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            Hematology

Please note that this was put together by a UNC MS2
for other UNC MS2s. If you find any mistakes or have
   any feedback, let us know – especially if this was
             remotely helpful in any way!
            Characteristics of
        Normal Adult Bone Marrow
•Consists of approximately 50% fat cells;
•Has more myeloid cells than erythroid cells
(myeloid:erythroid ratio 2:1 to 7:1)
•Megakaryocytes are 2-5 per high power field
•Plasma cells <3%
•Lymphocytes <20%
     Peripheral Blood Morphology
1.    Erythrocytes
2.    Granulocytes
     1.   Neutrophils
     2.   Eosinophils
     3.   Basophils
3.    Platelets
4.    Monocytes
5.    Lymphocytes (B & T cells)
    Erythropoiesis – what is the order?
                                     Polychromatophilic
   Proerythroblast Basophilic           erythroblast
                   erythroblast




Orthochromatophilic   Reticulocyte      Mature RBC
   erythroblast
 Granulopoiesis – what is the order?
 Myeloblast     Promyelocyte   Myelocyte*




Metamyelocyte     Band         Neutrophil
Identify the Type of Cell
   Basophil      Eosinophil




    Monocyte




               Neutrophil
Anemia: When do you give
 a transfusion right away?

.Angina pectoris – coronary
  insufficiency
.Shock
.Surgery
    Iron kinetics as a function of time

   1. Childhood – building both the hemoglobin and
    storage iron by the intake and conservation of
    iron- years

   2. Adolescent and adult males – full complement
    of hemoglobin and storage iron

   3. Adolescent and adult females – iron content is
    challenged by menses and childbirth
Causes of iron deficiency




1.   inadequate intake
2.   Malabsorption
3.   diversion of iron during pregnancy
4.   blood loss
       RBC Characteristics in Iron
          Deficiency Anemia?


   Microcytic – small RBCs
   Hypochromatic – pale RBCs
      Ways to diagnose iron
       deficiency anemia?


1)   Serum ferritin – will be decreased.
 Careful, it’ll also be low in diseased/ill
 patients (an acute phase reactant)
2)   Bone Marrow - staining
3)   Treatment – the simplest!
    Causes of Macrocytic Anemia
   B12 deficiency
   Folate deficiency

            Uses of B12 & Folate
   DNA synthesis
       B12 = co-factor
       Folate = transfer single carbon groups
How do we get folate and B12?
   Folate
       In leafy green veggies, liver, yeast
       Destroyed by cooking
       Need 100-200 micrograms daily
   Vitamin B12
       In animal products
       Unaffected by cooking
       Need 1-2 micrograms daily
  Folate Deficiency –
    3 major causes

Dietary
Malabsorption
Increased usage
  3 ways to diagnose
   folate deficiency

Morphology – macrocytic RBCs and
  hypersegmented neutrophils

Serum folate
Red cell folate
 What’s This?




Megaloblastic Anemia
  Possible Causes?
B12 or folate deficiency
    B12 Deficiency –
     3 major causes

Pernicious Anemia
Pancreatic Insufficiency
Malabsorption
  3 ways to diagnose
    B12 deficiency

Morphology
Serum B12
Neurologic findings – Demyelination
of spinal cord, cerebral cortex
Treating B12 & Folate Deficiencies

   B12
       IM B12 supplementation for life
   Folate
       Daily folate supplement (1mg/day)
What do you see in the RBCs below?
  How would we quantitate this?

                    Anisocytosis refers to
                     red cells which vary
                     widely in size.
                    The RDW
                     mathematically
                     measures the range
                     of red cell sizes.
What do you see in the RBCs below?
   What diseases might they be
         associated with?
                    Microcytosis refers to red
                     cells that are small.
                    You can use the
                     lymphocyte nucleus as a
                     visual reference, or you
                     can use the MCV
                    Associated with
                        Iron deficiency
                        Thalassemias
                        Sideroblastic anemia
    What do you see in
      the top slide?
    Characterizes what
        diseases?
   Macrocytosis refers to large
    red cells.
   Associated with
        Elevated reticulocyte count
        B12/folate deficiency
        Liver disease
        Thyroid disease
        Chemotherapy
        Anti-retrovirals (AZT)
What’s wrong with these RBCs?
Measured how? A likely cause?
                  Hypochromasia refers
                   to red cells that have
                   too little hemoglobin.
                  The area of central
                   pallor is more than 1/3
                   the total red cell
                   diameter.
                  This is measured by
                   the MCH (mean
                   cellular hemoglobin)
                  Iron deficiency
What do you see on this slide?

                 Poikilocytosis refers to
                  red cells that vary
                  widely in shape.
                 Remember that
                  anisocytosis refers to
                  red cells that vary
                  widely in size.
What do you see here?
      Diseases?
              Target cells look like
               bulls-eyes.
              Associated with
                  Liver disease
                  Thalassemias
                  Hemoglobin C
                  After splenectomy
What do you see here?
      Diseases?
              Spherocytes have a loss
               of central pallor.
              Can be seen in
                  Hereditary spherocytosis
                  Autoimmune hemolysis
              If due to autoimmune
               hemolysis, the cells are
               smaller (i.e.
               microspherocytes)
What do you see here?
      Diseases?

             Schistocytes are red
              cell fragments with
              sharp edges.
             They are a hallmark
              of Microangiopathic
              Hemolytic Anemia
              (MAHA)
What do you see here?

             Sickle Cells are seen
              in sickle cell anemia.
             Notice that this slide
              has target cells as
              well as a sickled cell.
What RBCs are here?
     How do you
distinguish the two?
Associated disease?
   Echinocytes, or burr cells,
    have small, regular
    projections. Seen in renal
    disease
   Acanthocytes, or spur
    cells, have larger, irregular
    projections, and are seen
    in liver disease.
What do you see here?
  What causes it?

             Teardrop cells
             Seen in myelophthisic
              processes, or diseases
              of marrow infiltration.
             Deformed as it tries
              to squeeze out of the
              bone marrow
                                   And what
                                    have we
                                  here? What
                                     causes
                                     them?
   Howell-Jolly bodies are peripheral, small,
    round, purple inclusions within red cells that
    represent nuclear remnants.
   They are seen after splenectomy, or in cases of
    splenic hypofunction.
                             What do you see
                             here? Causes?

   Rouleaux are linear arrangements of red cells typically
    described as “piles of coins on a plate”
   They are typically seen in disorders with increased
    levels of immunoglobulin, such as Multiple Myeloma or
    Waldenstrom’s macroglobulinemia.
   Severe hypo-albuminemia can also lead to reouleux
    formation
                              What do you
                               see here?

   Red cell agglutination occurs when the red
    cells are coated with IgM. IgM is large enough
    to bridge two red cells and cause agglutination.
   Unlike rouleaux, the red cell clumps are not
    orderly and linear.
          General Clinical Features of
             Hemolytic Anemias
   Splenomegaly is generally present
   Patients have an increased incidence of pigmented
    gallstones.
   Dark urine (tea-colored or red), jaundice, scleral
    icterus
   Patients may have chronic ankle ulcers.
   Aplastic crises associated with Parvovirus B19, may
    occur
   Increased requirement for folate
Post-splenectomy blood findings




   Howell-Jolly bodies - small round blue DNA
    remnants in periphery of RBCs
   Red cell abnormalities: target cells,
    acanthocytes, schistocytes, NRBCs
              Hemolytic Anemias -
          Sites of Red Cell Destruction
   Extravascular Hemolysis -
       Macrophages in spleen, liver, and marrow remove
        damaged or antibody-coated red cells
   Intravascular Hemolysis
       Red cells rupture within the vasculature, releasing
        free hemoglobin into the circulation    (and the
        circulation does NOT like this!)
    Evidence for increased red
         cell production
   In the blood:
      Elevated reticulocyte count

      May be associated with high MCV

      Circulating NRBCs may be present

   In the bone marrow:
      erythroid hyperplasia

      reduced M/E (myeloid/erythroid) ratio

   In the bone:
      Deforming changes in the skull and long bones
       (“frontal bossing”)
    Evidence for Increased Red Cell
              Destruction
   Biochemical consequences of hemolysis in general
          Elevated LDH
          Elevated unconjugated bilirubin  jaundice, scleral icterus
          Lower serum haptoglobin
          Hemoglobinemia
          Hemoglobinuria
          Hemosiderinuria
   Morphologic evidence of red cell damage
          Schistocytes
          Spherocytes
          Bite/blister cells
   Reduced red cell life-span
            Hemolytic Anemias -
          Classification by Etiology
   Congenital
       Defects in membrane skeleton proteins
       Defects in enzymes involved in energy production
       Hemoglobin defects
   Acquired
       Immune-mediated
       Non-immune-mediated
   Most common defect leading to anemia?
       Hereditary spherocytosis
   Frequency?
       Affects 1/5000 Europeans
   Transmission?
       Autosomal dominant
   Pathophysiology?
       Defect is in proteins of the membrane skeleton, usually spectrin or
        ankyrin
       Lipid microvesicles are pinched off in the spleen and other RE
        organs, causing decreased MCV and spherocytic change.
   Diagnosing?
       Increased osmotic fragility
   Treatment?
       Supplemental folate
       Splenectomy (but carefully consider timing in children)
• Functions of GP6D?
  •   Detoxification of metabolites of oxidative stress
  •   Elimination of methemoglobin
• Important Products of GP6D?
  •   NADPH
  •   Reduced glutathione
• Diagnostic methemoglobin precipitate?
  •   Heinz bodies
  •   Causes the formation of bite/blister cells
• Epidemiology of GP6D Deficiency?
  •   Type B is more prevalent
  •   Type A is in 20% of healthy Africans
  •   In 10-14% of African American men
  •   Also prevalent in the Mediterranean
  •   X-linked
                   G6PD Deficiency
                   Agents to avoid
For SKAND…
–   Fava beans                             What cell is below?
–   Sulfa drugs
–   Vitamin K
–   Anti-malarials
–   Naphtha
    compounds
    (mothballs)
–   Dapsone                                               Blister cell
        Sorry Skand – at least your girlfriend thought it was funny!
How will you diagnose
an autoimmune cause
of hemolytic anemia?
              Coomb’s Test
   The Direct Coomb’s = DAT (Direct
    Antiglobulin Test) - tests for IgG or C3
    DIRECTLY ON THE RED CELLS. You’re
    adding patient RBCs!
   The Indirect Coomb’s - tests for IgG or C3
    in the serum which react with generic
    normal red cells. This is also known as
    the antibody screen in blood-banking.
    You’re adding patient serum!
    Warm-Antibody Hemolytic Anemias
           Clinical Features

   Splenomegaly, jaundice usually present.
   Depending on degree of anemia and rate of fall in
    hemoglobin, patients can have VERY symptomatic
    anemia
   Lab Dx -
      reticulocytes,  bili,  LDH,

      positive Coomb’s test - both direct and indirect.

      SPHEROCYTES are seen on the peripheral smear.
         Warm-Antibody Hemolytic Anemias
                   Treatment
   Immunosuppressive Treatment
       First line is corticosteroids (i.e. prednisone).
       If steroids fail to work, or if patient relapses after steroid
        taper, splenectomy may be necessary.
       Immunosuppressives such as cyclophosphamide (Cytoxan)
        or azathioprine (Immuran) may be required as third-line
        therapy.
   Folate repletion
   Transfusion – determining factors:
       Heart failure, shock?
       Inadequate reticulocyte count?
        Drug-Induced Immune Hemolysis
               Three general mechanisms
   Innocent bystander
       the Ab was directed at the drug, but it cross reacted w/
        RBCs
       Drug must be present for hemolysis to occur
       Quinine, Quinidine, Isoniazide
   Hapten
       Drug binding to RBC  Abs that react to this complex
       Penicillins, Cephalosporins
   True autoimmune
       You don’t need the drug in the body any more to get the
        hemolysis
       Alpha-methyldopa, L-DOPA, Procainamide
           Cold Agglutinin Disease
   IgM antibodies bind to I antigens of RBCs when cold
    (falls off when warm)
   Causes agglutination  cyanosis & ischemia of
    extremities
   Direct Coomb’s test + for C3, but not IgM!
   Has both intravascular and extravascular hemolytic
    components
   Primary, or associated w/ Mycoplasma,
    Mononucleosis, or lymphoproliferative disease
   Treat by avoiding cold & folate repletion
   Corticosteroid and splenectomies uneffective (big
    difference from warm antibody-mediated hemolysis)
         Non-Immune Hemolytic Anemia
                Classification

   Mechanical trauma to red cells
       Microangiopathic Hemolytic Anemia
       Abnormalities in heart and large vessels
       March Hemoglobinuria
   Infections
   Drugs, Chemicals, and Venoms
       Chemical & Physical Agents
          Causing Hemolysis
“BAr CoIns”
   Severe Burns
   Arsenic
   Copper
   Insect and spider bites
    Infections Causing Hemolysis
   Malaroa
   Babesia microti
   Clostridium welchii
   Bartonella bacilliformis
             Basic Structure of All
             Human Hemoglobin
   Each hemoglobin molecule is composed of:
       4 iron-containing, tetrapyrrole heme rings
       4 polypeptide globin chains
           2 alpha chains
           2 non-alpha chains

   Each  globin chain has 141 amino acids
   All non- chains have 146 amino acids
   There is considerable structural homology
    among the non-alpha chains
    Normal Human Hemoglobins
   Gower Hemoglobin (Embryonic)
       2ε2
   Fetal Hemoglobin (HbF)
       22
   Major Adult Hemoglobin (HbA)
       22
   Minor Adult Hemoglobin (HbA2)
       22
          Heme Synthesis
   Begins with condensation of glycine & succinyl Co-
    A  -amino levulinic acid (-ALA).
       The rate-limiting step in heme synthesis
       Requires intra-mitochondrial enzyme ALA-
        synthase
   -ALA travels to cytoplasm; converted to
    porphobilinogen (PBG), a monopyrrole.
   PBG converted from monopyrrole to biologically
    active form protoporphyrin IX, a tetrapyrrole.
   Iron inserted into tetrapyrrole ring n the
    mitochondria
   Heme synthesis stimulated by iron & repressed
    when iron is inadequate (e.g., iron deficiency)
        Location of the Globin Genes
•   Genes for the non- chains are located on
    Chromosome 11. This is referred to as the -
    globin gene cluster
•    Chain genes are located on Chromosome 16
•   There is duplication of the genes for:
    •    Globin
    •    Globin (G and A) *
        •    and A differ from one another only at position 136
            G

            where they have glycine & alanine respectively
•   Synthesis of the non- chains involves a
    coordinated switching that proceeds from
    embryonic (ε) to fetal () to adult () globin
    chains
    •   Yolk sac (ε)  liver/spleen ()  marrow ()
    Structure of the Hemoglobin
              Molecule
   Each Hb is comprised of 4 subunits: 2 identical  chains & 2
    identical non- chains
   Each chain is arranged in the form of an -helix with 8
    individual helical segments (labeled A - H)
   Each globin molecule has both hydrophobic & hydrophilic
    areas
   The iron-containing heme ring is buried within a very
    hydrophobic region of the globin that is called the “Heme
    Pocket”
   The hydrophobic nature of this region protects the iron
    residue from oxidation, thereby maintaining it in the active,
    reduced form
   Each iron atom in the center of the heme residue is held in
    place and kept in the active, reduced Fe++ state by two
    histidine residues
       Possible Consequences of a
           Hemoglobinopathy
   No detectable effect
   Instability of the hemoglobin molecule
   An increase or a decrease in oxygen
    affinity
   Inability to maintain the heme iron in
    its active, reduced state
    (methemoglobinemia)
   Decreased solubility of the hemoglobin
    molecule
             Unstable
         Hemoglobinopathies
   Most of the unstable hemoglobinopathies
    involve a mutation in the region of the heme
    pocket
   These mutations enable water to gain access to
    this very hydrophobic region of the molecule
   The end result is heme instability, denaturation,
    and release of heme from its binding site
   The demonstration of Heinz Bodies in these red
    cells is evidence of the presence of an unstable
    hemoglobin mutant
         Hemoglobinopathy Altering
             Oxygen Affinity
   Increased Oxygen Affinity
      Stabilization of the Oxy conformation increases the oxygen
       affinity of the hemoglobin molecule
      The presence of such an effect can be confirmed by
       demonstrating a left shift in the Oxygen Saturation Curve
      Individuals with an increase in oxygen affinity typically
       exhibit erythrocytosis
   Decreased Oxygen Affinity
      Stabilization of the Deoxy conformation produces a
       decrease in the the oxygen affinity of the hemoglobin
       molecule
      The presence of such an effect can be confirmed by
       demonstrating a right shift in the Oxygen Saturation Curve
      Individuals with a decrease in oxygen affinity are typically
       somewhat anemic
    Hemoglobin M Diseases
   The Hemoglobin M disorders are seen when a
    substitution has occurred at the locus of either
    the proximal or distal histidine
   Typically, this involves a his   tyr substitution
    which then forms an iron-phenolate complex
   Hemoglobin with its iron in the oxidized Fe+++
    state is incapable of binding oxygen
   This form of hemoglobin (called Methemoglobin)
    has a brownish appearance
   Patients with Hemoglobin M disease are typically
    cyanotic
           The Sickle Cell Diseases:
    Inheritance, Appearance of Symptoms,
                  Diagnosis
   The most common sickle cell disease (SCD) is called sickle cell
    anemia (HbSS)
   However, there are a number of other SCD genotypes - compound
    heterozygous states
   The sickle mutation is inherited in an autosomal co-dominant
    fashion
   Individuals with sickle cell trait (AS) have roughly equal amounts
    of HbA & HbS and are generally asymptomatic
   Compound heterozygotes (e.g., SC or S-Thalassemia) generally
    express a significant sickle cell disease
-   We dx/ with electrophoresis:
    -   Hb C has a positive; HbS is neutral, HB A is negative.
    -   Movement: HbA > HbS > HbC
    Sickle Cell Anemia Pathophysiology
   The presence of the abnormal (or sickle) hemoglobin
    (HbS) within the cells of the affected individuals
   The decreased solubility & the tendency of this
    abnormal hemoglobin to polymerize when it assumes
    the deoxy conformation
   In HbS, the negatively charged glutamic acid at 6
    position is replaced by an uncharged valine residue
   In deoxy conformation, the valine at 6 position
    approaches the phenylalanine at  85 position on
    adjacent HbS molecule.
   Multiple critical contact points that enable the
    hemoglobin molecules to attach to one another
   The polymer begins as a small nucleus of hemoglobin
    molecules  aligned polymer with a total of 7 anti-
    parallel pairs (or 14 individual hemoglobin chains)
     SICKLE CELL DISEASE
       Clinical Features
   Painful Vaso-occlusive Crises
   Strokes
   Retinopathy
   Acute Chest Syndrome
   Pulmonary Hypertension
   Sickle Cell Nephropathy
   Biliary Tract Disease
   Leg Ulcers
   Avascular Necrosis of the Large Joints
        SICKLE CELL DISEASE
     Therapeutic Approaches
   Reactivate Fetal Hemoglobin
    Production using Hydroxyurea!
   Chemical inhibition of Hb S
    polymerization
   Increase in intracellular hydration
   Altering RBC/Endothelial cell interactions
   Bone marrow transplantation
   Gene therapy
 What is this an
  example of?
Typical Diseases?
     Megaloblastic
        Anemia
   Red cells are
    macrocytic.
   Hypersegmented
    neutrophils can be
    seen.
   Vitamin B12 or folate
    deficiency
What Disease?   Sickle Cell Anemia



                               Target Cell




            Sickled Cell
Platelet Function in Hemostasis – what is it called?
                       Primary Hemostasis!
                       What are the functions?
          (1) Adhesion
          •exposure to
          collagen;               (2) Accumulation and
          binding to von          Shape Change
          Willebrand
          factor via GPIb
          receptor

           (4) Aggregation and    (3) Granule
           Surface Coagulation    Content
                                  Release
                                  •ADP released,
                                  integrin
                                  activation,
                                  fibrinogen binding
Main Types of Coagulation Factors

•Zymogens/active enzymes:
     Vitamin K-dependent -- factors II, VII, IX, X
     Vitamin K-independent-- XI, XII, and XIII

•Cofactors:
     factor V, factor VIII, tissue factor, and
     von Willebrand factor

•Non-protein cofactors:
     calcium and phospholipid surfaces
•Fibrinogen:
     fibrinogen is converted to fibrin by thrombin
Laboratory Assays to Monitor Coagulation Parameters
   •Prothrombin Time (PT)

   •Activated Partial Thromboplastin Time (APTT)

   •Thrombin Clot Time (TCT)
Appropriate tube to use for specimen?


 Citrate solution as anticoagulant.
 Stops clotting by binding calcium.
 Blood to additive ratio 9:1
 Plasma, NOT Serum!
                                     PT – what does it
                   Prothrombin
  XII              Time (PT)
                                           do?
                                     •Test plasma + tissue
                       “Extrinsic”   thromboplastin (source
     XI                 Pathway      of tissue factor) + CaCl2
           IX                         Fibrin clot
                       VII           •Tests extrinsic
            VIII                     pathway:
                                        –Formation of tissue
                   X
                                        factor-factor VII
                   V                    complex to
“Common”                                formation of fibrin.
 Pathway
           Prothrombin (II)          •Prolonged PT:
                                        –Deficiencies of
             Fibrinogen                 factors II
                                        (prothrombin), VII, X,
                                        V, and fibrinogen.
                                APTT – What does it
    XII
         Activated Partial             do?
         Thromboplastin          •Test plasma + partial
      XI   Time (APTT)           thromboplastin (lipid) +
                                 particulate activator +
             IX                  CaCl2  Fibrin clot
“Intrisic”                      •Tests intrinsic pathway:
 Pathway      VIII       VII
                                   –Activation of factor
                                   XII to formation of
                     X
                                   fibrin
                     V          •Prolonged APTT:
“Common”
 Pathway                           –Deficiencies of
             Prothrombin (II)      factors XII, XI, IX,
                                   VIII, X, V, II,
               Fibrinogen          fibrinogen (and
                                   kallikrein and
                                   HMWK).
                           TCT – What does
XII        Thrombin Clot        it do?
            Time (TCT)
  XI                       •Test plasma + thrombin
      IX                     Fibrin clot

       VIII       VII      •Measures conversion of
                           fibrinogen to
              X            polymerized fibrin

              V
                           •Sensitive to
       Prothrombin (II)    quantitative and
                           qualitative fibrinogen
         Fibrinogen        deficiencies.
                       Hemophilia A
                             ?
                         Factor VIII
                           (VIII)


       Hemophilia B

Factor X
           ?  IXa
              (IX)
                     VIIIa
                             Factor Xa


                                         Fibrinogen
                Va    Xa
Prothrombin                  Thrombin

                                         Fibrin   Thrombus
Roles of Von Willebrand Factor



                                von Willebrand
                     Factor VIIIFactor (vWF)




Primary Hemostasis   Secondary Hemostasis
     von Willebrand Disease (vWD)
How does it differ from classic hemophilia?


(1) Suffer from mucocutaneous hemorrhage rather
than hemarthroses like in hemophilia.

(2) Autosomal inheritance trait, so men and women have
similar prevalence, rather than X-linked like hemophilia.

(3) Consistently had prolonged bleeding times unlike the
normal bleeding times in hemophilia.
                     Virchow’s Triad
•Virchow (1845) thought that
thrombosis was the result of
abnormalities in:
      A) the vessel wall;
      B) blood flow, and
      C) the properties of blood.
Thrombosis: 2 Types

•Arterial: Injury to the
endothelium; platelets adhere and
a dense platelet aggregate is
formed, and coagulation system
activated.

•”White thrombus”

       •Venous: Related to decrease blood flow (stasis);
       venous thrombosis is dominated by the
       coagulation system, the production of fibrin-rich
       thrombi.

       •”Red thrombus”
         Regulators of Blood Coagulation:
                3 useful systems
•Protein C Anticoagulant System:
    Thrombin-Thrombomodulin
    Protein C and S [Activated Protein C (APC) and Protein S]

•Protease Inhibition by Antithrombin with Heparin:
   Antithrombin (ATIII)
   Heparin (drug)/Heparan Sulfate (naturally-occurring on
   vessel wall)

  •Fibrinolytic System:
     Tissue plasminogen activator (tPA)
     Plasminogen/Plasmin
     Plasminogen activator inhibitor-1 (PAI-1)/Antiplasmin
          How does the Protein C
        Anticoagulant System Work?
   Thrombin binds to thrombomodulin on vessel
    wall
   Thrombin, once bound to thrombomodulin, can
    no longer cleave fibrinogen into fibrin or
    activate factor V or platelets
   Thrombin-thrombomodulin complex activates
    Protein C (vit K dep)  APC
   APC associates with Protein S
   APC + S cleaves/inactivates factors Va and
    VIIIa
        How Does the Antithrombin
        Anticoagulant System Work?
   Antithrombin = serine protease inhibitor
    (serpin)
   Circulates freely in the plasma
   Inhibits thrombin, IXa, Xa, XIa
   Activity increased by:
       Heparan sulfate (basement membrane)
       Heparin (drug)
    How does the Fibrinolysis/Clot Lysis
      Anticoagulant System Work?
   Plasminogen freely circulates in the plasma
   Endothelium secretes tissue-type plasminogen
    activator (tPA)
   tPA converst plasminogen  plasmin
   Plasmin lyses clots
   Plasminogen activator inhibitor-1 (PAI-1) is
    secreted by endothelium
   PAI-1 downregulates tPA activity
   It’s another fine balancing act!
                         Thrombosis

Why heparin therapy?
Inhibits further thrombus formation almost immediately.

Why warfarin therapy?
Depletes vitamin K-dependent factors to impair procoagulant
function.

Why tissue plasminogen activator therapy?
Degrades thrombus to re-establish blood flow.

Family history?
Necessary to determine if familial or acquired clinical scenario.

Common hereditary cause of venous thrombosis?
factor V Leiden: a plasma protein “resistant’ to inactivation by
the protein C system
Some Acquired Causes of Venous Thrombosis
Surgery and trauma
Prolonged immobilization
Older age
Cancer
Myeloproliferative disorders
Previous thrombosis
Pregnancy
Use of contraceptives or hormone-replacement therapy
Anti-phospholipid antibodies
Anticoagulant Therapy: Medications
   •Heparin-       Heparin binds to antithrombin, which
   converts it to a very potent and immediate inhibitor of
   thrombin, factor Xa and other proteases in the clotting
   cascade. IV

   •Warfarin (or Coumadin)-             Oral anticoagulants
   produce their effect by interfering with the cyclic inter-
   conversion of vitamin K and its 2,3 epoxide (vitamin K
   epoxide).

   •Fibrinolytic enzymes-          Induction of a fibrinolytic
   state by the infusion of plasminogen activators is used in
   massive pulmonary embolism and to restore the patency of
   acutely occluded arteries.
Benefits of Low Molecular Weight Heparins (LMWH)


 •LMWHs have a higher affinity for antithrombin-
 factor Xa.
 •Longer plasma half-life.
 •Safe and effective for venous thromboembolism, and
 with unstable angina or acute thrombotic stroke.
 •Convenient, given subcutaneously without laboratory
 assay monitoring (allowing for patient and home care
 options).

 GENERAL Heparin Targets
 -Thrombin
 -IXa, Xa, XIa, XIIa
 -Measure efficacy with APTT
           Vitamin K Cycle and Effect of Warfarin

•Vitamin K antagonists exert their anticoagulant effect by
inhibiting vitamin K epoxide reductase and vitamin K reductase
activities.
•All vitamin K-dependent coagulant proteins are impaired:
        prothrombin,
        factor VII,
        factor IX,
        factor X,
        anticoagulant protein C and protein S
•Oral anticoagulants cause hepatic production and secretion of
partially and fully de--carboxylated and dysfunctional proteins.
•Can reverse effects with emergency administration of Vitamin K
•Monitored by PT; most closely reflects VII (shortest K-dep ½
life)
•Must avoid use during pregnancy!
•PO administration
      Treatment of Venous Thromboembolism

•Treatment strategy differ between arterial from
venous circulation.

•Objective of treating/preventing venous thrombosis:
     -prevent extension of thrombus;
     -prevent thrombus from embolizing;
     -render fibrin more susceptible to fibrinolysis.
          (standard in threat of massive PE)
     -standard tx in acute venous thrombosis & PE
          heparin + oral vitamin K antagonists
                 Arterial Thrombosis
   Main pathogenic mechanism for acute MI,
    unstable angina, sudden coronary death
   Tx: heparin, LMWH, warfarin, anti-platelet
    cmpds, fibrinolytics, ASPIRIN
   Clopidogrel and Ticlopidine inhibit platelet
    aggregation by blocking ADP receptor on
    platelet and inhibiting activation of GPIIb/IIIa.
       But Ticlopidine may cause TTP!
   Abciximab (ReoPro), Eptifibatide (Integrilin),
    Tirofiban (Aggrastat) bind GPIIa/IIIa receptor
    on platelets preventing fibrinogen binding
What is this? What will it give rise to?
  A Megakaryocte that will shed off Platelets!
              Platelet Plug Formation
   Adhesion
     
          And stick to injured vessel platelets?
         Plateletsanother role of wall.
        GPIb/IX to vWF and collagen
   Aggregation
        Platelets stick to each other via fibrinogen bridges.
    Providing a phospholipid
        GPIIb/IIIa to fibrinogen
        Activators: ADP, collagen, 5HT, Epi, TXA2, thrombin
    scaffold for coagulation
    Secretion
     Platelets release granular contents and potentiate
    reactions, like generation
      clotting
      Spits out pro-clotting materials: ADP, Epi, factor V,
     
         of Xa and thrombin!
      vWF, fibrinogen
       Thrombocytopenia
three broad categories of causes

  Underproduction
  Peripheral Destruction

  Splenic sequestration
 If you saw this in a blood sample and were
 told the patient has too few platelets, what
               would you say?
WRONG!!!
It’s Pseudothrombocytopenia!

Or in Dr. Ma’s words, you
could say “damn, there’s more
than one platelet on this field”
              YIKES! What’s this?

                   Petechiae
What’s the difference?

 ACK, and this?
 Purpura are formed
when Purpura
     petichiae coalesce
            Thrombocytopenia –
           Underproduction Causes
   Marrow failure: myelodysplasia, aplastic
    anemia, vitamin deficiencies (B12/folate)
   Marrow infiltration: tumor, granulomatous
    diseases, fibrosis, leukemias, lymphomas
   Marrow toxins: drugs (esp. alcohol),
    radiation, infections
   Congenital: Wiskott-Aldrich Syndrome,
    Thrombocytopenia Absent Radius
    Syndrome (TAR), May-Hegglin
                  DIC- Diagnosis
   Elevated PT - due to consumption of Factor VII,
    which has the shortest half-life (4 hrs) of all
    clotting factors.
       When advanced, the APTT can be prolonged as well,
        as the other clotting factor levels fall.
   Low platelets
   Low/falling fibrinogen
   Elevated fibrin degradation products
       (FDPs/FSPs) or D-Dimers
   Can see a few schistocytes on the peripheral
    smear in most cases. (MAHA)
   Low clotting factor levels
DIC - Etiologies and Treatment
   Can be associated with:
       gram negative sepsis,
       severe burns,
       obstetrical disasters,
       certain leukemias or tumors,
       shock,
       insect or snake venoms
   TREAT THE UNDERLYING CAUSE!!!
   Supportive measures can include:
       transfusion of platelets
       clotting factors, fibrinogen
       +/- low dose heparin to halt thrombin generation.
            Low dose heparin can slow down the forest fire…
           TTP - Diagnostic Features
              (aka “The Pentad”)
   What’s normal in TTP that’s
    Microangiopathic Hemolytic Anemia (MAHA) – MUST BE
    PRESENT
           NOT in DIC?
      Elevated LDH, elevated bilirubin

      Schistocytes on the peripheral smear

      MUST BE PRESENT

   Low platelets - MUST BE PRESENT
   Fever
   Neurologic Manifestations
     - headache, sleepiness, confusion, stupor, stroke, coma,
        PT, fibrinogen levels,
       seizures
    Renal Manifestations

           FDPs/D-dimers
      hematuria, proteinuria, BUN/Creatinine
                        TTP - etiology
   Associated with an antibody against or a deficiency of
    the protease (ADAMTS-13) that cleaves the very high
    molecular weight multimers of von Willebrand’s factor
   vWF accumulates  abnormal platelet adhesion and
    activation
   Can be induced by drugs, including
       ticlopidine,
       quinine,
       cyclosporine,
       FK-506,
       mitomycin C
   Increased incidence with pregnancy or HIV
                TTP - Treatment
   Treatment relies on PLASMA EXCHANGE.
       Remove all inciting agents (ultra-high MW
        multimers of vWF)
       Restoring ADAMTS-13
       Adjunct therapies, including glucocorticoids and
        anti-platelet agents can be used but are of
        uncertain benefit.
   Secondary measures if no response to
    plasma exchange include splenectomy,
    vincristine.
   AVOID PLATELET TRANSFUSIONS -
    THEY “FUEL THE FIRE”
           Thrombocytopenia -
        Drugs/Immune Mechanism
   Drugs can lead to immune-mediated
    thrombocytopenia by a variety of mechanisms.
        1) directly stimulating anti-platelet
        antibody production
        2) a hapten mechanism
        3) “innocent bystander” phenomenon.
       Thrombocytopenia -
    Drugs/Immune Mechanism
“Qua – BASH” (don’t ask me, I’m sleepy)
 Quinine/quinidine

 Beta-lactam antibiotics

 Abciximab (ReoPro®)

 Sulfa drugs like Trimethoprim-
  sulfamethoxazole
 Heparin
                ITP - Therapy
   Initial therapy relies on use of
    corticosteroids (e.g. prednisone). These
    can take 48-72 hrs to take effect.
   If platelet count is <10K or if patient is
    bleeding, need more rapid therapy--use
    IVIg
   If patient is Rh positive, can use Anti-D
    (WinRho®) in place of IVIg. (need a
    spleen)
   2nd line – splenectomy
   3rd line - immunosuppression
             Compare TTP, DIC, ITP
                   TTP         DIC            ITP
Low platelets   Must have   Usually     Must have
Schistocytes    Must have   Maybe       Never
PT/FDP/         Normal      Low         n/A
Fibrinogen
Transfuse       NEVER       Maybe       Only if pt is
platelets?                              bleeding
Treatment       Plasma      Tx under- Steroids,
                exchange    lying cause IVIG, AntiD
Qualitative Platelet Disorders - Differential
       Congenital -
         Glanzmann’s thrombaesthenia - defect in IIb/IIIa
         Bernard-Soulier - defect in Ib/IX
       Acquired
         uremia
         Drugs - ASA, NSAIDs, antibiotics, ReoPro®,
         Herbs - ginkgo, garlic, Vitamin E
         Myeloproliferative diseases


Diagnosis?
Normal APTT/PT/TCT, prolonged bleed time
               Anti-Platelet Drugs
   Aspirin
       Inactivates COX-1, decreasing TXA2 (a platelet
        agonist)
       Prevent stroke, MI, CAD, peripheral arterial occlusion
   Thienopyridine Derivatives
       Ticlopidine, Clopidogrel
       Blocks ADP (platelet agonist)
       Ticlopidine may cause TTP
   GPIIb/IIIa inhibitors
       Abcizimab (ReoPro), Eptifibitide (Intergrillin),
        Tirofiban (Aggrastat)
       Blocks platelet aggregation by blocking fibrinogen
        receptor on platelets
            Donor screening criteria:
             Allogeneic (volunteer)
   Hgb >12.5
   BP, pulse: healthy
   Uniform Donor screening questionnaire
   Infectious Disease Screening of donor
       Hepatitis B
       Hepatitis C
       HIV I/II
       HTLV I/II
       Syphilis
   Autologous (for self): Less stringent criteria
   Parts Collected Out of a
   Whole Blood Collection
 pRBC

         rich plasma (platelet
 Platelet
  concentrate)
 Plasma (FFP)
                   pRBC Storage
   RBCs suspended in
      anticoagulant (citrate based) and,

      Additive Solution - AS

         Provides nutrients to support RBC metabolism

   42 days = Shelf life
   Volume= 250 to 300 mL
      65% RBCs, 35% plasma and AS

      contains WBC’s and some platelets

   may be frozen w/ glycerol (cryoprotectant) for 10 yrs
                      pRBC Transfusion
   1 unit = 1 g/dL Hb; 3% hematocrit
   Decide w/ clinical judgement NOT lab values
   Transfuse slowly, so you can catch adverse rxn
   RBCs should be infused alone or with 0.9% NaCl
    through a 170µm clot-screen filter
   NEVER mixed with :
       Calcium containing solutions
            May cause clumping or clots
       Dextrose
            Hypotonic,may cause hemolysis or clumping
       Medications
       Hypertonic solutions
   AVOID infusing with Lactated Ringers
                  Fresh Frozen Plasma:
                 Storage, Contents, Tx?
      Frozen w/in 8hrs of collection
      Stored -20º C for up to 1 year

      Once thawed, can be kept at 1-6º C for 24 hrs

   Contents:
      1 unit/mL of all clotting factors including labile Factors V and VIII

      ~400 mg fibrinogen

      Citrate as anticoagulant

      No platelets

   Treatment of multiple coagulation factor deficiencies
      Massive transfusion

      Trauma

      Liver disease

      DIC

      Unidentified deficiency
Platelets: Storage, Dosing, Treatment, Matching
   Pooled platelet concentrates (PC’s) from several whole
    blood donations or apheresis
   Suspended in citrated plasma
   Stored @ 20-24º C for 5 days only  highly
    susceptible to shortages!!!
   One therapeutic dose  platelet count 30-50k
   PLT surface
       ABO antigens but not Rh
       Platelet specific Ags
       HLA- A and HLA-B
   Trace amts RBC’s  Rh type important
       Rh- female gets Rh- PLT
   Tx: thrombocytopenia, qualitative defects
   Monitor efficacy of transfusion via PLT count w/in 1hr
    of transfusion  conserve resources…
    Cryoprecipitate: Contents, How
        to Get it, Tx, Dosing?
 Cold insoluble white precipitate
 Forms when FFP is thawed at 1-6º C

 Removed from FFP by centrifugation, then refrozen at –20º C

CONTAINS:
    80 to 150 IU Factor VIII:C (antihemophilic factor)

    150 mg fibrinogen

    Von Willebrand Factor

 Tx:

    Deficiency of fibrinogen, Factor VIII

    Improve platelet function in uremia

 Dose calculation based on

    Patient’s weight and hematocrit : plasma volume

    Desired increase in Factor level
ABO Blood Group: Population Frequency



     O        45%
     A        41%
     B        10%
     AB       4%
                      What is ABO?
   specific terminal sugar residues on a large
    glycolipid backbone on the RBC membrane
   The ABO genes
       Codominant inheritence
       Encode for a glycosyl transferase enzyme
       Adds the specific terminal sugar to the glycolipid
        backbone
       Convey immunogenicity
          O = fucose
          A = N-acetyl galactosamine

          B = galactose
                  ABO Discrepancy
   when the front and back types do not
    match
       Front = antigen on cells
       Back = antibody in serum
   Must resolve prior to transfusion
   Common Causes:
       Cold agglutinin
       Weak or absent antibodies in elderly or
        infants
       Interfering substance: protein, dextran
       Weak subgroup of A or B
 RECIPENT
             RED CELLS     PLASMA
BLOOD TYPE
             Whose      Whose
    O           O      O, A, B, AB
              RBCs     Plasma
    A             O       A, AB
               A, they Can they
             Can
    B          B, O
              Take?       B, AB
                        Take?
   AB        AB, A, B, O     AB
                       ABO Antibodies
ABO Antibodies             anti A , anti B
Predominantly IgM >> IgG > IgA
       IgM reacts at room temperature
   Can bind complement  intravascular
    hemolysis
   Naturally occurring
       Anti A and B form due to similar antigens in nature
            (bacteria, pollen, etc)
       Transfusion exposure or pregnancy NOT required
   IgM pentamer can agglutinate RBCs
   Immediate transfusion reactions possible
    Rh Blood Group: the 2nd most impt
Rh System : family of 51 antigens
 Integral membrane proteins, well formed during fetal development
 Rh Antigens of routine importance: D, C, c, E, e
 Rh null are individuals lack all Rh proteins
 Clinically significant in:
             Transfusion practice
             Transfusion reactions
             Hemolytic disease of newborn
D Antigen (Rh Type)
        D+ 85% prevalence              = Rh+
        D- 15%                         = Rh-
   Highly immunogenic
   Clinically significant with RBC transfusion & platelet transfusion
        Females of child bearing potential need Rh- blood
Immune sensitization required to develop Rh system antibodies
        Transfusion or pregnancy
   IgG , react at 37° C - must incubate in the lab to demonstrate them
   Typically cause extravascular hemolysis, if present
   Some may activate complement and cause intravascular hemolysis
           Comparison b/tw ABO and Rh
                  Blood Groups
              ABO                         Rh
   IgM >> IgG > IgA          IgG
   Test at room temp         Test at body temp
   Causes intravascular      Causes extravascular
    hemolysis                  hemolysis
   Naturally occurring       Sensitization required
       Bacteria, pollen          Pregnancy, transfusion
        RBC Blood Groups and
             Antibodies
   Other protein blood groups
       Kell  K
       Duffy Fy a , Fy b
       Kidd Jk a, Jk b
   Integral membrane proteins are well formed
    at birth
   Antibodies predominantly IgG
   Delayed Transfusion Reactions
       Extravascular hemolytic reactions
       Intravascular hemolysis more likely with Kidd Jka,
        Jkb due to complement binding
   Hemolytic disease of newborn
               Front & Back Types
FRONT TYPE –what’s on the cells?
       Mix 2 drops of patient cells with 2 drops of
        reagent antibodies to A, B and D antigens in
        different test tubes, Agglutination indicates
        presence of antigen
   BACK TYPE – what’s in the serum?
       Mix 2 drops patient serum with both A and B
        reagent cells. Agglutination indicates presence of
        antibody
   Front and back types should match
                    Antibody Screen
   Determines if patient has antibodies to the other
    major blood groups
   Requires
       Combining pt serum with 3 different RBCs with known
        blood group phenotype
       Incubate at 37 C to detect IgG antibodies
       Addition of Coombs serum
            Anti-human IgG : enables in vitro agglutination if IgG present
             due to monomeric structure of IgG
   If screen is +, antibody specificity is determined
    by a more extensive panel of testing RBCs
             Types of Crossmatch
   Immediate Spin Crossmatch
       Rapid, room temp mixing of patient serum with donor
        RBCs to confirm ABO compatibility
   Full Crossmatch
       For patients with antibodies
       Requires incubation and Coombs serum to confirm
        the patient’s IgG will not react with donor RBCs
   Electronic Crossmatch
       Alternative for Immediate spin crossmatch for
        patients without antibodies
          Special Circumstances
   Emergency Release
       When delaying transfusion poses risk of
        death
       Insufficient time to perform type screen and
        crossmatch
       Requires MD signature

   Conditional Release
       Blood may be crossmatch compatible
        however, blood bank testing is incomplete or
        cannot completely resolve antibody testing
        (ex: warm auto antibody)
       Requires MD signature
                  Component Modifications
Leukocyte reduction
 Filtration with specialized leukocyte removing filters  3 log leukocyte
  reduction
        Prevent CMV transmission
        Prevent alloimmunization to leukocyte antigens for those w/ chronic transfusion
        Prevent recurrent febrile non-hemolytic transfusion reactions
Washing
 Removal of plasma by washing RBC or platelets with saline
        For prevention of severe allergic reactions
        Anaphylaxis
        IgA deficiency
  Time consuming , labor intensive, delays transfusion, decreases transfusion
   increment slightly
 Does not substitute for leukocyte reduction
Irradiating
 Prevent graft versus host disease GVHD (Transfusion is a transplant)
 Indicated in severe immunodeficiency settings
        BMT
        Hematopoietic malignancies undergoing chemotherapy
        Premature infants
        Severe combined immunodeficiency
   Blood products from relatives must also be irradiated due to HLA antigens
        Adverse Effects of Transfusion
Acute Immune Transfusion Reactions < 24 hours
     Allergic
     Hemolytic
     Febrile, non-hemolytic
     Anaphylactic
     Transfusion related acute lung injury (TRALI)
Delayed Immune Transfusion Reactions > 24 hours
     Hemolytic
     GVHD
     Platelet refractoriness
     Post transfusion Purpura (development of anti-platelet antibodies)
Acute Non-Immune Transfusion Reactions
     Circulatory Overload (Volume excess)
     Septic shock from bacterial contamination of blood product
Delayed Non-Immune Transfusion Reactions
     Iron Overload
     Infectious Disease transmission
Suspected Transfusion Reaction
   Hemolytic reaction symptoms are not
    specific and include:
       Fever
       Chills
       Hypotension
       Oozing from IV site
       Back pain
       Hemoglobinuia – red urine
   If any of these occur STOP transfusion, provide
    appropriate supportive care, notify blood bank
   Send repeat samples for blood bank evaluation
   DO NOT restart the unit
       Exceptions: mild urticaria that responds to antihistamine
                White Cells
           What are the cell types?
   Granulocytes
       Neutrophils
       Band forms
       Eosinophils
       Basophils
   Lymphocytes
   Monocyte/Macrophages
             ID the cell!
                                     Band Cell
Eosinophil

                         Basophil




             Monocyte

      Lymphocyte
                        Neutrophil
        What is this? What does it do?
   Neutrophils!
       PMNs (polymorphonuclear neutrophils)
       polys
       segs (short for segmented neutrophils)
   Most common white cell
   Pale pink granular cytoplasm with
    condensed, segmented nucleus
   7 hr ½ life
   Functions include
       chemotaxis,
       phagocytosis,
       killing of phagocytosed bacteria
      What is this? What does it do?
Eosinophil
 Granulocytes with large, refractile,
  orange-pink granules.
 Nucleus is typically bilobed.

 Functions include all PMN functions,
          Chemotaxis
          Phagocytosis
          Killing of phagocytosed bacteria
     serving as effector cells for antibody-
      dependent damage to parasites,
     regulation of immediate-type
      hypersensitivity reactions
          inactivation of histamine and leukotrienes
           released by basophils and mast cells
  What is this? What does it do?
Basophils
 Large, dark blue granules which
  overlie the nucleus.
 The most uncommon of all
  granulocytes
 Functions include
     mediation of immediate-type
      hypersensitivity
     modulation of inflammatory responses
      by releasing heparin and proteases
     Precursor of tissue mast cells
  What is this? What does it do?
Lymphocyte
 Lymphocytes have an oval nucleus,
  with a thin rim of blue cytoplasm.
 There may be a few very fine
  purplish-red granules.
 The nuclear border is smooth.

 Functions in immune regulation and
  production of hematopoietic growth
  factors.
 Functions in
     immune regulation and
     production of hematopoietic growth
      factors.
  What is this? What does it do?
Monocyte
 Largest white cell normally found in the
  periphery
 Has a folded nucleus with uneven countour
 Slate grey cytoplasm--there may be
  vacuoles
 Functions Include:
      chemotaxis,
      phagocytosis,
      killing of some microbes,
      antigen presentation,
      release of IL-1 and TNF, which stimulates
       bone marrow stromal cells to produce
       growth factors, including: GM-CSF, G-CSF,
       M-CSF, and IL-6.
      Precursors of tissue macrophages
Causes of Elevated Neutrophil Count
   Physiologic –
       exercise,
       pregnancy,
       lactation,
       neonates
   Acute infections
   Acute inflammation – surgery, burns, infarcts, crush
    injuries, acute gout, rheumatoid arthritis
   Acute hemorrhage
   Non hematologic malignancies
   Myeloproliferative disorders, esp CML
   Drugs: corticosteroids, G-CSF, lithium
   Misc: seizures, electric shock, post-splenectomy,
    Leukocyte Adhesion Deficiency
             Causes of Neutropenia
   Physiologic - in African-Americans
   Drugs –
       anti-psychotics,
       anti-epileptics,
       anti-thyroid, and
       some antibiotics (gold, sulfa)
   Chemotherapy
   Infections: viral, overwhelming bacterial sepsis, TB,
    fungal
   Immune - lupus, rheumatoid arthritis (Felty
    syndrome)
   Familial
   Hypothyroidism, hypopituitarism
What is Agranulocytosis? Major Sxs?
   This is the complete or near-complete absence of
    neutrophils in the peripheral blood, with a normal
    platelet count and hgb
   Almost always drug-induced
       Clozaril (and other newer antipsychotics)
       Propythiouracil (antithyroid)
       Anti-convulsants
       Sulfa and chloramphenicol antibiotics
   Causes severe necrotizing ulcers in the mouth
    and throat

     What is basophilia a major symptom of?
          chronic myeloproliferative diseases
           Causes of Eosinophilia

   Differential Diagnosis for elevated
    eosinophil count “NAACP”:
       Neoplasm,
       Allergy/asthma,
       Addison’s disease,
       Collagen vascular disease
       Parasites
       Causes of Lymphocytosis
   Viral infections
   Bacterial infections - whooping cough
    (pertussis), TB, syphilis, brucellosis
   Chronic Lymphocytic Leukemia (CLL)
   Lymphomas and Waldenstrom’s
    macroglobulinemia

     Causes of Lymphocytopenia
   Immunodeficiencies, including HIV/AIDS
   Immunosuppresive drugs, including
    corticosteroids
   Lymphomas
   Granulomatous diseases, including sarcoid, TB
   Alcoholism, malnutrition, zinc deficiency
           Causes of Monocytosis
   Bacterial infex: TB, syphilis, subacute bacterial
    endocarditis, typhoid, brucellosis
   Protozoal infex: malaria
   Rickettsial infex: RMSF, typhus
   Myelodysplastic syndromes (just one of them)
   Leukemias
   Inflammatory bowel disease
         Normal Neutrophil Function
   Adherence
       Rolling mediated by selectins
       Adhesion mediated by beta-2 integrins
   Chemotaxis
       Moving along a concentration gradient to higher [ ]s
   Recognition/Phagocytosis
       Via complement and IgG
       Once it eats, it’s got a phagosome
   Degranulation
       Granules are released INTO the phagosome
            NADPH oxidase: O2  O2-
            Superoxide dismutase: O2-  H2O2
            MPO: H2O2  HOCl
   Oxidative Metabolism and Bacterial Killing
      Defects in Neutrophil Function
Acquired Defects
     Corticosteroid Use Alcoholism
     Leukemias
     Myelodysplasia
     Myeloproliferative disorders
Congenital Defects
     Leukocyte Adhesion Deficiency
     Chronic Granulomatous Disease
     Myeloperoxidase Deficiency
     Chediak Higashi Syndrome
          Erythrocytosis – What is it?
   An increase in the number of circulating RBCs per
    volume of blood.
   Reflected as an elevated hemoglobin and hematocrit.
       >60% in man, >57% in woman = true erythrocytosis
       Red cell mass study if elevated but not quite these levels
   Relative Erythrocytosis (Gaisbock’s syndrome)
       Depressed plasma volume, RBC mass is normal
       Common in middle age men w/ HTN, smoking hx
   Secondary Erythrocytosis
       Erythropoietin production increased by kidney/liver
       Tissue hypoxia, tumors, genetic disorders, drugs for athletics
        will all increase Epo
   Primary Erythrocytosis
       The bone marrow is going crazy without outside input
        Why is erythrocytosis bad?
Hyperviscosity Syndrome
   Your blood gets too sludgy
   Symptoms include:
       Headaches
       Visual changes
       Tinnitus
       Dizziness
       Paresthesias
       Decreased mental acuity
    Erythrocytosis due to appropriate
            increases in epo

   Life at high altitude
   High affinity hemoglobins
   Cardiopulmonary disease
   Obesity-Hypoventilation syndrome
   Obstructive sleep apnea
   High carboxyhemoglobin levels
   What are the Myeloproliferative
Diseases? Definition? Associated sxs?
   Includes:
       Polycythemia vera
       Essential Thrombocythemia
       Myelofibrosis
       Chronic Myelogenous Leukemia
   Myeloproliferative disorders are Stem Cell Disorders
    leading to autonomous production of hematopoietic
    cells from ALL THREE LINEAGES (red cells, white cells,
    platelets).
   All of these disorders are clonal (except for a subset of
    ET cases)
   Associated sxs:
       Basophilia
       Splenomegaly
   Potential to develop into AML
                        Polycythemia vera
 Most of cells in circulation are derived from a single,
  neoplastic stem cell
 Does not need Epo to produce more cells…

 Diagnosis based on low/absent levels of Epo

Natural History – 4 phases:
 Latent phase - asymptomatic

 Proliferative phase -pts may have sxs of:
        Hypermetabolism
        Hyperviscosity
        Thrombosis
   Spent phase -  red cell mass, anemia, leukopenia,
    secondary myelofibrosis, increasing HSM. 20% of pts
   Secondary AML aka when the body says “screw it, I’m not differentiating anymore”
        1-2% of pts treated with phlebotomy alone
          Symptoms of Polycythemia Vera
   Those common to ALL erythrocytosis
        Headache
        Decreased mental acuity
        Weakness
   Pruritis after bathing
   Hypermetabolic sxs
   Erythromelalgia
   Thrombosis
   Hemorrhage
   PE findings
        Facial plethora
        Splenomegaly
        Hepatomegaly
        Retinal vein distension
   Lab findings
        BASOPHILIA
        Low EPO levels
        Increased Hbg/HCT, WBCs, platelets, uric acid, B12, leukocyte alkaline
         phosphatase score
                         P vera - Treatment
   Phlebotomy – Draw 500 cc blood 1-2x/wk to target Hct 45%; maintain BP w/ saline
      Generally, the best initial treatment for P vera – rapid onset
      Downsides:
           Increased risk of thrombosis
           No effect on progression to spent phase
           May be insufficient to control disease
   Myelosuppressive agents
      Hydroxyurea
           can be used in conjunction with phlebotomy
           May increase the risk of leukemic transformation from 1-2% to 4-5%
      32P – kills some of the proliferating cells!
           increase the risk of leukemic transformation from 1-2% to 11%
           Single injection may control hemoglobin and platelet count for a year or more.
      Alkylating agents such as busulfan
   Interferon alpha
      Benefits
           No myelosuppression
           No increase in progression to AML
           No increase in thrombosis risk
      Drawbacks
           Must be given by injection up to daily
           Side effects may be intolerable in many pts: flu-like symptoms, fatigue, fever,
             myalgias, malaise
  So what disease are you thinking?




Arrow indicates a giant platelet, larger than
the red cells or lymphocyte

    Essential Thrombocythemia
          Essential Thrombocythemia
   Increased megakaryocyte production of platelets
   Must exclude secondary causes of thrombocytosis and
    other myeloproliferative disorders
   Major complications:
       Thrombosis: 20-30% of all patients; Budd-Chiari
       Microvascular thrombi/digital ischemia
       Pruritis & erythromelalgia
       Acquired von Willebrand’s disease
   Will see clusters of abnormal megakaryocytes on
    smear
   Platelet morphology will be big and odd-shaped
   Treatment:
       Anagrelide – platelet lineage specific
       Hydroxyurea
       Interferon alpha
                       Myelofibrosis
   Clonal stem cell disorder affecting megakaryocytes
    predominantly
   All myeloproliferative disorders can result in a spent
    phase which can be difficult to distinguish from
    primary MF
   Myeloid metaplasia refers to earlier proliferative phase
    where extramedullary hematopoiesis predominates.
   WILL become AML  median survival is 5yrs
   Splenomegaly and hepatomegaly
   Aspirate is a “dry tap”
   Peripheral blood smear: leukoerythroblastic
       Teardrop RBCs
       Nucleated RBCs
       Early granulocytes/precursors
              Myelodysplastic Syndromes
   Definition: disordered maturation in 1 or more cell lines
    producing cytopenias: anemia, leucopenia, thrombocytopenia
    or combos
   More common in the elderly
   Based on cytogenic abnormalities
   Peripheral cell abnormalities
       Macrocytic RBCs
       Large platelets
       Hypogranular or bilobed nuclei neutrophils
   Megaloblastic erythropoeisis
   Ringed sideroblasts
   Abnormal nucleus of RBC precursors (dyserythropoiesis)
   Small megakaryocytes with abnormally hypolobate nuclei
   Blast cells should account for <30% of marrow cells

				
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