Title: Red Cells Disorders The Anemias
1Slide 11
2WHO fig 6.111
3Plasma Cell Dyscrasias
- Multiple Myeloma
- Waldenstroms macroglobulinemia
- Plasmacytoma
- Associated signs/symptoms
- Immunocompomised
- Hyperviscosity syndrome
- Pathologic fractures
- Amyloid deposition
- Rouleaux
- Hypercalcemia
4Plasma Cells in Multiple Myeloma
5Monoclonal Spike on Serum Electrophoresis
6Before
After
Retina before and after plasmapheresis in a
patient with Waldenstroms Macroglobulinemia (IgM)
7Hodgkin 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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13Extranodal Marginal Zone Lymphoma
- AKA MALT lymphoma
- Develops in autoimmune diseases and with
continued immune activation - Hashimotos thyroiditis
- Sjogrens syndrome
- Helicobacter pylori gastritis
14Leukemia vs Lymphoma
Solid Lymphoid Tissue
Blood/Bone Marrow
Blasts
Mature Cells
Acute leukemia
Chronic leukemia
B cell
Hodgkin
T cell
Myeloid
Lymphoid
15Acute 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
16Myelodysplastic 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)
17Anisocytosis and Poikilocytosis in Myelodysplasia
18Iron Stain Demonstrating Ringed Sideroblasts
19Chronic 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
20Chronic Myelogenous Leukemia
- t(922)
- BCR-ABL fusion
- Philadelphia chromosome
- 3 phases
- Stable/chronic
- Accelerated
- Blast transformation
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22Leukocyte 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)
23Langerhans 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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25Hemostasis
26Hemostasis
- Coagulation Cascade
- Platelets
- Blood vessel wall
27Primary Hemostatic Plug
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29Coagulation 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)
30Extrinsic System
Intrinsic System
XII
Tissue Factor (III)
XI
IX
VII
X
VIII
V
Vitamin K Dependent
II
Fibrinogen
Fibrin
XIII
31Anticoagulation 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
32Anticoagulation 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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34Evaluation 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
35Bleeding 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)
36Prothrombin 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)
37Partial 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
38Mixing 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
39Thrombin Time
- Measures the rate of fibrin formation from
fibrinogen - Exogenous thrombin is added to test plasma
- Prolonged TT
- Heparin
- FSPs
- Abnormal fibrinogen
- Severe hypofibrinogenemia
40Bleeding Disorders
- Platelet defects
- Quantitative (too few)
- Qualitative (dont work)
- Coagulation factor defects
- Factor deficiency
- Factor inhibitor
- Blood vessel wall defects
- Von Willebrand disease
- Vasculitis
41Platelet 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
42Platelet 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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45Hemophilia
- 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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47von 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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49Vitamin 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
50Vitamin K Dependent Factors
- Factor II
- Factor VII
- Factor IX
- Factor X
- Protein C
- Protein S
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52Liver 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
53DIC
- 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
54DIC
- 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
55Hypercoagulable 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
56Fates of a Thrombus