Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Important mechanisms underlying immediate xenograft loss by hyperacute rejection (HAR), in the pig-to-primate combination, have been recently delineated. There are now several proposed therapies that deal with the problem of complement activation and xenoreactive natural antibody (XNA) binding to the vasculature that have been shown to prevent HAR. However, vascularized xenografts are still lost, typically within days, by delayed xenograft rejection (DXR), alternatively known as acute vascular rejection (AVR). This process is characterized by endothelial cell (EC) perturbation, localization of XNA within the graft vasculature, host NK cell and monocyte activation with platelet sequestration and vascular thrombosis. Alternative immunosuppressive strategies, additive anti-complement therapies with the control of any resulting EC activation processes and induction of protective responses have been proposed to ameliorate this pathological process. In addition, several potentially important molecular incompatibilities between activated human coagulation factors and the natural anticoagulants expressed on porcine EC have been noted. Such incompatibilities may be analogous to cross-species alterations in the function of complement regulatory proteins important in HAR. Disordered thromboregulation is potentially relevant to the progression of inflammatory events in DXR and the disseminated intravascular coagulation seen in primate recipients of porcine renal xenografts. We have recently demonstrated the inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C. The enhanced potential of porcine von Willebrand factor to associate with human platelet GPIb has been demonstrated to be dependent upon the isolated A1 domain of von Willebrand factor. In addition, the loss of TFPI and vascular ATPDase/CD39 activity following EC activation responses would potentiate any procoagulant changes within the xenograft. These developments could exacerbate vascular damage from whatever cause and enhance the activation of platelets and coagulation pathways within xenografts resulting in graft infarction and loss. Analysis of these and the other putative factors underlying DXR should lead to the development and testing of genetic approaches that, in conjunction with selected pharmacological means, may further prolong xenograft survival to a clinically relevant extent.
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PMID:Factors in xenograft rejection. 1041 73

The activities of NTPDase (EC 3.6.1.5, apyrase, CD39) and 5'-nucleotidase (EC 3.1.3.5, CD73) enzymes were analyzed in platelets from breast cancer patients. Initially, patients were compared in terms of length (years) of tamoxifen use. The following groups were studied: breast cancer patients who did not use tamoxifen, patients using tamoxifen for 1-48 months, patients using tamoxifen for 49-84 months, and controls (healthy subjects). Results demonstrated that adenosine triphosphate (ATP) hydrolysis was enhanced (F(3,114)=8.53; P<0.001) and adenosine diphosphate (ADP) hydrolysis was reduced (F(3,106)=5.09, P=0.002) as a function of tamoxifen use, while adenosine monophosphate (AMP) hydrolysis was unchanged. Next, patients were compared statistically according to disease stage, determined by the tumor-node-metastasis (TNM) staging system for classifying breast tumor. ATP hydrolysis was significantly elevated in patients with stage I and II breast cancer (F(4,113)=4.35; P=0.003), but was normal in patients with stage III and IV cancer. ADP hydrolysis was reduced in stages II to IV (F(4,105)=3.88, P=0.006) and AMP hydrolysis was elevated in stage II (F(4,105)=3.45 P=0.01), but was normal in stages III and IV. Platelet aggregation time was similar in all patients regardless of tamoxifen use or disease stage. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were also within the normal range and similar among all groups. Similarly, fibrinogen and fibrin degradation product (FDP) were unchanged in all groups. In conclusion, our study demonstrated for the first time that hydrolysis of adenine nucleotides is modified in platelets from breast cancer patients taking tamoxifen.
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PMID:Enzymes that hydrolyze adenine nucleotides in platelets from breast cancer patients. 1594 10

The ability to genetically engineer pigs that no longer express the Galalpha1,3Gal (Gal) oligosaccharide has been a significant step toward the clinical applicability of xenotransplantation. Using a chronic immunosuppressive regimen based on costimulatory blockade, hearts from these pigs have survived from 2 to 6 months in baboons. Graft failure was predominantly from the development of a thrombotic microangiopathy. Potential contributing factors include the presence of preformed anti-nonGal antibodies or the development of low levels of elicited antibodies to nonGal antigens, natural killer (NK) cell or macrophage activity, and inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an "anticoagulant" gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the gene for the prothrombinase, fibrinogen-like protein-2, is anticipated to inhibit the change in the endothelium to a procoagulant state that takes place in the pig organ after transplantation. The identification of the targets for anti-nonGal antibodies and/or human macrophages might allow further genetic modification of the pig, and xenogeneic NK cell recognition and activation may be inhibited by the transgenic expression of human leukocyte antigen molecules and/or by blocking the function of activating NK receptors. The ultimate goal of induction of T-cell tolerance may be possible only if these hurdles in the coagulation system and innate immunity can be overcome.
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PMID:Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? 1762 30

Xenotransplantation using pig organs could solve the significant increasing shortage of donor organs for allotransplantation. In the last two decades, major progress has been made in understanding the xenoimmunobiology of pig-to-nonhuman primate transplantation, and today we are close to clinical trials. The ability to genetically engineer pigs, such as human decay-accelerating factor (hDAF), CD46 (membrane cofactor protein), or alpha1,3-galactosyltransferase gene-knockout (GT-KO), has been a significant step toward the clinical application of xenotransplantation. Using GT-KO pigs and novel immunosuppressant agents, 2 to 6 months' survival of heterotopic heart xenotransplants has been achieved. In life-supporting kidney xenotransplantation, promising survival of close to 3 months has been achieved. However, liver and lung xenotransplantations do not have such encouraging survival as kidney and heart xenotransplantation. Although the introduction of hDAF and GT-KO pigs largely overcame hyperacute rejection, acute humoral xenograft rejection (AHXR) remains a challenge to be overcome if survival is to be increased. In several studies, when classical AHXR was prevented, thrombotic microangiopathy and coagulation dysregulation became more obvious, which make them another hurdle to be overcome. The initiating cause of failure of pig cardiac and renal xenografts may be antibody-mediated injury to the endothelium, leading to the development of microvascular thrombosis. Potential contributing factors toward the development of the thrombotic microangiopathy include: 1) the presence of preformed anti-non-Gal antibodies, 2) the development of very low levels of elicited antibodies to non-Gal antigens, 3) natural killer cell or macrophage activity, and 4) inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an 'anticoagulant' or 'anti-thrombotic' gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the gene for the prothrombinase, fibrinogen-like protein-2, is anticipated to inhibit the change in the endothelium to a procoagulant state that takes place in the pig organ after transplantation. A further limitation for organ xenotransplantation is the potential for cross-species infection. As far as exogenous viruses are concerned, porcine cytomegalovirus has been detected in the tissues of recipient non-human primates, although no invasive disease was reported. Until today, no formal evidence has been presented from in vivo studies in non-human primates or from humans exposed to pig organs, tissues, or cells that porcine endogenous retroviruses infect primate cells. Xenotransplantation is a potential answer to the current organ shortage. Its future depends on; 1) further genetic modification of pigs, 2) the introduction of novel immunosuppressive agents that target the innate immune system and plasma cells, and 3) the development of clinically-applicable methods to induce donor-specific tolerance.
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PMID:Xenotransplantation of solid organs in the pig-to-primate model. 1895 43