Geburtshilfe Frauenheilkd 2004; 64(10): 1098-1105
DOI: 10.1055/s-2004-821141
Fallbericht

Georg Thieme Verlag KG Stuttgart · New York

Management der akuten heparininduzierten Thrombozytopenie Typ II während der Schwangerschaft und peripartal

Management of Acute Heparin-Induced Thrombocytopenia Type II during Pregnancy and PeripartallyH. Schinzel1 , G. Bühler2 , D. Peetz3 , J. Wiechelt1 , D. Macciella4 , B. Tanner4
  • 1II. Medizinische Klinik und Poliklinik Johannes-Gutenberg-Universität, Mainz
  • 2Klinikum Idar-Oberstein, Akademisches Lehrkrankenhaus der Johannes-Gutenberg-Universität, Mainz
  • 3Institut für Klinische Chemie und Laboratoriumsmedizin Johannes-Gutenberg-Universität, Mainz
  • 4Klinik für Frauenheilkunde und Geburtshilfe Johannes-Gutenberg-Universität, Mainz
Further Information

Publication History

Publication Date:
11 October 2004 (online)

Zusammenfassung

In der Schwangerschaft und im Wochenbett wird nur bei akuten Thromboembolien bzw. bei Patientinnen mit deutlich erhöhtem Thromboembolierisiko Heparin appliziert. Da die Therapie inzwischen weit gehend mit niedermolekularen Heparinen erfolgt, bei denen die HIT-II-Inzidenz deutlich geringer ist als bei den unfraktionierten Heparinen, stellt die heparininduzierte Thrombozytopenie Typ II ein seltenes Ereignis bei diesem Kollektiv dar. Die HIT II ist eine vital bedrohliche Heparinnebenwirkung, die bereits bei Verdacht zum sofortigen Abbruch der Heparintherapie führen muss. Die Erfahrungen mit alternativen Antikoagulanzien in der Gravidität und Puerperium sind begrenzt. Der Einsatz von Vitamin-K-Antagonisten (Kumarinderivaten) ist in der Akutphase der HIT Typ II kontraindiziert. Auch ist ihre Gabe v. a. in der Phase der Organogenese wegen der Gefahr von Fetopathien und in der 2. Hälfte des dritten Trimenons wegen des erhöhten maternalen und kindlichen intra- und peripartalen Blutungsrisikos nicht unproblematisch und nur unter strengen Kautelen vertretbar. Danaparoid-Natrium und rekombinantes Hirudin stellen Alternativen dar, wobei wegen der besseren Datenlage und der intravenösen und insbesondere auch der subkutanen Applikationsform dem Danaparoid der Vorzug bei der Therapie der HIT II in der Gravidität zu geben ist. Im Wochenbett stellen Warfarin oder Phenprocoumon die Therapie der Wahl dar. Stillen ist hierunter möglich. Berichtet wird über eine Patientin mit akuter Sinusvenenthrombose in der Frühschwangerschaft und der Entwicklung einer HIT Typ II unter der darauf erfolgenden Heparintherapie. Das Management der Langzeit- und peripartalen Antikoagulation mit Danaparoid-Natrium wird dargestellt.

Abstract

In pregnancy and in puerperium heparin is prescribed only for acute thromboembolism and/or for female patients with a clearly increased risk of venous thromboembolism. Since treatment changed from unfractionated heparin to low-molecular- weight heparin, the incidence of heparin-induced thrombocytopenia type II (HIT type II) is therefore a rare event in this collective. HIT type II is a life threatening side effect of heparin which must immediately lead to the stop of heparin administration. Experiences with alternative anticoagulation in pregnancy and puerperium are limited. Oral anticoagulation with coumarin (vitamin K antagonists) is contraindicated for the initial therapy of HIT II. The treatment with these substances is dangerous, especially in the phase of organogenesis, because it can cause malformation and because of the elevated maternal and the child intra- and peripartal bleeding risk in the 2nd half of the third trimenon. Danaparoid Sodium and recombinant Hirudin represent treatment options, whereby because of the better data and the intravenous and especially the subcutaneous application form the application of Danaparoid in the therapy of HIT typ II in pregnancy would appear to be more favourable. In the puerperium Warfarin or Phenprocoumon represent the therapy of choice. Breast-feeding is possible with this option. We report on a female patient with an acute thrombosis of the cerebral sinus vein during early pregnancy who developed a HIT type II under heparin treatment. The long-term anticoagulation with Danaparoid Sodium and the peripartale management are presented.

Literatur

  • 1 Warkentin T E, Chong B H, Greinacher A. Heparin-induced thrombocytopenia: towards consensus.  Thromb Haemost. 1998;  79 1-7
  • 2 Warkentin T E, Levine M N, Hirsh J, Horsewood P, Roberts R S, Gent M. et al . Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1330-1335
  • 3 Lindhoff-Last E, Bauersachs R. Heparin-induced thrombocytopenia - alternative anticoagulation in pregnancy and lactation.  Semin Thromb Hemost. 2002;  28 439-446
  • 4 Warkentin T E. Clinical picture of heparin-induced thrombocytopenia. Warkentin TE, Greinacher A Heparin-Induced Thrombocytopenia. 2nd ed. New York; Marcel Dekker 2001: 43-86
  • 5 Greinacher A, Lubenow N, Hinz P, Ekkernkamp A. Heparininduzierte Thrombozytopenie.  Deutsches Ärzteblatt. 2003;  100 1753-1759
  • 6 Warkentin T E, Kelton J A. A 14-year study of heparin-induced thrombocytopenia.  Am J Med. 1996;  101 5027
  • 7 Pohl C, Klockgether T, Greinacher A, Hanfland P, Harbrecht U. Neurological complications in heparin-induced thrombocytopenia.  Lancet. 1999;  353 1678-1679
  • 8 Kemkes-Matthes B. Heparin-induzierte Thrombozytopenie. Bremen; Uni-Med Verlag 1999
  • 9 Fontana P. Skin necrosis is a clinical manifestation of low-molecular weight heparin-induced thrombocytopenia. A case report.  Thromb Haemost. 2004;  91 196-197
  • 10 Deschamps A, Mathelier-Fusade P, Bernaille J. Reaction cutanée à l'heparine pendant la grossesse: à propos d'un cas traité avec succes par le danaparoide.  Rev Française Allergol Immunol Clin. 2004;  43 131-134
  • 11 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344 1286-1292
  • 12 Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson L E, Greinacher A. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin.  Chest. 2002;  122 37-42
  • 13 Warkentin T E, Greinacher A. Clinical picture of heparin-induced thrombocytopenia. Warkentin TE, Greinacher A Heparin-Induced Thrombocytopenia. 2nd ed. New York; Marcel Dekker 2001: 231-270
  • 14 Magnani H N. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172).  Thromb Haemost. 1993;  70 554-561
  • 15 Magnani H N. Orgaran (danaparoid sodium) use in the syndrome of heparin-induced thrombocytopenia.  Platelets. 1997;  8 74-81
  • 16 Ortel T L, Chong B H. New treatment options for heparin-induced thrombocytopenia.  Semin Hematol. 1998;  35 (Suppl 5) 26-36
  • 17 Greinacher A, Volpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P. et al . Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.  Circulation. 1999;  99 73-80
  • 18 Greinacher A, Janssens U, Berg G, Bock M, Kwasny H, Kemkes-Matthes B. et al . Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators.  Circulation. 1999;  100 587-593
  • 19 Lewis B E, Wallis D E, Berkowitz S D, Matthai W H, Fareed J, Walenga J M. et al . Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation. 2001;  103 1838-1843
  • 20 Greinacher A, Warkentin T E. Treatment of heparin-induced thrombocytopenia: an overview. Warkentin TE, Greinacher A Heparin-Induced Thrombocytopenia. New York; Marcel Dekker 2003: 335-370
  • 21 Hall J G, Pauli R M, Wilson K M. Maternal and fetal sequelae of anticoagulation during pregnancy.  Am J Med. 1980;  68 122-140
  • 22 Iturbe-Alessio I, Fonseca M C, Mutchinik O, Santos M A, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves.  N Engl J Med. 1986;  315 1390-1393
  • 23 Ginsberg J S, Hirsh J, Rainbow A J, Coates G. Risks to the fetus of radiologic procedures used in the diagnosis of maternal venous thromboembolic disease.  Thromb Haemost. 1989;  61 189-196
  • 24 Wong V, Cheng C H, Chan K C. Fetal and neonatal outcome of exposure to anticoagulants during pregnancy.  Am J Med Genet. 1993;  45 17-21
  • 25 Ginsberg J S, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest. 2001;  119 (Suppl 1) 122S-131S
  • 26 Demers C, Ginsberg J S, Brill-Edwards P, Panju A, Warkentin T E, Anderson D R. et al . Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia.  Blood. 1991;  78 2194-2197
  • 27 Greinacher A. Heparin-induzierte Thrombozytopenie - Pathogenese und Behandlung.  Haemostaseologie. 1999;  19 1-12
  • 28 Stiekema J C, Wijnand H P, Van Dinther T G, Moelker H C, Dawes J, Vinchenzo A. et al . Safety and pharmacokinetics of the low molecular weight heparinoid Org 10172 administered to healthy elderly volunteers.  Br J Clin Pharmacol. 1989;  27 39-48
  • 29 Meuleman D G. Orgaran (Org 10172): its pharmacological profile in experimental models.  Haemostasis. 1992;  22 58-65
  • 30 Bradbrook I D, Magnani H N, Moelker H C, Morrison P J, Robinson J, Rogers H J. et al . ORG 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man.  Br J Clin Pharmacol. 1987;  23 667-675
  • 31 Stiekema J C, Wijnand H P, ten Cate H, ten Cate J W, Harenberg J, Egberts J F. et al . Partial in vivo neutralisation of plasma anticoagulant effects of Lomoparan (Org 10172) by protamine chloride.  Thromb Res. 1991;  63 157-167
  • 32 Danhof M, de Boer A, Magnani H N, Stiekema J C. Pharmacokinetic considerations on Orgaran (Org 10172) therapy.  Haemostasis. 1992;  22 73-84
  • 33 Warkentin T E. Danaparoid (Orgaran) for the treatment of heparin-induced thrombocytopenia (HIT) and thrombosis: Effects on in vivo thrombin and cross-linked fibrin generation, and evaluation of the clinical significance of in vitro cross-reactivity (XR) of danaparoid for HIT-IgG.  Blood. 1996;  88 626A (abstract)
  • 34 Markwardt F. Hirudin: The promising antithrombotic.  Cardiovasc Drug Rev. 1992;  10 211-232
  • 35 Bucha E, Nowak G, Czerwinski R, Thieler H. R-hirudin as anticoagulant in regular hemodialysis therapy: finding of therapeutic R-hirudin blood/plasma concentrations and respective dosages.  Clin Appl Thromb Hemost. 1999;  5 164-170
  • 36 Vanholder R C, Camez A A, Veys N M, Soria J, Mirshahi M, Soria C. et al . Recombinant hirudin: a specific thrombin inhibiting anticoagulant for hemodialysis.  Kidney Int. 1994;  45 1754-1759
  • 37 Vanholder R, Camez A, Veys N, Van Loo A, Dhondt A M, Ringoir S. Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients.  Thromb Haemost. 1997;  77 650-655
  • 38 Nowak G, Bucha E, Goock T, Thieler H, Markwardt F. Pharmacology of r-hirudin in renal impairment.  Thromb Res. 1992;  66 707-715
  • 39 Poetzsch B, Madlener K, Seelig C, Riess C F, Greinacher A, Muller-Berghaus G. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass - assessment of the whole blood ecarin clotting time.  Thromb Haemost. 1997;  77 920-925
  • 40 Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids.  Semin Thromb Hemost. 1996;  22 197-202
  • 41 Greinacher A, Eckhardt T, Mussmann J, Mueller-Eckhardt C. Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10, 172).  Thromb Res. 1993;  71 123-126
  • 42 Gill J, Kovacs M J. Successful use of danaparoid in treatment of heparin-induced thrombocytopenia during twin pregnancy.  Obstet Gynecol. 1997;  90 648-650
  • 43 Boshkov L K, Hamilton P, Lee A, Boldt K. Successful therapy of heparin-induced thrombocytopenia with thrombosis (HITTS) in pregnancy with danaparoid sodium (Orgaran).  Blood. 1999;  94 (Suppl 1) 102b (abstract)
  • 44 Macchi L, Sarfati R, Guicheteau M, Chamlian V, Pourrat O, Gruel Y. et al . Thromboembolic prophylaxis with danaparoid (Orgaran) in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia (HIT) and Widal's disease.  Clin Appl Thromb Hemost. 2000;  6 187-189
  • 45 Taylor A A. Successful use of heparinoids in a pregnancy complicated by allergy to heparin.  BJOG. 2001;  108 1011-1012
  • 46 Harrison S J, Rafferty I, McColl M D. Management of heparin allergy during pregnancy with danaparoid.  Blood Coagul Fibrinolysis. 2001;  12 157-159
  • 47 Schinzel H, Bahlmann F, Peetz D, Savvidis S, Himmrich L, Klotz M. Prevention of thromboembolism with low molecular weight heparin (Dalteparin-Na) in risk pregnancy.  Med Klin (Munich). 2002;  97 193-203
  • 48 Blombäck M. Changes in blood coagulation and fibrinolysis during pregnancy and the menstrual cycle: new methods for dedecting the changes.  Advances in Contraception. 1991;  7 (Suppl 3) 259-272
  • 49 Van Wersch J W, Ubachs J M. Blood coagulation and fibrinolysis during normal pregnancy.  Eur J Clin Chem Clin Biochem. 1991;  29 45-50
  • 50 von Hugo R, Theiss W, Kuhn W, Graeff H. Thromboembolism in obstetrics.  Gynäkologe. 1984;  17 115-123
  • 51 Toglia M R, Weg J G. Venous thromboembolism during pregnancy.  N Engl J Med. 1996;  335 108-114
  • 52 McColl M D, Ramsay J E, Tait R C, Walker I D, McCall F, Conkie J A. et al . Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost. 1997;  78 1183-1188
  • 53 Macklon N S, Greer I A. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience.  Scott Med J. 1996;  41 83-86
  • 54 Sachs B P, Brown D A, Driscoll S G, Schulman E, Acker D, Ransil B J. et al . Maternal mortality in Massachusetts. Trends and prevention.  N Engl J Med. 1987;  316 667-672
  • 55 Barbour L A. Current concepts of anticoagulant therapy in pregnancy.  Obstet Gynecol Clin North Am. 1997;  24 499-521
  • 56 McColl M D, Walker I D, Greer I A. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy.  Br J Obstet Gynaecol. 1999;  106 756-766
  • 57 McColl M D, Ellison J, Reid F, Tait R C, Walker I D, Greer I A. Prothrombin 20210 G → A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy.  BJOG. 2000;  107 565-569
  • 58 Lanska D J, Kryscio R J. Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis.  Stroke. 2000;  31 1274-1282
  • 59 Henny C P, ten Cate H, ten Cate J W, Prummel M F, Peters M, Buller H R. Thrombosis prophylaxis in an AT III deficient pregnant woman: application of a low molecular weight heparinoid.  Thromb Haemost. 1986;  55 301
  • 60 van Besien K, Hoffman R, Golichowski A. Pregnancy associated with lupus anticoagulant and heparin induced thrombocytopenia: management with a low molecular weight heparinoid.  Thromb Res. 1991;  62 23-29
  • 61 Gerhardt A, Zotz R B, Scheja J W. First successful use of danaparoid in a pregnant woman with tricuspidal valve prosthesis and heparin-induced thrombocytopenia in pregnancy with subcutaneous r-hirudin.  Blood. 2000;  96 95b
  • 62 Rondeau M, Weber J C, Haffner C. HELLP syndrome, catastrophic antipholspholipid syndrome or heparin-induced thrombocytopenia?.  J Autoimmun. 2000;  15 A68
  • 63 Saint-Blanquat L, Simon L, Toubas M F, Hamza J. Treatment with danaparoid during pregnancy for a woman with a cutanous allergy to low-molecular-weight heparin.  Ann Fr Anesth Reanim. 2000;  19 751-754
  • 64 Grainger J D, Hay C. Heparin induced thrombocytopenia caused by danaparoid sodium. (Abstract CD3458 presented at IVIII ISTH) Thromb Haemost 2001; Abstract. 
  • 65 Horellou M, Elalamy I, Achkar A. Efficacy and safety of danaparoid (Orgaran) in venous thrombosis in pregnant women with thrombophilia and heparin-induced thrombocytopenia. (Abstract of the XVIII ISTH.) Thromb Haemost 2001; (Suppl): Abstract.  . ; 
  • 66 Gould J, Meyers B. Prophylactic danaparoid in heparin-induced thrombocytopenia presenting with skin manifestations in pregnancy.  Blood Coagul Fibrinolysis. 2002;  13 Abstract
  • 67 Woo Y L, Allard S, Cohen H, Letsky E, de Swiet M. Danaparoid thromboprophylaxis in pregnant women with heparin-induced thrombocytopenia.  BJOG. 2002;  109 466-468
  • 68 Huhle G, Geberth M, Hoffmann U, Heene D L, Harenberg J. Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin.  Gynecol Obstet Invest. 2000;  49 67-69
  • 69 Peeters L L, Hobbelen P M, Verkeste C M, Vogel G M, Hasenack H G, Meuleman D G. et al . Placental transfer of Org 10172, a low-molecular weight heparinoid, in the awake late-pregnant guinea pig.  Thromb Res. 1986;  44 277-283
  • 70 Hamilton P. ABC of labour care: care of the newborn in the delivery room.  BMJ. 1999;  318 1403-1406
  • 71 Erikkson B I, Ekman S, Lindbratt S. et al . Prevention of thromboembolism with use of recombinant hirudin: results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement.  J Bone Joint Surg Am. 1997;  79 326-333
  • 72 Erikkson B I, Wille-Jörgensen P, Kälebo P. et al . A comparison of recombinant hirudin with low-molecular weight heparin to prevent thromboembolic complications after total hip replacement.  N Engl J Med. 1997;  337 1329-1335
  • 73 Frei U, Wilks M F, Boehmer S, Crisp-Lindgren N, Schwarzrock R, Stiekema J C. et al . Gastrointestinal blood loss in haemodialysis patients during use of a low-molecular-weight heparinoid anticoagulant.  Nephrol Dial Transplant. 1988;  3 435-439
  • 74 Eichler P, Friesen H J, Lubenow N, Jaeger B, Greinacher A. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance.  Blood. 2000;  96 2373-2378
  • 75 Liebe V, Bruckmann M, Fischer K G, Haase K K, Borggrefe M, Huhle G. Biological relevance of anti-recombinant hirudin antibodies - results from in vitro and in vivo studies.  Semin Thromb Hemost. 2002;  28 483-490
  • 76 von Felten A. Venöse Thromboembolieprophylaxe mit Heparin bei Risikopatientinnen während der Schwangerschaft: Monitorisierung mittels Messung der Thrombin-Antithrombin-III-Komplexe.  Therapeutische Umschau. 1992;  49 838-841

Priv.-Doz. Dr. Dr. Helmut Schinzel

II. Medizinische Klinik und Poliklinik der Johannes-Gutenberg-Universität Mainz

Langenbeckstraße 1

55131 Mainz

Email: schinzel@2-med.klinik.uni-mainz.de

    >