Table 2.

Proposed diagnostic approach and criteria.

Lineage	Diagnostic approach	Diagnostic criteria for IMC	Limitations
Red cells	• Rule out other attributable causes of severe anemia post HCT: bone marrow suppression due to infections (CMV, EBV, Adenovirus, HSV, and other related infections) or medications, graft insufficiency or graft failure based on clinical evaluation and diagnostic testing • Rule out other identifiable cause of hemolytic anemia after transplant: TA-TMA, GVHD, drug induced hemolysis, transfusion reaction and ABO or minor blood group incompatibility based on clinical evaluation and the diagnostic criteria for each	• Hemoglobin ≤7 g/dL (or 70 g/L) or a drop in previously stable hemoglobin of more than 2 g/dL within 5 days (or 20 g/L) without any other attributable cause AND • Presence of red cell directed antibody, DAT positive; if negative the diagnosis should still be considered if there is evidence of hemolysis as suggested by:  • Presence of spherocytosis and/or  other evidence of hemolysis on the peripheral smear such as RBC clumping or agglutination  • Suggestive findings: elevated LDH, elevated reticulocyte count, indirect hyperbilirubinemia, low serum haptoglobin	• DAT may not detect IgA and other low affinity antibodies • Haptoglobin not always interpretable • LDH is a non-specific marker • Reticulocytopenia can be seen in early IMC (recommend bone marrow evaluation to rule out red cell aplasia)
Platelets	• Rule out other attributable causes of severe thrombocytopenia post HCT: etiologies causing increased platelet destruction (TA-TMA, GVHD, and TTP), splenic sequestration; bone marrow suppression due to infections and/or medications, graft insufficiency or graft failure based on clinical evaluation and diagnostic testing	• Platelet count <20,000 cells/mm3 (20 × 109 cells/L) after initial platelet engraftmenta or a significant drop (>50% drop from previous stable platelet count) in platelet count from previously stable levels without any other attributable cause, AND either • Presence of platelet directed antibody  • Anti-GPIIb/IIIa  • Donor specific anti-HLA, OR • If antibody negative,  • Pattern of a transient response/refractory to platelet transfusions  • Other suggestive finding: bone marrow shows normal megakarypoiesis	• Poor sensitivity and specificity of antibody testing
Neutrophils	• Rule out other attributable causes of severe neutropenia post HCT: bone marrow suppression due to infections and/or medications, graft insufficiency or graft failure based on clinical criteria and diagnostic testing	• Absolute neutrophil count <500 cells/mm3 (0.5 × 109 cells/L) after initial neutrophil engraftmentb, or a significant drop (>50% drop from previous stable neutrophil count) AND either • Presence of neutrophil directed antibody  • Anti-HNA  • Donor specific anti-HLA, OR • If antibody negative, despite >95% donor myeloid chimerism  • Marrow myeloid arrest or absence with recovery of red cells and platelets  • Poor or no response to G-CSF	• Poor sensitivity and specificity of antibody testing • False positive neutrophil antibody testing in the setting of IVIG use

C3 complement 3, DAT direct antibody test, GCSF granulocyte colony stimulating factor, GPIIb/IIIa glycoprotein IIb/IIIa, GVHD graft versus host disease, HLA human leukocyte antigen, HNA human neutrophil antigen, IgG immunoglobulin G, IMC immune-mediated cytopenia, IVIG intravenous immunoglobulin, LDH lactate dehydrogenase, MMF mycophenolate mofetil, RBC red blood cell, TA-TMA transplant associated thrombotic microangiopathy, TTP thrombotic thrombocytopenic purpura.

^aPlatelet engraftment defined as platelet count of >50,000/mm³ for at least 7 consecutive days after transplant not supported by transfusion.

^bNeutrophil engraftment defined as absolute neutrophil count >500 cells/mm³ for 3 consecutive days after HCT.