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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

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

Measurement (units) Men Women

Hemoglobin (gm/dL) 13.617.2 12.015.0

Hematocrit (%) 3949 3343

Red cell count (106 /L) 4.35.9 3.55.0

Reticulocyte count (%) 0.51.5

Mean cell volume (m3 ) MCV 8296

Mean corpuscular hemoglobin (pg) MCH 2733

Mean corpuscular hemoglobinconcentration (gm/dL) MCHC

3337

RBC distribution width 11.514.5

http://home.mdconsult.com/das/book/body/0/1249/133.html

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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

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MARROW FEATURES

CELLULARITY50% MEGAKARYOCYTESat 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., HEMOSIDERINpresent FOREIGN CELLS

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MARROWDIFFERENTIATION

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ANEMIAS* BLOOD LOSS

ACUTE

CHRONIC

IN-creased destruction (HEMOLYTIC)

DE-creased production

* A good definition would be a decrease in OXYGEN CARRYINGCAPACITY, rather than just a decrease in red blood cells, because

you need to have enough blood cells THAT FUNCTION, and not justenough blood cells.

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Featuresof ALL anemias Pallor, where?

Tiredness

Weakness

Dyspnea, why? Palpitations

Heart Failure (high output), why?

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Blood LossAcute: 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 situationin which the production cannot keep up with

the loss.

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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

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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)

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MODIFIERS MCV, microcytosis, macrocytosis

MCH

MCHC, hypochromic

RDW, anisocytosis

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HEMOLYTIC ANEMIAS

Life span LESS than 120 days

Marrow hyperplasia (M:E), EPO+

Increased catabolic products,

e.g., bilirubin, serum HGB,

hemosiderin, haptoglobin-HGB

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HEMOLYSIS INTRA-vascular (vessels)

EXTRA-vascular (spleen)

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M:E Ratio normally 3:1

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HEREDITARY SPHEROCYTOSIS

Genetic defects affecting

ankyrin, spectrin, usually

autosomal dominant

Children, adults

Anemia, hemolysis,

jaundice, splenomegaly,

gallstones (what kind?)

cose osp ate

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ucose- - osp ateDehydrogenase (G6PD) Deficiency

A- and Mediterranean are most significant types

FEATURES f G6PD D fi

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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

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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

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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

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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 lowMCV)

A crew cut skull x-ray appearance may beseen in severeerythroid hyperplasia.

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Hemoglobin H Disease Deletion of THREE alpha chain genes

HGB-H is primarilly Asian

HGB-H has a HIGH affinity foroxygen

HGB-H is unstable and therefore has

classical hemolytic behavior

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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)

P l N l

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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!

GlycosylphosPhatidylInositol(lipid rafts)

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Immunohemolytic Anemia

All of these have the presence of antibodiesand/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

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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 ParoxysmalHemoglobinuria, hemo-LYSIS in body, ALSO oftenfollows mycoplasma pneumoniae

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COOMBSTEST DIRECT: Patients CELLS are

tested for surface Abs

INDIRECT: Patients SERUM is

tested for Abs.

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HEMOLYSIS/HEMOLYTIC ANEMIAS

DUE TO RBC TRAUMA

Mechanical heart valves

breaking RBCs

MICROANGIOPATHIES:TTP

Hemolytic Uremic Syndrome

NON Hemolytic Anemias:

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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

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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 VERYhyperplastic/hypercellular

marrow

Decreased intake

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Inadequate diet, vegetarianism

Impaired absorption

Intrinsic factor deficiencyPernicious anemiaGastrectomyMalabsorption states

Diffuse intestinal disease, e.g.,lymphoma, systemic sclerosisIleal resection, ileitisCompetitive parasitic uptakeFish tapeworm infestationBacterial overgrowth in blind loops anddiverticula of bowelIncreased requirement

Pregnancy, hyperthyroidism,disseminated cancer

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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 alsoMACROCYTIC (MCV>94 or

MCV~100), and that not only are

the RBCs BIG andhyperplastic/hypercellular, but so

are the neutrophils, and

neutrophilic precursors in the

bone marrow too, and even more

so, HYPERSEGMENTED!!!

PERNICIOUS ANEMIA

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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

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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

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Fe Deficiency Anemia

Due to increased loss or decreasedingestion, 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

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Clinical Fe-Defic-Anemia

Adult men: GI Blood Loss

PRE menopausal women:

menorrhagia POST menopausal women: GI Blood

Loss

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2 BEST lab tests:

Serum Ferritin

Prussian blue hemosiderinstain of marrow (also

called an iron stain)

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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!

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APLASTIC ANEMIAS

ALMOST ALWAYS involve platelet and

WBC suppression as well

Some are idiopathic, but MOST arerelated 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

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APLASTIC ANEMIAS

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APLASTIC ANEMIAS CHLORAMPHENICOL

OTHER ANTIBIOTICS

CHEMO INSECTICIDES

VIRUSES

EBV

HEPATITIS

VZ

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MYELOPHTHISIC ANEMIAS

Are anemias caused by metastatic

tumor cells replacing the bone

marrow extensively

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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

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P. VERA A myeloproliferative

disease

ALL cell lines are increased,

not just RBCs

BLEEDING DISORDERS

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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

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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

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THROMBOCYTOPENIAS

Like RBCs:DE-creased production

IN-creased destruction

Sequestration (Hypersplenism)

Dilutional

Normal value 150K-300K

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DE-CREASED PRODUCTION

APLASTIC ANEMIA

ACUTE LEUKEMIAS

ALCOHOL, THIAZIDES, CHEMO

MEASLES, HIV

MEGALOBLASTIC ANEMIAS

MYELODYSPLASTIC SYNDROMES

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IN-CREASED DESTRUCTION

AUTOIMMUNE (ITP)

POST-TRANSFUSION (NEONATAL)

QUINIDINE, HEPARIN, SULFA

MONO, HIV

DIC

TTP

MICROANGIOPATHIC

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THROMBOCYTOPENIAS

ITP (Idiopathic ThrombocytopenicPurpura)

Acute Immune

DRUG-induced

HIV associated

TTP, Hemolytic Uremic Syndrome

I T P

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I.T.P. ADULTS AND ELDERLY

ACUTE OR CHRONIC

AUTO-IMMUNE

ANTI-PLATELET ANTIBODIES PRESENT

INCREASED MARROWMEGAKARYOCYTES Rx: STEROIDS

ACUTE ITP

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ACUTE ITP CHILDREN

Follows a VIRAL illness (~ 2 weeks)

ALSO have anti-platelet antibodies

Platelets usually return to normal in a

few months

DRUGS

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DRUGS Quinine

Quinidine

Sulfonamide antibiotics

HEPARIN

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HIV BOTH DE-creased productionAND IN-creased destructionfactors are present

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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 l t l t di d

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QUALITATIVE platelet disorders

Mostly congenital (genetic): Bernard-Soulier syndrome (Glycoprotein-1-

b deficiency)

Glanzmanns thrombasthenia (Glyc.-IIB/IIIAdeficiency)

Storage pool disorders, i.e., platelets mis-

function AFTER they degranulate

ACQUIRED: ASPIRIN, ASPIRIN, ASPIRIN

BLEEDING DISORDERS due to

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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

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vonWillebrand 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

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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

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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,

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, ,

Coagulation

ENDOTHELIAL INJURY

WIDESPREAD FIBRIN DEPOSITION

HIGH MORTALITY

ALL MAJOR ORGANS COMMONLY INVOLVED

DIC, Disseminated INTRA-vascular,

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, ,

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 Coag lation TESTS

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Common Coagulation TESTS

PTT (intrinsic) PT INR (extrinsic) Platelet count, aggregation

Bleeding Time, so EASY to do

Fibrinogen

Factor Assays

RBC LAB

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RBC LAB