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Treatment of 51 Pregnancies with Danaparoid Because of Heparin

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Treatment of 51 Pregnancies with Danaparoid Because of Heparin ©2005 Schattauer GmbH,Stuttgart Blood Coagulation, Fibrinolysis and CellularHaemostasis Treatment of 51 pregnancies withdanaparoidbecause of heparin intolerance EdelgardLindhoff-Last1 ,Hans-Joachim Kreutzenbeck2 ,Harry N. Magnani3 1 Division ofVascular Medicine,Department of Internal Medicine,University Hospital Frankfurt, Germany 2 MedicalDepartment, Celltech, Essen, Germany 3 Clinical Consultant Marketing, OrganonBV, Oss,The Netherlands Summary Pregnant patients withacute venous thrombosis or ahistoryof required (3/14) or an adverse eventled to atreatment discon- thrombosis mayneed alternative anticoagulation, when heparin tinuation (11/14).Four maternal bleeding events were recorded intolerance occurs. Onlylimited dataonthe useofthe hepari- during pregnancy, deliveryorpostpartum, twoofthemwere noiddanaparoid areavailable in literature.We reviewedthe use fatal duetoplacental problems.Three fetal deathswererec- of danaparoid in 51 pregnancies of 49 patients identified in litera- orded,all associated with maternal complications antedating da- turebetween 1981 and 2004.All patients had developed hepa- naparoiduse.Danaparoid cross-reactivity was suspectedin4 rin intolerance (32 duetoheparin-induced thrombocytopenia, HITpatientsand 5non-HITpatientswith skin reactions and was 19 mainlydue to heparin-induced skin rashes)and had acurrent confirmedserologicallyinone of the twoHIT patients tested.In and/or pasthistoryofthromboembolic complications.The initial none of fivefetal cordblood- andthree maternal breast milk- danaparoid doseregimens ranged from 1000 to 7500 U/day ad- samplesanti-Xa activity transferwas observed.Inconclusion da- ministereds.c.ori.v..Themedian duration of danaparoid use was naparoid can be usedasanalternativeantithrombotic agentin 10 weeks.Danaparoid was useduntil deliveryofahealthyinfant pregnant womenwith high thrombotic riskand intolerance to in 37 pregnancies. In the remaining 14 pregnancies it was heparins. stoppedearlier, becauseanticoagulant treatment was no longer Keywords Pregnancy, heparin-induced thrombocytopenia,heparin-induced skin rash,danaparoid, heparin-intolerance ThrombHaemost 2005; 93: 63-9 Introduction Treatment alternatives forpregnant patients with heparinin- tolerance and ahigh risk of thrombosis are limited. Thus the pur- The antithromboticagent danaparoid is amixtureofglycosami- pose of our study wastoreviewthe efficacyand safety of dana- noglycans with an averagemolecular weight of 6000daltons.It paroid treatment in this clinicalsetting. mainlyconsistsofheparan sulphate (84%)and dermatan sulphate (12%)and inhibits factor Xa viaantithrombin (AT) and Methods thrombin via both AT and heparincofactor II.The ratio of anti- Xa to anti-IIa activity is approximately ≥ 22:1. Clinical develop- Literature search in Medline and Medscape wasperformed to ment of danaparoidfor thrombosis prophylaxis started in 1981. detect pregnancies treatedwith danaparoidbetween 1981 and Its lowdegree of sulphation and absence of heparinare respon- 2004.The following terms were used for search: danaparoid, Or- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. sible forits lowpotential of cross-reactivity with heparin-in- garan, Lomoparan, heparinoid, Org10172, HIT, heparin, throm- ducedantiplatelet antibodies. Thereforeitwas used as an alter- bocytopenia, heparin-induced thrombocytopenia, lowmolecular native anticoagulant in patients with heparin-induced throm- weight heparin, lepirudin,argatroban,skin-necrosis, necrosis, bocytopenia(HIT), whowere enrolledinacompassionate-use pregnancy, thrombosis. programme (1, 2). It wasfirst approvedfor HITin1994 and is In addition unsolicitedpost-marketing reportsand the dana- availableinmanycountries world-wide. paroid compassionate-use programme were screened for preg- Correspondence to: Received June 7, 2004 PD Dr.med. EdelgardLindhoff-Last Accepted after resubmission October 5, 2004 Division of VascularMedicine Department of InternalMedicine Prepublished onlineNovember 8, 2004 DOI:10.1160/TH04–06–0349 University Hospital Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt/ Main,Germany Te l.: +49696301 5096, Fax: +49 69 6301 7219 E-mail: [email protected] 63 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy Ta ble1:Age and presenting clinical prob- lems before startoftreatment. nant patients. Case reports were only includediftheyprovided i.v.bolus of 750 Uwas usually applied) or for thrombosis treat- detailed information about intensity and duration of medication ment (i.v.bolus of 2500 Ufollowedbyaninfusion-rate of 400 and the outcome of danaparoidtreatment.Duplicatedcasere- U/h for 4h, then 300 U/h for 4hfollowedbyamaintenance infu- portswere excluded. sion rate of 150–200U/h) were used. Confirmation of suspectedHIT Monitoring of anti-Xa activity SuspectedHIT wasconfirmed serologically usingthe platelet ag- Amidolytic anti-Xa activity wasmeasured in maternal plasma, gregation test (PAT)(3), the heparin-induced plateletactivation breast milkand fetal cordblood by modifications of the method assay(HIPAA) (4), theenzyme-linked immunoassay(ELISA) of Teienand Lie (7). (5) or the serotoninreleaseassay(SRA)(6). The same serologi- calmethods were used to test for danaparoidcrossreactivity.In Results This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. some patients with HITthe diagnostic method wasnot specified. Patientpopulation Confirmation of thromboembolic complications Fifty-one reportsofdanaparoid use in pregnancyin49women DVTwas confirmed by venographyorcompression ultrasound could be included. Twenty-onepregnancies were described in 19 and pulmonaryembolismbyhigh probability ventilation/perfu- independent publications (8–26), while 25 pregnancies were sion scans. One venous thrombosis wasdiagnosedbyclinical documented within the compassionate-use programme, which symptoms only. Arterial thrombosis wasidentified mainlyby includedfour published case-reports (13, 20–22). In addition, clinical evidenceofischemia and surgery,while computer to- five unsolicited post-marketing seriousadverse events, reported mographywas used fordiagnosis of intracranialarterial or ve- spontaneouslytoOrganonbetween 1981 and 2004,were in- nous thrombosis. cluded in the analysis. Thirty-twopregnancies in 30 womenwere associatedwith an Dosingofdanaparoid acuteorapasthistoryofHIT.Inthe remaining 19 pregnancies In most cases routine treatment regimens for thrombosis prophy- danaparoid wasstarted because of heparin intolerance (mainly laxis (750Us.c., b.d. or t.i.d.,inaddition to the first s.c. dose an skin reactions). Four patients had beenpreviouslytreated with 64 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy Ta ble2:Intensityand overallduration of danaparoid use. danaparoid and in twoHIT patients danaparoidwas used during ean sections (12,14, 16, 17). In these patients danaparoid was twin pregnancies (10, 25). stopped24–48h pre-operatively and restarted 3–6hours post- Threepublications were excluded fromthe analysis, either operatively.The duration of danaparoid use after delivery varied because the number of treatedpatients, treatment intensity/du- from 4daysto6weeks (median 1week). ration and outcome remained unknown(27) or because of dana- paroid use solelypost-partum (28, 29). Anti-Xa activity measurements Maternalblood Demographicdata Plasmaanti-Xa activities were reported in 22/51(43.1%) preg- Demographic data of patients before starting danaparoidtreat- nancies. During treatment of acute thrombosis the anti-Xaactiv- ment are summarised in Table1.Coagulation problems includ- ity wasbetween 0.4–0.6 U/ml and during long termthrombosis ing antithrombin- or protein S- deficiency, disseminated intrav- prophylaxis between0.1 –0.3 U/ml. In twopregnancies plasma ascular coagulation (DIC), heterozygote Factor VLeiden mu- anti-Xa levels were reported closetobleeding episodesand were tation, prothrombin mutation or antiphospholipid antibodies between 0.9–1.2 U/ml (9) in one case and 0.6 U/ml in the sec- were present in 45% (23/51) of pregnancies. All patients had ond case (unsolicited post-marketing report). either ahistoryofvenous or arterial thromboembolism in apre- viouspregnancyorpresentedwith arecent episode of throm- Cord blood andbreast milk boembolism. Cordblood of five infantswas testedatterm. No anti-Xa-activ- ity could be detected (16, 20,22). In addition in threelactating Timing, intensity and duration of danaparoid use women(12, 24, 25) no anti-Xaactivity wasfound in breast milk Danaparoid treatment data are summarised in Tables 2and 3. despite maternal danaparoid blood levels of 0.15–0.45 U/ml. The initial dosing regimens varied from 1000 to 7500U/day. In 26 pregnancies danaparoidwas started intravenouslytotreat Pregnancyoutcomes This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. acutethromboembolicevents. The remaining patients received In the 37 pregnancies carriedtotermduring or soon after dana- danaparoidfor thrombosis prophylaxis. paroid treatment wasstopped,anormal infant wasdelivered. Twelve patients were treated formore than 20 weeks during Twowomen died during caesariansections becauseofintra-op- their pregnancy. In 37 pregnancies danaparoidwas used until erative bleeding duetomisplaced placentas.Inthe remaining 14 vaginal delivery (n =23) or caesariansection (n =14). In the re- pregnancies danaparoid wasstopped prematurelyinthreecases, maining 14 pregnancies danaparoid treatment
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