Ch13-RBC

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RBC and BLEEDING DISORDERS

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RBC and Bleeding Disorders NORMAL Anatomy, histology Development Physiology ANEMIAS Blood loss: acute, chronic Hemolytic Diminished erythropoesis POLYCYTHEMIA BLEEDING DISORDERS

WHERE is MARROW? : 

WHERE is MARROW? Yolk Sac: very early embryo Liver, Spleen: NEWBORN BONE CHILDHOOD: AXIAL SKELETON & APPENDICULAR SKELETON BOTH HAVE RED (active) MARROW ADULT: AXIAL SKELETON RED MARROW, APPENDICULAR SKELETON YELLOW MARROW

MARROW FEATURES : 

MARROW FEATURES CELLULARITY 50% MEGAKARYOCYTES at least 1-2/hpf M:E RATIO  3:1 MYELOID MATURATION  1/3 bands or more ERYTHROID MATURATION  nucleus/cytoplasm LYMPHS, PLASMA CELLS  small percentage STORAGE IRON, i.e., HEMOSIDERIN present “FOREIGN CELLS”

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MARROW “DIFFERENTIATION”

ANEMIAS* : 

ANEMIAS* BLOOD LOSS ACUTE CHRONIC IN-creased destruction (HEMOLYTIC) DE-creased production * A good definition would be a decrease in OXYGEN CARRYING CAPACITY, rather than just a decrease in red blood cells, because you need to have enough blood cells THAT FUNCTION, and not just enough blood cells.

Features of ALL anemias : 

Features of ALL anemias Pallor, where? Tiredness Weakness Dyspnea, why? Palpitations Heart Failure (high output), why?

HEMOLYTIC : 

HEMOLYTIC HEREDITARY MEMBRANE disorders: e.g., spherocytosis ENZYME disorders: e.g., G6PD deficciency HGB disorders (hemoglobinopathies) ACQUIRED MEMBRANE disorders (PNH) ANTIBODY MEDIATED, transfusion or autoantibodies MECHANICAL TRAUMA INFECTIONS DRUGS, TOXINS HYPERSPLENISM

IMPAIRED PRODUCTION : 

IMPAIRED PRODUCTION Disturbance of proliferation and differentiation of stem cells: aplastic anemias, pure RBC aplasia, renal failure Disturbance of proliferation and maturation of erythroblasts Defective DNA synthesis: (Megaloblastic) Defective heme synthesis: (Fe) Deficient globin synthesis: (Thalassemias)

MODIFIERS : 

MODIFIERS MCV, microcytosis, macrocytosis MCH MCHC, hypochromic RDW, anisocytosis

HEMOLYTIC ANEMIAS : 

HEMOLYTIC ANEMIAS Life span LESS than 120 days Marrow hyperplasia (M:E), EPO+ Increased catabolic products, e.g., bilirubin, serum HGB, hemosiderin

HEMOLYSIS : 

HEMOLYSIS INTRA-vascular (vessels) EXTRA-vascular (spleen)

M:E Ratio normally 3:1 : 

M:E Ratio normally 3:1

HEREDITARY SPHEROCYTOSIS : 

HEREDITARY SPHEROCYTOSIS Genetic defects affecting ankyrin, spectrin, usually autosomal dominant Children, adults Anemia, hemolysis, jaundice, splenomegaly, gallstones (what kind?)

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency : 

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency A- and Mediterranean are most significant types

FEATURES of G6PD Defic. : 

FEATURES of G6PD Defic. Genetic: Recessive, X-linked Can be triggered by foods (fava beans), oxidant substances drugs (primaquine, chloroquine), or infections HGB can precipitate as HEINZ bodies Acute intravascular hemolysis can occur: Hemoglobinuria Hemoglobinemia Anemia

Sickle Cell Disease : 

Sickle Cell Disease Classic hemoglobinopathy Normal HGB is α2 β2: β-chain defects (Val->Glu) Reduced hemoglobin “sickles” in homozygous 8% of American blacks are heterozygous

Clinical features of HGB-S disease : 

Clinical features of HGB-S disease Severe anemia Jaundice PAIN (pain CRISIS) Vaso-occlusive disease: EVEREWHERE, but clinically significant bone, spleen (autosplenectomy) Infections: Pneumococcus, Hem. Influ., Salmonella osteomyelitis

THALASSEMIAS : 

THALASSEMIAS A WIDE VARIETY of diseases involving GLOBIN synthesis, COMPLEX genetics Alpha or beta chains deficient synthesis involved Often termed MAJOR or MINOR, depending on severity, silent carriers and “traits” are seen HEMOLYSIS is uniformly a feature, a microcytic anemia A “crew cut” skull x-ray appearance may be seen

Hemoglobin H Disease : 

Hemoglobin H Disease Deletion of THREE alpha chain genes HGB-H is primarilly Asian HGB-H has a HIGH affinity for oxygen HGB-H is unstable and therefore has classical hemolytic behavior

HYDROPS FETALIS : 

HYDROPS FETALIS FOUR alpha chain genes are deleted, so this is the MOST SEVERE form of thalassemia Many/most never make it to term Children born will have a SEVERE hemolytic anemia as in the erythroblastosis fetalis of Rh disease: Pallor (as in all anemias) Edema (hence the name “hydrops”) Massive hepatosplenomegaly (hemolysis)

Paroxysmal Nocturnal Hemoglobinuria (PNH) : 

Paroxysmal Nocturnal Hemoglobinuria (PNH) ACQUIRED, NOT INHERITED like all the previous hemolytic anemias were ACQUIRED mutations in phosphatidylinositol glycan A (PIGA) It is “P” and “N” only 25% of the time GlycosylphosPhatidylInositol

Immunohemolytic Anemia : 

Immunohemolytic Anemia All of these have the presence of antibodies and/or compliment present on RBC surfaces NOT all are AUTOimmune, some are caused by drugs Antibodies can be WARM (IgG) COLD AGGLUTININ (IgM) COLD HEMOLYSIN (paroxysmal) (IgG)

IMMUNOHEMOLYTIC ANEMIAS : 

IMMUNOHEMOLYTIC ANEMIAS WARM (IgG), will NOT hemolyze at room temp Primary Idiopathic (most common) Secondary (Tumors, especially leuk/lymph, drugs) COLD AGGLUTININS: (IgM), WILL hemolyze at room temp Mycoplasma pneumoniae, HIV, mononucleosis COLD HEMOLYSINS: (IgG) Cold Paroxysmal Hemoglobinuria, hemo-LYSIS in body, ALSO often follows mycoplasma pneumoniae

COOMBS TEST : 

COOMBS TEST DIRECT: Patient’s CELLS are tested for surface Ab’s INDIRECT: Patient’s SERUM is tested for Ab’s.

HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA : 

HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA Mechanical heart valves breaking RBC’s MICROANGIOPATHIES: TTP Hemolytic Uremic Syndrome

NON-Hemolytic Anemias:i.e., DE-creased Production : 

NON-Hemolytic Anemias:i.e., DE-creased Production “Megaloblastic” Anemias B12 Deficiency (Pernicious Anemia) Folate Deficiency Iron Deficiency Anemia of Chronic Disease Aplastic Anemia “Pure” Red Cell Aplasia OTHER forms of Marrow Failure

MEGALOBLASTIC ANEMIAS : 

MEGALOBLASTIC ANEMIAS Differentiating megaloblasts (marrow) from macrocytes (peripheral smear, MCV>94) Impaired DNA synthesis For all practical purposes, also called the anemias of B12 and FOLATE deficiency Often VERY hyperplastic/hypercellular marrow

Vit-B12 Physiology : 

Vit-B12 Physiology Oral ingestion Combines with INTRINSIC FACTOR in the gastric mucosa Absorbed in the terminal ileum DEFECTS at ANY of these sites can produce a MEGALOBLASTIC anemia

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Please remember that ALL megaloblastic anemias are also MACROCYTIC (MCV>94 or MCV~100), and that not only are the RBC’s BIG and hyperplastic/hypercellular, but so are the neutrophils, and neutrophilic precursors in the bone marrow too, and even more so, HYPERSEGMENTED!!!

PERNICIOUS ANEMIA : 

PERNICIOUS ANEMIA MEGALOBLASTIC anemia LEUKOPENIA and HYPERSEGS JAUNDICE NEUROLOGIC posterolateral spinal tracts ACHLORHYDRIA Can’t absorb B12 LOW serum B12 Flunk Schilling test, i.e., can’t absorb B12, using a radioactive tracer

FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS : 

FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS Decreased Intake: diet, etoh-ism, infancy Impaired Absorption: intestinal disease DRUGS: anticonvulsants, BCPs, CHEMO Increased Loss: Hemodialysis Increased Requirement: Pregnancy, infancy Impaired Usage

Fe Deficiency Anemia : 

Fe Deficiency Anemia Due to increased loss or decreased ingestion, almost always, in USA, nowadays, increased loss is the reason Microcytic (low MCV), Hypochromic (low MCHC) THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!

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Fe Transferrin Ferritin (GREAT test) Hemosiderin

Clinical Fe-Defic-Anemia : 

Clinical Fe-Defic-Anemia Adult men: GI Blood Loss PRE menopausal women: menorrhagia POST menopausal women: GI Blood Loss

2 BEST lab tests: : 

2 BEST lab tests: Serum Ferritin Prussian blue hemosiderin stain of marrow (also called an “iron” stain)

Anemia of Chronic Disease* : 

Anemia of Chronic Disease* CHRONIC INFECTIONS CHRONIC IMMUNE DISORDERS NEOPLASMS LIVER, KIDNEY failure * Please remember these patients may very very much look like iron deficiency anemia, BUT, they have ABUNDANT STAINABLE HEMOSIDERIN in the marrow!

APLASTIC ANEMIAS : 

APLASTIC ANEMIAS ALMOST ALWAYS involve platelet and WBC suppression as well Some are idiopathic, but MOST are related to drugs, radiation FANCONI’s ANEMIA is the only one that is inherited, and NOT acquired Act at STEM CELL level, except for “pure” red cell aplasia

APLASTIC ANEMIAS : 

APLASTIC ANEMIAS

APLASTIC ANEMIAS : 

APLASTIC ANEMIAS CHLORAMPHENICOL OTHER ANTIBIOTICS CHEMO INSECTICIDES VIRUSES EBV HEPATITIS VZ

MYELOPHTHISIC ANEMIAS : 

MYELOPHTHISIC ANEMIAS Are anemias caused by metastatic tumor cells replacing the bone marrow extensively

POLYCYTHEMIA : 

POLYCYTHEMIA Relative (e.g., hemoconcentration) Absolute POLYCYTHEMIA VERA (Primary) (LOW EPO) POLYCYTHEMIA (Secondary) (HIGH EPO) HIGH ALTITUDE EPO TUMORS EPO “Doping” CVAC, the trendy California bubble pods

P. VERA : 

P. VERA A “myeloproliferative” disease ALL cell lines are increased, not just RBCs

BLEEDING DISORDERS(aka, Hemorrhagic “DIATHESES”) : 

BLEEDING DISORDERS(aka, Hemorrhagic “DIATHESES”) Blood vessel wall abnormalities √ Reduced platelets √ Decreased platelet function √ Abnormal clotting factors √ DIC (Disseminated INTRA-vascular Coagulation), also has ↓ plats.

VESSEL WALL ABNORMALITIES(angiopathic thrombocytopenias)(NON-thrombotic cytopenic purpuras) : 

VESSEL WALL ABNORMALITIES(angiopathic thrombocytopenias)(NON-thrombotic cytopenic purpuras) Infections, especially, meningococcemia, and rickettsia Drug reactions causing a leukocytoclastic vasculitis Scurvy, Ehlers-Danlos, Cushing syndrome Henoch-Schönlein purpura (mesangial deposits too) Hereditary hemorrhagic telangiectasia Amyloid

THROMBOCYTOPENIAS : 

THROMBOCYTOPENIAS Like RBCs: DE-creased production IN-creased destruction Sequestration (Hypersplenism) Dilutional Normal value 150K-300K

DE-CREASED PRODUCTION : 

DE-CREASED PRODUCTION APLASTIC ANEMIA ACUTE LEUKEMIAS ALCOHOL, THIAZIDES, CHEMO MEASLES, HIV MEGALOBLASTIC ANEMIAS MYELODYSPLASTIC SYNDROMES

IN-CREASED DESTRUCTION : 

IN-CREASED DESTRUCTION AUTOIMMUNE (ITP) POST-TRANSFUSION (NEONATAL) QUINIDINE, HEPARIN, SULFA MONO, HIV DIC TTP “MICROANGIOPATHIC”

THROMBOCYTOPENIAS : 

THROMBOCYTOPENIAS ITP (Idiopathic Thrombocytopenic Purpura) Acute Immune DRUG-induced HIV associated TTP, Hemolytic Uremic Syndrome

I.T.P. : 

I.T.P. ADULTS AND ELDERLY ACUTE OR CHRONIC AUTO-IMMUNE ANTI-PLATELET ANTIBODIES PRESENT INCREASED MARROW MEGAKARYOCYTES Rx: STEROIDS

ACUTE ITP : 

ACUTE ITP CHILDREN Follows a VIRAL illness (~ 2 weeks) ALSO have anti-platelet antibodies Platelets usually return to normal in a few months

DRUGS : 

DRUGS Quinine Quinidine Sulfonamide antibiotics HEPARIN

HIV : 

HIV BOTH DE-creased production AND IN-creased destruction factors are present

Thrombotic Microangiopathies : 

Thrombotic Microangiopathies BOTH are very SERIOUS CONDITIONS with a HIGH mortality: TTP (THROMBOTIC THROMBOCYTOPENIC PURPURA) H.U.S. (HEMOLYTIC UREMIC SYNDROME) These can also be called “consumptive” coagulopathies, just like a DIC

“QUALITATIVE” platelet disorders : 

“QUALITATIVE” platelet disorders Mostly congenital (genetic): Bernard-Soulier syndrome (Glycoprotein-1-b deficiency) Glanzmann’s thrombasthenia (Glyc.-IIB/IIIA deficiency) Storage pool disorders, i.e., platelets mis-function AFTER they degranulate ACQUIRED: ASPIRIN, ASPIRIN, ASPIRIN

BLEEDING DISORDERS due toCLOTTING FACTOR DEFICIENCIES : 

BLEEDING DISORDERS due toCLOTTING FACTOR DEFICIENCIES NOT spontaneous, but following surgery or trauma ALL factor deficiencies are possible Factor VIII and IX both are the classic X-linked recessive hemophilias, A and B, respectively ACQUIRED disorders often due to Vitamin-K deficiencies (II, VII, IX, X) von Willebrand disease the most common, 1%

von Willebrand Disease : 

von Willebrand Disease 1% prevalence, most common bleeding disorder Spontaneous and wound bleeding Usually autosomal dominant Gazillions of variants, genetics even more complex Prolonged BLEEDING TIME, NL platelet count vWF is von Willebrand Factor, which complexes with Factor VIII, it is the von Willebrand Factor which is defective in von Willebrand disease Usually BOTH platelet and FactorVIII-vWF disorders are present

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PTT PT/INR

HEMOPHILIA A : 

HEMOPHILIA A The “classic” HEMOPHILIA Factor VIII decreased Co-factor of Factor IX to activate Factor X Sex-linked recessive Hemorrhage usually NOT spontaneous Wide variety of severities Prolonged PTT (intrinsic) only Rx: Recombinant Factor VIII

HEMOPHILIA B : 

HEMOPHILIA B The “Christmas” HEMOPHILIA Factor IX decreased Sex-linked recessive Hemorrhage usually NOT spontaneous Wide variety of severities Prolonged PTT (intrinsic) only Rx: Recombinant Factor IX

DIC, Disseminated INTRA-vascular, Coagulation : 

DIC, Disseminated INTRA-vascular, Coagulation ENDOTHELIAL INJURY WIDESPREAD FIBRIN DEPOSITION HIGH MORTALITY ALL MAJOR ORGANS COMMONLY INVOLVED

DIC, Disseminated INTRA-vascular, Coagulation : 

DIC, Disseminated INTRA-vascular, Coagulation Extremely SERIOUS condition NOT a disease in itself but secondary to many conditions Obstetric: MAJOR OB complications, toxemia, sepsis, abruption Infections: Gm-, meningococcemia, RMSF, fungi, Malaria Many neoplasms, acute promyelocytic leukemia Massive tissue injury: trauma, burns, surgery “Consumptive” coagulopathy

Common Coagulation TESTS : 

Common Coagulation TESTS PTT (intrinsic) PT INR (extrinsic) Platelet count, aggregation Bleeding Time, so EASY to do Fibrinogen Factor Assays

RBC LAB : 

RBC LAB http://www.chronolab.com/hematology/2_1.htm