Autoimmune Pure Red Cell Aplasia Research Articles

Thrombocytosis and Megakaryocyte Changes Associated with Pure Red Cell Aplasia

J.A., R.G.W, and G.R. contributed equally to this abstract. Introduction: Acquired pure red cell aplasia (PRCA) is a rare hematological disorder characterized by normocytic, normochromic anemia with severe reticulocytopenia and a notable absence of identifiable erythroid precursors in the bone marrow. PRCA is often without a clear etiology and can be associated with conditions such as Large Granular Lymphocytic (LGL) Leukemias, B-cell dyscrasias, thymomas, immunodeficiencies or infections. Discovery of an IgG inhibitor in primary autoimmune pure red cell aplasia (PRCA) has been an immensely significant breakthrough. This finding has not only shed light on the critical role of IgG inhibitors in the pathophysiology of PRCA but has also underscored the importance of aberrant T cell activity in this condition. Thrombocytosis refers to an elevation in platelet count of >450,000/μL, which is not a typical feature associated with PRCA. Based on observations in our clinical practice of patients with PRCA with concomitant thrombocytosis, we screened our cohort for the combination of these features to discover potential mechanisms underlying this phenomenon. Methods: In order to address this objective, we conducted a retrospective analysis of medical records from 90 patients diagnosed with acquired PRCA at the University of Texas Southwestern and Cleveland Clinic Foundation between 2000 and 2022. Our primary goal was to determine the frequency of thrombocytosis among these patients. For those in the subset displaying thrombocytosis, longitudinal hemoglobin and platelet counts before and after treatment of the condition were also collected for relevant comparisons utilizing paired t-tests after assessing for normality with Shapiro-Wilk test. Results: Among a cohort of 90 patients diagnosed with acquired PRCA, 12 individuals exhibited thrombocytosis at the time of PRCA diagnosis (Table 1). Demographically, this subset of individuals had a median age of 53.5, and a 3:1 ratio of women to men. 66.7% of those with thrombocytosis also exhibited megakaryocyte hyperplasia on bone marrow biopsy. Molecular analysis ruled out the presence of myeloproliferative neoplasms, and blood work was obtained ruling out iron deficiency. Patients were treated for PRCA with a variety of medications including prednisone, cyclosporine, tacrolimus, rituximab, and cyclophosphamide. After treatment, 8 of the 12 patients demonstrated complete resolution of their PRCA, defined as transfusion independence with hemoglobin levels above 10. Further examination of those 8 patients with resolution of PRCA revealed statistically significant differences in mean hemoglobin and platelet counts before and after treatment (Figure 1). Specifically, the mean hemoglobin count increased from 7.9 (SD 2.5) g/dL to11.6 (1.8) g/dL (p=0.0168), while the platelet count decreased from 557,300 (SD 104,700) /μL to 414,400 (SD 109,600) /μL (p=0.0049). Conclusion: Our report is the most comprehensive case series to date reporting on thrombocytosis in patients with acquired PRCA. We speculate that the arrest of erythropoiesis generating PRCA may lead to skewing of precursors towards the megakaryocytic lineage. Alternatively, EPO production secondary to PRCA could stimulate TPO receptors and thus stimulate platelet production. Clinicians should be aware of this particular PRCA presentation. Further investigations will aid in elucidating whether one of these mechanisms may also be playing a role in PRCA-related thrombocytosis. The significance of thrombocytosis or megakaryocyte alterations in PRCA remains enigmatic, necessitating further investigations to elucidate their role in disease pathophysiology, as well as their utility as biomarkers for treatment response prediction. The limitations of this study encompass a small sample size and the absence of post-treatment bone marrow biopsy results, which would have facilitated the visual assessment of any resolved megakaryocyte abnormalities. Future directions include examining megakaryocyte hyperplasia and other megakaryocyte abnormalities such as hyper- and hypo-lobation associated with PRCA.

A Paradoxal Reaction from Intravenous Immunoglobulin

Introduction: Intravenous immunoglobulin (IVIG) is among the commonly used agents for many autoimmune conditions, such as chronic inflammatory demyelinating polyneuropathy (CIDP), a progressive neurologic disorder that is characterized by weakness and sensory loss. While rare, adverse effects stemming from IVIG have been noted, these usually occur during or right after the infusion. Hematopoietic adverse events leading to anemia have been documented but are extremely rare. Two cases of IVIG-associated thrombocytopenia have been reported. We present a case of IVIG-induced thrombocytopenia in a patient with CIDP. Case Presentation: A 73-year-old female presented with severe back pain, absent reflexes, worsening sensory loss, and proximal and distal weakness resulting from her CIDP. She received 1000 mg of IV methylprednisolone and 2 grams per kilogram of IVIG (Gamunex) to manage her presenting symptoms. Patient symptoms improved and was subsequently discharged from the hospital. Following the treatment regiment in the hospital she had 2 subsequent infusions of IVIG in the outpatient setting, scheduled 2 weeks apart. On follow up, her platelet count dropped from 333,000 noted at time of hospital discharge to 35,000, 9 days after her second outpatient infusion of IVIG. No known antiplatelet antibodies were found; a formal thrombocytopenic workup for underlying causes was negative. Her count was restored once IVIG was withheld. No other treatment was implemented, and no other changes were made. Discussion: In a retrospective study of patients receiving IVIG, headache and fatigue were the most common adverse reactions. Less frequently, observed events were back pain and changes in blood pressure (mostly tachycardia). Serious complications such as anaphylaxis, infection or cardiac infarction have been noted. Hematological effects such as Coombs negative hypochromic anemia, autoimmune pure red cell aplasia, acute hemolysis, thrombosis, and embolism were stated to be extremely rare. These side effects generally occurred within 6 h after the start of the infusion, and lowering the infusion rate led to an improvement in the symptoms. However, rare late-onset adverse effects (LAe) have been described, none of which describe thrombocytopenia as a possibility. The temporal association between IVIG administration and the rapid decline in this patient's platelet count suggested a possible link. A comprehensive workup excluded common causes of cytopenia, such as viral infections (hepatitis B&C) and nutritional deficiencies (folic acid and copper). The exact mechanism underlying IVIG-induced thrombocytopenia remains unclear. Proposed mechanisms include immune-mediated destruction of platelets or drug-dependent antibody formation. Prompt recognition and appropriate management are crucial to prevent complications associated with severe thrombocytopenia. Our case highlights the significance of monitoring platelet counts in individuals receiving IVIG. Physicians and other providers should know the potential risk of IVIG-induced thrombocytopenia and promptly evaluate any unexplained platelet count decline after infusion. Further research is needed better to understand this rare complication's pathogenesis and risk factors. Heightened vigilance and early intervention can ensure optimal outcomes for IVIG therapy patients. While our patient had no complications from the developed thrombocytopenia, subsequent infusions will be needed for her inevitable CIDP flares. Closer observation and frequent lab draws will be needed to mitigate any future IVIG-associated thrombocytopenia.

Pure Red Cell Aplasia and Myelofibrosis in B-cell Neoplasm

We describe an unusual case of B-cell neoplasm accompanied by pure red cell aplasia (PRCA) and myelofibrosis in a 67-year-old male presenting with severe anaemia. A few unclassified, myeloperoxidase-negative blastoid cells were seen on bone marrow aspiration, and erythroid cell hypoplasia and myelofibrosis on bone marrow biopsy. An autoimmune PRCA was suspected, as serum CH50, C3 and C4 levels were consistently low. Ciclosporin was effective in treating the anaemia, but anaemia returned when the drug was discontinued. Thirteen months later, the patient was admitted with pleural effusion and ascites that contained monoclonal CD19+ CD20+ immature blast cells with a complex karyotype, thought to be neoplastic B-cells. The unclassified blastoid cells seen earlier may therefore have been from the same origin. The patient deteriorated rapidly and died. Only one case of non-Hodgkin's lymphoma with PRCA and myelofibrosis has been reported previously. We discuss the possibility that dysregulated T-cells induced by neoplastic B-cells may have given rise to concomitant PRCA and myelofibrosis.

TRANSIENT PURE RED CELL APLASIA CAUSED BY ANTILYMPHOBLAST GLOBULIN AFTER CADAVERIC RENAL TRANSPLANTATION

Transient pure red cell aplasia (PRCA) in three consecutive patients receiving ATG for management of kidney graft rejection prompted a systematic study of the effects on erythropoiesis of the ATG preparation used at our institution. We found that 90% of patients treated with rabbit anti-T lymphoblast globulin developed reticulocytopenia (less than 17,000 reticulocytes/mm3), with complete disappearance of reticulocytes in 65% of patients and increased requirement for red cell transfusion. PRCA, with selective aplasia of erythroblasts was confirmed by bone marrow aspiration in 4 patients volunteering for aspiration, and by the kinetic of the disappearance of blood reticulocytes in relation to the beginning of ATG treatment. The nadir of thrombocytes and lymphocytes, blood cells directly destroyed by ATG in circulation, followed the start of ATG treatment within 1 to 4 days. In contrast the nadir of reticulocyte counts occurred later, between day 7 and 13 after ATG was begun, reflecting the fact that toxicity was directed against red cell precursors rather than mature circulating cells. In agreement with these clinical findings ALG was found to be cytotoxic in vitro for erythroid precursors. Analogously to autoimmune PRCA caused by autoantibodies to erythroblasts, this type of PRCA could be viewed as "heteroimmune disease."