1. Clinical Case
Partha Choudhary/48/M
 LURRAR- date of transplantation 7/6/2011
 Developed progressive anemic symptoms after
transplantation, with chest pain on exertion.
 Pre Tx Hb-9.2, gradually decreasing Hb post Tx-
6.5 on discharge till 5.4g/dl one month after the
DOTx.
 History of EPO use (iv) for 2 yrs, max 10,000U till
Tx and sc after that for 3 doses.
 Preserved TLC and Plat with NC,NC picture and
retic of 0.5%, and MCV of 82

2. Clinical Case
 Ferritin-790mcg/ml and TSAT-80%
 Stool occult blood X3-negative
 UGI Endoscopy-normal
 USG abdomen-normal
 No response to Vit B12 and folic acid
supplementation.
 Mild rise of serum creat from 1.1mg% to
1.65mg%
 CMV DNA PCR-negative
 Anti-EPO antibodies-pending
 Parvovirus B19-positive

3. Mini review
CJASN:193-199; 2008

4.  First recognized in 2002.
Casadevall et al. N Engl J Med 346:
469–475, 2002
 It was initially reported in patients who were
treated with epoetin manufactured by Ortho-
Biotec outside the United States (Eprex, Erypo
[Ortho Biologics, LLC, Manati, Puerto Rico])
 But cases have since been reported with all
commercially available ESA (Epogen, Aranesp,
Procrit, NeoRecormon)

5. Diagnosis of ESA induced PRCA
 This is characterised by
progressive, severe, normocytic, normochromic
anemia of sudden on-set; reticulocytopenia; and
a striking, almost complete absence of erythroid
precursor cells in the bone marrow.
 Hemoglobin levels decrease at a rate of
approximately 0.1 g/dl per d (1 g/L per
d), corresponding to the red blood cell lifespan.
 The hallmark of PRCA is the absence of
erythroblasts from an otherwise normal bone
marrow.

6. Diagnosis of ESA induced PRCA

7. Bone marrow in PRCA

8. Classification of Pure Red Cell Aplasia
 Self-limited
 Transient erythroblastopenia of childhood
 Transient aplastic crisis of hemolysis (acute B19 parvovirus
infection)
 Fetal red blood cell aplasia
 Nonimmune hydrops fetalis (in utero B19 parvovirus infection)
 Hereditary pure red cell aplasia
 Congenital pure red cell aplasia (Diamond-Blackfan syndrome)
 Acquired pure red cell aplasia
 Thymoma and malignancy
 Thymoma
 Lymphoid malignancies (and more rarely other hematologic diseases)
 Paraneoplastic to solid tumors
 Connective tissue disorders with immunologic abnormalities
 Systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid
arthritis
 Multiple endocrine gland insufficiency
 Virus
 Persistent B19 parvovirus, hepatitis, adult T cell leukemia virus, Epstein-
Barr virus
 Pregnancy
 Drugs
 Especially

9. Drugs implicated in PRCA
Causality may be established using the following three criteria:
(1) at least five patients reported,
(2) reports from at least three separate investigators, and
(3) a minimum of one case of probable or higher causality using a published
assessment scale.

10. Pathogenesis of ESA induced
PRCA
 The pathogenetic mechanism has been shown
clearly to be secondary to the development of
neutralizing anti-erythropoietin antibodies.
 These antibodies, which recognize all available
ESA (epoetin alfa, epoetin beta, and darbepoetin
alfa) as well as endogenous erythropoietin, block
the interaction between erythropoietin and its
receptor.

11. Clinical approach to PRCA suspect
case
1. First thing to ascertain whether the ESA
resistance is partial or severe. ESA related
PRCA follows an “all or none”
phenomenon, which means that if there is less
than severe ESA resistance, then the cause is
not ESA induced PRCA.
2. Bone marrow examination to confirm the
presence of severe erythroid hypoplasia.
3. Anti-ESA antibodies are needed for completing
the diagnostic criteria, absence makes ESA
induced PRCA unlikely.
4. Other causes of hypo responsiveness to ESA
should also be evaluated

12. Conditions causing ESA
resistance

13. Treatment
 Patients who are diagnosed with ESA induced
PRCA should have the ESA stopped immediately
but cessation alone may not cause remission.
 Regular blood transfusions till the antibodies
disappear.
 In cases of PRCA induced by drugs other than
ESA’s, the disease generally remits in 1-2 weeks.
 Patients who develop antibody-mediated PRCA in
response to ESA treatment are unlikely to
respond to treatment with other erythropoietic
agents, because there is substantial
crossreactivity among erythropoietic agents,
including endogenous erythropoietin.

14. Treatment
 In patients with CKD and ESA-induced
PRCA, immunosuppressive treatment is usually
required to induce disappearance of anti-
erythropoietin antibodies.
 Recovery rates from PRCA is 2% without
immunosuppressive therapy, 52% after
immunosuppressive treatment(s) outside the renal
transplantation setting, and 95% after kidney
transplantation.
Bennett et al. Blood 106:3343–
3347, 2005
 In the absence of kidney transplantation, treatment of
PRCA includes oral administration of
prednisone, usually at a starting dosage of 1 mg/kg
per d. In patients with idiopathic
PRCA, corticosteroids produce responses in
approximately 50% of patients
 Similar response rates were reported in patients with

15. Treatment
 Other therapies like
cyclophosphamide, cyclosporine, daclizumab and
rituximab have also been tried with success.
 PRCA induced by parvovirus respond to IVIg but
the response is poor in ESA induced PRCA
 Rechallenge with a different epoetin preparation
should be considered with caution and only when
anti-epoetin antibody levels have become
undetectable.

16. Reasons for the development of
antibodies against EPREX
 The incidence rate rose drastically between 1998
and 2002, after a change in the formulation in
which human serum albumin was eliminated and
replaced by polysorbate-80 to avoid the risk for
virus or transmission.
 Several hypothesis have been put forth to explain
the breakage of the B cell tolerance but are not
satisfactory.
 The presence of epoetin-loaded micelles in the
stored formulation has been suggested as a

17.  It has been proposed that leachates released from
rubber stoppers used only in syringes from Ortho
Biotech could act as adjuvants and induce an immune
response against erythropoietin, but experimental
data substantiating this claim are controversial.
 However, the micelle hypothesis and the leachate
hypothesis were not convincing due the universal
presence in EPO syringes and the rarity of the
condition.
 Another explanation that was put forward was the use
of silicon in as lubricants in the Eprex syringes
(NEJM 2004)

18. NEJM 2004

19. Parvovirus B19 in renal transplant
recipients
Nature Reviews 2007

20. Parvovirus B19 related PRCA in
renal transplant recipients
 The onset of anemia after transplantation has
been reported to occur from 2 weeks to 63
months, although most of the documented cases
occurred within the first 3 months.
 Fever and flu-like symptoms can be seen at
presentation. Weakness, dyspnea and orthostatic
hypotension are often present, and are related to
the abrupt onset of severe anemia.
 Arthralgias and rashes are less common
manifestations because of impaired antibody

21. Parvovirus B19 related PRCA in
renal transplant recipients
Nature Reviews 2007

22. THANK YOU