RBC and BLEEDING DISORDERS Slide 2 RBC and Bleeding Disorders
NORMAL NORMAL Anatomy, histology Development Physiology ANEMIAS
ANEMIAS Blood loss: acute, chronic Hemolytic Diminished
erythropoesis POLYCYTHEMIA POLYCYTHEMIA BLEEDING DISORDERS BLEEDING
DISORDERS Slide 3 Slide 4 Slide 5 Slide 6 TABLE 13-2 -- Adult
Reference Ranges for Red Blood Cells ** Measurement (units)MenWomen
Hemoglobin (gm/dL)13.617.212.015.0 Hematocrit (%)39493343 Red cell
count (10 6 /L)4.35.93.55.0 Reticulocyte count (%)0.51.5 Mean cell
volume (m 3 ) MCV8296 Mean corpuscular hemoglobin (pg) MCH2733 Mean
corpuscular hemoglobin concentration (gm/dL) MCHC 3337 RBC
distribution width11.514.5 Slide 7 Slide 8 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 Slide 9 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
Slide 10 MARROW DIFFERENTIATION Slide 11 Slide 12 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. Slide 13 Features of ALL anemias Pallor,
where? Tiredness Weakness Dyspnea, why? Palpitations Heart Failure
(high output), why? Slide 14 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. Slide 15 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 (vascular
or mechanic) INFECTIONS DRUGS, TOXINS HYPERSPLENISM Slide 16
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)
Slide 17 MODIFIERS MCV, microcytosis, macrocytosis MCH MCHC,
hypochromic RDW, anisocytosis Slide 18 HEMOLYTIC ANEMIAS Life span
LESS than 120 days Marrow hyperplasia (M:E), EPO+ Increased
catabolic products, e.g., bilirubin, serum HGB, hemosiderin,
haptoglobin-HGB Slide 19 HEMOLYSIS INTRA-vascular (vessels)
EXTRA-vascular (spleen) Slide 20 M:E Ratio normally 3:1 Slide 21
HEREDITARY SPHEROCYTOSIS Genetic defects affecting ankyrin,
spectrin, usually autosomal dominant Children, adults Anemia,
hemolysis, jaundice, splenomegaly, gallstones (what kind?) Slide 22
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency A - and
Mediterranean are most significant types Slide 23 FEATURES of G6PD
Defic. Genetic: 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 Slide 24 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 Slide 25 Clinical features of
HGB-S disease Severe anemia Jaundice PAIN (pain CRISIS)
Vaso-occlusive disease: EVERYWHERE, but clinically significant
bone, spleen (autosplenectomy) Infections: Pneumococcus, Hem.
Influ., Salmonella osteomyelitis Slide 26 Slide 27 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 has a low
MCV) A crew cut skull x-ray appearance may be seen in severe
erythroid hyperplasia. Slide 28 Slide 29 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 Slide 30 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)
Slide 31 Paroxysmal Nocturnal Hemoglobinuria (PNH) ACQUIRED, NOT
INHERITED like all the previous hemolytic anemias were ACQUIRED
mutations in phosphatidylinositol glycan A (PIGA) Note: It is P and
N only 25% of the time! G lycosylphos P hatidyl I nositol (lipid
rafts) Slide 32 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 AGGLUTININ (IgG) COLD AGGLUTININ (IgM) COLD HEMOLYSIN
(paroxysmal) (IgG) Slide 33 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, hemo-LYSIS in body, ALSO often
follows mycoplasma pneumoniae Slide 34 COOMBS TEST DIRECT: Patients
CELLS are tested for surface Abs INDIRECT: Patients SERUM is tested
for Abs. Slide 35 HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA
Mechanical heart valves breaking RBCs MICROANGIOPATHIES: TTP
Hemolytic Uremic Syndrome Slide 36 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 Slide 37 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* (* exception to the rule) Slide
38 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 Slide 39 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 Slide 40 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!!! Slide 41 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
Slide 42 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 Slide 43
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! Slide 44 Fe
Transferrin Ferritin/apo- (GREAT test) Hemosiderin Slide 45
Clinical Fe-Defic-Anemia Adult men: GI Blood Loss PRE menopausal
women: menorrhagia POST menopausal women: GI Blood Loss Slide 46
Slide 47 2 BEST lab tests: Serum Ferritin Prussian blue hemosiderin
stain of marrow (also called an iron stain) Slide 48 ? Slide 49
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! Slide 50
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 Slide 51 APLASTIC ANEMIAS Slide 52 CHLORAMPHENICOL OTHER
ANTIBIOTICS CHEMO INSECTICIDES, benzene, toluene, TNT VIRUSES EBV
HEPATITIS VZ Slide 53 MYELOPHTHISIC ANEMIAS Are anemias caused by
metastatic tumor cells replacing the bone marrow extensively Slide
54 POLYCYTHEMIA Relative (e.g., hemoconcentration) Absolute
POLYCYTHEMIA VERA (Primary) ( LOW EPO), mutation in tyrosine
kinase, making RBCs hyper responsive to EPO POLYCYTHEMIA
(Secondary) (HIGH EPO) HIGH ALTITUDE EPO TUMORS EPO Doping CVAC,
the trendy California bubble pods Slide 55 P. VERA A
myeloproliferative disease ALL cell lines are increased, not just
RBCs Slide 56 BLEEDING DISORDERS (aka, Hemorrhagic DIATHESES) Blood
vessel wall abnormalities Reduced platelets Decreased platelet
function Abnormal clotting factors DIC ( D isseminated I
NTRA-vascular C oagulation), also has plats. Slide 57 VESSEL WALL
ABNORMALITIES (angiopathic thrombocytopenias) (NON-thrombotic
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 Slide
58 THROMBOCYTOPENIAS Like RBCs: DE-creased production IN-creased
destruction Sequestration (Hypersplenism) Dilutional Normal value
150K-300K Slide 59 DE-CREASED PRODUCTION APLASTIC ANEMIA ACUTE
LEUKEMIAS ALCOHOL, THIAZIDES, CHEMO MEASLES, HIV MEGALOBLASTIC
ANEMIAS MYELODYSPLASTIC SYNDROMES Slide 60 IN-CREASED DESTRUCTION
AUTOIMMUNE (ITP) POST-TRANSFUSION (NEONATAL) QUINIDINE, HEPARIN,
SULFA MONO, HIV DIC TTP MICROANGIOPATHIC Slide 61 THROMBOCYTOPENIAS
ITP (Idiopathic Thrombocytopenic Purpura) Acute Immune DRUG-induced
HIV associated TTP, Hemolytic Uremic Syndrome Slide 62 I.T.P.
ADULTS AND ELDERLY ACUTE OR CHRONIC AUTO-IMMUNE ANTI-PLATELET
ANTIBODIES PRESENT INCREASED MARROW MEGAKARYOCYTES Rx: STEROIDS
Slide 63 ACUTE ITP CHILDREN Follows a VIRAL illness (~ 2 weeks)
ALSO have anti-platelet antibodies Platelets usually return to
normal in a few months Slide 64 DRUGS Quinine Quinidine Sulfonamide
antibiotics HEPARIN Slide 65 HIV BOTH DE-creased production AND
IN-creased destruction factors are present Slide 66 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 Slide 67 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 because of defective granulation ACQUIRED: ASPIRIN,
ASPIRIN, ASPIRIN Slide 68 PTT PT/INR Slide 69 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% Slide 70 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, to join
platelets with the exposed ECM in endothelial disruption. it is the
von Willebrand Factor which is defective in von Willebrand disease
Usually BOTH platelet and FactorVIII-vWF disorders are present
Slide 71 PTT PT/INR Slide 72 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 Slide 73 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 Slide 74 DIC,
Disseminated INTRA-vascular, Coagulation ENDOTHELIAL INJURY
WIDESPREAD FIBRIN DEPOSITION HIGH MORTALITY ALL MAJOR ORGANS
COMMONLY INVOLVED Slide 75 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
Slide 76 Common Coagulation TESTS PTT (intrinsic) PT INR
(extrinsic) Platelet count, aggregation Bleeding Time, so EASY to
do Fibrinogen Factor Assays Slide 77 RBC LAB
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