causing the hardening and narrowing of vessels within the graft. Chronic rejection leads to pathologic changes of the organ, and is why transplants must be replaced after so many years. It is also anticipated that chronic rejection will be more aggressive in xenotransplants as opposed to allotransplants. Dysregulated coagulation Successful efforts have been made to create knockout mice without α1,3GT; the resulting reduction in the highly immunogenic αGal epitope has resulted in the reduction of the occurrence of hyperacute rejection, but has not eliminated other barriers to xenotransplantation such as dysregulated coagulation, also known as coagulopathy. Different organ xenotransplants result in different responses in clotting. For example, kidney transplants result in a higher degree of coagulopathy, or impaired clotting, than cardiac transplants, whereas liver xenografts result in severe thrombocytopenia, causing recipient death within a few days due to bleeding. An alternate clotting disorder, thrombosis, may be initiated by preexisting antibodies that affect the protein C anticoagulant system. Due to this effect, porcine donors must be extensively screened before transplantation. Studies have also shown that some porcine transplant cells are able to induce human tissue factor expression, thus stimulating platelet and monocyte aggregation around the xenotransplanted organ, causing severe clotting. Additionally, spontaneous platelet accumulation may be caused by contact with pig von Willebrand factor. Just as the α1,3G epitope is a major problem in xenotransplantation, so too is dysregulated coagulation a cause of concern. Transgenic pigs that can control for variable coagulant activity based on the specific organ transplanted would make xenotransplantation a more readily available solution for the 70,000 patients per year who do not receive a human donation of the organ or tissue they need. Physiology Extensive research is required to determine whether animal organs can replace the physiological functions of human organs. Many issues include size – differences in organ size limit the range of potential recipients of xenotransplants; longevity – The lifespan of most pigs is roughly 15 years, currently it is unknown whether or not a xenograft may be able to last longer than that; hormone and protein differences – some proteins will be molecularly incompatible, which could cause malfunction of important regulatory processes. These differences also make the prospect of hepatic xenotransplantation less promising, since the liver plays an important role in the production of so many proteins; environment – for example, pig hearts work in a different anatomical site and under different hydrostatic pressure