Bed side monitoring of low molecular weight heparin and its neutralization by protamine during hemodialysis Shinji Naganuma, Kazuo Takahashi, Hideki K

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1 Bed side monitoring of low molecular weight heparin and its neutralization by protamine during hemodialysis Shinji Naganuma, Kazuo Takahashi, Hideki Kobayashi, Seiji Maekawa, Tetsuji Hoshino, Kazuo Era, Kazuo Ota Department of Surgery, Kidney Center, Tokyo Women's Medical College Low molecular weight heparin (LMH) is a relatively new drug, fractionated from conventional unfractionated heparin, which has potential advantages over heparin for clinical use. Several problems should be resolved in applying LMH in hemodialysis; the need for bed side monitoring, neutralization by protamine, differences in pharmacological activity between products, pharmacological activities other than coagulation and long-term safety and side effects. We have identified a new parameter of blood coagulation with LMH, so called Xa activated coagulation time (XaACT), which involves a modified method of determining the blood coagulation time activated by celite and factor Xa, using hemocron method. It was found, in the present study, that XaACT had a better correlation with anti-xa activity than did ACT and APTT either in vitro or in vivo during hemodialysis. With regard to changes in coagulation time during hemodialysis with LMH, ACT and APTT were not prolonged, as expected, but anti-xa activity and XaACT were significantly prolonged during dialysis. XaACT is thought to be a useful blood

2 coagulation parameter of LMH in hemodialysis. Protamine has the effect of neutralizing heparin, but there have been no reports to date on neutralization of LMH by protamine during hemodialysis. We studied the effect of protamine on LMH in terms of ]a activity, ]aact, APTT and ACT. APTT and ACT were completely neutralized, to pretreatment levels, by protamine. Otherwise ]aact and ]a activity were inhibited 30 `50% by protamine. We think that there is only a slight risk of bleeding in LMH neutralization by protamine because anti- Ua activity is completely neutralized and ACT is normalized to the pre-treatment level.

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5 1) Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L: Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 05: 64-73, ) Blockmans D, Bounameaux H, Vermylen J, Ver straete M: Heparin-induced thrombocytopenia platelet aggregation studies in the presence of heparin fractions or semi-synthetic analogues of various molecular weights and anticoagulant activities. Thromb Haemostas 55: 90-93, ) Godal HC: Heparin-induced thrombocytopenia. In "Heparin" ed Lane DA and Lindahl U, p , Edward Arnold, London, ) Monreal M, Olive A, Lafoz E, Rio L: Heparins, coumarin, and bone density. Lancet 338: 706, 1991 S) Andersson LO, Barrowcliffe TO, Holmer E, John son EA, Sims GEC: Anticoagulant properties of

6 heparin fractionated by affinity chromatography on matrix-bound antithrombin III and by gel fil tration. Thrombosis research 9: , ) Holmer E, Kurachi K, Soderstrom G: The molec ular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin, Biochem J 193 : , ) Harenberg J, Giese Ch, Knodler A, Zimmermann R, Schettler G: Neutralization of a low molecu lar weight heparin kabi 2165 by protamine chlo ride, Klin Wochenschr 64: , ) Holmer E, Soderberg K, Bergqvist D, Lindahl U: Heparin and its low molecular weight deriva tives: Anticoagulant and antithrombotic prop erties. Haemostasis 16 (Suppl 2): 1-7, ) Kaiser B, Hauptmann J, Markwardt F: Experi mental studies on the antithrombotic and haemor rhagic effects of heparin and a low molecular weight heparin derivatives, Folin Haematol Leipz 115: , 1988

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