Hematology for Studs

HEMATOLOGY

Next step: determine MCV
Microcytic ( MCV <> 96 )
· Iron deficiency · Hemolytic anemia · B12 deficiency
· Thalasemia · ACD · Folate deficiency
· Sideroblastic Next step? – Reticulocyte
count
· Lead poisoning Reticulocyte count -
Hemolysis
· Anemia of chronic
diseases ( ACD )
¯ Reticulocytes – bone
marrow failure
* MCHC : Mean corpuscular Hb concentration (Avg. Hb concentration in RBC)
¯ MCHC ® central area of pallor – Microcytic
MCHC ® No central area of pallor – Spherocytosis
N MCHC ® Megaloblastic Anemia
· Hb A - a , b Hb F - a ,g Hb A2 - a , d
· Daily requirement of Iron – 1 mg/day in M, 2-3 mg/day in F
* Iron Deficiency Anemia :
· Low serum ferritin, serum iron , high TIBC
· Blood loss (menstruation), dietary deficiency
· Most specific test : Bone marrow biopsy
* ACD (Anemia of Chronic Diseases) :
· Normal / elevated serum ferritin
· Both serum iron & TIBC ® Low
· In treatment of ACD, if erythropoietin level is normal, then periodic blood
transfusion is the best choice to improve anemia
* Sideroblastic Anemia :
· Normal serum ferritin
· Very high transferrin saturation
· High serum iron & Low TIBC
· Most specific test : Prussian Blue stain of RBC in the marrow will show ringed
sideroblast
· Vit-B6 deficiency: ¯ Protoporphyrin & ¯ d ALA

· Iron deficiency: Protoporphyrin & N d ALA
· Lead poisoning: Protoporphyrin & d ALA
* Thalassemia :
· Underproduction of alpha/beta globin chain
· Mild – Moderate anemia with very low MCV
· Target cells, Normal serum iron & RDW
Electrophoresis
½
¯ ¯
Normal Abnormal
¯ ¯
a - Thalassemia trait b - Thalassemia
¯ ¯
All Hb requires a chain for synthesis Hb A2
So Hb concentration decrease but Hb F
Relative proportion of the normal
Hb remains the same
- Thalassemia traits of both a & b do not require specific treatment
- Thalassemia major ( b ) requires periodic blood transfusion
- Tx of Iron overload (due to periodic blood transfusion) ® Deferoxamine
 “Crew haircut” on skull X-ray is distinctive radiological change seen most often in patient with Sickle cell anemia & Thalassemia major.
¨ Macrocytic Anemia ¨
½
¯ ¯
Vit – B12 deficiency Folic acid deficiency
· Peripheral Blood smear: Hypersegmented Neutrophils seen in Both
· How to differentiate: Low B12 level Low RBC folic acid level
Methylmalonic acid
level is seen in only B12
· Schilling Test is occasionally used to determine etiology of B12 def
· Schilling Test : Oral Administration of Radioactive Vit – B12
· Reabsorption ® Pure vegan
· B12 + IF ® Reabsorption ® Pernicious Anemia
· B12 + Antibiotics ® Reabsorption ® Bacterial over growth
· B12 + Pancreatic extract ® Reabsorption ® chronic Pancreatitis.

· Important : Vit-B12 and folic acid require for DNA synthesis in all cells so their
deficiency affect all bone marrow cells, not just RBC.
· Treatment : Vit – B12 IM Folic acid orally
· Diamond-Blackfan Syndrome (congenital hypoplastic anemia) – intrinsic
defect of erythroid progenitor cells which results in increased apoptosis –
megaloblastic anemia without hypersegmented neutrophils [In Vit-B12 and
Folic acid deficiency, megaloblastic anemia with hypersegmented neutrophils]
Hemolytic Anemia
¯
¯ ¯
Extravascular hemolysis Intravascular Hemolysis
- Unconjugated bilirubin - plasma & urine Hb
- LDH - Hemoglobinuria
- Spherocytosis - Hemosiderinuria
- Sickle-cell - ¯Serum Haptoglobin
- Immune-hemolytic anemia - LDH
- PNH (Paroxysmal Nocturnal
Hemoglobinuria)
- G6PD

■ Sickle- cell-Anemia : Autosomal-recessive
- Substitution of Valine for glutamic acid at sixth position on β- globin chain
- Sickle-cell trait: Asymptomatic. Significant manifestation of trait is the renal
concentrating defect
- Screening test : Sickle prep test to diagnose traits
- Most specific test : Hemoglobin electrophoresis
- Treatment : Acute crisis ® fluid, Analgesics, O2
- Fever & leucocytosis with/without infection ® Antibiotics Þ ceftriaxone,
cefotaxime
- Severe (Acute chest syndrome, CNS, priapism) ® RBC transfusion
- Hydroxyurea -Prophylaxis - prevent vaso occlusive crisis
- Folic acid supplementation – prevent Aplastic anemia
- Most common complication of Sickle cell disease – splenic sequestration (not
splenic infarction)
· Sudden fall in Hb concentration and virtual absence of reticulocytes on the
peripheral blood smear in sickle cell disease patient – Parvo virus B-19 (slapped
cheek appearance)  Aplastic crisis
■ Hereditary Spherocytosis : Autosomal dominant
- RBC membrane protein defect [spectrin, ankyrin]
- Osmotic Fragility test & MCHC
- Treatment : Splenectomy

■ Autoimmune Hemolytic Anemia :
- Coomb’s test
- Warm – antibody (IgG), Cold – antibody (IgM)
- Drug – induced ® Penicillin, Quinidine, a - Methyldopa
■ Paroxysmal Nocturnal Hemoglobinuria (PNH) :
- Loss of anchor for DAF ( Decay Accelerating Factor )
- more complements bind to RBC & intravascular hemolysis occur
- Presentation : Hemoglobinuria in first morning urine
Sign / Symptoms of major venous structure thrombosis
· Treatment : Corticosteroid in severe disease for unclear reason
Anticoagulation for thrombosis
■ G6PD deficiency : ¯ Synthesis of NADPH & GSH (glutathione)
- X-linked recessive
- Hemolysis in the presence of Oxidant Stress
- Oxidant Stress ® Infection , fevabeans, Drugs (Sulfa, Dapsone, Primaquine,
Quinidine, Nitrofurantoin, INH)
- Diagnosis ® Heinz bodies, bite cells, G6PD level
- Treatment ® Avoid oxidant stress
■ Pyruvate kinase deficiency : ¯ Synthesis of ATP
- Autosomal recessive
- PK gives 2 ATPs – its deficiency produce membrane damage – RBC with thorny
projection (echinocytes)
¨ Leukemia ¨
ALL AML CML CLL
· Children
( < 14 yrs )
· 15-39 yrs · 40-60 yrs · > 60 yrs
· Thrombocytopenia · Thrombocytopenia · Thrombocytopenia
Thrombocytosis in
40%
· Thrombocytopenia
· Pre-B cells -
CALLA, CD10 &
TdT positive
· t (15; 17) in M3 · Philadelphia
chromosome,
t (9 ; 22)
· CD19 Antigen
· T cells - CD10 &
TdT negative
· DIC in M3 · Basophillia · Predominantly B
lymphocytes.
· t (12; 21) – good
prognosis
· Auer rods in M2 &
M3
· “Smudge cells”
CALLA (common
ALL antigen)
· CNS in M4 & M5
M3- Premyelocytic
M4-myelomonocytic
· Stages :
0 –lymphocytosis
1-lymphadenopathy

M5- monocytic
· Vit–A – useful in
Premyelocytic ( M3)
2-spleenomegaly
3-Anemia
4-thrombocytopenia
* Diagnosis : Bone marrow biopsy ® > 30 % blast ® Acute leukemia
< 30 % blast ® Chronic leukemia
Treatment Treatment Treatment Treatment
· Daunorubicin · Cytosine
arabinoside
· Imatinib · Stage 0, 1 ® No
Treatment
· Vincristine · daunorubicin /
Idarubicin
· if it fails, then
Bone marrow
· Advanced stage
¯
Fludarabine
· Prednisone · Vit-A in
Premyelocytic (M3)
· Autoimmune
hemolysis &
Thrombocytopenia
¯
Prednisone
· Asparaginase
· Intrathecal
Methotraxate for
CNS Prophylaxis
* Adult T-cell lymphoma : HTLV-1 [Human T-cell leukemia virus – 1]
- Activation of TAX gene – inhibits TP53 suppressor gene
- ↑ CD4 T-cells
- Skin infiltration and lytic bone lesion [lymphoblast release osteoclast activating
factor] (hypercalcemia)
- Negative TdT

* Hairy cell leukemia : only leukemia without lymphadenopathy
- B-cell leukemia
- Positive TRAP stain (tartrate-resistant acid phosphate)
- Treatment : Pentostatin / 2-Chlorohydroxy adenosine
* Infectious Mononucleosis : EBV – CD21 receptor on B-cells – heterophile antibody (IgM to sheep’s RBC) – danger of rupture of spleen – When patient
receive ampicillin, Ampicillin-associated maculopapular rash is well known phenomenon in patient with mononucleosis [Tx: discontinue drug, supportive treatment and observation]
* Sudden increase in WBC in patient with severe infection or inflammation with
high leukocyte alkaline phosphatase score, diagnosis?  Leukemoid reaction

* Myeloid stem cells : RBC, granulocytes, mast cells and platelets – Polycythemia
vera affect myeloid stem cells so increase everything in Polycythemia vera –
myelofibosis (tear drop cells, extramedullary hematopoesis)
* Aplastic Anemia : Pancytopenia [Everything is decreased including RBCs,
Platelets and WBCs]
˗ Bone marrow biopsy – most specific test
˗ Treatment – Allogenic bone marrow transplant (best treatment for < 50 yrs old)
– Antithymocyte globulin, cyclosporine, Prednisone
* Relative Polycythemia – increased RBCs count due to decrease plasma volume
* Appropriate absolute Polycythemia (secondary) – increase RBCs count due to
increase in erythropoietin (EPO) level due to hypoxia [eg. COPD, high altitude];
next step would be measure oxygen saturation (decrease Sao2) in these patients
* Inappropriate absolute Polycythemia (Polycythemia vera and ectopic EPO
secretion) – Polycythemia vera – clonal expansion of the trilineage myeloid stem
cells [increase RBCs, Granulocytes, Mast cells and Platelets]; decrease EPO
(increase Sao2 inhibits EPO secretion) Ectopic EPO secretion – Renal cell CA,
Hepatocellular CA – increase RBCs and increase EPO, normal Sao2 and plasma
volume
* Neonatal Polycythemia – hematocrit >65% - If increase on hematocrit on heel
prick sample, next step? – Recheck sample from peripheral blood (hematocrit 5-
15% lower than heel prick) – If symptomatic (hypoglycemia, hyperbilirrubinemia,
cardiac or respiratory compromise), next step? – hydration and partial exchange
transfusion
¨ Plasma Cell Disorder ¨
Multiple Myeloma Monoclonal Gammopathy of Uncertain
Significance
· Bone pain , Infection, Anemia ,
Renal failure
· No systemic manifestation like multiple
myeloma
· Electrophoresis – IgG monoclonal spike · IgG monoclonal spike on electrophoresis
· X-ray – punched out lytic lesion
(osteoclast activating factor)
· No lytic bone lesion on X-ray
· Hypercalcemia · Normal lab test (creatinine, calcium)
· Bence-Jones Protein (Acidification of
urine is required to test BJ protein)
· Bone marrow biopsy (most specific) –
>10% plasma cells
· Bone marrow - < 5 % Plasma cells
· First step – serum protein
electrophoresis, plain radiographic skeletal
survey & assessment of renal function

· Whole body X-ray should be done once a patient has been diagnosed with
multiple myeloma. Bone scans are not useful for these patients.
■ Treatment - Younger ® Bonemarrow transplant
Older ® Melphalan & Prednisone
Hypercalcemia ® Hydration & loop diuretics and then with
Bisphophonates
* Waldenstrom’s macroglobulinemia (Lymphoplasmatic lymphoma) : M spike
with IgM, BJ protein – no lytic lesions like multiple myeloma
 BJ proteins – kappa or lambda light chains
¨ Lymphomas ¨
* Stage of Lymphoma (Hodgkin’s & Non–Hodgkin’s) :
˗ A – Constitutional Symptoms Absent
˗ B – Constitutional Symptoms Present (fatigue, Wt .loss, night sweat, etc.)
 Stages : 1-Single lymphnode / single extralymphatic organ one side of
2-Two / more lymphnode / contiguous extralymphatic organ diaphragm
3-Involvement of lymphnode/extralymphatic organ both side of the
4-Multiple disease foci in extralymphatic organ diaphragm
(eg. liver, Bone marrow)

 Mycosis fungoides – cutaneous (begins in skin) T-cell lymphoma (not a fungal
infection)
¨ Bleeding Disorders ¨
· Tissue thromboplastin ® Factor 7 ® Extrinsic Pathway (PT) ® Warfarin
· Subendothelial collagen, HMWK ® Factor 12 ® Intrinsic Pathway (PTT) ®
Heparin
· Common final pathway ® Factor 10 , 5 , 2 , 1 [ 2-Prothrombin ]
· Heparin ® Å AT III ® neutralize 9 , 10 , 11 , 12 , Prothrombin & thrombin

Hodgkin Lymphoma Non-Hodgkin Lymphoma
· Reed-Sternberg cells · Reed-Sternberg cell Absent
· Lymphadenopathy is more common
(cervical, Supraclavicular, Axillary)
· Extralymphatic involvement is more common
(Spleen, liver, stomach)
· B-cells lineage involve · Both B & T cell lineages involve
· Lymphocyte Predominant (Best Prognosis) · HIV, EBV ® Burkitt lymphoma, t (8;14 )
· Mixed celluarity · H.pylori ® gastric lymphoma (mucosa
associated lymphoid tissues in stomach)
· Nodular Sclerosing (Female) ® lacunar cells · CNS involvement is more common in HIVpositive
patient
· Lymphocyte depletion (worst prognosis) · Follicular lymphoma – t (14;18 ), over
expression of BCL2 anti-apoptosis gene
· RS cells – CD15, CD 30 positive
- B-lymphocyte with somatic hypermutation
· Sjogren syndrome – salivary gland & GI
lymphoma
· Hashimoto’s thyroidits – thyroid malignant
lymphoma
· Diagnosis: Excisional lymphnode biopsy
Next step ® determine the extent of disease by
CXR, Chest CT, Abdominal CT/MRI
· Staging laparotomy
· Bone marrow biopsy
· Diagnosis: Excisional lymphnode biopsy
Next step ® Staging
· Bone marrow biopsy is best initial staging tool
for NHL
· Treatment
½
· Treatment : same as Hodgkin for stages IA ,
II A, CNS lymphoma
¯ ¯ · B, III , IV ® Chemotherapy
I A , II A B , III , IV ¯
¯ ¯ Cyclophophamide
Radiation Chemotherapy Hydroxy – Adriamycin
Adriamycin(doxorubicin) Oncovin [vincristine]
Bleomycin Prednisone
Vinblastine
Dacarbazine
· CD 20 antigen expression ®RITUXIMAB
· Thrombin ® convert fibrinogen into fibrin monomers [fibrin monomers then
aggregate which are soluble]
· Thrombin ® activate fibrin stabilizing factor (13) [once fibrin monomers
aggregate, factor-13 stabilize them by making them insoluble]
· Plasmin ® cleaves insoluble fibrin monomers and fibrinogen into fibrin
degradation products [FDP]
· D-Dimers ® fragments of cross-linked insoluble fibrin monomers
· Protein C & S ( Vit .K dependent ) ® inactivate 5 & 8 ® enhance fibrinolysis
· tPA – synthesized by endothelial cell , TxA2 –synthesized by Platelates
· VWF – synthesized by endothelial cell & Platelates – Func.n ® Platelate
Adhesion & Prevent degradation of factor VIII:C
· Platelate Storage ® VWF & Fibrinogen (1)
· Platelate receptors ® glycoprotein (gp) 1b – VWF ; GP2b:3a – Fibrinogen
· Platelate Factors ® PF3 ® Prothrombin complex (V, Xa, PF3, Ca+2).
PF4 ® Heparin neutralizing factor
■ Hemostasis in small vessel injury : injury ® tissue thromboplastin (activates
extrinsic pathway) & exposed collagen (activates intrinsic pathway) ®
Endothelial cells synthesize vWF so injury makes it expose to platelets and
platelets start attaching to them and ADP from platelets help aggregating them
(temporary plug) ® platelets have fibrinogen at gp2b:3a ® activated thrombin
(by intrinsic & extrinsic pathway) convert fibrinogen to fibrin monomers which
aggregate and make soluble plug ® thrombin also activate factor-13 which
convert soluble plug into insoluble plug ® bleeding stop ® tPA activates plasmin
which dissolve fibrin monomer & blood flow reestablish to the tissue
■ Idiopathic Thrombocytopenic Purpura :
- Sign of bleeding from superficial areas of body
- Absent spleenomegaly, Prolong Bleeding time
- Idiopathic Antibody (IgG) Production to the Platelets receptors (gp2b:3a)
- Diagnosis : Anti-platelate Antibody
Bone-marrow ® megakaryocytosis – indicate problem with
platelate destruction, not with production
* Treatment : Prednisone (initial therapy)

observe patient
˗ If count fails to raise after Prednisone therapy ® IV Immunoglobulin / Rhogam
˗ Platelate transfusion (if above fails to raise count)
 Thrombotic Thrombocytopenic Purpura (TTP) – deficiency in vWF cleaving
metalloprotease in endothelial cells leads to ↑↑vWF → more platelets attach to
vWF leads to thrombosis and thrombocytopenia (due to platelet consumption in
thrombosis) – microangiopathic anemia, Renal & CNS involvement – schistocytes
(fragmented RBCs), Helmet-shaped cells

 Hemolytic Uremic Syndrome (HUS) – microangiopathic anemia, thrombocytopenia
and renal involvement [no CNS involvement]
 Schistocytes – TTP, DIC, Aortic stenosis
■ Giant platelates, greater than expected bleeding for the degree of
thrombocytopenia, Normal vWF level, subnormal ristocetin assay, diagnosis?
 Bernal-Soulier Syndrome; defect?  glycoprotein Ib
■ Von Willebran Disease ( VWD ) : Autosomal – Dominant
- Sign of bleeding from superficial areas of body
- Low level of VWF , factor VIII : C
- Ristocetin Platelate Aggregation Test : Abnormal
- Elevated PTT, Normal PT
- Treatment : Desmopressin Acetate, VWF replacement
■ Hemophilia : Autosomal – recessive
- Hemophilia A – factor 8 deficiency, Hemophilia B – factor 9 deficiency
- Sign of deep bleeding ® hemarthrosis, hematoma, GI bleeding
- may become apparent at the time of circumcision
- Diagnosis : elevated PTT , Normal PT
- “Mixing Study” : 50 % Patient’s blood + 50 % Normal blood ® PTT corrected
® Hemophilic ® If PTT is not corrected ® Antibody inhibition of the factor
- Treatment : Desmopressin, Specific factor replacement
■ Vit–K Deficiency : ¯ Production of Factor 2, 7, 9, 10
- Both PT & PTT are elevated
- Diagnosis : correction of PT & PTT after giving Vit-K
- Treatment : Fresh Frozen Plasma in severe bleeding
■ Liver Disease : ¯ Production of All factors except VWF & Factor 8
- Both PT & PTT are elevated
- Diagnosis : H/O liver disease & No correction of PT & PTT after giving Vit-K
- Treatment : Fresh Frozen Plasma

■ DIC (Disseminated Intravascular Coagulation) :
- Platelates, PT & PTT, D- dimers & FDPS, Low fibrinogen level schiztocytes on peripheral blood smear
- Treatment : Fresh Frozen Plasma, Platelate transfusion

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Wednesday, February 3, 2010