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Red Cells Disorders The Anemias

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Retina before and after plasmapheresis in a patient with ... M5: Acute Monocytic Leukemia; NSE positive. M6: Erythroleukemia. M7: Megakaryoblastic Leukemia ... – PowerPoint PPT presentation

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Title: Red Cells Disorders The Anemias


1
Slide 11
2
WHO fig 6.111
3
Plasma Cell Dyscrasias
  • Multiple Myeloma
  • Waldenstroms macroglobulinemia
  • Plasmacytoma
  • Associated signs/symptoms
  • Immunocompomised
  • Hyperviscosity syndrome
  • Pathologic fractures
  • Amyloid deposition
  • Rouleaux
  • Hypercalcemia

4
Plasma Cells in Multiple Myeloma
5
Monoclonal Spike on Serum Electrophoresis
6
Before
After
Retina before and after plasmapheresis in a
patient with Waldenstroms Macroglobulinemia (IgM)
7
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

8
Slide 19
9
Slide 20
10
Slide 24
11
Slide 26
12
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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

14
Leukemia vs Lymphoma
Solid Lymphoid Tissue
Blood/Bone Marrow
Blasts
Mature Cells
Acute leukemia
Chronic leukemia
B cell
Hodgkin
T cell
Myeloid
Lymphoid
15
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

16
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)

17
Anisocytosis and Poikilocytosis in Myelodysplasia
18
Iron Stain Demonstrating Ringed Sideroblasts
19
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

20
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)
0
1
2
3
4
Used to Distinguish a Leukemoid Reaction from
CML (high in leukemoid reaction and low in CML)
23
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
26
Hemostasis
  • Coagulation Cascade
  • Platelets
  • Blood vessel wall

27
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)

30
Extrinsic System
Intrinsic System
XII
Tissue Factor (III)
XI
IX
VII
X
VIII
V
Vitamin K Dependent
II
Fibrinogen
Fibrin
XIII
31
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

32
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

35
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)

36
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)

37
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

38
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

39
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

40
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

41
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

42
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

43
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45
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)

46
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47
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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49
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

50
Vitamin K Dependent Factors
  • Factor II
  • Factor VII
  • Factor IX
  • Factor X
  • Protein C
  • Protein S

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52
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

53
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

54
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

55
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

56
Fates of a Thrombus
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