H EME -O NC S TEP 3 R EVIEW By James K. Rustad, M.D. Copyright © 2009 All Rights Reserved.
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Transcript of H EME -O NC S TEP 3 R EVIEW By James K. Rustad, M.D. Copyright © 2009 All Rights Reserved.
OUTLINE Anemia Iron Deficiency Anemia Beta and Alpha
Thalassemia Vitamin B12 deficiency
and Schilling test Hemolytic Anemia
(Autoimmune, Hereditary Spherocytosis, Drug-Induced, and Microangiopathic)
G6PD Deficiency Sickle cell Anemia
Blood Transfusion Reactions
Neutropenia ITP Heparin Induced
Thrombocytopenia Coagulation tree,
abnormalities, and testing
Oncology: Leukemias and Lymphomas
Multiple Myeloma
ANEMIA
What to do? Check CBC and Retic Count If Retic index > 2.5 OR Absolute retic count >
75000 ----- likely Hemolysis or Hemorrhage
MEAN CORPUSCULAR VOLUME (MCV)
Measure of average RBC volume (size) Microcytic anemia < 80 (Iron Deficiency) Normocytic/Normochromic 80-95: chronic
disease, renal failure, hypothyroidism Macrocytic > 95 (B12, Folate deficiency).
Remember “hypersegmented (lobed) neutophils”
IRON DEFICIENCY ANEMIA VS. ACD
Lab Value IRON Deficiency Anemia of Chronic Disease
Iron Decreased Decreased
TIBC Increased Decreased
Ferritin Decreased Normal or Elevated
CLINICAL CASE SCENARIO
CBC suggests Microcytic Anemia (low MCV), Next step?
Iron Studies. If normal, what is next step? Hb electrophoresis. If normal, what is
diagnosis? Alpha-Thalassemia Trait, which is a
Diagnosis of Exclusion
CLINICAL NUGGETS OF KNOWLEDGE
Retic Count will increase one week after starting oral iron.
Take iron 2 hours before and 4 hours after calcium/antacids (decreases absorption).
If not tolerating Ferrous sulfate (abdominal cramps), switch to Ferrous gluconate.
BETA THALASSEMIA MAJOR (COOLEY’S ANEMIA) Homozygous Severe anemia: patient
cannot survive without transfusion! To Diagnose?
Hb electrophoresis On Peripheral Smear: Target cells (also
present in sickle cell, S.C. disease)
Basophilic stippling (also present in alcohol abuse, lead poisoning)
BETA THALASSEMIA
Extramedullary and Intramedullary erythropoiesis
Chipmunk facies Hair on end
appearance in skull x-ray due to marrow expansion.
Treatment: Blood transfusion, allogenic bone marrow transplant.
ALPHA THALASSEMIA
There are four alpha globin genes.
One deleted: silent carrier, normal.
Two deleted: Thalassemia minor or Alpha Thalassemia Trait. Low Hct with very low MCV.
Three deleted: HbH disease. Severe hemolytic anemia, increased Retic count, Hb Electrophoresis shows HbH. Tx: repeated transfusion. Poor prognosis.
Four deleted: Hydrops Fetalis (Hb Electrophoresis shows Hb Bart): Death in utero.
SCHILLING TEST
To differentiate the cause of Vitamin B12 deficiency:
Decreased intake Decreased
production of intrinsic factor
Decreased absorption
Vitamin B12 IM to saturate plasma level then radio-labeled B12 administered orally.
ALGORITHM STEP ONE: 24 HOUR URINE TEST
If normal (7% of oral dose in urine), cause is decreased intake.
If abnormal, give Radio-labeled B12 and Intrinsic Factor.
ALGORITHM STEP TWO: RADIO-LABELED B12 AND IF
Normal: Intrinsic Factor Deficiency caused by Pernicious anemia or Gastrectomy
Abnormal: Cause is decreased absorption of B12 caused by Blind Loop syndrome, Crohn’s or Ileal Resection.
SUSPECTED BLIND LOOP SYNDROME
Treat with antibiotics and repeat testing. If normal: blind loop syndrome.
If still abnormal: caused by Crohn’s or ileal resection.
SCHILLING TEST ALGORITHM
NML:7% of
oral dose
in urine
24 hour urine
ABNL: Give B12
and IF
NML: I.F. DeficientPerniciousAnemia or
Gastrectomy
AABNL: Decreased absorption
If improved after ABX: Blind loop
syndrome.Otherwise: Crohn’s or ileal resection
HEMOLYTIC ANEMIA
Anemia and jaundice
Increased: retic index, LDH, indirect bilirubin
Decreased: haptoglobin
AUTOIMMUNE HEMOLYTIC ANEMIA
Warm antibody induced
Cold antibody induced
Antibody IgG against Rh antigen
IgM against I antigen
Causes Idiopathic, drug induced, lymphoma, leukemia
Idiopathic, mycoplasma, mono, Waldenstrom’s macroglobulinemia
Coomb’s Test + IgG or IgG and C3
- IgG Only C3 +
Cold agglutinin Negative Positive
Treatment Steroid, Splenectomy. If treatment refractory: immunosuppressive!Cyclophosphamide or Cyclosporin.
No Steroid or Splenectomy. Immunosuppressive treatment!! Cyclophosphamide or Chlorambucil.
INCREASED MHC AND SPHEROCYTES MHC: Mean corpuscular
hemoglobin Two causes: Autoimmune hemolytic
anemia (Coombs test positive)
Hereditary Spherocytosis (Coombs test negative)
Spherocytes are hyperchromic; they have no area of central pallor (normal red blood cells do!)
CLINICAL SCENARIO Child with anemia,
icterus, jaundice and splenomegaly on exam.
Spherocytes in peripheral smear.
Retic count and MCHC increased.
Coombs test negative.
Most likely diagnosis? Hereditary
spherocytosis!
HERIDITARY SPHEROCYTOSIS
Confirmatory test: Osmotic Fragility Test
Treatment: Splenectomy
You may also give Folic Acid.
DRUG INDUCED HEMOLYTIC ANEMIA
Alpha-Methyldopa Type
Penicillin Type
Quinidine Type
Direct Coomb’s
IgG+ C3+ IgG+ C3+ IgG negativeC3+
Indirect Coomb’s
Positive without adding Drug
Positive ONLY when adding drug
Positive ONLY when adding drug
CLINICAL CASE
30 year old pregnant patient with anemia. On Methyldopa for Hypertension and started
on Penicillin for recent UTI. On exam: pallor. Labs: increased retic count, increased LDH,
spherocytes present on smear. Direct Coombs + for IgG and C3.
Indirect Coombs positive ONLY when drug added.
Most likely cause of anemia? PENICILLIN
MICROANGIOPATHIC HEMOLYTIC ANEMIA
Fragmented RBC’s Schistocytes (black
arrows) Helmet cells (red
arrows) Causes: TTP HUS DIC Prosthetic Heart Valve HELLP syndrome in
pregnancy
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
Microangiopathic hemolytic anemia
Neuro: change in mental status (confusion waxes and wanes in minutes)
May have renal insufficiency
PT, PTT normal Cause: unknown Treatment:
plasmapheresis
HEMOLYTIC UREMIC SYNDROME
Causes: unknown OR diarrhea with E. Coli O157: H7, Shigella, Salmonella.
G6PD DEFICIENCY X-linked recessive
(usually male) Usually in Black
Americans G6PD Deficiency can
cause hemolytic anemia.
Common precipitants include:
Infection Drugs such as Dapsone,
Quinine, Sulfonamide, Primaquin, Quinidine, Nitrofurantoin
Bite cells
SICKLE CELL ANEMIA
Valine replaces glutamic acid at position 6 of beta chain
Sickle Hb forms polymer when dehydrated Hb electrophoresis HbS positive RBC containing HbF does not sickle (fewer
crises) Chronic hemolysis: RUQ pain secondary to
calcium bilirubinate gallstone Spleen not palpable Poorly healing ulcers of the lower extremity
SICKLE CELL ANEMIA (SS) VS. SICKLE CELL TRAIT (SA)
Sickle cell anemia (SS): Sickle cell trait (SA)
HbS: 75%-95%HbF: 2%-20%HbA2: 2-4%
HbS: 40%HbA: 60%
Factors precipitating sickling: Hypoxia, dehydration, acidosis, hypothermia
Crisis only w/ severe hypoxia: Examples include mountaineering and skiing. Hematuria more frequent than in SS.
CLINICAL CASE
Patient with sickle cell anemia complains of SOB, weakness. CBC shows hemoglobin of 5 (baseline 9-10)
Next study? Retic count to differentiate between
Hemolytic Crisis (Retic count high) secondary to splenic sequestration or co-existent G6PD deficiency vs. Aplastic crisis (Retic count low).
Treatment of sequestration is splenectomy. On exam of patient with splenic
sequestration: spleen palpable whereas it was not palpable on prior exams.
CLINICAL CASE
Patient with sickle cell complains of weakness.
Hematocrit 20 and low Retic index at 0.8. History of febrile illness and skin rash one
week ago. Most likely diagnosis? Aplastic crisis secondary to PARVOVIRUS.
CLINICAL CASE
Patient with sickle cell comes to ER with cough and chest pain worse on inspiration and lying down.
CXR shows infiltration and patient started on IV fluids and antibiotics.
In 48 hours NO clinical improvement, severe chest pain continues. Diagnosis and next step in management?
Acute Chest Pain Syndrome; arrange for Exchange Transfusion
CLINICAL CASE SCENARIO
Patient with anemia receives blood transfusion and develops chills/fever/chest and flank pain. Most likely diagnosis?
ABO incompatibility Treatment: Stop
transfusion and start IV hydration to prevent Acute Tubular Necrosis!
CASE SCENARIO Patient underwent
complete compatibility testing, receives blood transfusion and four hours later develops fever, chills. What happened?
Leukoagglutinin reaction (not secondary to hemolysis).
Treatment? Acetaminophen and
Diphenhydramine
CASE SCENARIO
Patient with lymphoma (immuno-compromised) needs blood transfusion. What to do?
Transfuse GAMMA Radiated Blood to prevent Graft vs. Host Disease.
CASE SCENARIO
History of Febrile Reaction with Blood Transfusion. Needs to be transfused again --- what to do?
Leukocyte depletion filter.
CASE SCENARIO
A blood transfusion leads to hives and bronchospasm caused by plasma proteins. If another transfusion is necessary, what is the next step?
Transfuse WASHED (“like the laundry”) packed RBC’s!
NEUTROPENIA18 y.o. black male, WBC
2000, Polymorphs
38%, asymptomatic
Repeat CBC in 3-4
weeks, if WBC same = Benign
neutropenia with no risk
infection
If after 3-4 weeks, WBC increased,
repeat again in 3-4 weeks. If WBC goes
down, Cyclic Neutropenia. Increased risk of
infection and treat with Granulocyte
Macrophage Colony Stimulating Factor!
IDIOPATHIC THROMBOCYTOPENIA (ITP)
Case: Young Female Patient with Platelets 8000. Started on Prednisone 40 mg. After 4 weeks, platelet count 150,000. When Prednisone tapered to 20 mg, platelet count drops below 20,000. Next step?
Plan for Splenectomy as patient needs high dose Prednisone to maintain platelet counts.
HEPARIN INDUCED THROMBOCYTOPENIA (HIT)
Type I usually mild and self limited; Type II (immune) is of clinical concern.
Type II occurs 5-15 days after starting therapy.
Increased risk of Thrombosis due to heparin induced platelet aggregation.
HIT II DIAGNOSIS
Diagnosis: 14C serotonin release assay; antiheparin/platelet factor 4 antibody.
Treatment: Stop all forms of heparin even the flush for the IV line.
HIT II TREATMENT
If anticoagulation needed use Danaproid, Lepirudin, Hirudin, or Argatroban. These have no Antidote!
Remember, “if you’ve got the poison (Heparin), then I’ve got the remedy (Protamine sulfate).”
CLINICAL CASE Patient in hospital
received heparin for DVT prophylaxis. Returned home and then after one week came back to ER in severe abdominal pain; on exam abdomen mildly tender in peri-umbilical area (subjective greater than objective pain).
Labs: WBC count and Lactic Acid high, Platelets law.
Most likely diagnosis?
Acute Mesenteric Ischemia secondary to HIT II.
COAGULATION CASCADE
Intrinsic (PTT)
12
11
9
8
Factor 10 (changes Prothrombin to
Thrombin)
Extrinsic (PT)
TF
7
COAGULATION CASCADE (CONTINUED)
Fibrinogen to Fibrin
Monomer via
Thrombin
Monomer to Polymer
Polymer to Cross linked
fibrin via Factor 13
VON WILLENBRAND’S DISEASE
Deficiency of vWF Most common
inherited bleeding disorder. Autosomal dominant.
Functions: Bridge for platelet adhesion and aggregation. Carrier for factor 8 (increases half life by five-fold).
Prolonged bleeding time despite normal platelet count.
Treatment? Desmopressin in
mild bleeding. Factor 8 concentrate
for severe bleeding or prior to surgery or if patient is still bleeding after desmopressin.
COAGULATION TESTS
Prolonged PTT and Normal PT
No bleeding: Factor 12 deficienc
y
Mild or rare bleeding: Factor 11 deficiency
Frequent and severe bleeding:
Factor 9 or 8 deficiency!!
HEMOPHILIA A VS. HEMOPHILIA B
Hemophilia A Hemophilia B
Affects only male Affects only male
Low factor 8 coagulation activity
Low factor 9 coagulant activity
Prolonged PTT (normal PTT on mixing study), normal PT
Prolonged PTT (normal PTT on mixing study), normal PT
Family history Family history
Spontaneous bleeding in the joints
Spontaneous bleeding in the joints
Treatment: Factor 8 concentrate
Treatment: Factor 9 concentrate
Normal Factor 8 antigen
COAGULATION TESTS
Prolonged PT, normal
PTT
Primary Factor 7 deficienc
y
Early Vitamin K deficiency (Vit K
dependent 2,7,9,10) due to
diet, broad spectrum ABX which kill gut
bacteria
Coumadin
COAGULATION TESTING
Both PTT and PT prolonged? Defect in common pathway DIC, Liver Disease, Vitamin K deficiency
MIXING STUDIES
Patient bleeding with platelets, PT,
bleeding time normal but PTT
elevated
Mixing Study with normal plasma: PTT
normal.
Factor 8 or 9 level
(deficiency?)
Tx: FFP
Mixing Study: PTT not corrected due to Lupus anticoagulant (not bleeding in
Lupus: hypercoagulable
state)
Mixing Study: PTT
not corrected
due to circulating anticoagulant Factor 8 antibody
(bleeding)
Patient with history of recurrent abortion
and stroke, increased PTT
CLINICAL CASE SCENARIO After a dental extraction,
patient develops severe bleeding. Normal platelets, bleeding time, PT, PTT. Most likely diagnosis?
Factor 13 deficiency (problem with forming cross-linked fibrin)
Diagnosis: Clot solubility in 5M urea
Treatment: FFP
ACUTE LEUKEMIA In children: 80% acute leukemia: ALL In adults 80% acute leukemia: AML S/Sx: fatigue, gum bleeding, epistaxis, ecchymosis,
purpura, petechiae, bone pain, recurrent infection. On exam: hepatosplenomegaly, lymphadenopathy
non tender, firm, rubbery (especially ALL). Labs: decreased platelet, decreased RBC and Hb/Hct,
increased WBC with 90% blast cell in peripheral smear (patients have leukopenia but due to blast cells total count increases).
Bone marrow: hypercellular with > 30% blast cells
ACUTE LEUKEMIA
AML cells have granules, Auer Rods, histochemical stain suggests myeloid enzyme such as peroxidase.
Worst prognosis: Monosomy 5 and 7
Treatment: Cytarabine and Daunorubicin. After remission consider Bone Marrow Transplant.
ALL cells have surface marker TdT (terminal dexy nucleotidal transferase).
Worst prognosis: t (9:22) and t (4:11)
Treatment: Vincristine, Prednisone, Daunorubicin, L-Asperginase – after remission CNS prophylaxis with intrathecal Methotrexate and cranial irradiation; also consider Bone Marrow Transplant.
AML ALL
CHRONIC MYELOGENOUS LEUKEMIA
Hallmark: WBC > 100,000
Most cells mature (less than 5% blast cells)
Low leukocyte Alk. phos.
: fatigue, night sweats, low grade fever
On exam: splenomegaly, sternal tenderness
Drug of choice: Imatinib mesylate (inhibit tyrosine kinase activty of bcl/abl oncogene).
Bone marrow transplant (only curative treatment < 60 year old with HLA matched sibling).
CML (PHILADELPHIA CHROMOSOME)
Philadelphia chromosome negative CML has poorer prognosis than Philadelphia chromosome positive.
CHRONIC LYMPHOCYTIC LEUKEMIA
Hallmark: lymphocytosis
WBC usually greater than 20,000 (75-95% of cells are mature lymphocytes)
Usually CD19 is a marker of B and CD5 of T lymphocyte.
Usually patient will be >65 yr of age.
If Anemia + Thrombocytopenia: IV Fludrabine (IV), Chlorambucil. Refractory CLL: Alemtuzumab
HODGKIN’S LYMPHOMA
Commonly presents as painless cervical lymphadenopathy in young children.
To diagnose? Lymph node biopsy
“Reed-Sternberg” cells
HODGKIN’S LYMPHOMA
Most common: nodular sclerosing type.
Staging: I: one lymph node II: two or more lymph
nodes on one side of diaphragm
III: both sides of diaphragm
IV: disseminated disease
A: No constitutional symptoms
B: fever, night sweats
Treatment: IA and IIA: radiation.
Others: chemotherapy
ABVD: Adriamycin, Bleomycin, Vincristine, Dacarbazine
BURKITT’S LYMPHOMA B-cell lymphoma Translocation of
protooncogene C-myc from Chromosome 8 to 14
Presentation: abdominal pain/fullness
Retroperitoneal or pelvic lymphadenopathy
Treatment: low risk – chemotherapy and high risk – autologous stem cell transplant
Dx: lymph node biopsy (uniform small cells with scant cytoplasm), “starry sky”
MULTIPLE MYELOMA Age > 65 Anemia, bone pain,
renal failure, increased calcium, proteinuria
Plasma cell malignancy (paraproteins produced)
Dx: SPEP, UPEP Bence Jones protein in
urine Dipstick (detects
albumin, intact globulin) will be negative, urine protein quantitation will have proteinuria
Monoclonal spike in beta or gamma globulin region. IgG – 60%, IgA – 25%, light chain – 15%
Bone x-ray with lytic lesion Bone marrow infiltrated
with plasma cells Treatment: Combination
chemo with VAD (Vincristine, Adriamycin, Dexamethasone). If not tolerated: Thalidomide + Dexamethasone
< 70 yo: consider autologous stem cell transplant.
THANK YOU FOR YOUR ATTENTION
Questions?