Hypofibrinogenemia in pregnancy and the puerperium

HYPOFIBRINOGENEMIA ROBERT

A.

Et.

IN PREGNANCY KINCH,

F.R.C.S.(C),

M.H.(:.O.G.,

AND

THE

PUERPERIUWt

TORONTO,

;Presented at thr Eleventh .\nnual RIeetin$+ uf the Sucicty of Obstetricians cologists of Canada, June 17, 18, and 19, 1955, Huntsville, Ontario. 746

ONTARIO

and

Gynae-

Volume

Number

71 4

HYPOFIBRTNOGENEMTA

45

LX

FIBRINOGEN

C&SES

PREGNANCP

ANI)

PUERPERITM

IN PREGNANCY

313TESTS

POST PARTUt.

GESTATION Fig. TABLE

I.

AVERAGE

FIBRINOGEK

1. LEVELS

DVRING

PKEGA-ANCY

FIBRINOGEN (MC./lo(j JC'erk

of Pregnrcwy.18 20 42 24 26

473 335

28

36U 360 390 455

300 315

30 32 34

Pnys

ii TPlTll Post 1 3 6

470 460 365 Pfl~tum420 435 440

LEVEl> C.C.)

74-i

748

Etiology of ~I-ly2)ofib~inogener,liu.-‘Vhe etiology of the syndroltlc~ rt~ltulins controversial, but is fully covered in thtr writings of Reid.“-” ‘I’hc~ comttlon factor in all these conditions is t,he rcndy availability of tissue thro~~~bul~l;~sti]I from damaged tleciclua or placenta in intimat,cl contact with the opchtl mal.(~rt1al venous sinuses. Tissue thromboplastin, entering the blootl StIY~alJl, initiates thtx sc~nsitiv(~ blood coagulation mechanism. This causes est,ensirc> intravascular clotting with the production of microscopic fibrin emboli anal a rclsultant depletion of blood fibrinogen.“‘* I1 Thcsc microscopic fibrin t~mboli cm1 up mainly in the lircar and lungs, where t,hcy have been found post mortem in cases of eclampsia and abruptio pla.centac.l’, I2 Animal txpcarimcnts using thromboplastin, amniotic fluid, mcc’onium, do:tdidual or placental estractP1” have all reproduced t,hc syndrome of cxtensivc formation of intravascular microscopic fibrin emboli followed by defibrination of the blood. Page,ly using radioactive-iodine-tagged thromboplastin, ha.s found that the bulk of the substance ends up in the liver and lungs. In certain cases 8. 2C’particularly those associated with intrautcrint death. a circulating fibrinoiysin is reported. It may be postulated that the osccssivc intravascular fibrin present may stimulate the protective fibrinolysin systeln (Lscessively in an attempt to keep the circulation free of clots. Na,ture of the Coagulation Defect.--From the therapcut,ic point of view, it is more important to establish the naturcb of t,hc clotting defect than to tlctermine its etiology. Hypofibrinogenemia seems to IJ~ the main factor? but, this does not account aclequat,cly for all the cases. It may not be th(J sol(. defect. We have observed many cases associated with sutlden severe blood loss in which the fibrinogen level is critically low, but in which the blood coagulation Jackson and associat&’ reported a case in which, ~n~~~cds satisfactorily. following an intrauterine death, the fibrinogen lrvt>l was consistently below the critical va,luc, yet bleeding did not occur at, dclivcry. In t,hcir series. the>are convinced that unless hypofibrinogenemia is accompanied by serious thrombocytopenia there is no real clangrr of failure of c4oagulation. Sccgers?” reported a case of abruptio placcntac in which the coagulation d(Jfect lay in the Ac-globulin or Factor V. Other authorities”* 7, ‘L ” c~r~~nsitlcr that a circulating fihrinolysin is the responsible factor. In view of these facts, mcrcly replacing the fibrinogen loss may not POP rect the situation. We must try to replace the cntirc coagulation scheme in active -form. Principles of l’herapy.--When confronted wit,h hypofibrinogenemia w(a have obta.ined our best results by rapid administration of freshly t.akcn vitrated whole blood. As a prrca,ution, after every 2,000 C.C. of blood we havt> given 10 C.C. of calcium glaconntc intravenously, in ortlcr t,o combat. t,hc rlffect of ex(‘ess sodium citrate.

Volume Number

7I 1

HYPOFIBRTNOGENEMTA

IX

PREGNANCY

AND

PUERPERTUM

749

In nearly every case, a large amount of blood has been lost. The danger of overloading with massive rapid replacement is consequently minimal. WC have a readily available source of fresh whole blood obtainable from our inthat of Welxr,z3 replacement of fibrintern staff. ln many series, particularly ogen in the indicated dose of 4 to 6 Cm. dissolved in dcstrosc in water has lxen used exclusively and effectively. As in most newly described medical syndromes, the more that hypofibrinogcncmia is sought after, the more cases arc found. Now that fibrinogen is more readily available, there is a temptation to use it when it is not indicated, Bearing in mind the admitted risk of hoor perhaps when contraindicated. mologous serum jaundice from this preparation, it would be well to caution to consider the use of against its indiscriminate use. We would do better fresh blood as the definitive treatment of hypofibrinogenemia, reserving fibrinogen for emergency use where fresh blood is either unavailable immediatelyor ineffective. Diay,nosis.-The diagnosis in these cases is made most practically by use of the clot observation test. A. Failure of freshly aseptically drawn venous blood to clot when incubated at 3’i’O C. in half an hour, or formation of a normal clot with poor clot retraction and evidence of gross hemolysis in the serum is believed sufficient evidence that the circulating blood fibrinogen is reduced to a critical level. This condition may make effective hemostasis impossible. B. If the clot when incubated at 37O C. for one hour either disintegrates or dissolves, a low level of fibrinogen also is suggested. Blood should also be taken for laboratory confirmation of the fibrinogen level, and a platelet count carried out. Piibrinadez.-The addition of purified human thrombin to the serum of the The rate at which the clot is produced is propatient will produce clotting. More important is the quality portional to the amount of fibrinogen available. of the fibrin clot when compared with that of a control subject. This rapid quantitative test can be carried out by E’ibrinadcx,” the possibilities of which So far, the clinical correlation is reasonably we are at present investigating. satisfactory, but more work is being clone on this problem.

Clinical

Discussion

Abruptio Placentae.-Twenty cases of abruptio placentae have been investigated with regard to fibrinogen levels. The normal delivery level was taken as 325 mg. per 100 C.C. There were 7 cases of mild abruptio placentae, 2 of which were toxemic. The average fibrinogen levels were 460 mg. per 100 C.C. No bleeding tendency was noted in these cases. There were 13 cases of severe abruptio placentae, 3 of which were toxemic. The average fibrinogen level was 190 mg. per 100 cc. Seven patients displayed fibrinogen levels of 150 mg. or below, all of whom gave anxiety by virtue of varyin g degrees of failure of coagulation. These figures support Reid’s’ contention that the best classification of abruptio placentae, from the point of view of management, is not on the basis of toxemic or nontoxemic cases, but into those with normally clotting blood, and those in which clotting power is deficient or abnormal. This is It is among the cases with a coagulation defect that illustrated in Table III. the maternal deaths occur. This is either directly from t)he hemorrhagic tcndcncy, or indirectly from renal or pit,uitnry insufficiency. -*Ortho

Pharmaceutical

Corporation.

Volunleil Number

4

HYPOFIBRINOGENEML-A

IN

PREGNAKCY

ANI)

PUERPERIUM

751

ology. In 2 cases, critical levels were observed about one month before delivery, but recovery of the normal level subsequently occurred. The other 8 cases were associated with normal levels and in these there was minimal bleeding. Speculation as to why one patient develops the coagulation defect and others (10 not is interesting. In the majority of ceases in which there is no tlcfect. the placenta appears firm and dry, suggesting that the placenta ant1 fetus arc retained as an inrrt mass in the uterus-so dead that nothing can 1~ absorbed from it. M OW iliWstigatiOI1 k rlcYd(vl ill+AJ this aspect Of the prObl('lll. In view of the danger of sepsis, thcrc is a natural rcluctancc to inclucdc> labor by rupture of th(J nlembrancs in casts of int~rauttrinr tlcath. It might bc argued, however, that since the development of the hypofibt,inogcrlerllia may b(, proportic~nal to the kngt,h of time the tlr~l fetus is rctninrtl, the sooner the prrgnancy is tcrminntctl thr lwttcr. In 4 of our c’ascs the, tlcnd fetus was Wtaincd for OW’I thirty days, ant1 in our cxperic>nccx SO long as the fibrinngcn l(LUPl is consistently ov(‘i’ 150 liig. pal* cent w(’ Call ec~llfitl~~lltl~ 110 PScchssive ltlcc~~ling will OV:‘W I’t’om this cause’. 1-n view ol’ tEicsc> factors the l)c+tclr tiianngcmcnt is basc4 on careful and frcquc~nt~ following of the fibrinog(~n levels at least twivo wc~~lrly. So long as the 1~~1 is maintained, no trouble nerd be anticipatctl. If the level falls, the patient should lw admitted for daily obsc~r~ation, and atlcquate quantities of fibrinogen ant1 fresh blood maclc~ :~vnilable for her dclivcry. ilnmiotic FlGd E’?)tboZisl)l.-(~)nly one point need lw st,rcssed in regarcl to predisposing factors in these tragic cases. In all, tumultuous cont,ractions, accompanying rapid multiparous labor following rupture of t,hc membranes. have been observed. Careful analysis of individual case reports in the literatures, 23. 26,37 reveals that in almost every case pituitary extract has been eshibit,ed, in the majority of instances in a multiparous labor which was already proccccling rcwxmnhly normally. This prnctirv cannot 1~ ton Arongly conc1et1111cc1. Delay& or Late Postpwtun~ IIelnol.r,k,rrg~.-I)clayctl postpartum hemorrhage is most often associated with retention of nrcrotic clccitlual or placental fragments. The prcrtquisit,cs a,~ again pr~scnt, for matc>rnnl autoc~st~*action. Tn fact, in our csgcricncc and in rcpnrts ~'YOIII the litrratnre, coagulation deI’ects have acc~ol~~panicd only this type of postpartum h(~ttlorrhage.“~ ” 111 these cases, bleeding starts typically hctwwn the sixth and t,welfth post,partutn days. An attempt is first made> to control it, by imdical nlci%SUWS. i.c., with Ergotrate and probably without hospitalization. Tf a coagulation def(lct is present, this is a dangerous course of action. Not only dots it prolong the opportunity for dissemination of throlnhopl;lst,in, but, the production of’ utcrinc contractions may dcfinitcly hasten th(J prnwss. On hospitalization, ovcrnnskty to explore the uterus with a curette, without a preliminary thorough invcstigatinn . of status, May . the> hcmatnlogical greatly increase the bleeding. In the maJorlty nt C:LWS, 11t operation bleeding is found to 1~ coming from a wc~ll-cnntr,azctcd uterus, together with oozing from the ccrvis, vaginal walls, and episiotomy incision. Occasionally. curetso ;I hysttwv4nmp is p(‘rform(d, nnnthcr intagc and packing ar’c incffcctivc, stnncc nf kansfcr of tlic blectling point. The logical thcra.pentic~ approach to t,hv p~h1c111 is first to 100k fw n coagulation defect, wit,h the rcc~otnmende(l tests. If it is present,, it, must bc cnrrcctcd by rapid transfusion with fresh blood or by tht use of fibrinogen. This should be clnnc hefore the utcrns is esplorccl, rather than when we arc once confronted by the condition as n result of csploration of the uterus. Stilt<'

that

11lood dotting is assured, the dcrus NII t)c csplorrcl safely, and should b(s csplorcd, in orrlcr to rcmovc t,hc nccrot,ica tissue rcqonsible for the situation. Delayed postpartum h(morrhagc is M IV. c:oa.gulatiun clcftd accompanying it is even more rare, so that a high intlcs nf suspicion is cnllcrl for in (~\-(~I*? ra~sc. to be preparccl.

Summary 1. The tot,al protein am1 fibrinogen Icvels have been followed in -0 v:Is(‘s of normal pregnancy, labor, and in the car*ly pucrperimn. The protcain 1~~~~1s show a slightly downward trend with a rise to normal just prior to clclivc~q-. the fibrinogen levels show an upward trend to tlelivcry. The ~vc~~~+x fibt*inogcn lcv-cl at delivery is 3% mg. per 100 C.C. 2. I~‘rcsh 1~100~1is the physiological therapy for coagulation det’c~i s tluring pregnancy. 1”rcsh blootl ijnil fibrinogen shouhl 1~1 readily ava.ilablt> ill (PI)stctrical units. 3. The classification of abruptio placcntac UII the basis 01 gootl OI* poor clotting power of the blood is recommcntl~~cl. 4. The necessity for complete restoration of clotting power in these serious casts and t.he danger of operating I~fore this has been carrid o\it arc strcsscd. 5. With a dead f&us, so long as the fibrinogen level is maintained. interference is unjustifiable. 6. The coincidence of thn nonintli~at~ed usi~g(~ of pituitary cl?;tr;lc$ ;rncl atnniot,ic fluid embolism is pointed out. 7. The managtmcnt~ of sc~~mdary l)ost,l)iIrtLUI1 h(~mor*rhag~~ asscAatc,fl with coagulation defcct,s is discussed. My thanks arc due to I)r. 1,. ‘I’. Armst.rong, Chief and Gynaecology at the Tororlt~J IVestern TTospital antI me to use their cases. 1?1,r tec~huical help I am inrlc~l~td and their technicians, and to I)r. .lohn Gillies.

of the Ikpartmerlt t.o those physicians to

Mr.

IL

13oylr,

of Ohstetriqas who alloyvrtl Mr. K. N. Ro).

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AND

PCERPERlURf

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195-l.