Transcript transfusion and microchimerism

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)
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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).
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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).
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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
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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.
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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:
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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)
•
•
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•
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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
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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
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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.
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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.
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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
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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
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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.
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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)
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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.
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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
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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”.
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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.
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