1. Anemia, Thrombocytopenia, & Blood Transfusions Joel Saltzman MD Hematology/Oncology Fellow Metro Health Medical Center

2. Objectives An overview and approach to the anemic patient. An overview and approach to the thrombocytopenic patient An overview of blood transfusions with an evidence based approach

3. Anemia A reduction below normal in the concentration of hemoglobin or red blood cells in the blood. Hematocrit (<40% in men,<36% in women) Hemoglobin (13.2g/dl in men, 11.7g/dl in women)

4. Symptoms of Anemia Nonspecific and reflect tissue hypoxia: –Fatigue –Dyspnea on exertion –Palpatations –Headache –Confusion, decreased mental acuity –Skin pallor

5. History and Physical in Anemia Duration and onset of symptoms Change in stool habits: Stool Guaiacs in all Splenomegaly? Jaundiced?

6. Components of Oxygen Delivery Hemoglobin in red cells Respiration (Hemoglobin levels increase in hypoxic conditions) Circulation (rate increases with anemia)

7. Classification of Anemia Kinetic classification Hypoproliferative Ineffective Erythropoiesis Hemolysis Bleeding Morphologic classification Microcytic Macrocytic Normocytic

8. Anemia: A Kinetic Perspective Erythrocytes in circulation represent a dynamic equilibrium between production and destruction of red cells In response to acute anemia (ie blood loss) the healthy marrow is capable of producing erythrocytes 6-8 times the normal rate (mediated through erythropoietin)

9. Reticulocyte Count Is required in the evaluation of all patients with anemia as it is a simple measure of production Young RBC that still contains a small amount of RNA Normally take 1 day for reticulocyte to mature. Under influence of epo takes 2-3 days 1/120 th of RBC normally

10. Absolute Retic count Retic counts are reported as a percentage: RBC count x Retic % = Absoulte retic count(normal: 40- 60,000/μl 3 ) Absolute Retic counts need to be corrected for early release ( If polychromasia is present) Absolute retic/2 (for hct in mid 20’s) Absolute retic/3 (hct <20)

11. Indirect Bilirubin: a marker of RBC destruction 80% of normal Bilirubin production is a result of the degradation of hemoglobin In the absence of liver disease Indirect Bilirubin is an excellent indicator of RBC destruction LDH and Haptoglobin are other markers

12. Anemia Low Retic count & Normal Bili/LDH Hypoproliferative Anemia High Retic count & High Bili/LDH Hemolytic Anemia Low Retic count & High Bili/LDH Ineffective Erythropoiesis High Retic count & normal Bili/LDH Blood Loss

13. Hypoproliferative Anemias Iron deficiency anemia Anemia of chronic disease Aplastic anemia and pure red cell aplasia Lead poisoning Myelophthistic anemias (marrow replaced by non-marrow elements) Renal Disease Thyroid disease Nutritional defieciency

14. Lab Evaluation of Hypoproliferative Anemias FeTIBCFerritin Fe DeficiencylowHigh(>300)low Anemia of Chronic Dx low Normal to high Aplastic anemiaHighExtremely high Normal to high

15. Anemia of Chronic Disease “Excessive cytokine release” (aka, infections, inflammation, and cancer) Pathophysiology –Decreased RBC lifespan –Direct inhibition of RBC progenitors –Relative reduction in EPO levels –Decreased availability of Iron

16. Ineffective Erythropoiesis B12 and Folate Deficiency –Macrocytosis –Decreased serum levels –Elevated homocysteine level Myelodysplastic Syndromes –Qualitative abnormalities of platlets/wbc –Bone marrow

17. Hemolysis Thalassemia –Microcytosis –RBC count elevated –Family history Microangiopathy –Smear with schistocytes and RBC fragments –HUS/TTP vs. DIC vs. Mechanical Valve

18. Hemolysis (cont.) Autoimmune (warm hemolysis) –Spherocytes –+ Coomb’s test Autoimmune (cold Hemolysis) –Polychromasia and reticulocytosis –Intravascular hemolysis –+ cold agglutinins –Hemoglobinuria/hemosiderinuria

19. Bleeding Labs directed at site of bleeding and clinical situation

20. RBC Transfusion What is the best strategy for transfusion in a hospitalized patient population? Is a liberal strategy better than a restrictive strategy in the critically ill patients? What are the risks of transfusion?

21. Risks of RBC Transfusion in the USA Febrile non-hemolytic RXN:1/100 tx Minor allergic reactions:1/100-1000 tx Bacterial contamination:1/ 2,500,000 Viral Hepatitis1/10,000 Hemolytic transfusion rxn Fatal:1/500,000 Immunosuppression:Unknown HIV infection1/500,000

22. Packed Red Blood Cells 1 unit= 300ml Increment/ unit: HCT: 3% Hb1/g/dl Shelf life of 42 days Frozen in glycerol+up to 10 years for rare blood types and unusual Ab profiles

23. Special RBC’s Leukocyte-reduced= 10 8 WBCs prevent FNHTR Leukocyte-depleted= 10 6 WBCs prevent alloimmunization and CMV transmission Washed: plasma proteins removed to prevent allergic reaction Irradiated: lymphocytes unable to divide, prevents GVHD

24. Hebert et. al, NEJM, Feb 1999 A multicenter randomized, controlled clinical trial of transfusion requirements in critical care Designed to compare a restrictive vs. a liberal strategy for blood transfusions in critically ill patients

25. Methods: Hebert et. al 838 patients with euvolemia after initial treatment who had hemoglobin concentrations < 9.0g/dl within 72 hours of admission were enrolled 418 pts: Restrictive arm: transfused for hb<7.0 420 pts: Liberal arm: transfused for Hb< 10.0

26. Exclusion Criteria Age <16 Inability to receive blood products Active blood loss at time of enrollment Chronic anemia: hb< 9.0 in preceding month Routine cardiac surgery patients

27. Study population 6451 were assessed for eligibility Consent rate was 41% No significant differences were noted between the two groups Average apache score was 21(hospital mortality of 40% for nonoperative patients or 29% for post-op pts)

28. Success of treatment 4.3%1.4%Noncompliance >48hrs 5.6+ 5.32.6+ 4.1# of transfusions 10.7+0.78.5+0.7Average Hemoglobin Liberal Group Restrictive Group

29. Outcome Measures Restrictive group Liberal group Rate of death at 30 days 18.7%23.3 Mortality rates22.2%28.1

30. Complications while in ICU restrictiveliberalP value cardiac13.2%21.0%<0.01 MI0.7%2.9%0.02 Pulm edema5.3%10.7%<0.01 ARDS7.7%11.4%0.06 Septic shock9.8%6.9%0.13

31. Survival curve Survival curve was significantly improved in the following subgroups: –Apache<20 –Age<55

32. Conclusions A restrictive approach to blood transfusions is as least as effective if not more effective than a more liberal approach This is especially true in a healthier, younger population

33. Thrombocytopenia Defined as a subnormal amount of platelets in the circulating blood Pathophysiology is less well defined

34. Thrombocytopenia: Differential Diagnosis Pseudothrombocytopenia Dilutional Thrombocytopenia Decreased Platelet production Increased Platelet Destruction Altered Distribution of Platelets

35. Pseudothrombocytopenia Considered in patients without evidence of petechiae or ecchymoses Most commonly caused by platelet clumping –Happens most frequently with EDTA –Associated with autoantibodies

36. Dilutional Thrombocytopenia Large quantities of PRBC’s to treat massive hemmorhage

37. Decreased Platelet Production Fanconi’s anemia Paroxysmal Nocturnal Hemoglobinuria Viral infections: rubella, CMV, EBV,HIV Nutritional Deficiencies: B12, Folate, Fe Aplastic Anemia Drugs: thiazides, estrogen, chemotherapy Toxins: alcohol, cocaine

38. Increased Destruction Most common cause of thrombocytopenia Leads to stimulation of thrombopoiesis and thus an increase in the number, size and rate of maturation of the precursor megakaryocytes Increased consumption with intravascular thrombi or damaged endothelial surfaces

39. Increased Destruction (Cont.) ITP HIV associated ITP Drugs: heparin, gold, quinidine,lasix, cephalosporins, pcn, H2 blockers DIC TTP

40. Altered Distribution of Platelets Circulating platelet count decreases, but the total platelet count is normal –Hypersplenism –Leukemia –Lymphoma

41. Prophylactic Versus Therapeutic Platelet Transfusions Platelet transfusions for active bleeding much more common on surgical and cardiology services Prophylactic transfusions most common on hem/onc services 10 x 10 9 /L has become the standard clinical practice on hem/onc services

42. Factors affecting a patients response to platelet transfusion Clinical situation: Fever, sepsis, splenomegaly, Bleeding, DIC Patient: alloimunization, underlying disease, drugs (IVIG, Ampho B) Length of time platelets stored 15% of patients who require multiple transfusions become refractory

43. Strategies to improve response to platelet transfusions Treat underlying condition Transfuse ABO identical platelets Transfuse platelets <48 hrs in storage Increase platelet dose Select compatible donor –Cross match – HLA match

44. Platelet Transfusions Reactions Febrile nonhemolytic transfusion: caused by patients leucocytes reacting against donor leukocytes Allergic reactions Bacterial contamination: most common blood product with bacterial contamination