Małopłytkowość indukowana protaminą — nowy problem czy inny typ małopłytkowości poheparynowej?

Protamine is widely used to neutralize the anticoagulant effects of unfractionated heparin, particularly after cardiac surgery. Recent reports suggest that some patients undergoing cardiopulmonary bypass exposed to heparin and protamine may develop thrombocytopenia. Multimolecular protamine-heparin complexes lead to immunization and production of immunoglobulin G class antibodies that may activate platelets through FcγIIa receptors. Some patients injected with protamine during cardiopulmonary bypass have increased the risk of early thromboembolic events due to the presence of these antibodies in the blood. In the present review, we will focus on studies investigating the mechanism of platelet activation by anti-protamine-heparin antibodies. We will compare antibodies that are associated with immune heparin-induced thrombocytopenia. In addition, we will describe the clinical consequences of protamine-induced thrombocytopenia, risk factors and general guidelines for management of thromboembolic complications in the post-cardiac surgery patients.Protamina jest powszechnie stosowanym środkiem odwracającym antykoagulacyjne działanie heparyny niefrakcjonowanej, szczególnie po zabiegach kardiochirurgicznych. Najnowsze badania wskazują, że część pacjentów poddanych zabiegowi krążenia pozaustrojowego jest narażona na trombocytopenię w trakcie ekspozycji na heparynę. Wielkocząsteczkowe kompleksy protaminy i heparyny wywołują immunizację i produkcję immunoglobulin G, które aktywują płytki krwi za pośrednictwem receptora FcγIIa. Podczas krążenia pozaustrojowego infuzja protaminy u niektórych pacjentów zwiększa ryzyko wczesnych powikłań zakrzepowych, spowodowanych obecnością tych przeciwciał we krwi. W niniejszym przeglądzie skupiono się na pracach, w których przebadano mechanizm aktywacji płytek krwi przez anty-protaminowo-heparynowe przeciwciała. Porównano je z przeciwciałami wywołującymi immunologiczną małopłytkowość poheparynową. Ponadto opisano kliniczne konsekwencje trombocytopenii indukowanej protaminą, czynniki ryzyka i ogólne wytyczne dotyczące terapii powikłań zakrzepowo-zatorowych u pacjentów kardiochirurgicznych

The toxicokinetic profile of Dex40-GTMAC3 : a novel polysaccharide candidate for reversal of unfractionated heparin

Though protamine sulfate is the only approved antidote of unfractionated heparin (UFH), yet may produce life threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. We have described 40 kDa dextrans (Dex40) substituted with glycidyltrimethylammonium chloride (GTMAC) as effective, immunogenically and hemodynamically neutral inhibitors of UFH. The aim of the present study was to evaluate in mice and rats toxicokinetic profile of the most promising polymer – Dex40-GTMAC3. Polymer was rapidly eliminated with a half-time of 12.5±3.0 min in Wistar rats, and was mainly distributed to the kidneys and liver in mice. The safety studies included the measurement of blood count and blood biochemistry, erythrocyte osmotic fragility and the evaluation of the histological alterations in kidneys, liver and lungs of mice and rats in acute and chronic experiments. We found that Dex40-GTMAC3 is not only effective but also very well tolerated. Additionally, we found that protamine may cause overt hemolysis with appearance of permanent changes in the liver and kidneys. In summary, fast renal clearance behavior and generally low tissue accumulation of Dex40-GTMAC3 is likely to contribute to its superior to protamine biocompatibility. Intravenous administration of therapeutic doses to living animals does not result in the immunogenic, hemodynamic, blood and organ toxicity. Dex40-GTMAC3 seems to be a promising effective and safe candidate for further clinical development as new UFH reversal agent

Reversal activity and toxicity of heparin-binding copolymer after subcutaneous administration of enoxaparin in mice

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously

New arginine substituted derivative of poly(allylamine hydrochloride) for heparin reversal

New derivatives of polyallylamine containing arginine moieties (PAH-ARG) were synthesized. The in vitro tests performed in heparinized blood plasma showed that the complexation of heparin by PAH-ARG polymers allowed the reduction of the activated partial thromboplastin time (aPTT) values to the normal level. The dose of PAH-ARG required for complete reversal of aPTT (prolonged by 1 U of heparin) was half of that required for protamine sulfate, the currently used heparin antagonist. The efficacy of these polymers in the neutralization of heparin was confirmed by in vivo tests using a rat model. PAH-ARG polymers were nontoxic to the fibroblast cells