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thrombotic disorders associated with organ and cell xenotransplantation
Coagulation/Thrombotic Disorders Associated With Organ and Cell Xenotransplantation I.P.J. Alwayn, L. Buhler, M. Basker, C. Goepfert, T. Kawai, T. Kozlowski, F. Ierino, D.H. Sachs, R. Sackstein, S.C. Robson, and D.K.C. Cooper
A
TTEMPTS to induce mixed hematopoietic chimerism are associated with disorders of hemostasis/coagulation.1 Delayed rejection of vascularized xenografts in the pig-to-baboon model has been associated with disseminated intravascular coagulation (DIC).2 Irradiation or drugs may potentiate vascular activation or injury. We investigated the roles of (1) the tolerance-inducing regimen (TIR), (2) pig hematopoietic cell (PCTx), and (3) pig organ (POTx) transplantation on platelet activation and coagulation parameters. METHODS The TIR included total body irradiation (WBI), T-cell depletion, and splenectomy. Five groups (total 29 experiments) were studied. Baboons were recipients except in Group 1. In Group 1 (n ⫽ 6), Cynomolgus monkeys underwent TIR plus hematopoietic cell and kidney (or heart) allo- or concordant xenotransplantation. In Group 2 (n ⫽ 4), TIR with or without autologous cell infusion was performed. In Group 3 (n ⫽ 12), PCTx with or without TIR was performed. In Group 4 (n ⫽ 5), POTx with or without TIR was performed. In Group 5 (n ⫽ 4) TIR plus PCTx plus POTx was performed. Platelet count, coagulation parameters (PT, PTT, fibrinogen [FIB], D-dimer), and lactate dehydrogenase (LDH) were measured, and blood smears were performed.
RESULTS TIR without PCTx or POTx (Groups 1 and 2)
There was a gradual decrease in platelets over 12 to 15 days, followed by rapid recovery. PT, PTT, and FIB remained normal.
POTx With or Without TIR (Group 4)
There was a gradual decline in platelets and fibrinogen over 7 days with a late prolongation in PT and increase in D-dimer levels, in keeping with DIC. Recovery generally occurred when the graft was excised (as an emergency). PCTx Plus POTx Plus TIR (Group 5)
Immediate decrease in platelets occurred with recovery beginning by day 16. Platelet supplementation was required. There was a greater prolongation of PT (⬍26 seconds) and PTT (⬎45 seconds), and FIB decreased steadily. However, the histopathologic features of rejection could be relatively mild. CONCLUSIONS
TIR (with or without allografting or autologous cell infusion) results in transient thrombocytopenia only, in keeping with marrow depression from WBI. PCTx with or without TIR gives rise to an immediate thrombocytopenia and transient coagulopathy consistent with a thrombotic thrombocytopenic purpura-like state. POTx with or without TIR results in DIC, which may recover following graft excision. TIR plus PCTx plus POTx results in a combination of the TTP-like state and DIC. REFERENCES 1. Kozlowski T, Shimuzu A, Lambrigts D, et al: Transplantation 67:18, 1999 2. Ierino FL, Kozlowski T, Siegel JB, et al: Transplantation 66:1439, 1998
PCTx With or Without TIR (Group 3)
A rapid decrease in platelets occurred, with a slight and transient prolongation in PT (⬍17 seconds), decrease in FIB, and increase in LDH. Furthermore, schistocytes were present on blood smears. Platelets recovered within 5 to 9 days if no TIR was given.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 1099 (2000)
From the Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston. Address reprint requests to D.K.C. Cooper, MD, PhD, FRCS, Transplantation Biology Research Center/Massachusetts General Hospital MGH-East, Building 149, 13th Street, Boston, MA 02129. E-mail: [email protected].
0041-1345/00/$–see front matter PII S0041-1345(00)01141-6 1099
A
TTEMPTS to induce mixed hematopoietic chimerism are associated with disorders of hemostasis/coagulation.1 Delayed rejection of vascularized xenografts in the pig-to-baboon model has been associated with disseminated intravascular coagulation (DIC).2 Irradiation or drugs may potentiate vascular activation or injury. We investigated the roles of (1) the tolerance-inducing regimen (TIR), (2) pig hematopoietic cell (PCTx), and (3) pig organ (POTx) transplantation on platelet activation and coagulation parameters. METHODS The TIR included total body irradiation (WBI), T-cell depletion, and splenectomy. Five groups (total 29 experiments) were studied. Baboons were recipients except in Group 1. In Group 1 (n ⫽ 6), Cynomolgus monkeys underwent TIR plus hematopoietic cell and kidney (or heart) allo- or concordant xenotransplantation. In Group 2 (n ⫽ 4), TIR with or without autologous cell infusion was performed. In Group 3 (n ⫽ 12), PCTx with or without TIR was performed. In Group 4 (n ⫽ 5), POTx with or without TIR was performed. In Group 5 (n ⫽ 4) TIR plus PCTx plus POTx was performed. Platelet count, coagulation parameters (PT, PTT, fibrinogen [FIB], D-dimer), and lactate dehydrogenase (LDH) were measured, and blood smears were performed.
RESULTS TIR without PCTx or POTx (Groups 1 and 2)
There was a gradual decrease in platelets over 12 to 15 days, followed by rapid recovery. PT, PTT, and FIB remained normal.
POTx With or Without TIR (Group 4)
There was a gradual decline in platelets and fibrinogen over 7 days with a late prolongation in PT and increase in D-dimer levels, in keeping with DIC. Recovery generally occurred when the graft was excised (as an emergency). PCTx Plus POTx Plus TIR (Group 5)
Immediate decrease in platelets occurred with recovery beginning by day 16. Platelet supplementation was required. There was a greater prolongation of PT (⬍26 seconds) and PTT (⬎45 seconds), and FIB decreased steadily. However, the histopathologic features of rejection could be relatively mild. CONCLUSIONS
TIR (with or without allografting or autologous cell infusion) results in transient thrombocytopenia only, in keeping with marrow depression from WBI. PCTx with or without TIR gives rise to an immediate thrombocytopenia and transient coagulopathy consistent with a thrombotic thrombocytopenic purpura-like state. POTx with or without TIR results in DIC, which may recover following graft excision. TIR plus PCTx plus POTx results in a combination of the TTP-like state and DIC. REFERENCES 1. Kozlowski T, Shimuzu A, Lambrigts D, et al: Transplantation 67:18, 1999 2. Ierino FL, Kozlowski T, Siegel JB, et al: Transplantation 66:1439, 1998
PCTx With or Without TIR (Group 3)
A rapid decrease in platelets occurred, with a slight and transient prolongation in PT (⬍17 seconds), decrease in FIB, and increase in LDH. Furthermore, schistocytes were present on blood smears. Platelets recovered within 5 to 9 days if no TIR was given.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 1099 (2000)
From the Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston. Address reprint requests to D.K.C. Cooper, MD, PhD, FRCS, Transplantation Biology Research Center/Massachusetts General Hospital MGH-East, Building 149, 13th Street, Boston, MA 02129. E-mail: [email protected].
0041-1345/00/$–see front matter PII S0041-1345(00)01141-6 1099