RBC and BLEEDING DISORDERS

TABLE 13-2 -- Adult Reference Ranges for Red Blood Cells *

Measurement (units) Hemoglobin (gm/dL)

Men 13.617.2

Hematocrit (%)

3949

Red cell count (106 /L)

4.35.9

Reticulocyte count (%)

0.51.5

Mean cell volume (m3 ) MCV

8296

Mean corpuscular hemoglobin (pg) MCH

2733

Mean corpuscular hemoglobin concentration (gm/dL) MCHC

3337

RBC distribution width

11.514.5

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 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

MARROW DIFFERENTIATION

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 Pallor, where? Tiredness Weakness Dyspnea, why? Palpitations Heart Failure (high output), why?

Blood Loss Acute: trauma Chronic: lesions of gastrointestinal tract, gynecologic disturbances. The features of chronic blood loss anemia are the same as iron deficiency anemia, and is defined as a situation in which the production cannot keep up with the loss.

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

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

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

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

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

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

HEMOLYSIS INTRA-vascular (vessels)

EXTRA-vascular (spleen)

HEREDITARY SPHEROCYTOSIS Genetic defects affecting ankyrin, spectrin, usually autosomal dominant Children, adults Anemia, hemolysis, jaundice, splenomegaly, gallstones (what kind?) Note lack of a central pallor and a microcytosis, i.e., low MCV

If most of the RBCs are chewed up in the spleen, do you think splenectomy is often helpful in the management of this

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

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 Classic hemoglobinopathy Normal HGB is 2 2: -chain defects (Val->Glu)

Reduced hemoglobin sickles in homozygous 8% of American blacks are heterozygous

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 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, and microcytic anemia, i.e, LOW MCV (just like iron deficiency anemia h A crew cut skull x-ray appearance may be seen in severe erythroid hyperplasia.

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 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), jaundice, kernicterus Edema (hence the name hydrops) Massive hepatosplenomegaly (hemolysis)

Paroxysmal Nocturnal Hemoglobinuria (PNH)

ACQUIRED, NOT INHERITED like all the previous hemolytic anem ACQUIRED mutations in phosphatidylinositol glycan A (PIGA) Note: It is P and N only 25% of the time!

Phosphatidylinositol N-acetylglucosaminyltransferase subunit A is an enzyme that in humans is encoded by the P

PIGA makes GPI, defective PIGA makes defective or inadequate GPI. Why does the term hemoglobinuria imply hemoly Sudden, UN-controllable, like a seizure

Immunohemolytic Anemia NOT all are AUTOimmune, some are caused by drugs Antibodies can be WARM (IgG)

All of these have the presence of antibodies and/or compliment p

 COLD AGGLUTININ (IgM) COLD HEMOLYSIN (paroxysmal) (IgG)

IMMUNOHEMOLYTIC ANEMIAS WARM AGGLUTININS (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, he ALSO often follows mycoplasma pneumoniae

COOMBS TEST
DIRECT: Patients CELLS are tested for surface Abs INDIRECT: Patients SERUM is tested for Abs.

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

Megaloblasts on top, macrocytes on bottom. What is the difference between a megaloblast and a macrocyte? What is the difference between a megaloblast and an erythroblast? Do the arrows point to macrocytes, i.e., RBCs with a high MCV. Why is it silly to say a single RBC has a high MCV?

Decreased intake

Inadequate diet, vegetarianism

Impaired absorption

Intrinsic factor deficiency

Pernicious anemia

Gastrectomy

Malabsorption states

Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis

Ileal resection, ileitis

Competitive parasitic uptake

Fish tapeworm infestation

Bacterial overgrowth in blind loops and diverticula of bowel

Increased requirement

Pregnancy, hyperthyroidism, disseminated cancer

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

PERNICIOUS ANEMIA MEGALOBLASTIC anemia LEUKOPENIA and HYPERSEGS JAUNDICE NEUROLOGIC posterolateral spinal tracts ACHLORHYDRIA Cant absorb B12 LOW serum B12 Flunk Schilling test, i.e., cant absorb B12, using a radioactive tracer

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 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!

Fe Transferrin Ferritin (GREAT test) Hemosiderin Clinical Fe-Defic-Anemia Adult men: GI Blood Loss PRE menopausal women: menorrhagia POST menopausal women: GI Blood Loss 2 BEST lab tests: Serum Ferritin Prussian blue hemosiderin stain of marrow (also called an iron stain) 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! Most are hypochromic (low MCHC), and microcytic (low MCV) like Fe deficiency anemias but have NORMAL iron stores (i.e., hemosiderin).

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

Fanconi syndrome and Fanconi anemia are two completely different disorders, but named after the same guy, even though the syndrome was NOT described by him. Fanconis Anemia is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C. If you understand the cell differentiation concept, why would an aplastic anemia be less likely to involve lymphocytes?

APLASTIC ANEMIAS CHLORAMPHENICOL OTHER ANTIBIOTICS CHEMO INSECTICIDES VIRUSES EBV HEPATITIS VZ MYELOPHTHISIC ANEMIAS Are anemias caused by metastatic tumor cells replacing the bone marrow extensively

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 A myeloproliferative disease ALL cell lines are increased, not just RBCs 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.

Doesnt this really boil down to TWO things? 1) Reduced platelet function/numbers, and, 2) everything else?

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-Schnlein purpura (mesangial deposits too) Hereditary hemorrhagic telangiectasia Amyloid THROMBOCYTOPENIAS Like RBCs: DE-creased production IN-creased destruction Sequestration (Hypersplenism) Dilutional Normal value 150K-300K DE-CREASED PRODUCTION APLASTIC ANEMIA ACUTE LEUKEMIAS ALCOHOL, THIAZIDES, CHEMO MEASLES, HIV MEGALOBLASTIC ANEMIAS MYELODYSPLASTIC SYNDROMES IN-CREASED DESTRUCTION AUTOIMMUNE (ITP) POST-TRANSFUSION (NEONATAL) QUINIDINE, HEPARIN, SULFA MONO, HIV DIC TTP MICROANGIOPATHIC

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

 ADULTS AND ELDERLY ACUTE OR CHRONIC AUTO-IMMUNE ANTI-PLATELET ANTIBODIES PRESENT INCREASED MARROW MEGAKARYOCYTES Rx: STEROIDS Any thrombocytopenia of increased destruction should have INCREASED megakaryocytes in the marrow! JUST LIKE a hemolytic anemia has an erythroid HYPER-plasia, same principle! Does this follow the pattern of a classic autoimmune disease? Yes!

ACUTE

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

DRUGS Quinine Quinidine Sulfonamide antibiotics HEPARIN

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

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

BLEEDING DISORDERS due to CLOTTING 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 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

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 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

For all practical purposes, the same as Hemophilia A. How to differentiate? Factor assays! Note the AMAZING similarities between Hemophilia A and B

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

What is a consumptive coagulopathy? Ans: the platelets and many clotting factors are consumed, i.e., used up!

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 PTT (intrinsic) PT INR (extrinsic) Platelet count, aggregation Bleeding Time, so EASY to do Fibrinogen Factor Assays Would you feel confident taking a patient to surgery if all these tests were normal, especially the first four? Answer: YES