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					                   Hematology




By: Bruce L. Hotchkiss, Pharm.D.
Clinical Presentation of
Hematologic Diseases
   History
   General Symptoms
   HEENT
   Chest/Heart
   GI
   GU
   Skin/ extremities
Components of Blood

   Cellular Elements
     – RBC, WBC, Platelets


   Plasma Proteins
     – Albumin, Immunoglobins, clotting factors…


   Serum electrolytes…

   Function: Homeostasis
Hematocyte diferentiation
Growth Factor/ Cytokine Control

   Erythropoietin (EPO)
   Thrombopoietin (TPO)
   Granulocyte Colony Stimulating Factor (G-CSF)
   Granulocyte-Macrophage CSF (GM-CSF)
   Interlukins (IL-1 to IL-13)
Stem Cell Disorders

   Aplastic Anemia
     – Drug Induced
     – Idiopathic
   Melodysplastic Diseases
     –   RA
     –   RAEB
     –   RAEBIT
     –   CMML
   Myeloproliferative Disease
     – Polycythemia vera
     – AML
             Myelodysplastic Syndromes
   A heterogenous group of clonal neoplastic hematologic disorders
    characterized by varying degrees of bone marrow failure abnormal
    hematopoiesis and proliferation of myeloid blasts advanced states
    may progress to Acute Myelogenous Leukemia (AML)

     – Refractory Anemia - (RA)

     – Refractory Anemia w Ringed Sideroblast (RARS)

     – Refractory Anemia w/ Excess Blast (RAEB)

     – Refractory Anemia Excess Blast in transformation (RAEBIT)

     – Chronic Myelomonocytic Leukemia (CMML)
Erythrocyte Disorders

   Pure Red Cell Aplasia
   Anemias
     – Iron Deficiancy
     – Folate/ B-12 Deficiency
     – Hemolytic
   Hemoglobinopathies
     – Sickle Cell
     – Thalasemia
Erythropoeisis Regulation

    Two erythyroid progenitor cells
          » BFU-E (more primative, high self replicating capacity)
          »       not reduced with anemia
          » CFU-E (immediate precursor of proerythroblast)
          »        CFU-E and normoblast are reduced in anemia
    Tissue hypoxia primary stimulus
          » increased 2,3 DPG


    Kinetics
      – Maturation
      – 120 day lifespan
          Anemia
   Definition:
     – Hgb < 13 men
     – Hgb < 12 females
   Term used incorrectly as a diagnosis
   More properly denotes a complex of signs and symptoms
   S & S manifest as cardiovascular/ pulmonary compensatory
    response to severity and duration of hypoxia
   S & S variable
        » weakness, headache, tinitis, spots, fatigue, drowsiness,
          irritability, GI complaints,...
        » tachypnea, tachycardia, and sometimes chelitis,
          peripheral neuopathy, splenomegaly, jaundice, heart
          failure, Shock
Pallor - nail bed in a patient with anemia
                    Laboratory Identification

   Automated                               RBC Indicies               Other Tests:
     –   RBC count                            – MCV                  - Transferrin Sat
     –   Hgb                                  – MCH                  - Ferritin
     –   Hct                                  – MCHC                 - Folate
     –   also WBC, Plt ...                                           - B-12
                                          Bone marrow aspiraton/ Bx
                                                                     - Shillings test
   Diferential                             – activity
                                                                     - Bilirubin
     – Smear wrights stain                                           - Hemosiderin
                                            – maturity
     – count 100 cells                                               - Coombs
                                              –   Cellular pattern
         » cell appearance                    –   Iron Content
                                                                          - complement
     – Reticulocyte count (colors RNA)        –   neoplasms
         » normal 40-50K/ day                 –   cytogenetics
         » 0.5-1.5%
Clinical Approach to Anemia
                           Hgb < 12
                         (Investigate)


                 Complete History and Physical


                      CBC w/ Diff, smear


                             MCV


      < 80                80< x <100              > 100
    Microcytic            Normocytic             Macrocytic


                      Reticulocyte index


                Low                   High
           hypoproliferative     Hemolytic anemia
Classification of Anemias
by mechanism
   Blood loss
     – Acute vs Chronic

   Deficient erythropoieis
     – Microcytic (MCV< 80 )
     – Normocytic-normochromic (MCV 80-100)
     – Megaloblastic Macrocytic (MCV > 100)

   Excessive hemolysis
          Classification and Etiologies of Anemia
Hypoproliferative                      Ineffective                Hemolytic
                                       Erythropoesis
Intrinsic marrow lesion                 Megaloblastic            Intrinsic
    Stem cell dysfunction                 Vitamin B12              Membrane Alterations
      Aplastic anemia                        deficiency              Metabolic
      RBC aplasia                          Folate deficiency        Hemoglobinopathy
    Marrow replacement                    Vitamin C deficincy
      Fibrosis                             Copper deficiency    Extrinsic
      Tumor                                                          Splenomegaly
    Myelophthisic anemia                                            Mechanical
    Mild marrow failure in the elderly Microcytic/Normocytic        Lytic agents
      (etiology unknown).                  Thalassemia
                                           Myelodysplastic      Immunologic
Erythropoietin Deficient                     syndrome                 Idiopathic
    Renal disease                         Sideroblastic anemia      Autoimmune
    Nutritional                                                      Secondary:
    Endocrine                                                          Drugs
                                                                        Leukemia/ Lymphoma
Iron deficient erythropoiesis                                           Collagen vascular disease
    Iron deficiency anemia
    Anemia of chronic disease
    Inflammation
Etiologies of Fe deficient
Erythropoesis in the elderly
                 Iron deficiency anemia (IDA)
                    Gastrointestinal blood loss
                      – Neoplasia
                        Angiodysplasia of the large bowel
                        Diverticular disease
                        Drugs (e.g. NSAID, aspirin)


                    Other sources of blood loss
                      – Epistaxis
                        Hematuria
                        Uterine bleeding
                        Bleeding diathesis (platelets or
                        coagulation factors)
                 Anemia of chronic disease and
                   inflammation (ACD)
                  Acute infections
                      – bacterial, viral and fungal
Anemia of Chronic Disease
   Charteristics
     – mild normocytic normochromic (may become microcytic)
   Etiology
     – Acute infections - bacterial, viral and fungal
       Chronic infections (e.g., tuberculosis)
       Neoplasia
       Tissue necrosis
       Collagen vascular disease
       Arthritis
          Protein Calorie malnutrition

   Mechanism
     – failure of erythropoiesis, lack of iron for hemoglobin synthesis, and
       decreased RBC survival.
     – IL-1 induced macrophage phagocytosis, decreased hepatic production of
       transferin, increased neutrophil lactoferrin.

   Treatment
     – Tx underlying condition
     – Erythropoietin 50-100 IU/kg SC threee times week
Iron Deficiency anemia with
hypochromasia & pokilocytosis
Iron Deficiency Anemia Lab Assessment
  Lab Parameter             Number Iron-Deficient # Not Iron-Deficient   Likelihood Ratio

  Ferritin
  > 100                               8                    108                0.13
  > 45 < 100                          7                     27                0.46
  > 18 < 45                          23                     13                3.12
  < 18                               47                     2                 41.47
  Total                              85                    150

  Transferring saturation
  > 0.21                              9                     55                0.28
  > 0.8 < 0.21                       23                     70                0.57
  > 0.05 < 0.08                      14                     17                1.43
  < 0.05                             38                     4                 16.51
  Total                              84                    146

  Mean cell volume
  > 95                                2                     32                 0.11
  > 91 - < 95                         5                     26                 0.34
  > 85 - < 91                        16                     44                 0.64
  > 74 - < 85                        32                     42                 1.35
  < 74                               30                     6                  8.82
  Total                              85                    150

  Red cell protoporphyrin
  > 0 < 0.75                         10                     53                 0.34
  > 0.75 < 0.1                        8                     28                 0.51
  > 1 - < 1.25                        9                     21                 0.77
  > 1.25 < 2                         17                     24                 1.26
  >2                                 40                     24                 2.98
  Total                              84                    150
Iron Deficient Anemia
   Etiology -  Intake, blood loss, GI absorption
     – Neoplasia                             Diverticular disease
         Alcoholics                          Gastrectomy / duodenal resection
       Drugs (e.g., NSAID, aspirin)          Peptic ulcers
         Anticoagulants                      Epistaxis / hematuria
       Hemorrhoids                           Uterine bleeding

   Characteristics
     – Decreased ferritin < 45,  Transferin Saturation, Microcytic,  Fe

   Treatment
     – Oral Iron
          » 60mg tid, limited absorption about 30 mg/ day
          » anemia correction about 6 week
          » Iron stores takes 4 to 6months
     – IV Iron (only for Severe cases, oral intolerance)
          » Iron Dextran, Ferrleit
Vitamin B-12 Deficiency
acanthtosis (hypopigmentation)
Vitamin B-12 Absorption
Vitamin B-12 and Folate Action
Megaloblastic Anemias

   Characteristics
     –   MCV > 95, most > 60 yr
     –   early changes are hypersegmented neutrophils (>5)
     –   Late neuropathic changes
     –   Bone marrow identical for B-12 and Folate deficiencies
     –   many Drug induced causes ( Phenytoin, metformin…)
   Treatment
     – B-12 Inj 1000mcg qd x 7 day then weekly x 1 month then
       monthly for life

     – Folate 1mg/day for four weeks
     – Hazard of masking B-12 deficiency - neurologic impairment
Etiology for B-12 deficiency
       » Inadequate intake (strict vegetarians)
       » Defective absorption
       » Decreased availability of intrinsic factor
         Congenital intrinsic factor deficiency
         Abnormal intrinsic factor molecule
         Gastrectomy (total or partial)
         Gastric atrophy secondary to ingestion of caustic material (i.e., lye)
       » Failure of absorption in the small intestine for reasons other than decreased
         availability of intrinsic factor:
       » Ileal resection
         Ileitis (Crohn's disease)
         Infiltrative disorders of the ileum or small intestine (lymphoma, scleroderma)
         Celiac disease
         Tropical sprue
         Bacterial overgrowth syndromes (small bowel diverticulosis, blind loop syndromes,
         fistulas and strictures)
  – Disorders affecting cobalamin-intrinsic factor interaction
       » Chronic pancreatitis
         Gastric bypass surgery
  – Miscellaneous: Fish tapeworm infestation
    Drugs inducing cobalamin malabsorption (colchicine, para-aminosalicylic acid, neomycin
    and potassium chloride)
Hemolytic Anemias


   Autoimmune
     – Warm Agglutins (IgG - extravascular, Direct Coombs +)
     – Cold Agglutin (IgM- intravascular, Indirect Coombs +)

     – Treatment Corticosteroids, Spleenectomy for Warm only



   Hemoglobinopatrhies
     –   Thalasemias
     –   Hg S
     –   Hg C
     –   Hg E
Hemolytic anemias
Extravascular vs Intravascular
Sickle Cell (hand and foot syndrome)
Pigmented Gallstone
from chronic hemolytic anemia
      Cellular Host Defense Mechanisms
– Myeloid:
        Macrophage/monocyte
            – alveolar, Kupffer,spleen, renal, etc
            – long life - Ig & Complement Receptors
        Neutrophils -
            – Phagosomes- Resp Burst, Superoxide
            – Granules - bactericidal prot, lactoferin lysozyme
        Eosinophils
            – Granules - hist, ECP, basic prot - parasites
– Lymphoid
        T - Cells - perforins - viral, Tumors
        B- Cells - IG synthesis
   Humoral Host Defense Mechanisms


– Complement:
   » Serine Proteases - Anaphylactotoxins, MAC
– Immunogloubins:
   » IgM, IgG, IgA, IgD, IgE
– Acute Phase Proteins
   » CRP - binds C-protein of Pneumococcus
– Cytokines
   » INF, IL, TNF, etc
Complement Cascade
Neutrophil Disorders

   Neutrophil Kinetics
     – Pools
     – T1/2= 6hr
     – Moprphology
   Neutropenia

   Neutrophilia

   Qualatative Abnormalities
Eosinophil/ Basophil/ Mast Cell Disorders


   Eosinopenia

   Eosinophilia

   Basophilopenia

   Basophilia

   mastocytosis
Monocyte/ Macrophage Disorders

   Kinetics
     – T 1/2 = 3 day circulation
         »     3 month tissue


   Storage Diseases
Lymphocytic Disorders

   T- cell
     – CD4, CD8
     – HIV


   B-cell
   Leukemias/ Lymphomas
   Plasma Cell Dyscrasias
Major Histiocompatability Antigens
Platelet Disorders

   Thrombocytopenia
     – ITP, TTP


   Thrombocytosis

   Thromboembolic Diseases
Virchow’s Triad
Venous Thromboembolism

A Significant Medical Problem
Deep vein thrombosis (DVT) and pulmonary embolism (PE)
 Significant morbidity and mortality
 Nearly 2/3 of patients’ incidents asymptomatic,
  undiagnosed, untreated
 Estimated 600,000 cases/year; ~260,000 diagnosed
 5%-10% of all hospital deaths/year from PE




Anderson et al. Clin Chest Med. 1995;16:235-251.
Bick. Clin Appl Thrombosis/Hemostasis. 1999;5:2-9.
 Clinical Risk Factors for VTE
Medical/Disease Factors
 Trauma
 Surgery >2 hours
 General anesthesia >30 minutes
 Recent MI, heart failure
 Paralysis of lower limbs
 Malignancy
 Sepsis
 Nephrotic syndrome
 Hypercoagulable states
  (eg, antiphospholipid antibody syndrome, Prot C , S or AT III
  deficiencies)

 Anderson et al. Clin Chest Med. 1995;16:235-251.
 Bick et al. Med Clin North Am. 1998;82:409-458.
   Clinical Risk Factors for VTE

 Patient Factors
  Age 40 years ( with increasing age)
  Obesity
  History of VTE
  Prolonged immobility
  Pregnancy/parturition
  High-dose estrogen
  Genetic thrombophilia



Anderson et al. Clin Chest Med. 1995;16:235-251.
Bick et al. Med Clin North Am. 1998;82:409-458.
Platelet involvement in Clot formation




     White HD. Am J Cardiol. 1997; 80 (4A): 2B-10B.
GP IIb-IIIa: the final common
pathway to platelet aggregation




      White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
Drug effects on Platelet Function




          White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
                Intrinsic
                Pathway
                                    Clotting                 Extrinsic
                                                             Pathway
          Endothelial injury        Cascade              Tissue Damage


          XII               XIIa
                                                         Tissue Factor, VII

          XI                XIa
Ca++/phospholipid                                                 Ca++/phospholipid
           IX               IXa

                    VIII Ca++/phospholipid

                X              Xa                       Xa              X     Antithrombin III
                                                                              (ATIII)
                                      V Ca++, Phospholipid
Common          II (prothrombin)                    IIa(thrombin)
Pathway                                Ca++
                       Fibrinogen              Fibrin                       Ca++

                                                                XIIIa              XIII

                                       Stable Fibrin Clot
Nonthrombogenic & Thrombogenic
Endothelial Mechanisms
Protein C & Protein S
               Heparin-induced thrombocytopenia


   Heparin-induced thrombocytopenia (HIT) /thrombosis (HITTS)
    – Mechanism:
      UH binds to PF4              antibodies        UH/PF4/Ab

                                                     further PF4 release
      UH/PF4/Ab bind to platelets

    – Incidence 1%-3%
                                                       HIT / HITTS

Warkentin et al. N Engl J Med. 1995;332:1330-1335.
Hirsh. Circulation. 1998;98:1575-1582.
Hirsh et al. Blood. 1992;79:1-17.
           Antithrombotic Effects of LMWHs


Pentasaccharide containing fractions                  Pentasaccharide containing fractions
     with <18 saccharide units                             with >18 saccharide units


      ATIII                  Thrombin                           ATIII             Thrombin


            5             LMWH                                           5          13     LMWH
       No inhibition of thrombin                                    Inhibition of thrombin



      ATIII            Xa                                       ATIII            Xa


              5            LMWH                                         5               LMWH
     Inhibition of Factor Xa                                  Inhibition of Factor Xa


                              Hirsh. Circulation. 1998;1575-1582.
Inherited and Acquired Bleeding
disorders
   Hemophilia
     – A - Factor VIII
     – B - Factor IX


   DIC
            Disseminated intravascular
            Coagulation (DIC)
» Pathophysiology
     Endotoxin activates both intrinsic(Factor Xii) via LPS and extrinsic
      pathways(Factor VII) via Tissue Factor
     deposition of fibrin/ clot in microvascular, tissue ischemia, hemolytic anemia
     consumption of Plt, clotting factors, plasmin activation,  FDP &  factors V/
      VIII, bleeding diathesis
» Etiology:
     Malignancy
     Pregnancy
     Infection: GNR, Meningococcemia, Riketsia, Histoplasmosis, Aspergillus
» Sites of Thrombosis:
     Brain, heart, lungs, renal, adrenal, spleen, liver
           Disseminated intravascular
           Coagulation (DIC)
– Diagnosis:
    » Clinical:
         bleeding, S/S of organ involvement:  Mental status, dyspnea, oliguria
    » Lab:
         Plt, Fibrinogen,  ATIII, FDP/ D-Dimers
– Treatment:
         Treat underlying cause,
         Plt Tx, FFP, Cryo ppt, Whole blood
         low dose heparin 20-40 u/hr (for refractory or emboli)
– Monitoring/ prognosis
         Plt Count, Fibrinogen levels, PT/PTT
         underlying condition/ organ involvement

				
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posted:11/6/2012
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