Preflush With Plasminogen Activator in Non-Heart-Beating Donors: Is It Worth It?

Warm Preflush with Streptokinase Improves Microvascular Procurement and Tissue Integrity in Liver Graft Retrieval from Non-Heart-Beating Donors. Transplantation 2000; 69: 1780. Yamauchi J-I, Richter S, Vollmar B, Menger MD, and Minor T. The growing discrepancy between demand and supply of organs for transplantation has triggered a renewed interest in the use of grafts from non-heart-beating (NHB) donors (1). Extensive research and improvements in preservation technique have contributed to improved outcome after transplantation of kidneys from NHB donors in recent years. However, the percentage of delayed graft function and primary nonfunction is still higher than after transplantation of kidneys from brain death donors with an intact circulation (1). The crucial factor for organ viability from NHB donors is the period of poor and no perfusion before organ procurement. In combination with the subsequent cold preservation and reperfusion injury, this initial warm ischemic injury can cause severe damage to the donor organ. Although kidneys may eventually recover from prolonged warm ischemic injury while the patient is kept alive with the use of dialysis, warm ischemia is a main obstacle in the liver and lung, where no alternative substitution therapies are available. Therefore, better graft preservation techniques are needed before liver and lung transplantation from NHB donors can be safely and widely used. It is often believed that the cardiac standstill in NHB donors not only results in warm ischemic injury, but also leads to the formation of thrombi in the microvasculature of the donor organs (23). However, the clinical relevance of early postmortem thrombus and fibrin formation remains unclear. Very few studies have focused on blood coagulation after cardiac standstill, and the knowledge about postmortem fibrin formation is limited. Most information comes from forensic studies, which in fact have indicated that activation of platelets is reduced early after death, and that coagulation is altered with less stable clot formation (45). Furthermore, the fibrinolytic system is markedly activated (4). These observations suggest that intravascular fibrin formation does not occur at a very high rate during the early postmortem period. In contrast, perfusion of NHB donor organs is often associated with a high resistance and inadequate microperfusion, which suggests the presence of thrombi and fibrin deposits in the microcirculation (1). It is possible that microthrombi are formed in the period immediately before cardiac arrest occurs. This period is often characterized by low blood pressures and inadequate circulation in the presence of normal coagulation, which are known risk factors for intravascular thrombus formation. To prevent formation of (micro-) thrombi in organs that will be used for transplantation, high dose heparin is routinely given during organ procurement in heart-beating (brain death) donors. However, in NHB donors adequate heparinization is hampered by the lack of an intact circulation at the time of organ procurement. In most centers with a clinical protocol for NHB donors, the majority of cases are so called “ventilated switch off” procedures (also known as “controlled,” or category 3 NHB donors). In these cases, administration of heparin before cardiac standstill is obtained would be a violation of the necessary separation between the treatment team and the transplant team (1). In case of an unsuccessful resuscitation (“uncontrolled” or category 2 NHB donors), it has been proposed to resume cardiac message and give i.v. heparin after a waiting period of 10 min, marking the transition from treatment to donation procedure (1). Some centers have added heparin to the preservation fluid, but the efficacy of this strategy is questionable. Heparin prevents new fibrin formation but will have no effect on preexisting thrombi. Adequate removal of such fibrin deposits and microthrombi can only be obtained with profibrinolytic agents, such as plasminogen activators. Plasminogen activators available for exogenous administration are streptokinase, urokinase, and recombinant tissue-type plasminogen activator (r-tPA). There is extensive clinical experience with these agents in the treatment of pulmonary emboli and coronary artery thrombosis, and the thrombolytic activities are very similar. Based on its lower antigenicity, there is a small advantage of using r-tPA in clinical practice. In a canine model of lung transplantation using non-heart-beating donors, Umemori et al. (6) have shown that injection of high dose urokinase (120,000 IU) into the main pulmonary artery after flushing with a preservation solution results in better lung functions after transplantation. In a similar model, Akasaka et al. (7) have shown that infusion of r-tPA (2.5 or 5.0 mcg/kg/min for 90 min) into the main pulmonary artery, commencing 15 min before reperfusion, significantly improves early lung function and pulmonary hemodynamics. Application of fibrinolytic drugs after perfusion with preservation fluid or short before graft reperfusion has the potential risk of inducing serious bleeding complications in the recipient. In this issue of Transplantation, Yamauchi et al. (8) describe a technique of warm preflush with streptokinase (7500 IU) before cold perfusion with UW solution of liver grafts retrieved from NHB rats. The authors hypothesized that the high viscosity of UW solution in combination with microthrombi in the microvasculature can be responsible for the heterogeneous and inadequate perfusion of the donor grafts. Using in situ microscopic techniques, the quality of microperfusion with UW solution of liver grafts from NHB donors was studied after warm preflush with streptokinase-enhanced Ringer’s lactated solution. After 30 min of warm ischemia it was shown that microvascular UW perfusion of sinusoids and acini is markedly improved in animals who received warm preflush with streptokinase, compared with animals receiving warm preflush with Ringer’s lactated solution alone, or no preflush. The originality and importance of this study lies in the use of a fibrinolytic agent before, rather than after preservation, as in previous reports (6). Moreover, this study provides indirect evidence that thrombus formation in the microcirculation does play a role in NHB donors. Injury to the sinusoidal endothelial cells (SEC) has been recognized as the key mechanism of ischemia and reperfusion injury of liver grafts and several compounds of the UW preservation solution have been shown to have protective effects on these cells (9). Therefore, it seems crucial that adequate microperfusion of UW solution is obtained throughout the entire graft. Although Yamauchi et al. (8) have convincingly shown that streptokinase improves flush out and microperfusion of livers from NHB donors, they have not studied whether this is also associated with less SEC injury and improved graft function after transplantation. This would require additional studies using an isolated liver perfusion model or survival studies of animals after transplantation of streptokinase-treated grafts. Furthermore, it is unknown how effectively streptokinase will be washed out by the subsequent perfusion with UW solution. In human liver transplantation, it has been shown that heparin used in heart beating donors can bind to the endothelium and be released upon reperfusion contributing to the development of coagulation disorders in the recipient (10). Liver transplantation itself is often characterized by coagulopathy and hyperfibrinolysis, especially after graft reperfusion (10). The possible release of streptokinase used during organ procurement could further enhance fibrinolysis and result in uncontrollable bleeding in the recipient. Therefore, it needs to be established whether streptokinase is adequately flushed out by the UW solution rather than released from the graft upon reperfusion, before its application is attempted in the clinical situation. Another issue that needs to be clarified is the effect of fibrinolytic therapy, and thus plasmin formation, on SEC injury during cold preservation. It was recently shown by Upadhya et al. (11) that cold preservation of liver grafts is associated with increased secretion of matrix metalloproteinases (MMP), which contributes to SEC detachment and increased graft preservation injury. Plasmin is a very strong activator of MMPs, and one could hypothesize that activation of fibrinolysis during organ procurement may enhance SEC injury by activation of MMPs. The improved microperfusion obtained with plasminogen activator-enhanced preflush during organ procurement in NHB donors is very encouraging. If the above mentioned issues concerning safety and side-effects are adequately addressed, the use of plasminogen activator-enhanced preservation or preflush solutions can be an important step forward towards better preservation of organs from NHB donors.