Neoplasia

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					LFS 319: Pathophysiology                                 Blood Disorders

                           Bleeding Disorders
Bleeding results from:

   1.      Platelets abnormalities
   2.      Clotting factors abnormalities
   3.      Abnormal fragility of fine blood vessels


1. Platelet Disorders:
Thrombocytopenia:
        o Decrease in number of circulating platelets
        o Bleeding as a result of minor vascular pressure or trauma
        o Results in petechiae and purpura
        o Platelet counts < 100,000/mm3  thrombocytopenia
        o Bleeding only occurs when platelet count < 50,000/mm3

Causes:

   i.      Decreased platelet production
   ii.     Increased platelet clearance from the blood


   i.      Decreased platelet production: Caused by:
              marrow suppression:
                    o  RBC, WBC & platelets
                    o  Megakaryocytes
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LFS 319: Pathophysiology                                    Blood Disorders


              Therapeutic agents:
                    o Thiazide diuretics, gold, phenylbutazone &
                       some antibiotics: selectively inhibit platelet
                       formation
              Chronic alcohol consumption: ethanol marrow
                suppression
              Congenital defects & folic acid / vitamin B12
                deficiencies
              Marrow tumor metastasis


   ii. Increased clearance:

    Autoimmune: Idiopathic thrombocytopenia
     purpura (ITP)

          o Increased removal of platelets from blood
          o Cause is unknown
          o Hence the name
          o Characterized by petechial and purpuric bleeding in
             skin & mucous membranes
          o Often arises following a viral infection
          o Acute ITP: affects children < 6 yrs
              Most cases resolve in few weeks to 6 months
          o Chronic ITP: affects mostly adults and women

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LFS 319: Pathophysiology                               Blood Disorders



    Thrombotic thrombocytopenia purpura (TTP)
          o Antibodies damage endothelium 
          o Widespread adherence to damaged blood vessels 
                    o Thrombocytopenia
                    o Widespread coagulation in small blood vessels

    Non-immune: Disseminated intravascular coagulation
     (DIC)

       Systemic coagulation  consumption of platelets 
        thrombocytopenia
       Certain hemangiomas  endothelial damage 
        thrombocytopenia
       Some protozoan infections  platelet damage
       Splenomegaly  more platelets sequestered 
        thrombocytopenia
       Widespread coagulation in small blood vessels




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LFS 319: Pathophysiology                            Blood Disorders

2. Acquired Clotting Factor Disorders:

i. Impaired hepatic synthesis

   Most clotting factors are produced in the liver
   Occurs if liver damage is severe
   Lack of vitamin K
         o Antibiotic therapy (moxalactum)   vit. K –
           producing bacteria   clotting factor synthesis
         o Malabsorption
                 bile synthesis or bile duct obstruction  
                  absorption of vitamin K  clotting factor
                  synthesis

ii. Disseminated Intravascular Coagulation (DIC)

    Leads to consumption of clotting factors

iii. Anticoagulant therapy

    e.g. Heparin and warfarin
    May lead to:
          o GI bleedings
          o Skin ecchymoses
          o Hematoma

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LFS 319: Pathophysiology                               Blood Disorders



Erythrocyte Disorders
    Polycythemia:  RBC
    Anemia:                RBC or Hemoglobin


Anemia
                             Hemoglobin levels
                  (normal range: ♂= 14–18, ♀= 12–16 )
                                     
                            O2-carrying capacity
                                     
                              Tissue hypoxia
                                     
                               Compensatory
                                mechanisms


                Adequate                      Inadequate
              compensation                   compensation


                  O2-levels                       Anemia
                  restored




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LFS 319: Pathophysiology                                   Blood Disorders



Assessment of anemia (Table 7.3):

Test                        Description
                            Measurement of erythrocyte volume.
Hematocrit                  Expressed as % of total blood volume
                            (Normal 45%).

MCV                         Mean Corpuscular Volume

                            Mean Corpuscular Hemoglobin
MCHC
                            Concentration
Reticulocyte                Increases with abnormally high RBC
count                       production



                    Laboratory Red Cell Assessment
                           Volume               Hb content

Normal                     Normocytic           Normochromic

Increased                  Macrocytic           Hyperchromic
                            MCV                 MCHC
Decreased                  Microcytic           hypochromic
                            MCV                 MCHC



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LFS 319: Pathophysiology                 Blood Disorders



Causes of anemia:

1. Impaired Erythrocyte Production
        o Marrow defects
        o Deficiencies
               Iron deficiency
               Vitamin B12 deficiency
               Folic acid deficiency
        o Anemia of chronic disease


2. Hemolytic Anemia
        o Intrinsic hemolytic anemia
               Sickle cell anemia
               Thalassemia


3. Hypersplenism




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LFS 319: Pathophysiology                                  Blood Disorders



1. Impaired Erythrocyte Production

     A. Marrow defects


      In most cases it is idiopathic
      Other causes include infections, chemotherapy, radiation,
       drug reactions


      Pure red cell aplasia
             o A rare condition of defective red cell progenitors


      Aplastic anemia
             o   There is pancytopenia
             o   Reduction of all blood cells
             o   Leads to anemia, bleeding & infections
             o   Therapy: bone marrow transplant




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LFS 319: Pathophysiology                            Blood Disorders



B. Deficiencies
      i. Iron deficiency

  o   Recycling of iron (Figure 7.19)
  o   An average 1-2 mg of iron must be replaced daily from diet
  o   An additional 1 mg in women is lost (loss via menstruation)
  o   Most women do not compensate for this additional loss
      and are therefore at marginal iron deficiency state.

Sources of iron:
 o Meat, liver, eggs, nuts, legumes & beans

Absorption of iron:
 o Animal products (contained in heme)  easily absorbed
 o Iron in plants must first be processed by gastric acids
      Therefore removal of stomach   iron absorption

Storage of iron:
 o Intestinal epithelium
 o Liver
 o Macrophages
 o Depletion of iron stores  anemia




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LFS 319: Pathophysiology                              Blood Disorders



  o   Causes of iron deficiency anemia:
  o   Dietary iron deficiency
  o   Absorption disorders
  o   Chronic blood loss
         GI bleeding
         Heavy menstrual flow

Blood picture:
  o Microcytic ( MCV), hypochromic ( MCHC)


ii.     Vitamin B12 (cobalamin) Deficiency

      o Vit. B12 is required for normal DNA synthesis

                            Lack of Vit. B12
                                  
               Mitosis in progenitor lines  Pancytopenia
                                  
  Marrow precursors remain enlarged (megaloblastic anemia)
        Enlarged erythrocytes released in circulation
       (quickly destroyed & removed from circulation)

Sources of Vit. B12:
   o Meat, liver, seafood, dairy products
   o Daily requirement: 1microgram


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LFS 319: Pathophysiology                                  Blood Disorders



Stores of Vit. B12:
      o 2 – 5 mg (many years supply)

Vit. B12 absorption (Figure 7.20)

Causes of Vit.12 deficiency:
     o Rarely diet
     o Malabsorption (most common)
           Lack of Intrinsic Factor (IF)
           Resection of stomach or ileum

Pernivious anemia:

                           Autoimmune chronic gastritis
                                       
                 Autoimmune attack on IF & parietal cells
                                       
                           Lack of Vit. B12 absorption
                                       
                              Megaloblastic anemia

Many patients who suffer from Vit. B12 deficiency anemia
experience some degree of neuropathy (CNS or PNS)

Blood Picture:
      o macrocytic, normochromic

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LFS 319: Pathophysiology                          Blood Disorders



iii. Folic Acid (or Folate) Deficiency

     o Produces megaloblastic anemia (similar to Vit. B12
       deficiency)
     o  Serum folate
     o No neuropathy

Sources of folate:
   o Meat, eggs, leafy vegetables

Stores of folate:
  o Body stores provide about 5 months of folate supplies

Causes of folic acid deficiency
  o Fad diet
  o Overcocking of food
  o Intestinal resection
  o High demand states:
     o Pregnancy
     o Infant growth spurts
     o Prolonged marrow overactivity
     o Rapidly growing malignancies




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LFS 319: Pathophysiology                         Blood Disorders



2. HEMOLYTIC ANEMIA
     A. INTRINSIC HEMOLYTIC ANEMIA

   o Caused by hereditary defects  hemolysis
       o Defective RBC enzyme systems
       o Defective RBC membrane
       o Abnormal hemoglobins (hemoglobinopathies)
            SICKLE CELL ANEMIA
            THALASSEMIA

SICKLE CELL ANEMIA

   o RBCs contain HbS hemoglobin instead of HbA

                       Under certain conditions
                           HbS polymarises
                                    
                       Long, insoluble filaments
                                    
                   Distortion of RBC shape (sickle)
                             Less flexibility
                                    
            Sickled RBCs removed by spleen and marrow
                             (in ~ 20 days)
                                    
                                 Anemia
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LFS 319: Pathophysiology                          Blood Disorders



Clinical course

   o Variable
   o Chronic anemia
   o Weakness
   o Sickle crisis

        Hypoxemia, acidosis, pregnancy, cold weather
                             
                       acute sickling
                             
               blockage of small blood vessels
                             
            widespread ischemic organ damage
           in bone  bone necrosis  deep pain



     o Sickle cell trait
             One defective gene
             Few complications
             Can pass the defective gene to their children




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LFS 319: Pathophysiology                                Blood Disorders



THALASSEMIA


 o Hb is made of 2 alpha-globin chains and 2 beta-
      globin chains

 o In thalassemia there is defective production of beta-
      globin


                           Lack of beta-globin



                            Accumulation of
                             alpha-globin




      Destruction of                           Marrow stem
     RBC membrane                             cell suppression


         Hemolysis                               Reduced RBC
                                                  production




                            Severe anemia




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LFS 319: Pathophysiology                        Blood Disorders



Thalassemia occurs in two forms:

Thalassemia major (Cooley’s thalassemia)
     o Two defective genes
     o Life-threatening disease
     o Requires continuous blood transfusions


Thalassemia minor
   o One defective gene (heterozygous)
   o A milder form of the disease
   o Essentially asymptomatic




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LFS 319: Pathophysiology                                Blood Disorders



Leukocyte Disorders

Leukopenia:                Deficiency of leukocytes
Leukocytosis:              Non-neoplastic elevation of WBCs numbers
Leukemia:                  Neoplastic proliferation of leukocytes


Leukemia

o Primary malignant tumors of leukocyte precursors in
  the marrow
o Aleukemic leukemia: Proliferation of precursors is
  confined to the marrow.
o Leukemia: appearance of cells showing varying
  degrees of differentiation in the blood.


Pathogenesis (Figure 7.28)

Classification:
    A. Classification according to progression:
         1. acute
         2. chronic

        B. Classification according to cell line affected
            1. granulocytic (myeloblastic) leukemias
            2. lymphoblastic (lymphocytic) leukemias
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LFS 319: Pathophysiology                        Blood Disorders



Acute Lymphocytic Leukemia (ALL)

   o Mostly seen in children and adolescents

   o Is the most common malignancy affecting children


Signs and Symptoms:

   o Erythropoiesis  anemia  weakness

   o Thrombocytopenia   bleeding tendency

   o Susceptibility to infections

   o Bone pain

   o Cervical lymphadenopathy


Treatment & Prognosis:

     o Aggressive combination chemotherapy

     o Bone marrow transplantation

     o Prognosis: good in children, less optimistic in
        adults



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LFS 319: Pathophysiology                     Blood Disorders



Acute Myeloblastic Leukemia (AML)

  o Typically occur in persons > 55 years of age

  o Presentation is similar to ALL

  o Diagnosis is confirmed by bone marrow biopsy

  o Prognosis: more optimistic than ALL

  o 70% of cases are cured following intensive therapy

  o Many patients relapse within 18 months


Chronic Lymphocytic Leukemia (CLL)

  o Most common forms of leukemias

  o Typically seen in persons > 50 years of age

  o Onset: Gradual

  o Cells involved: mostly B lymphocytes

  o Non-functional lymphocytes  defective antibody
      production

  o Infiltration of lymph nodes  lymphadenopathy

  o Survival can be prolonged by chemotherapy

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LFS 319: Pathophysiology                         Blood Disorders



Chronic Myeloblastic leukemia (CML)

  o Age group: 25 – 60

  o Cell line affected: Granulocyte

  o Liver & spleen infiltration  hepatomegaly &
      splenomegaly

  o Blast crisis:

          Occurs in the disease’s later stage
          Resembles acute leukemia, where
          Large numbers of immature leukocytes enter the
            blood

  o Therapy has no impact on survival

  o 90% of cases have damaged chromosome #22
      (Philadelphia chromosome)




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LFS 319: Pathophysiology                        Blood Disorders



Lymphoma

   o Solid malignant tumor of lymphoid tissue
     (lymphocytes and their precursors)
   o Marrow and lymphoid tissue replacement
   o Tumor expansion produces local effects
   o Immune deficiencies
   o Anemia
   o Lymphadenopathy




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LFS 319: Pathophysiology                                 Blood Disorders



Hodgkin’s lymphoma

   o Relatively rare
   o Possible etiology: genetic & EBV infection
   o Occur mostly in young males and blacks
   o Usually arises in a single, painless cervical LN
   o Then spread to adjacent LNs and lymphoid organs
   o Splenomegaly & lymphadenopathy
   o Fatigue, wasting, fever
   o Depression of T-cell function
   o Diagnosis: Presence of Reed-Sternberg (RS) cell
   o Therapy and prognosis: depends on:
       o Age & Stage (Table 7.9)

Stage I            Tumor present at a single LN region


Stage II           Tumor present at 2 or > LN regions
                   Same side of the diaphragm

Stage III          Tumor present in 2 or > LN regions
                   Both sides of the diaphragm

Stage IV           Widespread metastasis to one or more non-
                   lymphoid organs




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LFS 319: Pathophysiology                        Blood Disorders



Non-Hodgkin’s lymphomas (NHLs)

   o Arises in lymphoid tissue

   o Cell lines affected: T- & B-cells in particular

   o Primary site: LNs

   o Spread to other LNs and lymphoid organs




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