Management of Severe Anemia in Crohn's Disease Patient on Upadacitinib
This patient requires immediate hospitalization, urgent transfusion, discontinuation of upadacitinib, hematology consultation, and comprehensive workup to identify the cause of this life-threatening hemoglobin drop.
Immediate Life-Saving Interventions
Admit the patient immediately – A hemoglobin of 3 g/dL represents severe, life-threatening anemia requiring inpatient management 1.
Transfuse packed red blood cells urgently – With hemoglobin below 7 g/dL, transfusion is indicated regardless of symptoms 1. Target hemoglobin of 7-8 g/dL in stable patients, though higher targets (9 g/dL) should be considered given the massive bleeding and potential cardiovascular compromise 1. Transfuse 2-3 units initially, with each unit expected to raise hemoglobin by approximately 1.5 g/dL 1.
Discontinue upadacitinib immediately – The FDA label documents that anemia (hemoglobin <8 g/dL) occurs in patients on upadacitinib, though rarely 2. Given the temporal relationship and severity, this drug must be stopped pending investigation 1.
Obtain immediate hematology consultation – This is explicitly recommended for grade 3-4 anemia (hemoglobin <8 g/dL) 1.
Critical Diagnostic Workup
Immediate Laboratory Evaluation
Complete blood count with peripheral smear – Assess for hemolysis (schistocytes, spherocytes), macrocytosis, or evidence of bone marrow suppression 1, 3.
Hemolysis panel – Obtain LDH, haptoglobin, indirect and direct bilirubin, reticulocyte count, and direct antiglobulin test (Coombs) 1. Elevated reticulocyte count suggests hemolysis or bleeding; low count indicates production defect 3.
Coagulation studies – PT/INR, PTT, fibrinogen, and D-dimer to evaluate for disseminated intravascular coagulation 1.
Iron studies – Serum iron, ferritin, total iron-binding capacity, and transferrin saturation to assess for iron deficiency versus anemia of chronic disease 3, 4.
Inflammatory markers – ESR and CRP to assess Crohn's disease activity, as active inflammation is a clear indicator of disease requiring optimization 1, 4.
Additional Targeted Testing
Nutritional deficiencies – Vitamin B12, folate, copper, and thyroid function, as thiopurines (commonly used in Crohn's) cause macrocytosis and can cause pure red cell aplasia 1, 4.
Drug-induced causes – Review all medications for potential bone marrow suppression, particularly if the patient is on azathioprine or 6-mercaptopurine, which cause leukopenia in 3.2% and can cause autoimmune hemolytic anemia 1.
Autoimmune serology – Given the rapid drop, consider autoimmune hemolytic anemia workup 1.
ADAMTS13 activity and inhibitor titer – If thrombocytopenia is also present, evaluate for thrombotic thrombocytopenic purpura (TTP), which presents with precipitous hemolysis and anemia 1.
Bone marrow biopsy – If no obvious cause identified, perform cytogenetic analysis to evaluate for myelodysplastic syndromes or bone marrow failure 1.
Gastrointestinal Bleeding Evaluation
Assess for active GI bleeding – A drop from 8.5 to 3 g/dL over 20 days suggests ongoing blood loss, likely from active Crohn's disease 1.
Hemodynamic assessment – Check orthostatic vital signs and assess for signs of shock 1.
Endoscopic evaluation – In hemodynamically stable patients, perform sigmoidoscopy and esophagogastroduodenoscopy to localize bleeding source 1. In Crohn's disease, bleeding typically results from focal erosion into intestinal vessels 1.
Consider CT angiography – If bleeding source unclear, contrast-enhanced CT before colonoscopy increases detection rate for vascular lesions (35.7% vs 20.6%) 1.
Management of Anemia
Transfusion Strategy
Transfuse to hemoglobin 7-8 g/dL – Do not transfuse more than the minimum necessary to relieve symptoms or return to safe range 1.
Coordinate with blood bank – Discuss with transfusion service that patient has possible drug-related severe adverse event 1.
Follow transfusion with IV iron – Subsequent intravenous iron supplementation is essential after transfusion 1, 5.
Iron Replacement
Administer intravenous iron – IV iron is strongly preferred over oral iron in inflammatory anemia because oral absorption is impaired in inflammatory states, with >90% remaining unabsorbed and potentially exacerbating inflammation 5.
Target ferritin >100 μg/L – In the presence of inflammation, the lower limit of ferritin consistent with normal iron stores should be increased to 100 μg/L 5.
Monitor transferrin saturation – Maintain levels <800 g/L to avoid toxicity 5.
Corticosteroid Therapy
Initiate prednisone 1-2 mg/kg/day – For grade 3-4 anemia, administer oral or IV corticosteroids depending on symptoms and speed of development 1.
Consider additional immunosuppression – If no improvement or worsening on corticosteroids, initiate rituximab, IVIG, cyclosporine A, or mycophenolate mofetil 1.
Optimize Crohn's Disease Treatment
Escalate IBD therapy – The presence of anemia of chronic disease indicates active Crohn's disease requiring optimization 1, 5. Treating underlying inflammation is essential, as biologics like infliximab significantly improve hemoglobin levels even after adjusting for disease activity 1.
Do not restart upadacitinib – Permanently discontinue given grade 4 toxicity 1. Note that gastrointestinal perforations occurred in 4 patients on 45-mg upadacitinib in clinical trials 6.
Monitoring Protocol
Weekly CBC – Recheck hemoglobin weekly until stable and cause identified 3.
Daily monitoring during hospitalization – Assess for hemodynamic stability, ongoing bleeding, and response to transfusion 1.
Iron studies every 2-4 weeks – Monitor ferritin and transferrin saturation during IV iron therapy 4, 5.
Long-term surveillance – After correction, monitor every 3-6 months as recurrence is common (>50% after 1 year) and often indicates ongoing inflammation 3, 4.
Critical Pitfalls to Avoid
Do not delay transfusion – With hemoglobin of 3 g/dL, this is a medical emergency requiring immediate intervention 1.
Do not use oral iron alone – In inflammatory states, oral iron is poorly absorbed and may worsen inflammation 5.
Do not overlook drug causes – Upadacitinib, azathioprine, and other IBD medications can cause bone marrow suppression 1, 2.
Do not miss TTP – If platelets are also dropping precipitously, ADAMTS13 testing is urgent as delay in TTP diagnosis increases mortality 1.
Do not restart JAK inhibitor – This represents grade 4 toxicity requiring permanent discontinuation 1.