RBC and BLEEDING DISORDERS

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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

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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

• CELLULARITY
• MEGAKARYOCYTES
• ME RATIO
• MYELOID MATURATION
• ERYTHROID MATURATION
• LYMPHS, PLASMA CELLS
• STORAGE IRON, i.e., HEMOSIDERIN
• FOREIGN CELLS

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MARROW DIFFERENTIATION
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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
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.
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Features of ALL anemias

• Pallor
• Tiredness
• Weakness
• Dyspnea
• Palpitations
• Heart Failure (high output)

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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 (ME), EPO
• Increased catabolic products, e.g., bilirubin,
  serum HGB, hemosiderin
• Decreased haptoglobin

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HEMOLYSIS

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

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ME Ratio normally 31
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HEREDITARY SPHEROCYTOSIS
Genetic defects affecting ankyrin, spectrin,
usually autosomal dominant Children,
adults Anemia, hemolysis, jaundice,
splenomegaly, gallstones (what kind?)
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Glucose-6-Phosphate Dehydrogenase (G6PD)
Deficiency

• A- and Mediterranean are most significant types

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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 a2 ß2 ß-chain defects
  (Val-gtGlu)
• 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 EVERYWHERE, 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, a microcytic
  anemia
• A crew cut skull x-ray appearance may be seen

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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

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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)
• Edema (hence the name hydrops)
• Massive hepatosplenomegaly (hemolysis)

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Paroxysmal Nocturnal Hemoglobinuria (PNH)
GlycosylphosPhatidylInositol

• 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

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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)

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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

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COOMBS TEST

• 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

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NON-Hemolytic Anemiasi.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, MCVgt94)
• Impaired DNA synthesis
• For all practical purposes, also called the
  anemias of B12 and FOLATE deficiency

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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 also MACROCYTIC (MCVgt94 or MCV100), and
that not only are the RBCs BIG, but so are the
neutrophils, and neutrophilic precursors in the
bone marrow too, and even more so,
HYPERSEGMENTED!!!
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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

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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 decreased ingestion,
  almost always, in USA, nowadays, increased loss
  is the reason
• Macrocytic (low MCV), Hypochromic (low MCHC)
• THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD

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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 hemosiderin stain 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 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

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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

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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)

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VESSEL WALL ABNORMALITIES(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

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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 Thrombocytopenic Purpura)
• Acute Immune
• DRUG-induced
• HIV associated
• TTP, Hemolytic Uremic Syndrome

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I.T.P.

• ADULTS AND ELDERLY
• ACUTE OR CHRONIC
• AUTO-IMMUNE
• ANTI-PLATELET ANTIBODIES PRESENT
• INCREASED MARROW MEGAKARYOCYTES
• Rx STEROIDS

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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

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DRUGS

• Quinine
• Quinidine
• Sulfonamide antibiotics
• HEPARIN

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HIV

• BOTH DE-creased production AND IN-creased
  destruction factors 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

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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

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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
• von Willebrand disease the most common, 1

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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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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

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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

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DIC, Disseminated INTRA-vascular, Coagulation

• ENTOTHELIAL INJURY
• WIDESPREAD FIBRIN DEPOSITION
• HIGH MORTALITY
• ALL MAJOR ORGANS COMMONLY INVOLVED

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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

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Common Coagulation TESTS

• PTT (intrinsic)
• PT? INR (extrinsic)
• Platelet count, aggregation
• Bleeding Time
• Fibrinogen
• Factor Assays