 "9$ or ty(e 1 "9$ *ith 2<444 !0 48 dl O10 "96)RCo !0 48 dlO1 or a history o6 se"ere bleeding sho&ld be re6erred to a centre *ith a((ro(riate cons&ltants0 laboratory and blood ban. 6acilities+ Post(art&' hae'orrhage (PP;) is a co''on co'(lication in (art&rients *ith "9$+42 Be"els o6 "96 begin decreasing E h (ost(art&'0 ret&rning to (re?(regnancy le"els by - 20 days+ $es'o(ressin ($$3<P) is considered sa6e 6or (art&rients *ith ty(e 1 "9$+ 43 4! /he nor'al dose is 0+3 'g .gO10 &( to a 'a>i'&' o6 20 'g .gO1+ $es'o(ressin i''ediately increases "96 and 2<444)RCo3 by 200 300P+ 3s hy(onatrae'ia is a co'(lication o6 re(eated doses o6 $$3<P0 so'e reco''end a 'ini'&' o6 12 ho&rly inter"als and restriction o6 >&ids+ 40 $es'o(ressin is contraindicated or the res(onse is "ariable in ty(e 2 and ine66ecti"e in ty(e 3 "9$+ 4E

3naesthetic i'(lications o6 "9$ Based on case re(orts and retros(ecti"e st&dies0 ne&ra>ial anaesthesia a((ears sa6e in ty(e 1 "9$ (art&rients *ith nor'al third tri'ester coag&lation (2<444 U!0 48 dl O1)+4204- 4n a st&dy o6 E4 "9$ (art&rients0 1! (1- deli"eries) recei"ed &ne"ent6&l0 e(id&ral anaesthesia *itho&t (ro(hylactic $$3<P or 6actor concentrate+4- ;o*e"er0 eight had a PP;0 coinciding *ith the (ost(art&' 6all in 2<444 and "96 le"els+ #e"en o6 the eight *ith PP; had ty(e 1 "9$ *hilst the eighth had ty(e 23+ 4- 3n e(id&ral catheter sho&ld not be re'o"ed i6 coag&lation is abnor'al+ 1ost anaesthetists consider ne&ra>ial bloc. contraindicated in ty(es 2 and 3 "9$ b&t there is a re(ort o6 s(inal anaesthesia in a (art&rient *ith ty(e 21 "9$ *hose coag&lation *as nor'al e>ce(t 6or (rolonged (latelet adhesion and aggregation+4E

b+ 2actor <444 $e>ciency 3lso .no*n as hae'o(hilia 30 2<444 de>ciency is rare in 6e'ales as it is an L?lin.ed0 recessi"e condition+ Rarely0 lyonisation o6 the L chro'oso'e occ&rs and a *o'an has lo* 2<444 le"els+ 11 ;ae? 'o(hilia 3 is diagnosed *hen 2<444 acti"ity is 3!P+ Reco'binant 2<444 (r2<444) is the treat'ent o6 choice0 i6 reC&ired0 in (regnant hae'o(hilia 3 carriers+ 3ltho&gh 2<444 le"els &s&ally nor'alise d&ring (regnancy0 there are a 6e* case re(orts o6 se"ere 2<444 de>ciency so chec. 2<444 le"els early in (reg? nancy and in the third tri'ester+9042 4n t*o cases o6 se"ere 2<444 de>ciency0 the (art&rients had s&ccess6&l e(id&ral analgesia 6or labo&r a6ter r2<444+ 4H049 One (art&rient had a s(ontaneo&s "aginal deli"ery4H and the other a caesarean deli"ery+49 /he latter (art&rient had a brachial "ein thro'bosis 10 days (ost(art&'+49

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2

34!

c+ 2actor 4L de>ciency #i'ilar to hae'o(hilia 30 24L de>ciency (hae'o(hilia B0 Christ'as disease) is L lin.ed0 recessi"e and hence rare in 6e'ales+ 3s 24L le"els 'ay decrease d&ring (regnancy these *o'en 'ay ha"e inadeC&ate coag&lation+ =no*n carriers o6 hae'o(hilia B sho&ld ha"e 24L le"els chec.ed in the third tri'ester to ens&re adeC&ate coag&lation 6or deli"ery+ Reco'binant 24L is the treat'ent o6 choice+

3naesthetic i'(lications o6 hae'o(hilia carriers Fe&ra>ial anaesthesia is not contraindicated (ro"ided) (i) 2actor <444 le"el is U!0 48 dlO1 at ter'I (ii) P/ and 3P// are nor'alI (iii) /here is no e"idence o6 bleeding or br&isingI (i") Re(lace'ent thera(y has raised the le"el to U!0 48 dl O1 *ith nor'al coag&lation in *o'en *hose 2<444 le"els *ere !0 48 dlO1+901104204H

4n !3 hae'o(hilia 3 carriers and 12 hae'o(hilia B carriers *ho had 90 (regnancies0 2<444 and 24L le"els increased d&ring (regnancy b&t 2<444 le"els increased 'ore+ 11 4n a s&bset0 HP o6 hae'o(hilia 3 carriers and !0P o6 hae'o(hilia B carriers had 2<444 or 24L le"els !0 48 dl O1at ter'+ Regional anaesthesia *as &sed in 2! deli"eriesI 20 had nor'al 6actor le"els (U!0 48 dl O1) and nor'al coag&? lation screens+11 2i"e other (art&rients recei"ed regional anaesthesiaI one a6ter (ro(hylactic reco'binant 6actor and in the re'aining 6o&r the carrier stat&s *as &n.no*n+ /here *ere no co'(lications+

d+ Rarer coag&lation disorders and their anaesthetic i'(lications (/able 1) /he rarer coag&lation disorders incl&de abnor'alities in 6actors 40 440 <0 <440 L and L444+ 400!0 4n a (art&rient *ith a history o6 coag&lo(athy0 ne&ra>ial bloc. is contraindicated i6 coag&lation is abnor'al+ 3s 6actor le"els 'ay dro( s&ddenly (ost(art&'0 'any anaesthetists are rel&ctant to (ro"ide ne&ra>ial anaesthesia+ 46 ne&ra>ial anaesthesia is ad'inistered0 close 'onitoring o6 coag&lation is essential and an e(id&ral catheter sho&ld not be re'o"ed &nless coag&lation is nor'al+ 46 ne&ra>ial bloc. is contraindicated intra"eno&s o(ioids are a((ro(riate 6or labo&r analgesia and general anaes? thesia 6or caesarean deli"ery+

i+ 2actor 1 (>brinogen) de>ciency!0 B 3>brinogenae'ia is the total absence o6 21+ B ;y(o>brinogenae'ia is a decreased le"el o6 nor'al 21+ B $ys>brinogenae'ia is an abnor'ality o6 21 res&lting in altered 6&nction+ B 3>brinogenae'ia and hy(o>brinogenae'ia are associated *ith rec&rrent 'iscarriage and ante(art&' and (ost(art&' hae'orrhage+ B $ys>brinogenae'ia 'ay ha"e a thro'botic or bleeding (henoty(e+ B 1anage'ent is challenging+ B 3naesthetic 'anage'ent) Regional anaesthesia is contraindicated in (atients *ith dys>? brinogenae'ia+ /hose *ith a bleeding (henoty(e are at ris. o6 a ne&ra>ial hae'ato'a *ith ne&ra>ial bloc. *hile those *ith a thro'botic (henoty(e are li.ely on lo*?'olec&lar?*eight he(arin (B19;)+ /heoretically0 (atients *ith hy(o? and a>brinogenae'ia co&ld be consid? ered 6or ne&ra>ial bloc. a6ter treat'ent *ith >brinogen concentrate and adeC&ate le"els+ 3 6&ll disc&ssion o6 the ris.s and bene>ts o6 analgesia,anaesthesia sho&ld be held *ith each (atient+ ii+ 2actor 44 ((rothro'bin) de>ciency!0 B A>tre'ely rareI

34E

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2

/able 1 Rarer 6actor de>ciencies and their i'(lications+ !0 $e>ciency Pregnancy co'(lications Rec&rrent 'iscarriage 3P;0 PP;0 /hro'bosis /reat'ent (rod&cts Pregnancy 'anage'ent 3naesthetic i'(lications

24

24 conc+I 3"oid cryo(reci(itate0 i6 (ossibleI 2ibrin gl&e0 /L3

244 2< 2<44

PP; Bleeding!1 Fo re(orts o6 co'(lications *ith 6&ll?ter' (regnancies+ ;ae'orrhage *ith 'iscarriage Bleeding d&ring (regnancy0 (reter' deli"ery

3 or 4 6actor PCCI 22P 22P r<44aI P/CCI 22PI 2ibrin gl&eI /L3

32) 24 conc (ro(hyla>is $2) 3"oid (roced&res in nn+ Obser"e &nless bleedingI /hro'bo(ro(hyla>is i6 history thro'bosis Reasonable to increase 244 le"el to V2! 48 dBO1 Reasonable to gi"e 22P to raise le"el V1! 48 dBO1 1 case o6 contin&o&s in6&sion o6 r2<44a 6or electi"e C$!!

32) Possibly F3 a6ter 24 conc & le"els V1 g dBO1 $2) F3 contraindicatedI 24 conc+ only i6 bleeding 6or C$

Fo re(orts in (regnancy G3 &sed 6or C,$ in one case+ F3 (robably C4 r2<443 allo*ed e(id&ral in se"ere cases!!

2L

/L3I 2ibrin gl&eI 22PI PCCI (las'a e>change in one case!-

2L4

PP;

22PI 2L4 conc+I r2<44aI /L3I 2ibrin gl&e

2L increases in (regnancy 3d"erse (regnancy o&tco'e 'ay bene>t *ith re(lace'ent ris. thro'bosis <$) 2L4 le"el 1! -0 48 dBO1 G no bleeding history *atch & *ait 46 sa'e le"el G bleeding history O /L3 S 3 days #e"ere 2L4 de>ciency O 2L4 conc C$) as 6or <$ 2L444 conc 'onthly in6&sions 6ro' diagnosis o6 (regnancy

F3 (robably O= i6 2L le"els V20 48 dBO1

Re(orts o6 F3 6ollo*ing 2L4 conc & nor'al le"els!H

2L444

1iscarriage0 PP;

2L444 concI 22PI Cryo(reci(itate

F3 C4

3P; W ante(art&' hae'orrhageI PP; W (ost(art&' hae'orrhageI /L3 W trane>a'ic acidI 32 W a>brinogenae'iaI $2 W dys? >brinogenae'iaI conc W concentrateI F3 W ne&ra>ial anaesthesiaI C4 W contraindicatedI C$ W caesarean deli"eryI PCC W (ro? thro'bin co'(le> concentrateI 22P W 6resh 6roQen (las'aI G3 W general anaesthesiaI <$ W "aginal deli"ery

/*o B clinical (henoty(es) hy(o(rothro'binae'ia and dys(rothro'binae'iaI B Re(orts o6 PP; and 6oetal loss in early (regnancyI B 1ay ha"e (rolonged P/ and 3P// b&t 'ay also be nor'alI B Prothro'bin co'(le> concentrate is treat'ent o6 choice (contains 2440 24L and 2L)I B 3naesthetic 'anage'ent) Fo re(orts+ iii+ 2actor < de>ciency!0 B RareI B Prolonged P/ and 3P// b&t *ith a nor'al thro'bin ti'eI !1B /reat'ent is 6resh 6roQen (las'a (22P) I O1B 46 2< le"els1 48 dl 0 ad'inister 22P (1! 'l .gO1) *hen (atient is in contin&e *ith close 'onitoringI
!0B 46

established labo&r and

(atient has an o(erati"e deli"ery0 contin&e 22P &ntil *o&nd healing I !2B 3naesthetic 'anage'ent) General anaesthesia 6or caesarean deli"ery re(orted

in one case+ Other re(orts do not 'ention anaesthesia+!10!3 i"+ 2actor <44 de>ciency!0 !4B 1ost co''on o6 the Xrare: disorders I B Prolonged P/ corrects *ith !0)!0 'i> nor'al (las'a0 (ro"iding no inhibitor or 3PB3+ B 3naesthetic 'anage'ent) /here *as one re(ort o6 6o&r (regnancies in three *o'en *ith a .no*n diagnosis o6 2<44 de>ciency+!4 2or all 6o&r0 (ro(hylactic r2<44a *as ad'inistered (rior

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2

34-

to deli"ery+ /hree o6 the 6o&r had a caesarean deli"ery &nder &ne"ent6&l e(id&ral anaesthesia+ /*o other (art&rients had &ne"ent6&l e(id&ral anaesthesia 6or three (regnancies (rior to the diagnosis+ /here is a re(ort o6 e(id&ral anaesthesia 6or caesarean deli"ery 6ollo*ing ad'in? istration o6 reco'binant 2<44 (r2<44a)+!! B Reco'binant 2actor <44) 9hilst e"idence is lac.ing0 r2<44a is being &sed 6or li6e?threatening PP;0 es(ecially *hen con"entional treat'ent 6ails+ /hro'bosis is a .no*n co'(lication o6 r2<44a+ P&blished g&idelines highlight the i'(ortance o6 atte'(ting all s&rgical and non? s&rgical hae'ostatic (roced&res to arrest acti"e bleeding (rior to ad'inistering r2<44a+ !E /hese (&blished reco''endations are!E) O1B r2<44a (90 'g .g ) ad'inistered as a single bol&s in%ectionI B 46 no res(onse a6ter 20 'ins and (ersistent bleeding0 ens&re that te'(erat&re0 acid, base balance0 ser&' calci&'0 (latelets and >brinogen are o(ti'al be6ore gi"ing a second dose o6 r2<44aI B 46 bleeding (ersists a6ter t*o doses0 consider hysterecto'y+ 2actor L de>ciency!0 B Be"els &s&ally increase in (regnancy0 ret&rning to nor'al E *ee.s (ost(art&'+ O1B Be"els U10 48 dldo not reC&ire re(lace'ent0 b&t belo* that it reC&ires a hae'atology cons&ltation+ "+ B 1anage'ent o6 se"ere 2L de>ciency) 22P0 inter'ediate (&rity 24L concentrates ((rothro'bin co'(le> concentrates) and (las'a e>change+ !B 3 '&ltidisci(linary a((roach is essential+ B 3naesthetic 'anage'ent) #o'e *o'en had caesarean deli"ery b&t anaesthesia *as not s(eci>ed+ 2actor L4 de>ciency!0 B 3lso .no*n as hae'o(hilia C0 2L4 de>ciency increases 3P//+ O1B 2L4 le"els 1! 48 dlreC&ire re(lace'ent *ith 22P 6or s&rgery B 3naesthetic 'anage'ent) 4n 13 (art&rients *ith 2L4 de>ciency0 nine had &ne"ent6&l ne&ra>ial anaesthesia+!H 2i"e had (ro(hylactic 22P be6ore ne&ra>ial anaesthesiaI those *itho&t 22P had 'ild disease *ith no bleeding history+ "i+ 2actor L44 de>ciency!9 B ;o'oQygo&s "ery rare a&toso'al recessi"eI B Prolonged 3P//0 b&t bleeding not a (roble'I B 1ay be associated *ith 'iscarriageI B 3naesthetic 'anage'ent) /here are no re(orts+ 2actor L444 de>ciency!0 !0B O6ten 'iscarry as 2L444 is essential 6or (lacentation I B 8( to !0P o6 se"erely a66ected (regnant *o'en reC&ire 'onthly in6&sion o6 2L444 concentrateI O1B 1onitor 2L444 le"els as 6all d&ring (regnancy+ /ro&gh sho&ld be V3 48 dl I "ii+ B 3naesthetic 'anage'ent) /here are no re(orts+ ;ereditary co'bined "ita'in =?de(endent 6actor de>ciency !00E0 B 3 *ide "ariation in bleeding tendencyI B Prolonged P/ and 3P//I B 1ost i'(ro"e *ith "ita'in = thera(yI B /here is a re(ort o6 a *o'an *ho recei"ed oral <ita'in = (1! 'g) thro&gho&t (regnancy b&t "iii+ reC&ired 22P 6or bleeding 6ro' an e(isioto'y+E0 B 3naesthetic 'anage'ent) /here are no re(orts+

i>+

/hro'boe'bolic disease <eno&s thro'boe'bolis' (</A) is the leading ca&se o6 'aternal 'ortality in the de"elo(ed *orld+E10E2 /he ris. o6 (&l'onary e'bolis' and dee( "ein thro'bosis is increased d&ring (reg? nancy and 6&rther increased by an inherited or acC&ired thro'bo(hilia+ </A occ&rs in 10 (er 100 000 *o'en o6 childbearing age and a66ects 100 (er 100 000 (regnancies+ E3 Pregnancy?related hy(ercoag&lation is 'a>i'al i''ediately (ost(art&'0 increasing the ris. o6 </A at that ti'e+

34H

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2

/able 2 Ris. 6actors 6or thro'boe'bolis' d&ring (regnancy+E!0EH0-0 Ris. 6actor ;istory o6 </A 4nherited thro'bo(hilia Ris. 1+4 11+1P 0 !0P de(ending on condition0 e+g+ 0 EP *ith Protein # de>ciency0 !0P *ith 3/ de>ciency 4ncreased Ris. *ith C$ 20 S V<$ 4ncreased 4ncreased 4ncreased

Obesity #&rgery Prolonged i''obiliQation 3PB3 syndro'e Other) age V3!0 s'o.ing0 "aricose "eins0 '&lti(le gestation0 (re?ecla'(sia

</A W "eno&s thro'boe'bolis'I 3/ W antithro'binI C$ W caesarean deli"eryI <$ W "aginal deli"eryI 3PB3 W anti(hos(holi(id antibody+

/hro'boe'bolis' is 20 ti'es 'ore li.ely to occ&r 6ollo*ing caesarean deli"ery than "aginal deli"ery+E4 4nherited thro'bo(hilia is (resent in 30 !0P o6 *o'en *ith (regnancy?associated </A+ 2actor < Beiden (2<B) is the 'ost 6reC&ently identi>ed inherited thro'bo(hilia in the Ca&casian (o(? &lation+E! /hro'bo(hilias associated *ith a high ris. o6 </A d&ring (regnancy incl&de 3/ de>? ciency0 (rotein C or # de>ciency0 co'(o&nd heteroQygosity 6or 2<B and (rothro'bin gene '&tation (G202103) or other co'binations o6 thro'bo(hilia0 and ho'oQygosity 6or these condi? tions+E30EE Bo*er?ris. thro'bo(hilias incl&de heteroQygosity 6or 2<B or the (rothro'bin gene '&tation+E30EE /here is con>icting e"idence abo&t ad"erse (regnancy o&tco'es (e+g+0 (regnancy loss and (re? ecla'(sia) in *o'en *ith inherited thro'bo(hilia0 e"en *ith he(arin (ro(hyla>is+ E- ;o*e"er0 *o'en *ith 3PB3 are at high ris. 6or ad"erse (regnancy o&tco'es+ E- 3ltho&gh e"idence o6 ad"erse (regnancy o&tco'e has not been con>r'ed in *o'en *ith thro'bo(hilia *itho&t 3PB3 (e+g+0 2<B heteroQygotes) 'any obstetricians reco''end he(arin (ro(hyla>is d&ring (regnancy+ G&idelines ha"e been de"elo(ed 6or antithro'botic thera(y d&ring (regnancy+ E!0EH -0 /hese reco''endations are &s&ally consens&s0 rather than e"idence?based and in"ol"e assessing </A ris.+ ;e(arin (ro(hyla>is is reco''ended 6or those in higher?ris. categories (/able 2)+ One st&dy o6 the e66ecti"eness o6 he(arin (ro(hyla>is in (regnancy0 based on ris. strati>cation0 concl&ded that the he(arin (ro(hyla>is *as e66ecti"e and sa6e in (re"enting </A+ -1 3s !0P o6 </A occ&rs (ost(art&'0 these g&idelines reco''end he(arin or *ar6arin 6or E *ee.s (ost(art&' in *o'en *ith a history o6 </A or thro'bo(hilia+EH0-0 </A d&ring (regnancy is treated *ith thera(e&tic he(arin+

3naesthetic i'(lications o6 thro'bo(hilia 3naesthetists are co''only as.ed to (ro"ide e(id&ral anaesthesia 6or labo&r and,or deli"ery in *o'en &sing (ro(hylactic he(arin+ /here is %&sti>able concern abo&t ad'inistering ne&ra>ial anaesthesia in *o'en on he(arin d&e to the ris. o6 a ne&ra>ial hae'ato'a+ -2 Fe&ra>ial anaesthesia is contraindicated *hen a *o'an is on thera(e&tic he(arin+ Consens&s?based reco''endations regarding ne&ra>ial anaesthesia in (atients on antithro'botics ha"e been de"elo(ed (/able 3)+-30-4 1ost anaesthetists 6ollo* these or si'ilar g&idelines *hen deter'ining *hether and *hen to ad'inister ne&ra>ial anaesthesia in (art&rients on anticoag&lants+

#&''ary /he 'ost co''on 6actor de>encies enco&ntered d&ring (regnancy are "9$ and hae'o(hilia carrier states+ 9o'en *ith "9$ do *ell in (regnancy as the associated increases in coag&lation 6actors

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2 /able 3 Fe&ra>ial anaesthesia in (atients on anticoag&lants+ -30-4 3nticoag&lant Coag&lation tests /i'e to/i'e to nor'al Fe&ra>ial anaesthesia (ea. e66ect coag&lation a6ter discontin&ed 1in&tes 4 Eh 1&st ha"e nor'al coag&lation (chec. 3P// i6 R4 E h a6ter last dose0 or i6 additional concerns)+ 9ait 4 E h a6ter last #; doseI 9ait 1 h a6ter (roced&re be6ore gi"ing he(arin dose 46 on !000 -!00 & C12 h no need to 'eas&re 3P// i6 ela(sed ti'e 4 E h (ost?dose in the absence o6 s(eci>c (atient concerns F3 not contraindicated Y ris. i6 also on anti?(latelet dr&gs 9ait 10 12 h a6ter lo* dose 9ait 24 h a6ter high dose A(id&ral catheter re'o"al

349

4< #;

Y P/ YYY 3P//

4 E h a6ter last he(arin 9ait 1 h to gi"e 1st dose a6ter catheter re'o"al

#C he(arin (#;)

Y P/ YYY 3P//

40 !0 'in

4 Eh

4 E h a6ter last he(arin dose or 1 h (rior to ne>t dose

B19;

3nti?La acti"ity2 4 h not reco''ended as not (redicti"e o6 ris. o6 bleeding

12G h

9ar6arin

YP/I Y 4FR

4 E days ;o&rs

4 E days

For'al coag&lation (4FR) reC&ired be6ore F3 F3 not contraindicated FB) Y ris. i6 also on he(arin

Bo* dose) 10 12 h a6ter last doseI ;igh dose) 24 h a6ter last dose 9ait U2 h to gi"e 1st dose a6ter catheter re'o"alI 46 tra&'atic insertion0 *ait 24 h to gi"e 1st dose+ 1ay be sa6er to *ait 24 h 6or 1st dose+ Re'o"e catheter i6 *ar6arin *ithin 24 h o6 restart Fo Y ris.

3s(irin Other F#34$s

Bleeding ti'e not reliable to (redict (latelet 6&nction

! H days 1 3 days

4< W intra"eno&sI #; W standard he(arinI P/ W (rothro'bin ti'eI 3P// W acti"ated (artial thro'bo(lastin ti'eI #C W s&bc&taneo&sI & W &nitsI B19; W lo* 'olec&lar he(arinI F3 W ne&ra>ial anaesthesiaI (reo( W (reo(erati"elyI 4FR W international nor'aliQed ratioI F#34$ W non?steroidal anti?in>a''atory dr&gs+

are considered (rotecti"e+ ;ae'o(hiliac carriers '&st be assessed care6&lly thro&gho&t (regnancy and 'anaged a((ro(riately+ 4n (art&rients0 bleeding associated *ith ne&ra>ial anaesthesia 'ay rarely occ&r in the e(id&ral or s(inal s(ace+ /his can (rod&ce a ne&ra>ial hae'ato'a0 *hich can ca&se ne&rological co'(lications+ 3 ne&ra>ial hae'ato'a is rare in (art&rients *itho&t coag&lation abnor'alities+ Fe&ra>ial anaesthesia is contraindicated in coag&lo(athic states+ /hro'boe'bolic disease is signi>cantly increased in (regnancy and is 6&rther increased in the (resence o6 thro'bo(hilia+ /here are g&idelines 6or the &se o6 antithro'botic thera(y in (regnancy+ #i'ilarly0 there are g&idelines *hich assist the anaesthetist to deter'ine *hether to ad'inister ne&ra>ial anaesthesia in (art&rients on anticoag&lants+

Con>ict o6 interest state'ent /he a&thors ha"e no >nancial or (ersonal relationshi(s *ith any (eo(le or organisations that co&ld ha"e in>&enced the content o6 this article+

3!0

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2

Practice (oints Pregnancy is a hy(ercoag&lable state d&e to the (hysiological changes o6 (regnancy+ /he (latelet co&nt is decreased at ter' co'(ared to (re?(regnant states in nor'al (regnancy+ 1ost coag&lation 6actors increase d&ring (regnancy b&t so'e do not+ Part&rients *ith inherited 6actor de>ciencies 'ay reC&ire treat'ent d&ring (regnancy0 /hro'boe'bolis' is the leading ca&se o6 'aternal 'ortality and is increased in *o'en *ith inherited thro'bo(hilia+ Pro"ision o6 ne&ra>ial anaesthesia in (art&rients *ith coag&lation abnor'alities is de(en? dent on the condition and the c&rrent stat&s o6 coag&lation+

Research agenda $&e to the rarity o6 'any o6 the hae'atological conditions it is i'(ossible to design rando? 'ised controlled trials 6or 'anage'ent o6 these conditions+ 2&t&re care o6 (art&rients *ith these conditions *ill contin&e to rely on case re(orts0 case series and a greater &nderstanding o6 the &nderlying (atho(hysiology o6 each condition+

Concl&sion 4n s&''ary0 (regnancy is associated *ith 'a%or changes in hae'ostasis incl&ding increases in the 'a%ority o6 clotting 6actors0 decreases in the C&ality o6 nat&ral anticoag&lants and a red&ction in >brinolytic acti"ity+ /hese changes are greatest at the ti'e o6 deli"ery+ Platelet co&nts 'ay be lo*er in (regnancy 'ost co''only d&e to gestational thro'bocyto(aenia or 4/P+ ;ae'ostasis is nor'al in gestational thro'bocyto(aenia and o6ten in 4/P des(ite lo* (latelet n&'bers+

Re6erences
1+ Forris B3+ Blood coag&lation+ Best Pract Res Clin Obstet Gynaecol 2003I 1-) 3E9 3H3+ 72+ Bre''e =3+ ;ae'ostatic changes in (regnancy+ Best Pract Res Clin ;ae'atol 2003I 1E) 1!3 1EH+ Z3+ $ahl'an /0 ;ellgren 1 & Blo'bac. 1+ Changes in blood coag&lation and >brinolysis in the nor'al (&er(eri&'+ Gynecol Obstet 4n"est 19H!I 20) 3- 44+ 74+ O:Riordan 1F & ;iggins 5R+ ;ae'ostasis in nor'al and abnor'al (regnancy+ Best Pract Res Clin Obstet Gynaecol 2003I 1-) 3H! 39E+ !+ #attar F0 Greer 430 R&'ley 3 et al+ 3 longit&dinal st&dy o6 the relationshi(s bet*een hae'ostatic0 li(id and oestradiol changes d&ring nor'al (regnancy+ /hro'b ;ae'ost 1999I H1) -1 -!+ E+ Boehlen 20 ;ohl6eld P0 A>ter'ann P et al+ Platelet co&nt at ter' (regnancy) a rea((raisal o6 the threshold+ Obstet Gynecol 2000I 9!) 29 33+ -+ $ala.er = & PrydQ ;+ /he coag&lation 6actor <44 in (regnancy+ Br 5 ;ae'atol 19H4I !E) 233 241+ H+ Persson BB0 #tenberg P0 ;ol'berg P et al+ /ransa'idating enQy'es in 'aternal (las'a and (lacenta in h&'an (regnancies co'(licated by intra&terine gro*th retardation+ 5 $e" Physiol 19H0I 2) 3- 4E+ 79+ Bee C30 Chi C0 Pa"ord #R et al+ /he obstetric and gynaecological 'anage'ent o6 *o'en *ith inherited bleeding disorders re"ie* *ith g&idelines (rod&ced by a tas.6orce o6 8= ;ae'o(hilia Centre $octors: OrganiQation+ ;ae'o(hilia 200EI 12) 301 33E+ Z10+ ;ellgren 1 & Blo'bac. 1+ #t&dies on blood coag&lation and >brinolysis in (regnancy0 d&ring deli"ery and in the (&er(eri&'+ Gynecol Obstet 4n"est 19H1I 12) 141 1!4+ 11+ Chi C0 Bee C30 #hiltagh F et al+ Pregnancy in carriers o6 hae'o(hilia+ ;ae'o(hilia 200HI 14) !E E4+ 12+ =%ellberg 80 3ndersson FA0 Rosen # et al+ 3PC resistance and other hae'ostatic "ariables d&ring (regnancy and the (&er(eri&'+ /hro'b ;ae'ost 1999I H1) !2- !31+ 13+ =r&itho6 A=0 /ran?/hang C0 G&dinchet 3 et al+ 2ibrinolysis in (regnancy) a st&dy o6 (las'inogen acti"ator inhibitors+ Blood 19H-I E9) 4E0 4EE+ 14+ Bo&'a BF & 1ei%ers 5C+ Fe* insights into 6actors a66ecting clot stability) a role 6or thro'bin acti"atable >brinolysis inhibitor (/324I (las'a (rocarbo>y (e(tidase B0 (las'a (rocarbo>y(e(tidase 80 (rocarbo>y(e(tidase R)+ #e'in ;e'atol 2004I 41) 13 19+ 1!+ $onohoe #0 D&enby #0 1ac.ie 4 et al+ 2l&ct&ation in le"els o6 anti(hos(holi(id antibodies and increased coag&lation acti"ation 'ar.ers in nor'al and he(arin treated anti(hos(holi(id syndro'e+ B&(&s 2002I 11) 11 20+

P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2 1E+ 2rancalanci 40 Co'eglio P0 3lessandrello Biotta 3 et al+ $?di'er (las'a le"els d&ring nor'al (regnancy 'eas&red by s(eci>c AB4#3+ 4nt 5 Clin Bab Res 199-I 2-) E! E-+ 1-+ ChabloQ P0 Reber G0 Boehlen 2 et al+ /324 antigen and $?$i'er le"els d&ring nor'al (regnancy and at deli"ery+ Br 5 ;ae'atol 2001I 11!) 1!0 1!2+ 71H+ $o&glas 15+ /he &se o6 ne&ra>ial anesthesia in (art&rients *ith thro'bocyto(enia) *hat is an adeC&ate (latelet co&nt[ 4n ;al(ern #; & $o&glas 15 (eds+)+ A"idence?based obstetric anesthesia+ O>6ord) B15 boo.s0 200!0 ((+ 1E! 1--+ 19+ Practice g&idelines 6or obstetric anesthesia+ 3n &(dated re(ort by the 3'erican #ociety o6 3nesthesiologists tas. 6orce on obstetric anesthesia+ 3nesthesiology 200-I 10E) H43 HE3+ 20+ Ra'anathan 50 #ibai B10 <&t / et al+ Correlation bet*een bleeding ti'es and (latelet co&nts in *o'en *ith (re?ecla'(sia &ndergoing cesarean section+ 3nesthesiology 19H9I -1) 1HH 191+ 21+ 1c$onagh R50 Ray 5G0 B&rro*s R2 et al+ Platelet co&nt 'ay (redict abnor'al bleeding ti'e a'ong (regnant *o'en *ith hy(ertension and (re?ecla'(sia+ Can 5 3naesth 2001I 4H) !E3 !E9+ 22+ Rodgers RPC & Be"in P5+ 3 critical rea((raisal o6 the bleeding ti'e+ #e'in /hro'b ;e'ost 1990I 1E) 1 20+ 23+ Peterson P0 ;ayes /A0 3r.in C2 et al+ /he (reo(erati"e bleeding ti'e lac.s clinical bene>t+ 3rch #&rg 199HI 133) 134 139+ 24+ 1allet #< & Co> $53+ /hro'boelastogra(hy+ Br 5 3naesth 1992I E9) 30- 313+ 2!+ #a'a'a C1+ #ho&ld a nor'al thro'boelastogra' allo* &s to (er6or' a ne&ra>ial bloc.[ 3 strong *ord o6 *arning+ Can 5 3naesth 2003I !0) -E1 -E3+ 2E+ $a"ies R0 2ernando R & ;all*orth #P+ ;e'ostatic 6&nction in healthy (regnant and (re?ecla'(tic *o'en) 3n assess'ent &sing the (latelet 2&nction 3nalyQer (P23T)and /hro'boelastogra(h (/AGT)+ 3nesth 3nalg 200-I 104) 41E 420+ 2-+ 1cCrae =R+ /hro'bocyto(enia in (regnancy) di66erential diagnosis0 (athogenesis and 'anage'ent+ Blood Re"+ 2003I 1-) - 14+ 2H+ #ainio #0 =e.o'a.i R0 Rii.onen # et al+ 1aternal thro'bocyto(enia at ter') a (o(&lation based st&dy+ 3cta Obstet Gynecol #cand 2000I -9) -44 -49+ 29+ B&rro*s R2+ Platelet disorders in (regnancy+ C&rr O(in Obstet Gynecol 2001I 13) 11! 119+ 30+ Beilin N0 \ahn 5 & Co'er6ord 1+ #a6e e(id&ral analgesia in thirty (art&rients *ith (latelet co&nts bet*een E90000 and 9H0000 ''O3+ 3nesth 3nalg 199-I H!) 3H! 3HH+ 31+ =elton 5G+ /he serological in"estigation o6 (atients *ith a&toi''&ne thro'bocyto(aenia+ /hro'b ;ae'ost 199!I -4) 222 233+ 32+ G&idelines 6or the in"estigation and 'anage'ent o6 idio(athic thro'bocyto(enic (&r(&a in ad&lts0 children and in (regnancy+ Br 5 ;ae'atol 2003I 120) !-4 !9E+ 33+ 2elbinger /9+ Ba(arosco(ic s(lenecto'y in a (regnant (atient *ith i''&ne thro'bocyto(enic (&r(&ra+ 4nt 5 Obstet 3nesth 200-I 1E) 2H1 2H3+ 34+ Beilin N0 Bodian C30 ;addad A1 et al+ Practice (atterns o6 anesthesiologists regarding sit&ations in obstetric anesthesia *here clinical 'anage'ent is contro"ersial+ 3nesth 3nalg 199EI H3) -3! -41+ 3!+ Breen /90 1cFeil / & $ieren>eld B+ Obstetric anesthesia (ractice in Canada+ Can 5 3naesth 2000I 4-) 1230 1242+ 3E+ <igil?$e Gracia P0 #il"a #0 1ont&6ar C et al+ 3nesthesia in (regnant *o'en *ith ;ABBP syndro'e+ 4nt 5 Gynaecol Obstet 2001I -4) 23 2-+ 3-+ 1oen <0 $ahlgren F & 4restedt B+ #e"ere ne&rological co'(lications a6ter central ne&ra>ial bloc.ades in #*eden 1990? 1999+ 3nesthesiology 2004I 101) 9!0 9!9+ 3H+ #har'a #=0 Phili( 50 9hitten C9 et al+ 3ssess'ent o6 changes in coag&lation in (art&rients *ith (reecla'(sia &sing thro'boelastogra(hy+ 3nesthesiology 1999I 90) 3H! 390+ 39+ Orli.o*s.i CAP0 Roc.e $30 1&rray 9B et al+ /hro'boelastogra(hy changes in (re?ecla'(sia and ecla'(sia+ Br 5 3naesth 199EI --) 1!- 1E1+ 740+ Bee 5?9+ "on 9illebrand $isease0 ;e'o(hilia 3 and B and other 6actor de>ciencies+ 4nt 3nesthesiol Clin 2004I 42) !9 -E+ 41+ Ragni 1<0 Bonte'(o 23 & ;assett 3C+ "on 9illebrand disease and bleeding in *o'en+ ;ae'o(hilia 1999I !) 313 31-+ 742+ =adir R30 Bee C30 #abin C3 et al+ Pregnancy in *o'en *ith "on 9illebrand:s disease or 6actor L4 de>ciency+ Br 5 Obstet Gynaecol 199HI 10!) 314 321+ 43+ 1ann&cci P1+ ;o* 4 treat (atients *ith "on 9illebrand disease+ Blood 2001I 9-) 191! 1919+ 44+ Ray 5G+ $$3<P &se d&ring (regnancy) an analysis o6 its sa6ety 6or 'other and child+ Obstet Gynecol #&r" 199HI !3) 4!0 4!!+ 4!+ 1ann&cci P10 Canciani 1/0 Rota B et al+ Res(onse o6 6actor <444,"on 9illebrand 6actor to $$3<P in healthy s&b%ects and (atients *ith ;ae'o(hilia 3 and "on 9illebrand:s $isease+ Br 5 ;ae'atol 19H1I 4-) 2H3 293+ 4E+ Cata 5P0 ;anna 30 /etQla66 5A et al+ #(inal anesthesia 6or a cesarean deli"ery in a *o'an *ith ty(e?21 "on 9illebrand disease) case re(ort and 'ini?re"ie*+ 4nt 5 Obstet 3nesth 2009I 1H) 2-E 2-9+ 4-+ <ar&ghese 5 & Cohen 35+ A>(erience *ith e(id&ral anaesthesia in (regnant *o'en *ith "on 9illebrand disease+ ;ae? 'o(hilia 200-I 13) -30 -33+ 4H+ $har P0 3bra'o"itQ #0 $i1ichele $ et al+ 1anage'ent o6 (regnancy in a (atient *ith se"ere hae'o(hilia 3+ Br 5 3naesth 2003I 91) 432 43!+ 49+ R&ssell \0 Riconda $0 Pollac. B et al+ /hro'bosis in a (regnant he'o(hilia 3 carrier a6ter intra(art&' reco'binant 6actor <444+ Obstet Gynecol 200!I 10!) H-! H-E+ 7!0+ Bolton?1aggs P;B0 Perry $50 Chal'ers A3 et al+ /he rare coag&lation disorders?re"ie* *ith g&idelines 6or 'anage'ent 6ro' the 8nited =ingdo'+ ;ae'o(hilia Centre $octors: Organisation+ ;ae'o(hilia 2004I 10) !93 E2H+ !1+ Girola'i 30 #candellari R0 Bo'bardi 31 et al+ Pregnancy and oral contrace(ti"es in 2actor < de>ciency) a st&dy o6 22 (atients (>"e ho'oQygotes and 1- heteroQygotes) and re"ie* o6 the literat&re+ ;ae'o(hilia 200!I 11) 2E 30+ !2+ O:Connell 1P0 Aogan 10 1&r(hy =1 et al+ #ol"ent?detergent (las'a as re(lace'ent thera(y in a (regnant (atient *ith 2actor < de>ciency+ 5 1atern 2etal Feonatal 1ed 2004I 1E) E9 -0+ !3+ <ellinga #0 #teel A0 <angenechten 4 et al+ #&ccess6&l (regnancy in a (atient *ith 6actor < de>ciency) case re(ort and re"ie* o6 the literat&re+ /hro'b ;ae'ost 200EI 9!) H9E H9-+ !4+ =&l.arni 330 Bee C3 & =adir R3+ Pregnancy in *o'en *ith congenital 6actor <44 de>ciency+ ;ae'o(hilia 200EI 12) 413 41E+ !!+ 5i'ineQ?N&ste <0 <illar 30 1orado 1 et al+ Contin&o&s in6&sion o6 reco'binant acti"ated 6actor <44 d&ring caesarean section deli"ery in a (atient *ith congenital 6actor <44 de>ciency+ ;ae'o(hilia 2000I E) !HH !90+

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P+ /hornton0 5+ $o&glas , Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 339 3!2

7!E+ 9elsh 30 1cBintoc. C0 Gatt # et al+ G&idelines 6or the &se o6 reco'binant 6actor <44 in 'assi"e obstetric hae'orrhage+ 3&st F \ 5 Obstet Gynaecol 200HI 4H) 12 1E+ !-+ Chiossi G0 #(ero 530 Asa.a A5 et al+ Plas'a e>change in a case o6 se"ere 6actor L de>ciency in (regnancy) critical re"ie* o6 the literat&re+ 3' 5 Perinatol 200HI 2!) 1H9 192+ !H+ #ingh 30 ;arnett 150 Connors 51 et al+ 2actor L4 de>ciency and obstetrical anesthesia+ 3nesth 3nalg 2009I 10H) 1HH2 1HH!+ !9+ 1c1ahon 15 & 5a'es 3;+ Co'bined de>ciency o6 6actors 440 <440 4L0 and L (Borgsch&lte?Grigsby de>ciency) in (regnancy+ Obstet Gynecol 2001I 9-) H0H H09+ E0+ Girola'i 30 \occa F0 Girola'i B et al+ Pregnancies and oral contrace(ti"e thera(y in se"ere (ho'oQygo&s) 2L44 de>ciency) a st&dy in 12 (atients and a re"ie* o6 the literat&re+ 5 /hro'b /hro'bolysis 2004I 1H) 209 212+ E1+ Chang 50 Ala'?A"ans0 Berg C5 et al+ Pregnancy related 'ortality s&r"eillance?8nited #tates0 1991 1999+ 119R #&r"eill #&'' 2003I !2) 1 H+ E2+ $ri6e 5+ /hro'boe'bolis'+ 4n) 9hy 'others die+ Re(ort on con>dential enC&iries into 'aternal deaths in the 8nited =ingdo' 2002 2004+ Bondon) RCOG Press0 2004+ E3+ 1artinelli 40 Begnani C0 B&cciarelli P et al+ Ris. o6 (regnancy?related "eno&s thro'bosis in carriers o6 se"ere inherited thro'bo(hilia+ /hro'b ;ae'ost 2001I HE) H00 H03+ E4+ Gher'an RB0 Good*in /10 Be&ng / et al+ 4ncidence0 clinical characteristics0 and ti'ing o6 ob%ecti"ely diagnosed "eno&s thro'boe'bolis' d&ring (regnancy+ Obstet Gynecol 1999I 94) -30 -34+ E!+ $&hl 350 Paidas 150 8ral #; et al+ 3ntithro'botic thera(y and (regnancy) consens&s re(ort and reco''endations 6or (re"ention and treat'ent o6 "eno&s thro'boe'bolis' and ad"erse (regnancy o&tco'es+ 3' 5 Obstet Gynecol 200-I 19-) 4!-+ e1 e21+ ]EE+ 1iddeldor( #0 Bibo&rel A50 ;a'&lya. = et al+ /he ris. o6 (regnancy?related "eno&s thro'boe'bolis' in *o'en *ho are ho'oQygo&s 6or 6actor < Beiden+ Br 5 ;ae'atol 2001I 113) !!3 !!!+ E-+ Pabinger 4+ /hro'bo(hilia and its i'(act on (regnancy+ /hro'b Res 2009I 123) #1E #21+ 7EH+ Royal College o6 Obstetricians and Gynaecologists+ /hro'bo(ro(hyla>is d&ring (regnancy0 labo&r and a6ter nor'al "aginal deli"ery+ G&ideline no+ 3-+ Bondon) RCOG0 2004+ 3"ailable at0 ***+rcog+org+&.+ E9+ #a'a'a C10 3lbalade%o P0 Benha'o& $ et al+ <eno&s thro'boe'bolis' (re"ention in s&rgery and obstetrics) clinical (ractice g&idelines+ A&r 5 3naesthesiol 200EI 23) 9! 11E+ -0+ Ginsberg 50 ;irsh 5 & 2i6th 3CCP+ Consens&s con6erence on antithro'botic thera(y+ 8se o6 antithro'botic agents d&ring (regnancy+ Chest 199HI 114) !24 !31+ -1+ Ba&sersachs R10 $&denha&sen 50 2aridi 3 et al+ Ris. strati>cation and he(arin (ro(hyla>is to (re"ent "eno&s thro'bo? e'bolis' in (regnant *o'en+ /hro'b ;ae'ost 200-I 9H) 123- 124!+ -2+ =o(( #B & ;orloc.er //+ 3nticoag&lation in (regnancy and ne&ra>ial bloc.s+ 3nesthesiol Clin 200HI 1E) 1 22+ -3+ Gogarten 9+ /he in>&ence o6 ne* antithro'botic dr&gs on regional anesthesia+ C&rr O(in 3naesthesiol 200EI 19) !4! !!0+ 7-4+ ;orloc.er //0 9edel $50 BenQon ; et al+ Regional anesthesia in the anticoag&lated (atient) de>ning the ris.s+ Reg 3nesth Pain 1ed 2003I 2H) 1-2 19-+