approach to abnormal blood picture (1).pptx

approach towards patient with anemia, thrombocytopenia, leukopenia and abnormal cells in peripheral smear

1. Approach towards patient with abnormal blood picture

2. Anemia

3. Anemia is defined as a reduction of the hemoglobin ( Hb ) concentration, red-cell count or packed cell volume below normal levels. Mild anemia is defined as an Hb concentration of 11.9 g/dl and 10 g/dl Moderate anemia as Hb of 9.9 and 8.0 g/dl severe anemia as Hb <8.0 g/dl.

4. Treatment-related anemia is graded according to the National Cancer Institute-Common Toxicity Criteria of Adverse Events (CTCAE v4.02) grade 1: lower normal limit to 10.0 g/dl; grade 2: 8.0 to <10.0 g/dl; grade 3: 6.5 to <8.0 g/dl; grade 4: <6.5 g/dl). Anemia of cancer is present in 40% of patients with non-myeloid malignancies. Overall incidence of anemia during chemo- or radiotherapy is 54% (mild 39%, moderate 14% and severe 1%). The incidence increases with the number of chemotherapy cycles.

5. What are the causes of anemia in cancer patients ?

6. Anemia in patients with cancer may be caused by:

7. 1. Anemia caused by blood loss or iron deficiency Pathogenesis - ulcerating tumors - extensive surgery - benign GIT diseases - gastrectomy Blood studies microcytosis and hypochromia , elevated soluble transferrin receptor.

8. Stools should be tested for occult blood. Treatment of the cause & try to minimize or stop the blood loss. Therapeutic trials: Ferrous sulfate, 325 mg PO given 3 times daily usually elevate the hemoglobin concentration in patients with iron deficiency

9. 2. Anemia caused by nutritional deficiencies Folic acid deficiency is the most common cause of megaloblastic anemia in cancer patients & is due to: Decreased intake of folate Increased requirements with : * autoimmune hemolytic anemia * postoperative state * prolonged IV therapy * excess use by proliferating tumor cells - Folate antagonist drugs (e.g., methotrexate)

10. Vitamin B 12 deficiency is usually seen after gastrectomy or in patients having malabsorption secondary to lymphoma that involves the ileum. Blood studies megaloblastic anemia, neutrophil hypersegmentation .

11. 3. Anemia of chronic disease (ACD) Pathogenesis immune activation with the production of cytokines that inhibit both the action and production of EPO - ACD is more severe with widespread metastases but may occur with localized tumors - There is increased levels of tumor necrosis factor (TNF) and IL-1. - TNF stimulates marrow stromal cells to produce IFN- β , while IL-1 acts on T lymphocytes to produce IFN-gamma. Both IFN- β IFN-gamma inhibit erythropoiesis directly - Neopterin levels, which indicate the activation of macrophages by IFN-gamma, are also increased in malignancies.

12. The hemoglobin concentrations are inversely proportional to blood concentrations of neopterin and IFN-gamma. Blood studies normocytic and normochromic anemia, decreased levels of both serum iron and transferrin, the levels of soluble transferrin receptor are normal Bone marrow studies ineffective erythropoiesis with shortened RBC life spans and decreased sideroblasts . Treatment Recombinant human EPO can correct ACD and rarely transfusion may be needed in severe conditions.

13. 4. Anemia caused by parvovirus B 19 In Immunocompromised patients who are unable to produce neutralizing antibodies against the virus, an infection can persist & cause chronic bone marrow failure Bone marrow studies erythroid hypoplasia Treatment hyperimmune gamma globulins

14. 5. Pure red cell aplasia (PRCA) PRCA is the isolated severe hypoplasia of erythroid elements in the marrow Associated with thymoma in 10% of the cases, with lymphoprolepherative disorders and various carcinomas Blood studies normocytic , normochromic anemia Bone marrow studies markedly decreased-to- absent erythroid precursors and normal megakryocytes and myeloid elements

15. . Maslak, P. ASH Image Bank 2008;2008:8-00047 Erythroid elements are absent in this patient with thymoma and pure red cell aplasia

16. Chest radiographs mediastinal mass if associated with thymoma Treatment removal of thymoma results in remission in 20% of cases. Patients with or without thymoma responded to therapy with cyclophosphamide, cyclosporine or antithymocyte globulin

17. 6. Warm antibody immune hemolysis Pathogenesis Autoimmune hemolysis because of IgG antibodies most commonly in patients with lymphoproliferative neoplasms, only 2% of cases are associated with solid tumors Also reported after treatment with cytostatic drugs (e.g., fludarabine) The IgG coated erythrocytes are removed by the reticuloendothelial system, predominantly the spleen (extravascular hemolysis)

18. Diagnosis insidious onset of severe anemia, mild jaundice, and splenomegaly Blood studies spherocytosis, nucleated RBCs, increased reticulocytes Positive Coombs’test or the direct antiglobulin test (DAT) with anti-IgG or anticomplement antisera Treatment Prednisone and treatment of the tumor are necessary, patients with unsatisfactory response to corticosteroids require spleenectomy Treatment with rituximab may be considered

19. 7. Cold antibody immune hemolysis Pathogenesis Cold agglutinins are IgM molecules that attach to RBC membranes at cold temperature & fix complement. At 37 C, the IgM molecule dissociate from the cell, but the complement remains fixed. Most common with lymphoma. Diagnosis patients with high titers of cold agglutinins may have acrocyanosis or Raynaud phenomenon. RBC agglutination may be observed on blood smears.

20. The DAT is strongly positive when performed at 4 C but is positive only with anticomplement antisera at 37 C Treatment Rituximab 375 mg/m 2 weekly for 4 weeks is often effective chlorambucil or cyclophosphamide may be helpful for symptomatic patients

21. ESMO recommendations

22. The use of erythropoiesis-stimulating agents (ESAs) All causes of anemia should be taken into account and, if possible, corrected before the use of erythropoiesis-stimulating agents (ESAs) [A]. The indication of ESAs is the treatment of symptomatic chemotherapy-induced anemia in adult patients with non-myeloid malignancies. The aim is to prevent transfusions and their possible complications and possibly to improve QoL by increasing the Hb level.

23. In patients treated with chemotherapy and an Hb level of ≤10 g/dl, treatment with ESAs might be considered to increase Hb by < 2 g/dl or to prevent further decline in Hb [II, A]. In patients not treated with chemotherapy, there is no indication for the use of ESAs and there might be an increased risk of death when ESAs are administered to a target Hb of 12–14 g/dl [I, A]. In patients treated with curative intent, ESAs should be used with caution [D].

24. Causes of thrombocytopenia

25. Decreased production Marrow hypoplasia After viral infection (Dengue, Rubella, Mu m ps, V ar i cel l a, Parv o , HC V , EB V , H IV) Childhood bone marrow failure syndromes, e.g. Fanconi's anaemia Idiopathic aplastic anaemia Drug-induced: cytotoxics, antimetabolites

26. Decreased production Marrow infiltration Leukaemia ,Myeloma ,Carcinoma (rare), Myelofibrosis Haematinic deficiency Vitamin B12 and/or folate deficiency Familial (macro-)thrombocytopathies Myosin heavy chain abnormalities, e.g. Alport's syndrome

27. Increased consumption of platelets Immune mechanisms Idiopathic thrombocytopenic purpura ( ITP )* Post-transfusion purpura Neonatal alloimmune thrombocytopenia Drug-associated, especially quinine and Heparin Coagulation activation Disseminated intravascular coagulation ( DIC )

28. Increased consumption of platelets Mechanical pooling Hypersplenism Thrombotic microangiopathies Haemolytic uraemic syndrome ( HUS ) Thrombotic thrombocytopenic purpura Others Gestational thrombocytopenia Type 2B von Willebrand disease

29. Evaluation of Patient with Low Platelets History Onset(new/chronic/relapsing) Recent medication or vaccination Recent transfusion (haemodillution) Recent organ transplant Autoimmune disease/Malignancy Pregnancy Travel hi story( m a l a ri a ,rick e ttsi a , d e n g u e )

30. Evaluation of Patient with Low Platelets Dietary Habit (Megaloblastic Anaemia) Ingestion of alcohol/ Quinine containing beverage Risk factors for HIV and HCV

31. Clinical examination Organomegaly (Leukaemia, Myelofibrosis) Joint or Soft tissue bleeding- DIC Ischemic limb /skin necrosis- HIT

32. Isolated thrombocytopenia It is thrombocytopenia with normal RBC, WBC and no sign or symptoms of systemic illness. Limited DD: Drug induced thrombocytopenia ITP

33. Drug induced throm b ocytopenia epito p es of Antibo d y agai n st new platelet glycoprotein. Moderate to severe thrombocytopenia. Drop in platelet count within 2-3 days upto 1-3 weeks. Recove r y i n 5 -10 da y s after drug stoppage Should be suspected when patient has recurrent episodes of thrombocytopenia with prompt recovery.

34. Drugs commonly associated with thromb o cyto p enia Abciximab Amiodarone A m pho tericin B Carbamazepine Cimetidine Digoxin Eptifibatide Fluconazole Furosemide Heparin I n terfer o n A l ph a Phenytoin Piperacillin Quinidine Quinine Ranitidine Trimethoprim/Sulfamethoxazole V al p r o ic A cid Vancomycin

35. Inve s tigations Drug dependent anti Platelet antibody by flow cytometry, Platelet Immunofluroscence test, ELISA and western blotting Treatment: If a patient’s platelets fall, all unnecessary drugs need to be stopped. give platelet transfusions , IVIg is particularly helpful in quinine-induced ITP.

36. Disseminated Intravascular Coagulation (DIC) DIC is a consumptive coagulopathy complicating several diseases. It is characterized by activation of intravascular coagulation with microvascular thrombi formation, thrombocytopenia, depletion of clotting factors, variable bleeding complications, and end-organ damage.

37. Acute DIC Acute DIC is commonly seen in severe sepsis and septic shock, after trauma (especially neurotrauma), after surgery, as an obstetric complication (eg, abruptio placentae, amniotic fluid embolism, and preeclampsia), after ABO- incompatible blood transfusion, and as a complication of acute promyelocytic leukemia. Consumptive coagulopathy in these cases is severe and leads to bleeding manifestations (eg, mucocutaneous bleeding and blood oozing from wound sites) and frequent organ damage (eg, renal and hepatic damage).

38. Chronic DIC Chronic DIC is more frequently observed in solid tumors and in large aortic aneurysms, usually with few obvious clinical or laboratory indications of the presence of DIC. In chronic compensated DIC, such as a patient with metastatic prostate or GI malignancy in coagulation factors may be balanced whom a slower rate o f co n sumpti o n of by enhanced synthesis. Thus, patients may have only a modest thrombocytopenia and normal PT and aPTT. The diagnosis is based on the presence of microangiopathy on peripheral blood smear and elevated fibrin degradation products (FDP) and D-dimer levels.

39. Investigations PT - increased APTT - increased Fibrinogen - decreased FDP – increased BT- Increased. CT- Increased

40. Treatment Focus on addressing underlying disorder Administration of Blood Components and Coagulation Factors – platelet , FFP, cryopricipitate Anticoagulation – heparin, protein C. Patients with DIC should not in general be treated with antifibrinolytic therapy, e.g. tranexamic acid.

41. Thrombotic Thrombocytopenic Purpura TTP - Diagnostic Features Microangiopathic Hemolytic Anemia (MAHA) Elevated LDH, elevated bilirubin Schistocytes on the peripheral smear MUST BE PRESENT Low platelets - MUST BE PRESENT Fever Neurologic Manifestations - headache, sleepiness, confusion, stupor, stroke, coma, seizures Renal Manifestations - hematuria, proteinuria, elevated creatinine, BUN

42. TTP - etiology An inherited or acquired deficiency (due to autoantibodies) of von Willebrand factor-cleaving protease known as ADAMTS13. leads to accumulation of large multimers of VWF which cause spontaneous platelet aggregation and thrombi. Can be induced by drugs, including ticlopidine, quinine, cyclosporine, tacrolimus, mitomycin C. Increased incidence with pregnancy or HIV

43. TTP -lab CBC normal or slightly elevated WBC. Hb is moderately depressed at 8-9 g/dL. Platelet count ranges from 20,000-50,000 per microliter. PB F : Red blood cells are fragment e d and appear as schistocytes. Certain schistocytes have the appearance of helmet cells (H). Spheroi d al cells of t en are pres e nt (S). Occasional nucleated erythroid precursors may be present.

44. TTP - Course and Prognosis Treatment relies on Plasma Exchange. Plasma exchange is superior to plasma infusion, but if PLEX is delayed, give FFP. Remove all inciting agents. Platelet transfusions contra-indicated . Multiple case reports of stroke and/or death during or immediately after platelet transfusion. Can consider giving if life-threatening hemorrhage is present, but avoid routine platelet transfusions. Secondary measures if no response to plasma exchange include splenectomy, vincristine

45. Neutropenia Neutropenia, is a granulocyte disorder characterized by an abnormally low number of neutrophils. Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Patients with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis). Figure : A Neutrophil

46. Neutropenia Neutropenia can be acute or chronic depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for longer than three months. It is sometimes used interchangeably with the term leukopenia , as neutrophils are the most abundant leukocytes, but neutropenia is more properly considered a subset of leukopenia as a whole.

47. Classification There are three general guidelines used to classify the severity of neutropenia based on the absolute neutrophil count (ANC) measured in cells per micro liter of blood: 1 Mild neutropenia (1000 ≤ ANC < 1500) — minimal risk of infection Moderate neutropenia (500 ≤ ANC < 1000) — moderate risk of infection Severe neutropenia (ANC < 500) — severe risk of infection. Ann. Intern. Med. 146 (7): 486–92

48. Duration of Neutropenia < 7 days – LOW risk 7 to 14 days – INTERMEDIATE RISK > 14 days – HIGH RISK

49. Febrile Neutropenia Febrile neutropenia exists when a patient with a neutrophil count less than 1.0 (x10 9 /L) has a temperature greater than or equal to 38 o C , or if a patient is systemically unwell with a clinical suspicion of sepsis.

50. Management of Febrile Neutropenia

51. Management Febrile neutropenia (FN) remains one of the most feared complications of cancer chemotherapy, and is a major cause of morbidity, healthcare resource use, and results in delays and dose reductions in chemotherapy which compromise efficacy. Mortality from FN has diminished steadily but remains significant. Overall mortality rates are ∼5% in patients with solid tumors (1% in low-risk patients) and as high as 11% in some hematological malignancies.

52. High risk patients Patients with cancer plus at least one or more of the following factors: Haematological malignancy Myelosuppresive chemotherapy Concurrent chemotherapy and radiotherapy Age >60 Co-morbidities eg. Diabetes, poor nutritional status. Bone marrow involvement of cancer Delayed surgical healing or open wounds Significant mucositis Unwell ( eg hypotensive, oliguric) On steroid dose >25mg prednisolone daily Rapidly falling neutrophil count History of neutropenia Recent hospitalisation for infection

53. Initial assessment Symptoms or signs of infection focus   Investigations   Respiratory system     Gastrointestinal tract     Skin care      Perineal region/genitourinary discharges     Oropharynx     Central nervous system Routine blood test Renal and liver function     Coagulation screen     C-reactive protein     Blood cultures Urinalysis and culture     Sputum microscopy and culture      Stool microscopy and culture Chest radiograph (if respiratory symptoms present or outpatient therapy considered)

54. Risk factors & complications Adapted from G H Layman The Oncologist 2005

55. MASCC Risk Score Tool for calculating FN Ann Oncol (2009) 20 (suppl 4): iv166-iv169.

56. Breast Cancer Regimens and FN Risk: NCCN Guidelines High risk (>20%) for febrile neutropenia Doxorubicin, cyclophosphamide, docetaxel (AC→T) Doxorubicin, paclitaxel (AT) Docetaxel, doxorubicin, cyclophosphamide (TAC) Intermediate risk (10%-20%) for febrile neutropenia Docetaxel Doxorubicin, cyclophosphamide (AC) Docetaxel, capecitabine (DX) FN = febrile neutropenia. NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.

57. Lung Cancer Regimens and FN Risk: NCCN Guidelines High risk (>20%) Small cell Cyclophosphamide, doxorubicin, etoposide (CAE) Topotecan Topotecan, paclitaxel ( TopT ) Non–small cell Docetaxel, carboplatin (DP) Gemcitabine, ifosamide , vinorelbine (VIG) Intermediate risk (10%-20%) Small cell Cisplatin, topotecan ( TopC ) Etoposide, carboplatin (EP) Non–small cell Cisplatin, paclitaxel (TC) FN = febrile neutropenia; NCCN = National Comprehensive Cancer Network. NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.

58. Prophylaxis - Treatment There are many factors that need to be evaluated to determine a patient’s risk categorization; these include type of chemotherapy regimen and patient risk factors. One criterion that places a patient at high risk is a previous neutropenic complication in the immediate previous cycle with no plan to reduce dose intensity. Consider CSF if patients are at significant risk for serious medical consequences of febrile neutropenia, including death. This table applies to prophylaxis for the first and all subsequent cycles of chemotherapy for solid tumors and non-myeloid malignancies. ONCOLOGY NURSING FORUM – VOL 33, NO 6, 2006

59. Pegfilgrastim Pegylated Filgrastim / Pegylated G-CSF (Recombinant human G-CSF) Extended half-life and Enhanced biological activity Glomerular filtration: nil / negligible Granulocyte (Neutrophil) mediated clearance: predominant Adverse effect profile is no different from Filgrastim Equivalent efficacy to Filgrastim (once/cycle vs once/day) Less disruption of a patient’s daily routine

60. Dosage and Administration Recommended dose: 6mg (protein weight) 1, 2 Route of administration: Subcutaneous 1 Frequency of administration: Single dose administered once per chemotherapy cycle 1 It should be stored in the refrigerator at 2° to 8°C (36° to 46°F). Avoid shaking. Prior to injection, it may be allowed to reach room temperature for a maximum of 24 hours. Any vial or prefilled syringe left at room temperature for greater than 24 hours should be discarded Drugs 2002; 62 (8): 1207-1213 Amgen Inc, Thousand Oaks, California. Physician Package Insert Neulasta (Pegfilgrastim). 2002

61. Patient Education Success in FN management requires prompt recognition of, and reaction to, potential infection. Vital to this is educating outpatients to monitor symptoms including body temperature, and clear written instructions on when and how to contact the appropriate service in the event of concerns.

62. Recommendations for Patient care For high risk patients intravenous fluids should be commenced immediately. Administer antibiotics as ordered immediately after blood culture collection. Do not delay administration of antibiotics while waiting for results of pathology investigations unless advised by medical oncologist/ physician. Assess vital signs at least every four hours, document and report changes. Assess vital signs more frequently if (document and report changes): temperature > 38 o C or <36 o C , Blood Pressure <90 systolic or a drop of >40mm Hg, pulse > 90, respiratory rate >20, oxygen saturation <90%

63. Recommendations for Patient care Administer anti- pyretics as ordered by medical officer, do not nurse initiate anti- pyretics , fever may be masked by antipyretics. Cleanse hands thoroughly before and after all direct patient contact. Ensure staff caring for the neutropenic patient have no sign and symptoms of infection. Give nursing care to neutropenic patient first to decrease the risk of cross-contamination. Provide and encourage meticulous skin, peri-anal and oral hygiene for patient. Assess skin and mucous membranes eg. Mouth and perianal areas each shift.

64. Recommendations for Patient care Document in medical record and report changes. Observe IV site and Central Venous Access Device site (if relevant) each shift, document and report changes. Do not administer rectal medication unless specifically ordered by medical staff. Do not insert in-dwelling catheter unless specifically ordered by medical staff. If insertion necessary then aseptic technique must be observed Do not allow live plants or cut flowers in standing water in room