Pancytopenia resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sanjana Nethagani, M.B.B.S.[2]

Synonyms and keywords: Approach to pancytopenia, Pancytopenia management, Pancytopenia work-up

Pancytopenia Resident Survival Guide Microchapters
Overview
Causes
Diagnosis
Treatment
Do's
Don'ts

Overview

Pancytopenia is described as a decrease in the 3 cell lines which are red blood cells, white blood cells, and platelets. Clinically, pancytopenia is defined as hemoglobin< 9gm, white blood cell count< 4,000/cmm and platelets < 100,000/cmm. It can be due to decreased production in the bone marrow or increased destruction of cells in the periphery. Pancytopenia can also be caused due to drugs such as chemotherapy agents. Treatment involves identifying the underlying cause and appropriate therapy.

Causes

Decreased production of cells

• Aplastic anemia
• Myelodysplasia
• Myelofibrosis
• Diamond-Blackfan syndrome
• Fanconi's anemia
• Leukemia

Increased peripheral destruction

• Splenomegaly
• Hypersplenism

Other causes

• Chemotherapy
• Parvovirus B-19 infection
• Autoimmune conditions
• Human immunodeficiency virus infection
• Tuberculosis
• Lymphoma

For a full list of pancytopenia causes, click here.

Diagnosis

Diagnosis of pancytopenia is outlined in the algorithm below in accordance with the Approach to pancytopenia: Diagnostic algorithm for clinical hematologists published in Blood Reviews,2018 and Pancytopenia: A Clinico Hematological study published in the Journal of Laboratory Physicians in 2011.

Abbreviations: RBC- Red blood cell, WBC-White blood cell, HIV- Human Immunodeficiency Virus, LD body- Leishman-Donovan body, PCR- Polymerase chain reaction

Thorough history must be taken including ❑ Symptoms of autoimmune disease such as * Joint pain and swelling *Rash * Lymphadenopathy etc ❑ History of malignancy ❑ History of recent infections ❑ History of usage of drugs which cause marrow suppression such as * Azathioprine and other chemotherapy drugs * Corticosteroids * Linezolid * Chloramphenicol etc ❑ History of chemo or radiotherapy ❑ Nutritional status ❑ Family history of anemia or pancytopenia

Manifestations of decrease in each cell line Decrease in RBCs ❑ Dyspnea ❑ Fatigue ❑ Pallor ❑ Chest pain Decrease in WBCs ❑ Increased susceptibility to infections ❑ Fever Decrease in platelets ❑ Petechiae ❑ Easy bruising ❑ Bleeding Other signs to look for are ❑ Signs of liver disease ❑ Splenomegaly ❑ Lymphadenopathy ❑ Signs of eating disorders ❑ Signs of alcoholism ❑ Signs of Vitamin B12 or folate deficiency

First line investigations ❑ Peripheral smear Look for dysplastic cells such as Macrocytes and blasts ❑ Complete blood count with reticulocyte count ❑ Iron studies ❑ Erythrocyte sedimentation rate ❑ C reactive protein ❑ Liver function tests ❑ Lactate dehydrogenase level

Additional investigations ❑ HIV serology ❑ Hepatitis serology ❑ Screening for tuberculosis ❑ Antinuclear antibody level ❑ Coomb's test ❑ Thyroid profile

Bone marrow aspiration

Hypocellular marrow

Cellular marrow

Morphology

Investigate for following conditions ❑ Aplastic anemia ❑ Congenital aplastic anemia such as Diamond blackfan syndrome ❑ Blast cell morphology and CD cell markers ❑ Paroxysmal nocturnal hemoglobinuria

Normal morphology

Dysplastic cells, marrow fibrosis or infiltration

Systemic causes

Additional tests to confirm ❑ Leukemia ❑ Lymphoma ❑ Myelodysplastic syndrome

Infections such as ❑ HIV serology ❑ Hepatitis serology ❑ PCR for tuberculosis ❑ Smear for malarial parasite ❑ LD body for leishmaniasis

❑ Megaloblastic anemia ❑ Vitamin assays ❑ Antiparietal cell antibodies ❑ Evaluation for malabsorption syndromes

Other causes like ❑ Hypersplenism ❑ Systemic lupus erythematosus ❑ Sarcoidosis

Treatment

Treatment of pancytopenia is outlined in the algorithm below.

Abbreviations: LDH- Lactate dehydrogenase, RBC- Red blood cell, G-CSF - Granulocyte colony stimulating factor, CNS- Central nervous system, ATG- Anti-thymocyte globulin, HIV- Human Immunodeficiency Virus, ART- Anti Retroviral Therapy

Pancytopenia diagnosis established ❑ Hemoglobin < 10gm/dl ❑ Leucocyte count < 4000/mcL ❑ Platelet count < 150,000/mcL

Initial investigations ❑ Peripheral blood smear ❑ Coagulation profile ❑ Serum LDH level ❑ Complete blood count with reticulocyte level ❑ Bilirubin level ❑ Coomb's test

Acute bleeding Prompt treatment with ❑ Insert two large bore IVs ❑ Type and match blood ❑ IV fluids to correct hypovolemia ❑ Packed RBCs ❑ Fresh frozen plasma ❑ Platelet transfusion for platelet count < 10,000/mcL to prevent intracranial bleeding ❑ Monitor vital signs and laboratory parameters at frequent intervals

Neutropenic fever ❑ Send two sets of blood cultures ❑ Empirical intravenous antibiotic therapy should be started with an antipseudomonal beta lactam such as cefepime/ a carbepenem or piperacillin-tazobactam ❑ Modify antibiotics once culture and sensitivity results come back ❑ If MRSA is suspected, vancomycin/daptomycin or linezolid may be started ❑ Empirical treatment with antifungals is not recommended ❑ Periodic assessment of response to therapy ❑ Monitor vitals regularly ❑ G-CSF therapy is recommended in patients undergoing chemotherapy

Hypocellular marrow Investigate for and treat probable causes such as ❑ Aplastic anemia * ATG * Drugs such as cyclophosphamide * Blood transfusions * Bone marrow transplant is curative ❑ Paroxysmal nocturnal hemoglobinuria * Warfarin to decrease risk of thrombosis * Blood transfusions when needed * Eculizumab therapy * Meningococcal vaccination ❑ Congenital aplastic anemia * Hematopoietic stem cell transplant

Dysplastic cells in bone marrow or infiltration ❑ Leukemia * Induction and consolidation chemotherapy * CNS prophylaxis * Bone marrow transplant ❑ Lymphoma * Chemotherapy * rituximab * stem cell transplantation ❑ Myelodysplasia * Supportive care with blood products and erythropoietin * Eligible candidates may receive bone marrow transplantation * Chemotherapy

Nutritional causes ❑ Vitamin B12 deficiency * Initially, a single intramuscular dose of cobalamin is sufficient to reverse Vitamin B12 deficiency anemia * Injections of cobalamin are associated with allergic reactions which can be circumvented with antihistamine therapy prior to treatment * Maintenance therapy with a dose of 1000 mcg every week or 6-8 times per month is required ❑ Folate deficiency * Folate deficiency often co-exists with Vitamin B12 deficiency * Oral doses of 1-5 mg daily treats anemia * In patients taking methotrexate, folonic acid is used to prevent folic acid deficiency * Patients must be encouraged to take a diet rich in fresh fruit and vegetables

Other causes ❑ Hypersplenism * Partial splenic embolisation * Splenectomy ❑ Systemic Lupus Erythematous * Erythropoietin stimulates erythropoiesis in anemia * Autoimmune hemolytic anemia and thrombocytopenia in SLE responds to steroid therapy * Refractory pancytopenia may be treated with cyclophosphamide * Mycofenolate mofetil is used as an immunosuppressive agent in some refractory cases * Other agents used are rituximab and eltrombopag ❑ Sarcoidosis * Hypersplenism in sarcoidosis is treated with splenectomy * Steroids and methotrexate are also used in treatment

Infectious causes ❑ HIV infection * ART is effective in preventing and correcting pancytopenia in HIV infected individuals * Opportunistic infections in HIV infection lead to pancytopenia through bone marrow suppression, thus prompt prophylaxis with relevant drugs may prevent this complication ❑ Hepatitis * Hepatitis associated aplastic anemia is treated with bone marrow transplant * ATG and cyclosporine are also used * Other agents such as erythropoietin, G-CSF, androgens etc are used to improve cell counts ❑ Tuberculosis * Antitubercular medication such as rifampicin and pyrazinamide cause immune mediated hemolytic anemia, sideroblastic anemia and even agranulocytosis in some cases * Prompt treatment with antituberular therapy regimen induces a reversal ❑ Parvovirus B19 infection * Supportive therapy with blood and packed cell transfusions * Bone marrow transplant with immunosuppressive therapy in severe cases ❑ Malaria * Chloroquine therapy started immediately after detection of malarial infection reduces the risk of development of pancytopenia * Frequent blood smears must be done to detect response to therapy

Do's

• Screen for infections like hepatitis, HIV, Parvovirus-B19, Epstein Barr virus, etc.
• Periodic, regular blood tests must be done for patients on methotrexate or other marrow suppressing drugs.
• Patients with malignancies such as leukemia, lymphoma, myelodysplastic syndrome, etc should be informed about the risk of pancytopenia.

Dont's

• Don't prescribe Aspirin or NSAIDs, or any other drugs that may precipitate bleeding in patients with pancytopenia.
• Don't wait for culture and sensitivity reports in case of neutropenic fever or sepsis in pancytopenic patients. Prompt treatment with broad-spectrum antibiotics is key.
• Don't progress to treatment without correcting underlying nutritional deficiencies such as Vitamin B12 or folate deficiency.