Red Cells Disorders The Anemias

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Slide 11
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WHO fig 6.111
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Plasma Cell Dyscrasias

• Multiple Myeloma
• Waldenstroms macroglobulinemia
• Plasmacytoma
• Associated signs/symptoms
• Immunocompomised
• Hyperviscosity syndrome
• Pathologic fractures
• Amyloid deposition
• Rouleaux
• Hypercalcemia

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Plasma Cells in Multiple Myeloma
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Monoclonal Spike on Serum Electrophoresis
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Before
After
Retina before and after plasmapheresis in a
patient with Waldenstroms Macroglobulinemia (IgM)
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Hodgkin Lymphoma

• Reed-Sternberg Cells neoplastic cell (most
  cases of B-cell origin)
• Popcorn cell NLPHL
• Lacunar cell NS
• Divided into Classic HL (NS, LP, LD, MC) and
  NLPHL
• Contiguous spread of LN
• Curable in lower stages

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Slide 19
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Slide 20
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Slide 26
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Extranodal Marginal Zone Lymphoma

• AKA MALT lymphoma
• Develops in autoimmune diseases and with
  continued immune activation
• Hashimotos thyroiditis
• Sjogrens syndrome
• Helicobacter pylori gastritis

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Leukemia vs Lymphoma
Solid Lymphoid Tissue
Blood/Bone Marrow
Blasts
Mature Cells
Acute leukemia
Chronic leukemia
B cell
Hodgkin
T cell
Myeloid
Lymphoid
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Acute Myeloid Leukemias

• M0
• M1
• M2 t(821)
• M3 t(1517) DIC
• M4e i(16)
• M5 Acute Monocytic Leukemia NSE positive
• M6 Erythroleukemia
• M7 Megakaryoblastic Leukemia

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Myelodysplastic Syndromes

• Dysplasia (improper cellular maturation) of one
  or more cell lines
• Refractory anemia
• Refractory anemia with ringed sideroblasts
• Refractory anemia with multi-lineage dysplasia
• Refractory anemia with excess blasts (5-20)
• Myelodysplastic syndrome, unclassifiable
• Myelodysplastic syndrome associated with isolated
  del(5q)

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Anisocytosis and Poikilocytosis in Myelodysplasia
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Iron Stain Demonstrating Ringed Sideroblasts
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Chronic Myeloproliferative Syndromes

• Packed bone marrow with over-production of 1
  cell line
• Dysplastic changes of MDS are not prominent
• Often extremely high blood counts, with resultant
  hyperviscosity symptoms
• CML
• CMML
• Polycythemia rubra vera
• Essential thrombocythemia
• Myelofibrosis

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Chronic Myelogenous Leukemia

• t(922)
• BCR-ABL fusion
• Philadelphia chromosome
• 3 phases
• Stable/chronic
• Accelerated
• Blast transformation

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Leukocyte Alkaline Phosphatase Test (LAP score)
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1
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Used to Distinguish a Leukemoid Reaction from
CML (high in leukemoid reaction and low in CML)
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Langerhans Cell Histiocytosis

• AKA histiocytosis X
• Neoplasm of Langerhans cells (histiocytes found
  throughout tissues of body)
• CD1a positive Birbeck granules
• 3 overlapping syndromes
• Eosinophilic granuloma unifocal disease
• Hand-Schuller-Christian multifocal, unisystem
• Letter-Siwe Syndrome multifocal, multisystem

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Hemostasis
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Hemostasis

• Coagulation Cascade
• Platelets
• Blood vessel wall

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Primary Hemostatic Plug
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Coagulation Cascade

• Classically divided into intrinsic, extrinsic and
  common pathways
• Extrinsic and intrinsic cascades converge to
  common pathway with formation of thrombin and
  subsequent fibrin lattice
• Many of the proteins involved in these reactions,
  are proenzymes, which are activated to serine
  proteases
• Calcium (factor IV) is required in both pathways
• Gamma carboxylation of II, VII, IX, X, C, and S
  is mediated by vitamin K
• All protein factors are synthesized by liver
  except vWF
• vWF is synthesized by megakaryocytes and
  endothelial cells (Weibel-Palade bodies)

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Extrinsic System
Intrinsic System
XII
Tissue Factor (III)
XI
IX
VII
X
VIII
V
Vitamin K Dependent
II
Fibrinogen
Fibrin
XIII
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Anticoagulation Mechanisms

• Multiple mechanisms exist to stop hemostatic
  pathways
• Dissolve thrombus
• Plasminogen is converted to plasmin with
  subsequent fibrinolysis
• Tissue plasminogen activator (fibrin dependent)
• Urokinase (fibrin independent)
• Plasmin degradation of cross-linked fibrin
  produces FDPs known as D-Dimers

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Anticoagulation Mechanisms

• Prevent further thrombosis
• Activated coagulation factors are diluted by
  blood flowing past thrombus
• Activated coagulation factors are cleared by RES
  and liver
• Protein C and S
• Plasmin also degrades factors V and VIII
• Circulating plasma proteins inhibit activated
  coagulation factors
• alpha2-macroglobulin
• alpha2-antiplasmin
• alpha1-antitrypsin active site binding
• antithrombin III (ATIII) the principal inhibitor
  of thrombin
• C1-esterase inhibitor

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Evaluation of Hemostasis

• Platelet Count
• Platelet function
• Bleeding time
• Coagulation assays
• PT extrinsic pathway (factor VII)
• PTT intrinsic pathway
• Thrombin time conversion of fibrinogen to fibrin
• Fibrinogen level
• Mixing studies

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Bleeding Time

• Assesses primary hemostatic plug formation
• Affected by platelet number
• Below 100,000 platelets/mm3 the bleeding time can
  be prolonged
• Affected by platelet function
• Both inherited and acquired qualitative platelet
  defects may prolong the bleeding time
• Medications may prolong BT (aspirin and
  ibuprofen)

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Prothrombin Time (PT)

• Measures extrinsic system
• Prolonged with deficiencies of factor VII or
  common pathway factors (I, II, V, and X)
• INR (international normalized ratio) is an
  adjusted ratio of patient PT to control PT
• Used to monitor oral anticoagulant therapy
  (coumadin/warfarin)

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Partial thromboplastin time (aPTT)

• Measures intrinsic coagulation system
• Prolonged with deficiencies of factors VIII, IX,
  XI, XII, HMWK, prekallikrein and the common
  pathway factors (I, II, V and X)
• In selective VIII, IX, XI, XII, HMWK, and
  prekallikrein deficiencies only the APTT is
  prolonged
• Sensitive to heparin and is used to monitor
  heparin therapy

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Mixing Studies

• PT and APTT mixing tests differentiate between
  factor inhibitors and factor deficiencies
• Patients plasma is mixed at a 11 ratio with
  normal pooled plasma
• If the prolonged PT/APTT corrects when mixed with
  normal pooled plasma, then this suggests factor
  deficiency
• If the prolonged PT/APTT remains prolonged, then
  this suggests the presence of an inhibitor

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Thrombin Time

• Measures the rate of fibrin formation from
  fibrinogen
• Exogenous thrombin is added to test plasma
• Prolonged TT
• Heparin
• FSPs
• Abnormal fibrinogen
• Severe hypofibrinogenemia

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Bleeding Disorders

• Platelet defects
• Quantitative (too few)
• Qualitative (dont work)
• Coagulation factor defects
• Factor deficiency
• Factor inhibitor
• Blood vessel wall defects
• Von Willebrand disease
• Vasculitis

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Platelet Defects - Quantitative

• Congenital Disorders
• Ineffective platelet production
• May-Hegglin anomaly AD large platelets
  thrombocytopenic
• Wiskott-Aldrich syndrome X-linked
  thrombocytopenia, eczema, infections
• Acquired Disorders
• Decreased production occurs with chemotherapy,
  antibiotic therapy, infections, toxins and
  radiation
• Marrow replacement in metastatic carcinoma,
  myeloma, leukemia, lymphoma and myelofibrosis
• B12 and folate deficiency
• Splenomegaly
• Dilutional thrombocytopenia occurs with massive
  hemorrhage and transfusion with crystalloid
• Increased platelet destruction
• DIC
• TTP
• HUS
• Heart valves ventricular assist devices
• ITP
• Drugs

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Platelet Defects - Qualitative

• Congenital Disorders
• Adhesion Bernard-Soulier syndrome AR GPIb
  platelet receptor
• Aggregation thrombasthenia (Glanzmanns disease)
  AR GPIIb/IIIa
• Acquired Disorders
• acquired von Willebrand disease autoantibodies
  are directed against vWF
• Uremia abnormal aggregation and PF3 availability
• Drugs (most common cause) aspirin
• FSPs can inhibit platelet aggregation

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Hemophilia

• Hemophilia A (factor VIII) and B (factor IX)
• Prevalence of hemophilia is approximately 1 in
  10,000
• 80 of hemophiliacs are factor VIII deficient
• X-linked recessive disorders (males)
• Signs/Symptoms
• Prolonged bleeding after circumcision
• Ecchymoses, bleeding into joints is common,
  muscle hematomas, intracranial bleeds
• APTT is usually prolonged
• BT is usually normal
• Treatment
• Hemophilia A highly purified factor VIII
  concentrates DDAVP (desmopressin)
• Hemophilia B highly purified factor IX
  concentrates
• Previously high risk of HIV infection with
  therapy
• 10 patients with severe hemophilia A develop
  factor VIII inhibitors (alloantibodies)

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von Willebrand Disease

• Abnormal vWF multimeric structure or low plasma
  concentration of vWF
• Prevalence 11000
• AD
• APTT may be normal or prolonged (carrier molecule
  for factor VIII)
• Bleeding times are usually prolonged
• 3 major subtypes
• Type I reduced level most common type
• Type II decreased or absent large vWF multimers
• Type III AR bleeding time is prolonged.
  Patients have less than 1 normal vWF and
  ristocetin cofactor activity. The plasma level
  of factor VIIIC is usually 2-10 of normal.
  Bleeding may be severe. Patients may develop
  anti-vWF antibodies.
• DDAVP (desmopressin) stimulates the endothelial
  cells to release vWFVIIIC
• DDAVP may be used to treat type I and some type
  II patients, but not type III
• Cryoprecipitate is prepared by thawing fresh
  frozen plasma at a low temperature and collecting
  the precipitate which is rich in vWFVIIIC

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Vitamin K Deficiency

• Obtained from leafy green vegetables in the diet
  and from the large bowel where bacteria
  synthesize the molecule
• Vitamin K deficiency
• malabsorption
• warfarin
• inadequate intake
• broad spectrum antibiotics
• PT/PTT greatly prolonged
• TT is normal
• Functional levels of factors II, VII, IX and X
  are reduced
• Treatment FFP IM vitamin K replacement therapy

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Vitamin K Dependent Factors

• Factor II
• Factor VII
• Factor IX
• Factor X
• Protein C
• Protein S

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Liver Disease

• Severe hepatocellular disease results in
  decreased protein synthesis
• Vitamin K therapy does not increase the plasma
  concentration of factors II, VII, IX, X, protein
  C and protein S
• FSPs can accumulate in the plasma secondary to
  decreased hepatic clearance
• The fibrinogen in cirrhotic patients may become
  sialated resulting in dysfibrinogenemia
• In alcoholic liver disease ineffective
  megakaryopoesis and splenic pooling result in
  thrombocytopenia

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DIC

• Syndrome resulting from generation of thrombin
  with activation of platelets and coagulation
  factors
• Bleeding results as coagulation factors and
  platelets are consumed
• Fibrin deposition in small vessels results in
  distal ischemic damage
• Laboratory diagnosis microangiopathic hemolytic
  anemia
• Low platelets
• Low fibrinogen
• Prolonged PT/PTT
• Elevated FSPs

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DIC

• Always associated with underlying disease
• Infection (endotoxin)
• Malignancy
• Amniotic fluid
• Treatment
• Correct/remove underlying disorder
• Platelets, cryoprecipitate (rich in fibrinogen),
  FFP, and RBCs are transfused when indicated
• Mortality is secondary to bleeding, thrombosis or
  the underlying disease

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Hypercoagulable States

• Alterations in normal blood flow
• Endothelial injury
• Protein C deficiency
• Protein S deficiency
• Factor V Leiden
• most common heritable disorder associated with
  hypercoagulability
• mutation prevents degradation by activated
  protein C
• Prothrombin gene mutation
• Elevated homocysteine level
• Antiphospholipid antibodies
• anticardiolipin antibodies
• lupus anticoagulants are also associated with
  thrombosis

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Fates of a Thrombus