Evaluation and approach to Pancytopenia.pptx

Pancytopenia

1. PANCYTOPENIA

2. Contents INTRODUCTION PATHOPHYSIOLOGY ETIOLOGY EMERGENCIES EVALUATION MANAGEMENT

3. INTRODUCTION Pancytopenia is considered to be present when all three cell lines are below the normal reference range. Definition as per cut offs established by WHO reference values is : Red blood cells – Hemoglobin <12 g/dL for women and <13 g/dL for men White blood cells – Because neutrophils constitute the majority of leukocytes in the peripheral blood and bone marrow, nearly all cases of low white blood cells (leukopenia) manifest as neutropenia.

4. Absolute neutrophil count (ANC) <1800/microL – Calculated as the total white blood cells/microL x (percent [polymorphonuclear cells + bands] ÷ 100) Platelets – Platelet count <150,000/microL

5. Epidemiology Male = Female Biphasic Age Distribution Major Peak - Teens (20s) Second Rise- Old age > 65yrs

6. PATHOPHYSIOLOGY Hematopoiesis (blood cell production) in the healthy adult takes place in the bone marrow, from which mature blood cells migrate into the circulation, spleen, and other sites. The bone marrow is a dynamic organ and a hematopoietic reservoir that responds to ongoing needs for blood cell production. A balance between blood cell production, distribution in other organs, and ongoing cellular destruction (eg, white blood cells fighting infections, platelet consumption in blood clots, cellular senescence) determines the levels of circulating blood cells

7. Pancytopenia may be caused by one or more of the following mechanisms: Bone marrow infiltration/replacement – Such disorders include hematologic malignancies (eg, leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes), metastatic cancer, myelofibrosis, and infectious diseases (eg, miliary tuberculosis, fungal infections). Bone marrow aplasia – Nutritional disorders (eg, deficiencies of vitamin B12 or folate), aplastic anemia, infectious diseases (eg, HIV, viral hepatitis, parvovirus B19), immune destruction, and medications are among the causes of marrow aplasia.

8. Blood cell destruction or sequestration – Excessive blood cell destruction occurs in disseminated intravascular coagulation, thrombotic thrombocytopenia purpura, and ineffective hematopoiesis (eg, myelodysplastic syndromes, megaloblastic disorders), while excessive sequestration may be due to hypersplenism (eg, from liver cirrhosis, storage diseases, lymphoma, or autoimmune disorders). Some diseases may cause pancytopenia by multiple mechanisms. As an example, a lymphoma may infiltrate the bone marrow, cause hypersplenism, induce immune destruction of blood cells, and require treatment with cytotoxic agents. Similarly, Crohn disease may impair absorption of iron, folate, and vitamin B12; induce an inflammatory state that exacerbates anemia; require partial bowel resection that affects absorption of nutrients and calories; and require treatment with myelosuppressive agents.

9. Etiology The likely causes of pancytopenia are influenced by geography, socioeconomic conditions, and endemic illnesses. As examples, the likelihood of infectious (eg, malaria, tuberculosis, leishmaniasis) or nutritional causes (eg, folate deficiency) of pancytopenia may be increased in developing countries. Similarly, the prevalence of human immunodeficiency virus (HIV) infection and alcohol use may influence the likely causes of pancytopenia. The vast majority of pancytopenia in adults is caused by acquired disorders; rarely, a previously unrecognized inborn error may account for cytopenias that are first detected in adulthood

10. Evaluation History : Time course and clinical severity – Prior laboratory results (when available) and severity and duration of symptoms should be evaluated. Symptoms associated with cytopenias : Recurrent, severe, or unusual infections that may be due to leukopenia/neutropenia Fatigue, dyspnea, chest pain, hemodynamic instability, or claudication due to anemia Bleeding or easy bruising due to thrombocytopenia or disseminated intravascular coagulation Constitutional symptoms, including fevers, night sweats, and/or weight loss Nausea, vomiting, and jaundice that may be associated with liver disease

11. Previous treatments : Determine if the patient has previously been treated for hematologic disorders, including prior transfusions, hematinics (eg, vitamin B12, folate, iron), or other treatments (eg, apheresis, plasma exchange). Other medical conditions : Almost any comorbid medical condition or surgical procedure can contribute to or exacerbate cytopenias. As an example, a history of Crohn disease is relevant because the inflammatory bowel disease and previous surgeries may affect the patient’s nutritional status and impair absorption of essential nutrients and vitamins (eg, iron, folate, vitamin B12), while the inflammatory state may exacerbate anemia, and therapeutic agents may suppress bone marrow function.

12. Problematic medications : Many medications (including prescription and over-the-counter medications, health supplements, and home or folk remedies) may cause or contribute to cytopenias. The relationship between the onset of pancytopenia and the administration of medications should be defined as much as possible. Some medications (eg, cytotoxic or immunosuppressive agents) cause predictable decreases in blood counts that are generally reversible if the agent is reduced or stopped. Other medications that are not commonly associated with dose-related cytopenias may cause idiosyncratic reactions leading to severe cytopenias. Personal and occupational exposures – Certain personal habits (eg, alcohol consumption, diet), infection history (eg, HIV, viral hepatitides), exposure to toxic agents at work or home (eg, organic solvents), and travel history (eg, exposure to malaria, leishmania) may also be relevant.

13. Physical Findings Rashes that may be related to drug reactions, rheumatologic disorders, infections, and malignancies Oral lesions; as examples, thrush suggests immune compromise; oral ulcers may be seen in diseases such as systemic lupus erythematosus Lymphadenopathy and/or splenomegaly Jaundice and stigmata of liver disease

14. Laboratory investigations Complete blood count (CBC), with white blood cell differential count and red blood cell indices. Examination of the peripheral blood smear Reticulocyte count. An absolute reticulocyte count <20,000 indicates a marked decrease in red blood cell production and suggests a hypoproliferative condition. Prothrombin time (PT) and partial thromboplastin time (PTT). Serum chemistry tests, including electrolytes, renal and liver function tests, lactate dehydrogenase, calcium, and uric acid.

15. Citation: Chapter 102 Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia, Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. Harrison's Principles of Internal Medicine, 21e; 2022. Copyright © 2023 McGraw-Hill Education. All rights reserved Normal and aplastic bone marrow. A. Normal bone marrow biopsy. B. Normal bone marrow aspirate smear. The marrow is normally 30–70% cellular, and there is a heterogeneous mix of myeloid, erythroid, and lymphoid cells. C. Aplastic anemia biopsy. D. Marrow smear in aplastic anemia. The marrow shows replacement of hematopoietic tissue by fat and only residual stromal and lymphoid cells.

16. Citation: Chapter 102 Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia, Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. Harrison's Principles of Internal Medicine, 21e; 2022. Copyright © 2023 McGraw-Hill Education. All rights reserved Pathognomonic cells in marrow failure syndromes. A. Giant pronormoblast, the cytopathic effect of B19 parvovirus infection of the erythroid progenitor cell. B. Uninuclear megakaryocyte and microblastic erythroid precursors typical of the 5q– myelodysplasia syndrome. C. Ringed sideroblast showing perinuclear iron granules. D. Tumor cells present on a touch preparation made from the marrow biopsy of a patient with metastatic carcinoma.

17. Management Blood Products Stem Cell Transplantation Androgens Supportive care Treat the underlying cause

18. STEM CELL TRANSPLANTATION Best for Younger patients Transplant Mortality & Morbidty are ↑ in adults Unrelated Donor Transplant High resolution HLA matching Effective Conditioning Regimens GVHD Prophylaxis Cord Blood HLA Haploidentical family donor Post Transplant Cyclophosphamide Regimens does not include Post Transplant Radiation

19. IMMUNOSUPPRESSION Anti Thymocyte Globulin + Cyclosporine Prognosis : Children > Adults Improvement in Granulocyte Number Serum Sickness Complications: Relapse Development of MDS

20. ELTROMOPAG A thrombopoietin mimetic which showed unexpected activity in refractory disease, producing robust, trilineage, and usually durable hematologic responses. Likely the mechanism of action of thrombopoietin mimetics is stimulation of the hematopoietic stem cells.

21. Androgens The effectiveness of androgens has not been verified in controlled trials, but occasional patients will respond or even demonstrate blood count dependence on continued therapy. Sex hormones upregulate telomerase gene activity in vitro, which is possibly also their mechanism of action in improving marrow function. For patients with moderate disease, especially if a telomere gene defect is present, a 3 to 4month trial may improve all blood counts.

22. SUPPORTIVE CARE Infection in the presence of severe neutropenia must be aggressively treated by prompt institution of parenteral, broadspectrum antibiotics. Therapy is empirical and must not await results of culture,although specific foci of infection such as oropharyngeal or anorectal abscesses, pneumonia, sinusitis, and typhlitis (necrotizing colitis) should be sought on physical examination and with radiographic studies. When indwelling plastic catheters become contaminated, vancomycin should be added. Persistent or recrudescent fever implies fungal disease: Candida and Aspergillus are common, especially after several courses of antibacterial antibiotics.

23. A major reason for the improved prognosis in aplastic anemia has been the development of better antifungal drugs and the timely institution of such therapy when infection is suspected. Granulocyte transfusions can be effective when bacterial or fungal infection is progressive or refractory to antibiotics. Hand washing, the single best method of preventing the spread of infection, remains a neglected practice.

24. Both platelet and erythrocyte numbers can be maintained by transfusion. Alloimmunization historically limited the usefulness of platelet transfusions and is now minimized by several strategies, including use of single donors to reduce exposure and physical or chemical methods to diminish leukocytes in the product; HLAmatched platelets are usually effective in patients refractory to random donor products. Inhibitors of fibrinolysis such as aminocaproic acid have not been shown to relieve mucosal oozing; the use of lowdose glucocorticoids to induce “vascular stability” is unproven and not recommended.

25. With prophylactic platelet transfusions, the goal is to maintain the platelet count >10,000/μL (oozing from the gut increases sharply at counts <5000/μL). Menstruation should be suppressed either by oral estrogens or nasal folliclestimulating hormone/luteinizing hormone antagonists. Aspirin and other nonsteroidal antiinflammatory agents must be avoided in the presence of thrombocytopenia. RBCs should be transfused so as to allow patient a normal level of activity, usually at a hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary disease); a regimen of 2 units every 2 weeks will replace normal losses in a patient without a functioning bone marrow. In chronic anemia, the iron chelators deferoxamine and deferasirox should be added at approximately the fiftieth transfusion to avoid secondary hemochromatosis.

26. PROGNOSIS Rapid deterioration & Death Major Prognostic determinant = Blood Counts Severe disease: presence of 2 out of 3 parameters ANC <500 / mm3 Platelet Count <20,000 / mm3 Absolute Reticulocyte Count <60,000 (CRC <1%)

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