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Blood Transfusion: A Newly Recognized Cause of Microchimerism. C. Michael Gibson, M.S., M.D. Association of Transfusion and Adverse Clinical Outcomes • Transfusion with red blood cells is associated with decreased survival among trauma patients • Massive transfusion was independently associated with poor survival. • Blood transfusion in the setting of an acute coronary syndrome is associated with increased mortality (GUSTO Iib, PURSUIT, PARAGON) Copyleft from Kunadian … Gibson ,JTT 2008 in press. Spinella PC et al. J Trauma 2008 February;64(2 Suppl):S69-S77. Rao SV et al. JAMA 2004 October 6;292(13):1555-1562. Association of Transfusion and Poor Outcomes • Among anemic patients undergoing PCI following a myocardial infarction, transfused patients compared with those who were not transfused had a higher unadjusted inhospital mortality rate (14.5% vs. 3.0%, p<0.0001). • After adjustment for co-morbidities and propensity for transfusion, blood transfusion was associated with a higher risk of in-hospital mortality (adjusted OR=2.02, 95% CI 1.47-2.79, p<0.0001). Copyleft from Kunadian … Gibson ,JTT 2008 in press. Jani SM et al. Clin Cardiol 2007 October;30(10 Suppl 2):II49-II56. Association of Transfusion, Long-term Survival and Poor Outcomes in Cardiac Surgery patients • Blood transfusion is an independent predictor of mortality and the relative risk of death within 10 years increased by 4.1% per unit of red cells transfused (p<0.0001). This study consisted of all cohorts who underwent transfusion. • Red cells stored for more than two weeks are associated with increased short and long term mortality and postoperative complications following cardiac surgery (CABG, valve surgery or both). Copyleft from Kunadian … Gibson ,JTT 2008 in press. Vamvakas EC et al. Transfusion 1994 June;34(6):471-477. Malone DL et al. J Trauma 2003 May;54(5):898-905. Koch CG et al. N Engl J Med 2008 March 20;358(12):1229-1239. Hypotheses Regarding Association of Transfusion with Increased Mortality • Prolonged storage time has been associated with multiorgan failure. – Red cells depleted of NO promotes vasoconstriction, platelet aggregation and ineffective oxygen delivery – Red cells are low in 2,3 diphosphoglyceric acid – Increase in inflammatory myocardial ischemia mediators that can exacerbate • RBCs may increase viscosity and lower cardiac output • Presence of donor leukocytes can result in fever, chills, HLA autoimmunization and mortality from GvHD. • Transfused cells may act as a nitric oxide sink Copyleft from Kunadian … Gibson ,JTT 2008 in press. Zallen G et al. Am J Surg. 1999;178:570 –572, Williamson LM, Warwick RM. Blood Rev. 1995;9:251–261, McMahon TJ et al. Nat Med.2002;8:711-717, Welch HG.Ann Intern Med. 1992;116:393-402, Fransen E. Chest. 1999;116:1233-1239. Microchimerism • Each of us harbors some cells that originated in other, genetically distinct individuals—a condition called microchimerism. • All of us save some cells we have acquired from our mother during gestation, and women who have been pregnant retain cells that come from the fetus. • The acquired cells can persist for decades and may establish residence inside tissues, becoming an integral part of the body’s organs. • Microchimerism could contribute to an immune attack in some cases. Copyleft from Kunadian … Gibson ,JTT 2008 in press. Adams, K. M. et al. JAMA 2004;291:1127-1131. Diseases Associated with Michrochimerism Fetus-to-mother transfer has been found in: Mother-to-child transfer has been found in: • • • • • • Biliary atresia (fetal liver disorder) Juvenile dermatomyositis (immune attack on skin and muscle) Neonatal lupus (immune attack on various tissues in fetus) Scleroderma (immune attack that thickens skin and can damage other tissues) Type 1 (insulin-dependent) diabetes (immune attack on pancreas) Pityriasis lichenoides (inflammatory skin condition) • • • • • • • • • Copyleft from Kunadian … Gibson ,JTT 2008 in press. Breast cancer Cervical cancer Multiple sclerosis (immune attack on neurons of central nervous system) Preeclampsia (pregnancy-induced hypertensive disorder) Polymorphic eruption of pregnancy (inflammatory skin condition) Rheumatoid arthritis (immune attack on joints) Scleroderma Systemic lupus erythematosus (immune attack on multiple organs) Thyroid diseases (Hashimoto’s, Graves’ and other diseases) Adams, K. M. et al. JAMA 2004;291:1127-1131. Fetal Microchimerism: Autopsy findings in Woman who Died of Scleroderma Involving the Lung Ratio of fetal cells to maternal cells in lung tissue: 3,750 fetal to 760 maternal cells Copyleft from Kunadian … Gibson ,JTT 2008 in press. Adams, K. M. et al. JAMA 2004;291:1127-1131. Clinical Correlates of Microchimerism • Pregnancy (both from mother to fetus and from fetus to mother) • Multiple pregnancies (among siblings) • Solid organ and hematopoietic transplantation • Blood transfusion Copyleft from Kunadian … Gibson ,JTT 2008 in press. Utter et al. Vox Sanguinis 2007;93:188-195 Reed et al. Semin HematolJan;44(1):24-31 Blood Transfusion and Microchimerism • Blood transfusion is a newly recognized cause of microchimerism. • Relatively recent advances in polymerase chain reaction (PCR) technology have spawned new information about the frequency of transfusion-associated microchimerism (TA-MC). • Although conceptually related to fetal-maternal microchimerism, TA-MC is a distinct and separate entity. Copyleft from Kunadian … Gibson ,JTT 2008 in press. Utter et al. Vox Sanguinis 2007;93:188-195 Reed et al. Semin HematolJan;44(1):24-31 TA-MC: Incidence • TA-MC is present in approximately half of transfused severely injured patients (40-50%) at hospital discharge and is not affected by leukoreduction. • In approximately 10% of patients, the chimerism from a single blood donor may increase in magnitude over months to years, reaching as much as 2-5% of all circulating leukocytes. Copyleft from Kunadian … Gibson ,JTT 2008 in press. Reed et al. Semin HematolJan;44(1):24-31 Utter GH et al. Transfusion 2006;46(11):1863-1869. TA-MC: Incidence • Traumatic injury may induce an immunosuppressive milieu (immunomodulation) in which fresh blood products with replicationcompetent leukocytes can sometimes cause TAMC • MC is very uncommon with transfusion for elective surgery Copyleft from Kunadian … Gibson ,JTT 2008 in press. Reed et al. Semin HematolJan;44(1):24-31 Utter et al. Vox Sanguinis 2007;93:188-195 TA-MC: Cell Lineages • There is persistence of leukocytes including T-lymphocytes, B-lymphocytes and myelomonocytes. • Patients continue to demonstrate TA-MC 23 years following the initial injury and transfusion Copyleft from Kunadian … Gibson ,JTT 2008 in press. Lee TH et al. Blood 1999 May 1;93(9):3127-3139. Utter GH et al. J Trauma 2004 October;57(4):702-707. Lee TH et al. Transfusion 2005 August;45(8):1280-1290. TA-MC: Predictors • The number of units of blood transfused, trauma severity, gender and the proportion of patients who had underwent splenectomy was not different among those patients who did and did not develop TA-MC. • Patients with TA-MC had reduced activation in response to phytohemagglutinin shortly following the injury and at hospital discharge. Copyleft from Kunadian … Gibson ,JTT 2008 in press. Lee TH et al. Blood 1999 May 1;93(9):3127-3139. Utter GH et al. J Trauma 2004 October;57(4):702-707. TA-MC: Diagnosis Several techniques are available to detect TA-MC • Polymerase chain reaction (PCR) • DR panel • InDel-based assay is frequently used (although not 100% sensitive) Copyleft from Kunadian … Gibson ,JTT 2008 in press. Utter et al. Vox Sanguinis 2007;93:188-195 Does Leukoreduction Reduce the Risk of TA-MC? Leukoreduction of blood transfusions reduces the concentration of donor WBCs from 109 to 106 cells/liter. At median follow-up of 8 months, 9 of 32 patients in the non-leukoreduced group (28%) and 13 of 35 patients in the leukoreduced group (37%) developed TA-MC (P=0·43). Thus, although leukoreduction removes the vast majority of donor leucocytes, it fails to prevent or even substantially reduce the likelihood of developing TA-MC. Copyleft from Kunadian … Gibson ,JTT 2008 in press. Utter GH et al. Transfusion 2006 November;46(11):1863-1869. Does Radiation of Blood Products Reduce the Risk of TA-MC? Unknown In mice models did not Copyleft from Kunadian … Gibson ,JTT 2008 in press. Brubaker DC Scientific Basis of Transfusion Medicine Implications for Clinical Practice. Philadelphia, PA: W.B. Saunders; 1994:544 –579 Transfusion Associated Graft Versus Host Disease • Transfusion-associated graft versus host disease (TA-GvHD) is a rare complication of blood transfusion, in which the donor T lymphocytes mount an immune response against the recipient's lymphoid tissue. • Donor lymphocytes are usually identified as foreign and destroyed by the recipient's immune system. Gibson CM. Transfusion associated Graft Versus Host Disease at www.wikidoc.org Transfusion Associated Graft Versus Host Disease • However, in situations where the recipient is immunocompromised (inborn immunodeficiency, acquired immunodeficiency, malignancy), or when the donor is homozygous and the recipient is heterozygous for an HLA haplotype (as can occur in directed donations from first-degree relatives), the recipient's immune system is not able to destroy the donor lymphocytes. • This can result in graft versus host disease. Gibson CM. Transfusion associated Graft Versus Host Disease at www.wikidoc.org Transfusion Associated Graft Versus Host Disease Clinical manifestations • The clinical presentation the same as in GvHD occurring in other settings, such as bone marrow transplantation. TA-GvHD can develop four to thirty days after the transfusion. Typical symptoms include: • Fever • Erythematous maculopapular rash, which can progress to generalised erythroderma • Toxic epidermal necrolysis in extreme cases • Other symptoms can include cough, abdominal pain, vomiting, and profuse diarrhea (up to 8 liters/day). Gibson CM. Transfusion associated Graft Versus Host Disease at www.wikidoc.org TA-MC and Atherosclerosis Given that 250,000 patients per year in the US receive a transfusion: “A thorough evaluation of TA-MC as a potential risk factor for acute and/or chronic consequences would be worthwhile”. Copyleft from Kunadian … Gibson ,JTT 2008 in press. Utter et al. Vox Sanguinis 2007;93:188-195 TA-MC: Conclusions TA-MC seems to be: • Common (affecting approximately 10% of transfused trauma patients) incidence in ACS patients not known. • Enduring (lasting years to decades) . • Pronounced (involving up to 5% of circulating leucocytes and multiple immunophenotypic lineages suggestive of hematopoietic engraftment). • Further study is needed to understand the long clinical consequences, if any. Copyleft from Kunadian … Gibson ,JTT 2008 in press.