| 8.1. Hemolytic anemia |
Work-up and evaluation: - History and physical examination (with special consideration of history of new drugs, insect, spider, or snake bites).
- Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear. LDH, haptoglobin, bilirubin, reticulocyte count, and free hemoglobin.
- DIC panel, which could include PT or INR or PTT, and infectious causes.
- Autoimmune serology.
- PNH screening.
- Direct and indirect bilirubin, direct agglutinin test, and if no obvious cause, bone marrow analysis, and cytogenetic analysis to evaluate MDS.
- Evaluation for viral or bacterial (mycoplasma etc) causes of hemolysis studies.
- Protein electrophoresis and cryoglobulin analysis.
- Work-up for BM failure syndrome if refractory including B12, folate, copper, parvovirus, iron, and thyroid, infection.
- Glucose-6-phosphate dehydrogenase level.
- Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine or quinidine, fludarabine, ciprofloxacin, lorazepam, and diclofenac).
- Assessment of methemaglobinemia.
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| Grading | Management |
| G1: Hgb <LLN to 10.0 g/dL; <LLN to 6.2 mmol/L; <LLN to 100 g/L. | - Continue ICPi with close clinical follow-up and laboratory evaluation.
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| G2: Hgb <10.0 to 8.0 g/dL; <6.2 to 4.9 mmol/L; <100 to 80 g/L. | - Hold ICPi and strongly consider permanent discontinuation.
- Administer 0.5 to 1 mg/kg/day prednisone equivalents.
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| G3: Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated. | - Permanently discontinue ICPi.
- Should use clinical judgment and consider admitting the patient.
- Hematology consult.
- Prednisone 1 to 2 mg/kg/day (oral or IV equivalent depending on symptoms or speed of development).
- Consider RBC transfusion per existing guidelines. Do not transfuse more than the minimum number of RBC units necessary to relieve symptoms of anemia or to return a patient to a safe hemoglobin range (7 to 8 g/dL in stable, noncardiac inpatients).
- Should offer patients supplementation with folic acid 1 mg daily.
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| G4: Life-threatening consequences; urgent intervention indicated. | - Permanently discontinue ICPi.
- Admit patient.
- Hematology consult.
- IV corticosteroids (equivalent to prednisone 1 to 2 mg/kg/day).
- If no improvement on or if worsening on corticosteroids or severe symptoms on presentation, initiate other immunosuppressive drugs, such as rituximab, IVIG, cyclosporine, infliximab, MMF, or ATG.
- RBC transfusion per existing guidelines. Discuss with blood bank team before transfusions that a patient with possible ICPi SAE is in the hospital.
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Additional considerations: - Monitor hemoglobin levels weekly until the steroid tapering process is complete. Thereafter, less frequent testing is needed.
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| 8.2. Acquired TTP |
Work-up and evaluation: - History with specific questions related to drug exposure (eg, CTX, sirolimus, tacrolimus, oxymorphone, antibiotics, and quinine).
- Hematology consult.
- Physical examination, peripheral smear to check for schistocytes.
- ADAMTS13 activity level and inhibitor titer.
- LDH, haptoglobin, reticulocyte count, bilirubin, and urinalysis to rule out other causes.
- Prothrombin time, activated partial thromboplastin time, and fibrinogen.
- Blood group and antibody screen, and direct antiglobulin test.
- Consider CT or MRI brain, echocardiogram, electrocardiogram.
- Cytomegalovirus serology.
- NOTE: this disorder is usually associated with severe drop in platelets and hemolysis or anemia precipitously (microangiopathy).
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| Grading | Management |
| All grades. | - The first step in the management of TTP is a high index of suspicion for the diagnosis and timely recognition. Hematology consult should immediately be called, as delay in identification is associated with increased mortality or morbidity.
- Initially, the patient should be stabilized, and any critical organ dysfunction stabilized.
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G1: Evidence of RBC destruction (schistocytosis) without anemia, renal insufficiency, or thrombocytopenia clinically.
G2: Evidence of RBC destruction (schistocytosis) without clinical consequence with G2 anemia and thrombocytopenia. | - Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits, noting that there are currently no data to recommend restarting ICPi therapy.
- Administer prednisone 0.5 to 1 mg/kg/day.
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G3: Laboratory findings with clinical consequences (G3 thrombocytopenia, anemia, and renal insufficiency >2).
G4: Life-threatening consequences, (eg, CNS hemorrhage or thrombosis or embolism or renal failure). | - Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits, noting that there are currently no data to recommend restarting ICPi therapy.
- In conjunction with hematology, initiate therapeutic PEX according to existing guidelines with further PEX dependent on clinical progress.
- Administer methylprednisolone 1 g IV daily for 3 days, with the first dose typically administered immediately after the first PEX. For patient who has an initial platelet count response, discontinue PEX.
- May offer rituximab.
- Consider caplacizumab if ADAMTS13 activity level is <10 units/dL or <10% of normal, with an inhibitor or elevated anti-ADAMTS13 IgG.
- If no exacerbation within 3 to 5 days after stopping PEX, taper steroids over 2 to 3 weeks, complete course of rituximab (if receiving), and discontinue caplacizumab (if receiving).
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| 8.3. HUS |
Work-up and evaluation: - History and physical examination (special consideration for new history of high-risk drugs, hypertension, or cardiac causes).
- CBC with indices.
- Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis.
- Serum creatinine.
- ADAMTS13 (to rule out TTP).
- Homocysteine or MMA.
- Complement testing C3, C4, and CH50 (complement inhibitory antibodies for suspected familial).
- Evaluate reticulocyte count and MCV.
- Evaluation of infectious cause including screening for viral EBV, CMV, and HHV6.
- Evaluation for nutritional causes of macrocytosis (B12 and folate).
- Pancreatic enzymes.
- Evaluation for diarrheal causes, shiga toxin, and Escherichia coli 0157.
- Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia.
- Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, and sirolimus).
- Evaluation for neurologic changes (alteration in consciousness, concurrent confusion, seizures, pyramidal syndrome, and extrapyramidal syndrome with hypertonia).
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| Grading | Management |
| G1-2: Evidence of RBC destruction (schistocytosis) without clinical consequences of anemia, and thrombocytopenia grade II. | - Continue ICPi with close clinical follow-up and laboratory evaluation.
- Supportive care.
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G3: Laboratory findings with clinical consequences (eg, renal insufficiency and petechiae).
G4: Life-threatening consequences, (eg, CNS thrombosis or embolism or renal failure). | - Permanently discontinue ICPi.
- Hematology consult.
- Begin therapy with eculizumab (anti-C5 antibody)¶ 900 mg once weekly for 4 doses, 1200 mg once at week 5, then 1200 mg once every 2 weeks.
- Red blood transfusion according to existing guidelines.
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| 8.4. Aplastic anemia |
Work-up and evaluation: - History and physical examination (close attention to medications, exposure to radiation, toxins, and recent viral infections).
- CBC, smear, and reticulocyte count.
- Viral studies including CMV, HHV6, EBV, and parvovirus.
- Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, and vitamin D.
- Serum LDH and renal function.
- Evaluation for infectious causes.
- Identify marrow hypo/aplasia.
- BM biopsy and BM aspirate analysis.
- Peripheral blood analysis including neutrophil count, proportion of GPI-negative cells by flow for PNH.
- Flow cytometry to evaluate loss of GPI-anchored proteins.
- Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and filtered.
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| Grading | Management |
| G1: Mild: >0.5 PMNs for 109/L hypocellular marrow, with marrow cellularity <25%, peripheral platelet count >20,000, reticulocyte count >20,000. | - Hold ICPi, provide growth factor support, and close clinical follow-up and laboratory evaluation.
- Supportive transfusions as per local guidelines.
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| G2: Moderate: Hypocellular marrow <25% and two of the following ANC <500, peripheral platelet <20,000 and reticulocyte <20,000. | - Hold ICPi and provide growth factor support and close clinical laboratory evaluations daily.
- Hematology consult.
- Administer horse ATG plus cyclosporine.
- Supportive transfusions as per local guidelines. All blood products should be irradiated and filtered.
- HLA typing and evaluation for bone marrow transplantation if patient is a candidate.
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| G3-4: Severe: ANC <200, platelet count <20,000, reticulocyte count of <20,000, plus hypocellular marrow <25%. | - As per G2.
- Hold ICPi and monitor weekly for improvement. If not resolved, discontinue treatment until AE has reverted to G1.
- If no response, repeat immunosuppression with rabbit ATG plus cyclosporine, and cyclophosphamide.
- For refractory patients, consider eltrombopag plus supportive care.
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| 8.5. Lymphopenia |
Work-up and evaluation: - History (special attention to nutritional status and for lymphocyte depleting therapy such as fludarabine, ATG, steroids, cytotoxic CTX, and radiation exposure, as well as history of AD and family history of AD).
- Physical examination with special attention to spleen size.
- CBC with differential, peripheral smear, and reticulocyte count.
- CXR for evaluation of presence of thymoma.
- Bacterial cultures and evaluation for infection (fungal, bacterial, and viral – specifically CMV or HIV).
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| Grading | Management |
| All grades. | - No specific action is required for lymphopenia G1-G3 and ICPi therapy should be continued.
- For G4 (<250 PB lymphocyte count), continue ICPi therapy and initiate Mycobacterium avium complex prophylaxis and Pneumocystis jirovecii prophylaxis, CMV screening. HIV or hepatitis screening if not already done.
- May consider EBV testing if evidence of lymphadenopathy or hepatitis, fevers, and hemolysis occur consistent with lymphoproliferative disease occurs.
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| 8.6. ITP |
Work-up and evaluation: - History and physical examination (special attention for history of viral illness and lymphocyte depleting therapy such as fludarabine, ATG, steroids, and cytotoxic therapy).
- FH of autoimmunity or personal history of AD.
- CBC, peripheral blood smear, and reticulocyte count.
- Bone marrow evaluation only if abnormalities in the above testing results and further investigation is necessary for a diagnosis.
- Patients with newly diagnosed ITP should undergo testing for HIV, HCV, HBV, and H. pylori.
- Direct antigen test should be checked to rule out concurrent Evans' syndrome.
- Nutritional evaluation.
- BM evaluation if other cell lines affected and concern for aplastic anemia.
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| Grading | Management |
| G1: Platelet count 75 to <100/microliter. | - Continue ICPi with close clinical follow-up and laboratory evaluation.
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| G2: Platelet count 50 to <75/microliter. | - Hold ICPi but monitor for improvement. If not resolved, interrupt treatment until AE has reverted to G1.
- Administer prednisone 1 mg/kg per day (dosage range, 0.5 to 2 mg/kg per day) orally for 4 weeks followed by taper over 4 to 6 weeks to the lowest effective dose.
- IVIG may be used in conjunction with corticosteroids if a more rapid increase in platelet count is required.
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G3: Platelet count 25 to <50/microliter.
G4: Platelet count <25/microliter. | - As per G2.
- Hematology consult.
- Consider dexamethasone 40 mg daily for 4 days as alternative to prednisone.
- If IVIG is used, the dose should initially be 1 g/kg as a one-time dose.
- If previous treatment with corticosteroids and/or IVIG has been unsuccessful, subsequent treatment may include rituximab, thrombopoietin receptor agonists, or more potent immunosuppression.
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| 8.7. Acquired hemophilia A |
Work-up and evaluation: - Hematology consult.
- Full blood count to assess platelet number, fibrinogen, PT, PTT, and INR. The typical finding in patients with acquired hemophilia A is a prolonged aPTT with a normal PT.
- MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location and response of bleeding.
- Medication review to assess for alternative causes.
- Determination of Bethesda unit level of inhibitor.
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| Grading | Management |
| G1: Mild: 5 to 40% of normal factor activity in blood; 0.05 to 0.4 units/mL of whole blood. | - Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits.
- Administer prednisone 0.5 to 1 mg/kg/day.
- Transfusion support as required.
- Treatment of bleeding disorders with hematology consult.
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| G2: Moderate: 1 to 5% of normal factor activity in blood; 0.01 to 0.05 units/mL of whole blood. | - Hold ICPi and discuss resumption with patient only after taking into account the risks and benefits.
- Administration of factor replacement (choice based on BU of titer).
- Administer prednisone 1 mg/kg/day ± rituximab (dose 375 mg/m2 once weekly for 4 weeks) and/or cyclophosphamide (dose 1 to 2 mg/kg/day). Choice of rituximab versus cyclophosphamide is patient specific and should be done with assistance of hematology consult. Prednisone, rituximab, and cyclophosphamide should be given for at least 5 weeks.
- Factors should be provided to increase level during bleeding episodes, with choice of factor based on presence or absence of inhibitor.
- Transfusion support as required for bleeding.
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| G3-4: Severe: <1% of normal factor activity in blood; <0.01 unit/mL of whole blood. | - Permanently discontinue ICPi.
- Admit patient.
- Administration of factor replacement; choice based on BU level of inhibitor.
- Bypassing agents may be used (Factor VII FEIBA). Caution should be taken in elderly patients and those with CAD.
- Prednisone 1 to 2 mg/kg/day (oral or IV equivalent depending on symptoms) ± rituximab (dose 375 mg/m2 once weekly for 4 weeks) and/or cyclophosphamide (dose 1 to 2 mg/kg/day).
- Transfusion support as required for bleeding.
- If worsening or no improvement add cyclosporine or immunosuppression or immunoadsorption.
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Additional considerations: - Acquired hemophilia A requires special clinical and laboratory expertise. Consult and/or transfer to a specialist center is often appropriate. If consultation with or transfer to a hemophilia center is not immediately possible, then investigation and treatment should be initiated while a liaison is being established.
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