HEME_MS2

HEMORRHAGE

HEMOLYSIS

• MEGALOBLASTIC
• --B12 DEF
• --FOLATE DEF
• --DRUG INDUCED
• --MDS

• NONMEGALOBLASTIC
• --ALC
• --LIVER DISEASE
• --APLASTIC ANEMIA
• --ENDOCRINOPATHY

HEMORRHAGE

HEMOLYSIS

• STEM CELL
• --APLASTIC ANEMIA
• --RBS APLASIA

LIVER DISEASE

RENAL DISEASE

CHRONIC DISEASE

Fe DEF

CHRONIC DISEASE

THALASSEMIA

Hg-OPATHY

SIDERBLASTIC ANEMIA

LEAD INTOX

PORPHYRIA

ANEMIA PRESENTING WITH MCV < 80

MICROCYTIC ANEMIA

KOILONYCHIA -- spoon shaped nails

PICA

ESOPHAGEAL WEBS -- PLUMMER-VINSON SYND

CHLOROSIS -- GREEN-TINGED SKIN COLOR

• LOW:
• --Hgb/Hct/RBC
• --MCV
• --MCHC

• HIGH:
• --RDW
• --Plt Ct

ANISOCYTOSIS

POIKILOCYTOSIS

HYPOCHROMIA

PENCIL-SHAPED CELLS

TARGET CELLS

ELLIPTOCYTES TYPICAL OF ANEMIA BUT NOT Dx

(Fe DEF COVERED IN MICROCYTIC ANEMIA LECT)

TOTAL BODY IRON ~ 2-3,000 mg

TOTAL STORAGE IRON ~ 1,000 mg

• DIET
• --ABS 10% OF INTAKE ~ 1mg

--TRANSPORT - TRANSFERIN, CAPACITY TO BIND ~ 300ugFe/dL

--USAGE - MOSTLY BY RBCs TO MAKE Hg, SMALL AMOUNTS USED TO PROD NON-HEME ENZs. 1ml PACKAGED RBC (2ml whole blood) IS ~ 1mg/day

--STORAGE - FERRITIN = APOFERRITIN + IRON; STORAGE IN BN MW OTHER SITES. INC FERRITIN ~ INFLAM

--EXCRETION - 1mg/day

DIET -- #1 WORLDWIDE; USA INFANTS AND CHILDREN

BLOOD LOSS -- MENSTRAL, OCCULT, GI

DEC ABS

•Serum Fe

• •TIBC – Total Iron Binding Capacity of
• Transferrin

•% Saturation = Fe/TIBC

• •Ferritin – serum level closely follows
• storage amount

SERUM Fe (--)

TIBC ++

%SAT <10 (--)

FERRITIN (-)

L SERUM Fe

TIBC (nL or -)

%SAT <15 (-)

FERRITIN (nL OR +)

MICROCYTIC ANEMIA

ALL nL

MICROCYTIC ANEMIA

MICROCYTIC ANEMIA

SERUM Fe ++

TIBC (nL OR -)

%SAT ++

FERRITIN ++

MICROCYTIC ANEMIA

BN MW STORAGE OF IRON IS DEPLETED

SERUM FERRITIN DEC THEN SERUM Fe DEC AND TIBC INC

RBC PRECURSORS DEC IN SIZE & RDW INC. NO MCV DEC YET

Hgb/Hct BEGIN TO DEC

MCV DEC

RBC BECOME HYPOCHROMIC

MCHC DEC

MICROCYTIC ANEMIA

CAUSES DEC PROD OF RBC AS WELL AS AN IMPAIRED IRON UTILIZATION

STORAGE IRON IN MACROs OF THE BONE MARROW IS NOT RELEASED TO THE RBC PRECURSORS. THEREFORE, FERRITIN IS INC, SERUM Fe IS DEC, AND TIBC IS nL OR DEC

--CHRON MICROBIAL INF SUCH AS OSTEOMYELITIS, TB, ABCESS, ENDOCARDITIS

--IMMUNE DISORDERS SUCH AS RHEUM ARTH

--CHRON GI DISORDERS

--NEOPLASMS - VARIOUS CARCINOMAS, LYMPHOMAS

MICROCYTIC ANEMIA

• DEFINED BY BONE MARROW FINDINGS
• --15% RBC PRECURSORS MUST BE RINGED SIDEROBLASTS (rbc precursor w iron abnormally in mito that rim the nuclear mem giving an appearance of blue pearl necklace)

• HEREDITARY
• --X LINKED
• --AUTOSOMAL RECESSIVE
• --d-AMINOLEVULINIC ACID SYNTHETASE (ALA)

• ACQUIRED
• --DRUG INDUCED
• --TOXIN
• --DISEASE ASSOC
• --IDIOPATHIC (myelodysplastic state)

MICROCYTIC ANEMIA

HYPOCHROMIC

ABL BASOPHILIC STIPPLING

RBC CHANGE LATE IN DISEASE COURSE

LEAD INH HEME PROD AT SEVERAL POINTS, AND SPECIFICALLY, INH ALA DEHYDRATASE AND FERROKETOLASE

MCV >= 100

Grp OF ANEMIAS w DEFECTIVE DNA SYNTH

RESULTING IN ABN LARGE ERYTH PRECURSORS (megaloblasts)

• MOST OFTEN CAUSED BY VIT B12 OR FOLATE DEF
• --BOTH NEC IN PROD OF THYMIDINE FOR DNA SYNTH
• --DOES NOT EFFECT RNA SYNTH FOR TRANSCRIPT/TRANSLATE OF GENES

NUC REMAIN IMMATURE WHILE CELL GROWS AND CYTO MATURES

HEMATO CELLS MOST APPARENT, BUT AFFECTS ALL OTHER CELLS UNDERGOING MITOTIC DIVISION

•Defective DNA synthesis due to decreased thymidine production

•Most cases are due to B12/Folate deficiency

• •RNA uses uracil, not thymidine, hence transcription/translation is not
• affected

• •In developing cells, nuclei remain large and immature, cytoplasm continues to
• mature

GLOSSITIS AND VAGUE ABN PAINS

INH OF DNA SYNTH --> CAN'T REPLACE GI LINING

–Hgb/Hct/RBC ↓

MCV ↑

MCHC Nl

–Plt Ct nl or ↓

WBC nl or ↓

–LDH ↑↑

T. Bili nl or ↑

Indirect Bili ↑

PREDOMINANTLY MACRO-OVALOCYTES

ANISOCYTOSIS AND POIKILOCYTOSIS

ALSO FEW FRAG RBCs

HYPERSEG NEUTS (>5 lobes)

HYPERCELLULAR BONE MARROW

MACROCYTIC ANEMIA

•Daily requirements – 1-2 µg

•Body stores – 3,000 – 5,000 mg

•If diet lacks B12, 5-6 years for deficiency to develop

•Dietary source – animal origin foods

• B12 ABS REQ IF
• --ONLY ABS IN TERM ILEUM
• --BINDS TO TRANSCOBALAMIN FOR TRANS

B12 = COBALAMIN

•Pernicious anemia

•Dietary lack

•Diphyllobothrium latum

• •Bacterial overgrowth (Blind-loop
• syndrome)

•Malabsorption syndrome

•Transcobalamin deficiency

•Drug inhibition

B12 DEFICIENCY

•Atrophic gastritis, hypochlorhydria, decreased or absent IF

•Anti-parietal cell antibodies sensitive (present in 90%), but not specific

•Anti-Intrinsic factor antibodies specific (75%), but not sensitive

• •Schilling test
• --LOADING DOSE OF IM B12
• --ORAL LABELED B12 --> OUTPUT MEASURED IN URINE
• --IF LOW --> GIVE w I.F. --> RETURN TO nL THEN IF DEFICIENCY
• --IF STILL LOW, THEN MALABSORPTION OTHER THAN I.F.

• MYELIN MAINTENANCE
• --B12 DEFICIENCY --> DEMYELINATION OF POSTERIOR AND LAT COLUMNS OF SPINAL CORD
• --CAN OCCUR w/o ANEMIA

• LOW RBC FOLATE
• --B12 AIDS IN PASSING FOLATE THROUGH RBC MEM (most consistent measure of folate

LARGE DOSES OF FOLATE CAN CORRECT ANEMIA IN B12 DEF, BUT NEURO DAMAGE WILL CONTINUE AND BECOME IRREV

• Dx
• --SERUM AND RBC FOLATE LEVELS
• --SERUM FOLATE FLUCs QUICKLY, HENCE RBC FOLATE IS MORE ACCURATE

•Daily requirements – 200 µg

•Body stores – 20 - 70 mg

•If diet lacks Folate, 3 months for deficiency to develop & MEGALOBLASTIC ANEMIA

•Dietary source – vegetables (esp. green leafy) and fruits (heat labile)

•FOLATE (Pterylmonoglutamic acid) is in food as polygutamates

•After ingestion, split into monoglutamates

•Absorbed in proximal jejunum

•Converted to 5-methyltetrahydrofolate for transport

•Serum B12 level

•Serum Folate level (fluctuates)

•RBC Folate level better indicator of folate stores

•Large doses of folate can improve anemia in B12 deficiency, but not the neurologic affects

• OTHER CAUSES OF MEGALOBLASTIC ANEMIA
• --DRUG/TOXIN
• --MYELODYSPLASTIC STATES

FOLATE and/or B12 DEFICIENCY

•Once treated with appropriate substance:

–Megaloblastic changes in BM revert to normal maturation within hours

–Reticulocytes begin to increase in 2-3 days

–10 days – two weeks for peak retic rise

–4 weeks for Hgb to improve

–Variable time for Hgb to return to normal

• –Large doses of Folate can correct anemia in B12 deficiency, but neurologic deficits will progress and
• become irreversible

• •Macrocytic anemia, macro-ovalocytes
• --NRBC and Howell-Jolly bodies

•Pancytopenia, hypersegmented neuts

•Hypercellular bone marrow

•Increased LDH

•Increased Total bilirubin d/t indirect bili

• NON-MEGALOBLASTIC MACROCYTIC ANEMIA
• --MCV >= 100 w ROUND, NOT OVAL MACROCYTES

• •Failure of hematopoietic stem cell resulting in pancytopenia
• --MARKEDLY HYPOCELLULAR BONE MARROW

• •Clinical Findings:
• –Usual signs/symptoms of anemia

–Petechiae

–Bacterial infections

•Laboratory Findings:

• Hgb/HctRBC ↓
• WBC ↓
• Plt Ct ↓
• MCV nl. or ↑

• nL

• APLASTIC

•Inherited – Fanconi anemia

•Acquired

–Idiopathic (most common)

–Chemical agents

–Idiosyncratic drug reaction

–Radiation

–Viral infections

Miscellaneous

ALC ABUSE

LIVER Dz -- MORE TARGET CELLS

ENDOCRINOPATHIES

•Hemolysis - RBC have a shortened live span, < 120 days

•RBC are destroyed either within the peripheral blood circulation = intravascular

•Or, RBC are destroyed outside of the peripheral blood - extravascular

RBCs FRAGMENTED IN BLOOD STREAM

RELEASED Hg BIND TO HAPTOGLOBIN --> REMOVED BY LIVER WHERE Hg BROKEN DOWN

WHEN HAPTOGLOBIN DEPLETED, FREE Hg CLEARED THROUGH RENAL TUBULES AND APPEARS IN URINE

SOME ABS BY TUBULAR CELLS, BROKEN DOWN, AND IN FEW DAYS CONTAIN HEMOSIDERIN SEEN IN URINE SEDIMENT (hemosiderinuria)

SERUM HAPTOGLOBIN -

PLASMA Hg +

URINE Hg +

URINE HEMOSIDERIN + (after several days)

LDH +

PERIPHERAL BLOOD SMEAR - SCHISTOCYTES

RBCs DESTROYED OUTSIDE OF BLOOD STREAM BY MACROPHAGES

USUALLY IN THE SPLEEN

REMNANTS OF RBCs FORM MICRO-SPHEROCTES

MACROPHAGES PROCESS Hg & RELEASE END PROD BILIRUBIN

--> BILI BINDS TO ALBUMIN AND CLEARED BY LIVER

INC BILI INTO GI CONVERTED TO UROBILINOGEN WHICH IS REABSORBED AND EXCRETED IN URINE

INDIRECT BILI +

URINE UROBILI +

LDH +

• PERIPH BLOOD SMEAR =
• MICRO-SPHEROCYTES

Inherent defect of RBC, most often inherited, involving membrane, hemoglobin or enzymes

• •Membrane Disorders
• –Spherocytosis
• –Elliptocytosis
• –Stomatocytosis

• •Hemoglobinopathy
• –SS Disease
• –Thalassemias
• –Others

• •Enzyme Deficiency
• –G-6-PD Deficiency
• –Pyruvate kinase deficiency
• –Paroxysmal Hgb

RBC is inherently normal, something extrinsic to RBC is causing damage, most often immune-related, vascular, infectious, toxic or mechanical

INTRINSIC HEMOLYTIC ANEMIA

MEM DEFECT

•Autosomal dominant

•Ankyrin/spectrin gene mutations

•Spherical shaped RBC are sequestered/destroy by spleen

•Variable clinical course

SPLENECTOMY MAY BE BENEFICIAL TO REDUCE HEMOLYSIS, BUT RBCs STILL SPHERICAL

OSMOTIC FRAGILITY TEST

Major Normal Hemoglobins:

A α2β2 (adult)

A2 α2δ2

F α2γ2 (fetal)

Abnormal Hemoglobins:

Bart’s γ4

H β4

S α2β2 6glutamic→valine

C α2β2 6glutamic→lysine

ELONGATION OF RBC WITH OVAL OR ELLIPTICAL SHAPE

NON-SPECIFIC FINDING

CAN BE INC w CHEMOTHERAPY

MANY ELLIPOs INDICATE HEREDITARY ELLIPTOCYTOSIS (autosomal dominant)

LOSS OF MEM SURFACE AREA CAUSING SPHERE SHAPE

APPEAR ROUND w DENSE STAINING AND NO CENTRAL PALLOR

MICROSPHEROCYTES ARE INDICATIVE OF EXTRAVASCULAR HEMOLYSIS

nL SIZED SPHEROCYTES INDICATIVE OF HEREDITARY SPHEROCYTOSIS (autosomal dominant)

CENTRAL PALLOR IS SLIT-LIKE INSTEAD OF ROUND

NON-SPECIFIC FINDING -- POSS IN MYELODYSPLASTIC STATES

ASSOC w Rh NULL Dz, HEREDITARY STOMATOCYTOSIS (autosomal dominant)

CODOCYTE

CAUSED BY INC CELL MEM FOR AMOUNT OF Hg

ASSOC w LIVER Dz, ASPLENIA, HYPOCHROMIC ANEMIA, AND Hg-opathies

DACROCYTE

NON-SPECIFIC FINDING

ASSOC w MYELOFIBROSIS

FRAG RBCs

INDICATIVE OF INTRAVASC HEMOLYSIS

CAN BE HELMET OR BITE SHAPED CELL

SPUR CELL

MEM HAS LONG PROJs, NONSYM DISTRIBUTION, w BULBOUS ENDS

ASSOC w SOME TYPES OF LIVER Dz AND a-b-LIPOPROTEINEMIA

ECHINOCYTE

MEM HAS SHORT SPIKES, SYM DISTRIBUTION, SHARP POINTED ENDS

ASSOC w RENAL FAILURE

PERIPH MEM SHAP IS SCALLOPED

USUALLY DRYING ARTIFACT BUT CAN BE ASSOC w HYPEROSMOLALITY

DEPRANOCYTE

CELL IS ELONGATED AND CURVED w POINTED ENDS

MOST OFTEN SEEN IN S-S Dz

CAN BE ASSOC w FEW OTHER Hg-OPATHIES

RBC INCLUSIONS

SMALL BLUE DOTS DISTRIBUTED THROUGHOUT THE CELL

REMNANTS OF RNA

FINE STIPPLING IS INDICATIVE OF YOUNF RBC

• COURSE STIPPLING IS SEEN IN: --THALASSEMIA
• --LEAD INTOX
• --MYELOBLSTIC STATES

RBC INCLUSION

USUALLY SINGLE, DENSE ROUND INCLUSION OF MAGENTA COLOR

REMNANT OF NUCLEUS

MOST OFTEN SEEN IN ASPLENIA, BUT ALSO IN MEGALOBLASTIC ANEMIA AND MYELODYSPLASTIC STATES

NUC RBC PRECURSORS SHOULD NOT BE SEEN IN PERIPH CIRC

IF PRESENT, MAY BE ASSOC w STRESS SUCH AS ACUTE HEMORR, SEVERE ANEMIA, HEMOLYSIS, etc, OR TRUE NEOPLASM

RBC INCLUSION

SMALL BLUE INCLUSIONS

USUALLY ECCENTRICALLY LOCATED, ONE OR SEVERAL

CONSISTS OF STAINABLE IRON

ASSOC w IRON OVERLOAD IN MARROW AND ASPENIA

CELL w PAPP BODIES IS A SIDEROCYTE,

NUCLEATED RBC w IRON IS A SEDEROBLAST,

NUCLEATED RBC w IRON AROUND NUC IS A RINGED SIDEROBLAST

RBC INCLUSION

INLY SEEN WITH SUPRA-VITAL STAINING

CONSISTS OF PRECIPITATED Hg

INDICATIVE OF UNSTABLE Hg

ASSIC w G-6-PD DEFICIENCY, SOME DRUGS, AND SOME Hg-OPATHIES

DIFFUSE BLUE COLOR OF RBC

REMNANT OF RNA

INDICATIVE OF YOUNG RBC (RETICULOCYTE)

YOUNG RBC THAT IS SLIGHTLY LARGER THAN MATURE RBC

MAY BE SEEN AS POLYCHROMASIA, BUT BEST DETECTION IS BY RETICULOCYTE COUNT

STICKING TOGETHER OF RBC

DUE TO LOSS OF ZETA POTENTIAL CAUSED BY INC FIBRINOGEN OR GAMMA GLOBULINS

RBCs NORMALLY (-) CHARGE

AGGLUTINATED CLUMPS OF RBC DUE TO AUTO ANTI-BODIES OF IgM

RC X (Pt Hct / 45) x 1/F = RI


1 45

1.5 35

2 25

2.5 15

•Weakness, malaise, fatigue

•Dyspnea on exertion

•Pallor – skin, conjunctiva, nail beds

•Angina

•Headache, faintness, dim vision

•RBC count

•Hematocrit

•Hemoglobin

•MCV - Mean cell volume

•MCH – Mean cell hemoglobin

•MCHC – Mean cell hemoglobin conc.

•RDW – Red cell distribution width

HEMOLYTIC ANEMIA

•Β-Thal Major

• –Severe
• anemia, 6-9 months

–Hemolysis

–↓↓ or absent HbA

• –Skeletal
• changes

• –Requires
• transfusions

• –Secondary
• hemochromatosis

• –Β0/β0, β+/β+
• -----------------------------------

•β-Thal Intermedia

–β0/β and β+/β+

• –Moderate microcytic anemia not requiring transfusion
• ----------------------------------------

•β-Thal Minor

–β0/β and β+/β

• –Microcytosis
• with or without anemia

–MCV < 80, RBC may be normal count

–RDW normal

–Hb A2 is mildly increased, 4 – 8%

•Alpha chain gene locus chromosome 16

•Two loci, hence 4 alleles

•Most common cause of alpha-thalassemia is gene deletion as opposed to mutation

•Normal genotype αα/αα

•-α/αα silent carrier, no anemia

•--/αα, -α/-α similar to beta-thal minor with microcytosis, mild anemia

• •--/-α resembles beta-thal intermedia,
• forms HbH

•--/-- lethal to fetus; hydrops fetalis

PROBS w HEXOSE MONOPHOSPHATE SHUNT OR GLUTATHIONE MET MAY LEAVE RBC VULN TO OX INJ

• G-6-P DEHYDROGENASE DEFICIENCY
• --X-LINKED RECESSIVE
• --MANY VARIANTS BUT ONLT 2 HARMFUL

• OXIDANT STRESS
• --GLOBIN CHANS BECOME UNSTABLE
• --PRECIPITATE AS HEINZ BODIES
• --INTRA/EXTRA VASCULAR HEMOLYSIS

SELF LIMITED AS OLDER RBCs ARE MOST VULNERABLE

ANTI-MALARIALS, SULFONAMIDES, VARIOUS INF, INGESTION OF FAVA BEANS

RARE

• ACQUIRED INTRINSIC RBC DEFECT
• --MUTATION IN PHOPHATIDYLINOSITOL GLYCAN A
• --PROD CERTAIN MEM PROTS

RBC SENSITIVE TO LYSIS BY COMPLEMENT DUE TO DEFICIENCY OF CERTAIN CELL MEM PROTS

PLATELETS AND WBCs MAY BE SIMILARLY AFFECTED

• •Sickle Hb
• – Beta chain gene point mutation causes one AA substitution:

6th position, valine substituted for glutamic acid

•HbS, with de-oxygenation, polymerizes

•Polymerized HbS may be reversible to a point

•RBC becomes deformed into “sickle” shape

•Heterozygote genotype: β/β6glutamic→valine

• Sickle trait:
• 40% HbS
• 60% HbA

•Usually asymptomatic

• •Can have sickle crisis if under extreme conditions
• --------------------------------------------------

•Homozygous genotype:

β6glutamic→valine/β6glutamic→valine

•HbF is protective until 6-9 months of age

•Patient’s have a hemolytic anemia

•Most serious problems relate to irreversible sickling and vaso-occlusion

Autosplenectomy

Vaso-occlusive crisis

• Sequestration crisis
• --CHILDREN w INTACT SPLEENS
• --MASSIVE ENTRAPMENT OF SICKLE RBC --RAPID SPLENIC ENLARGEMENT, HYPOVOLEMIA, SHOCK

Infections with encapsulated organisms

• Aplastic crisis
• --RBC PROGENITOR CELLS INF w PARVOVIRUS B19
• -- AFTER MARROW GIVES OUT, CAN REGENERATE

2ND MOST COMMON STRUCTURALLY ABN Hg DETECTED IN U.S.

MAY HAVE MILD HEMOLYSIS

MANY TARGET CELLS

EXTRINSIC DEFECTS OF RBC

Auto-immune

•“Warm antibody” IgG

• •Diagnostic test is DAT
• --DIRECT ANTI-GLOBULIN TEST

•Can be acute or chronic

•Usually associated with other autoimmune disorders (SLE)

•Most hemolysis is extra-vascular

COLD ANTIBODY DUE TO IgM AUTO-ANTIBODIES (rarely in vivo)

• Allo-immune
• --FROM TRANSFUSION

• Drug induced
• --Dg STICKS TO RBC AND Ab BINDS TO Dg
• --ANTI-Dg Ab BINDS TO Dg, AND IMMUNE COMPLEX ACTIVATES COMPLEMENT
• --Dg INDUCES FORMATION OF AUTO-Ab TO INTRINSIC Ag ON RBC MEM

EXTRINSIC DEFECTS OF RBC

BUT CAUSES INTRAVASCULAR HEMOLYSIS

RBCs CHEWED UP IN BLOOD STREAM BY SMALL VESSLES

RBCs MECHANICALLY SHEARED AS PASS THROUGH

• –Thrombotic thrombocytopenic purpura
• ----MUST Dx QUICKLY
• ----FRAG RBCs FOUND

–Disseminated intravascular coagulation

–Hemolytic uremic syndrome

–Severe vasculitis

•Immune Related

•Micro-angiopathic

• •Infectious agents
• --Direct hemolysis by micro-organism
• --Toxin production

•Chemical agents

• •Mechanical
• --March hemoglobinuria
• --Prosthetic Heart valve

MICROANGIOPATHIC HEMOLYTIC ANEMIA

PLATELET AND FIBRIN THROMBI FORM IN SMALL ARTERIOLES AND CAPILLARIES IN WIDESPREAD DISTRIBUTION

• MUST Dx QUICKLY
• --MUST DISTINGUISH FROM DIC
• --DIC HAS FIBRIN THROMBI AND INC PT AND aPTT
• --TTP HAS PLATELET THROMBI AND nL PT AND aPTT

•Deficiency of vWF cleaving-protease

•Most cases are acquired

•F:M 3:2

•Most cases are fulminant – survival directly relates to time period of initiation of therapy

• PENTAD OF CLINICAL SYND
• --THROMBOCYTOPENIA
• --HEM ANEMIA
• --NEURO ABN
• --FEVER
• --RENAL DYSFUNCTION

PLATELET FUNCTION ANALYSIS

CEPI = COLLAGEN AND EPINEPHRINE

CADP = COLLAGEN AND ADP

• CEPI <180 = NORMAL PLATELET FUNCTION
• --NO SIGNIFICANT PLATELET DEFECT

CEPI > 180 and CADP <116, ASPIRIN OR OTHER MED EFFECT

• CEPI > 180 and CADP >116, ABN PLATELET FUNCTION
• --THROMBOCYTOPENIA AND ANEMIA SHOULD FIRST BE EXCLUDED

PT -- EXTRINSIC CLOTTING SYSTEM

PROLONGED IN:

• INHERITED
• --I, II, V, VII, X

• ACQUIRED MULTI DEFICIENCIES OF
• --II, VII, X IN WARFARIN-TYPE ANTOCOAG THERA

INSENSITIVE TO HEPARIN

METHOD FOR MONITORING HEPARIN THERAPY AND CLOTTING DEFICIENCIES

PROLONGED TIME CAUSED 6 POSS CONDITIONS

1) HEPARIN -- MOST COMMON CAUSE

2) FACTOR DEF -- VIII & IX MOST COMMON. MULTI DEFs SEEN IN LIVER Dz OR DIC

• 3) FACTOR DEF w LITTLE/NO CLINICAL SIG
• --DEF IN "CONTACT FACTORS". MARKED PROLONGATION OF aPTT BUT NOT CAUSE BLEEDING. SEVERE DEF MAY CAUSE HYPERCOAG STATE

4) SPECIFIC FACTOR INHIBITOR CAUSING BLEEDING -- NEARLY ALWAYS DUE TO Ab OR FACTOR VIII AND LEAD TO SEVERE BLEEDING DIATHESIS

5) LUPUS ANTICOAG, RISK FACTOR FOR THROMBOSIS -- Ab TO PHOSPHOLIPID-PROT COMPLEXES. CAUSE PROLOGATION OF THE aPTT AND/OR OTHER COAG TESTS BUT, PARADOXICALLY, ARE ASSOC WITH HYPERCOAG and THROMBOSIS

6) SPURIOUS

IF CORRECTED ~ DEFICIENCY OF COAG FACTOR

STILL PROLONGED ~ INHIBITOR OR COAG PRESENT

THROMBIN ADDED TO Pt FIBRINOGEN

DETECT INH OF THROMBIN-FIBRINOGEN INTRACTION OR INH TO FIBRON-MONOMER POLYMERIZATION

• PROLONGED IN PRESENCE OF:
• --LOW CONC OF HEPARIN
• --FIBRINOGEN DEGRADATION PRODS
• --ABN FIBRINOGENS (fetal fibrinogen in newborn)
• --SEVERE HYPOFIBRINOGENEMIA

UNAFFECTED BY VIT K ANTAGONIST THERAPY AND IS NORMAL IN DEF STATES OF ALL CLOTTING FACTORS EXCEPT SEVERE FIBRINOGEN DEF

FIBRINOGEN < 100 ~ ONE STAGE CLOTTING TESTS WILL TEND TO BE ABN LONG DUE TO HYPOFIBRINOGENEMIA ALONE

• ACQUIRED HYPOFIBRINOGENEMIAS CAN OCCUR SEC TO:
• --SEVERE LIVER Dz
• --DEPLETION PHASE OF CONSUMPTION COAG
• --RARE COND OF PRIMARY FIBRINOLYSIS

PRESENT POST OP, w ESTROGEN THERA, AND PREGO

FIBRINOGEN IS ACUTE PHASE REACTANT AND RISES w INFLAM AND STRESS

HEPATOs SYNTH ALL NATURAL COAG INH FACTORS EXCEPT vWF

MEGAKARYOCYTES AND ENDOTHELIUM SYNTH AND SECRETE vWF

• VIT K
• --FAT SOL
• --HEPATOs, COFACTOR IN SYNTH OF FACTORS II, VII, IX, X PROT C, PROT S -- ALL BIND Ca2+ AND INTERACT w PHOSPHOLIPID

• FIBRIN DEGRADATION PRODS CLEARED BY LIVER
• --POST-RIBO MODIFICATION
• --

SUSPECTED VENOUS THROMBOEMBOLISM

ELEV MODESTLY IN INTAVASCULAR (venous or arterial) THROMBOSIS

ELEV MODESTLY WHENEVER THERE IS AN EPISODE OF HEMOSTASIS

ELEV MILD OR MOD IN DIC (acute or chronic)

ELEV MILD TO MOD IN PRE-ECLAMPSIA

• MYELOID:
• CD 13, 33, 11c, 34

• PRE-B-LYMPHOBLASTIC:
• CD 19, 20, 10, 34

• T-LYMPHOBLASTIC:
• CD 2, 5, 7

• B-LYMPHOBLASTIC:
• CD 19, 20, 10, MONOCLONAL SIg

• SIg ~ SURFACE Ig = OLDER
• NO SIg = YOUNGER

• MYELOID:
• CD 13, 33, 11c, 34

• PRE-B-LYMPHOBLASTIC:
• CD 19, 20, 10, 34

• T-LYMPHOBLASTIC:
• CD 2, 5, 7

• B-LYMPHOBLASTIC:
• CD 19, 20, 10, MONOCLONAL SIg

• SIg ~ SURFACE Ig = OLDER
• NO SIg = YOUNGER

• MYELOID:
• CD 13, 33, 11c, 34

• PRE-B-LYMPHOBLASTIC:
• CD 19, 20, 10, 34

• T-LYMPHOBLASTIC:
• CD 2, 5, 7

• B-LYMPHOBLASTIC:
• CD 19, 20, 10, MONOCLONAL SIg

SIg ~ SURFACE Ig = OLDER

NO SIg = YOUNGER

• MYELOID:
• CD 13, 33, 11c, 34

• PRE-B-LYMPHOBLASTIC:
• CD 19, 20, 10, 34

• T-LYMPHOBLASTIC:
• CD 2, 5, 7

• B-LYMPHOBLASTIC:
• CD 19, 20, 10, MONOCLONAL SIg

SIg ~ SURFACE Ig = OLDER

NO SIg = YOUNGER

AML w t(8;21)

FUSION OF GENES AML1 AND ETO

5-12% OF ALL AML

USUALLY IN YOUNGER Pts

BM SHOWS MATURATION OF MYELOID w AT LEAST 10% PROMYELOCYTES, MYELOCYTES, AND METAMYELOCYTES. AUER RODS FREQUENT

PROG -- USUALLY GOOD RESPONSE TO CHEMO

inv(16) OR t(16:16)

10-12% OF AMLs

USUALLY IN YOUNGER Pts

LEUK BLASTS SHOW EVIDENCE OF MONOCYTIC AND NEUTROPHILIC MATURATION

BM SHOWS INC EOSINOPHILS AND PRECURSORS w ABNORMAL GRANULES.

REARRANGEMENTS OF GENE CBFb (core binding factor beta) AT 16q22 TO MYHII (smooth musc myosin heaby chain) AT 16q13

PROG -- RELATIVELY BETTER w HIGH RATES OF COMPLETE REMISSION AND LONG TERM REMISSION

ACUTE PROMYELOCYTIC LEUKEMIA

RARa on 17, PML on 15

5-8% OF AMLs

PREDOM MIDDLE AGED ADULTS

MALIG PROMYELOCYTES w VARIABLE "KIDNEY BEAN" SHAPE

TYPICAL HYPERGRANULAR FORM w NUMEROUS PROMINENT PRIMARY GRANULES

MULTI AUER RODS

TRANSLOCATION -- FUSION OF RARa (RETINOIC ACID-RECEPTOR-a = vit a -- cell differentiation) w PML (proto-oncogene)

HIGH RISK DIC DUE TO PRO-COAG ACTIVITY OF GRANULES

GIVE VIT A (more neuts grow to maturity) FOLLOWED BY CHEMO

SHOWS MONOCYTIC DIFFERENTIATION w OR w/o NEUT DIFFERENTIATION

GENE MML

MONOCYTIC DIFF DETECTED BY +NONSPECIFIC ESTERASE & +SUDAN

5-6% OF AMLs

t(9;11) or t(11;19) RESULTS IN REARRANGEMENT OF GENE MLL (dev regulator) AT 11q23

INTERMEDIATE SURVIVAL

NOT OTHERWISE CATEGORIZED

>20% BLASTS IN BM

NO AUER RODS

NEG CYTOCHEM STAINS

• MYELOID MARKERS BY IMMUNOPHENOTYPING
• --CD 13, 33, 11

NOT OTHERWISE CATEGORIZED

>20% BLASTS IN BM

<10% CELLS OF MYELOID MATURATION

AUER RODS MAY BE SEEN

NOT OTHERWISE CATEGORIZED

SIMILAR TO t(8;21)

>20% BLASTS

• >10% CELLS OF MATURATION
• --PRO, META, MYELOCYTES

FREQUENT AUER RODS SEEN

30-45% OF AMLs

USUALLY IN YOUNGER AGE GROUPS AND RELATIVELY BETTER PROG

NOT OTHERWISE CATEGORIZED

BLASTS SHOW MYELOID AN MONOCYTIC DIFF

>20% but <80% MONOCYITIC CELLS

MANY CASES INV 11q

15-20% OF AMLs

NOT OTHERWISE CATEGORIZED

>80% MONOCYTIC DIFF

CLINICALLY -- MORE OFTEN HAS TISSUE INFILTRATION, esp GINGIVAL HYPERTROPHY DUE TO LEUKEMIC INFILTRATE

MONOBLASTIC -- PREDOM OF MONOBLASTS

MONOCYTIC -- SOME MATURATION

11q FREQUENTLY INV

5-8% OF AMLs

NOT OTHERWISE CATEGORIZED

PROLIF OF MEGA-BLASTS AND ABN MATURE MEGA-CYTES

ASSOC w FIBROSIS IN BM HAMPERING Dx

GROUP OF ACQUIRED CLONAL HEMATOPOIETIC STEM CELL DISORDERS

CHAR CLINICALLY AND MORPH BY INEFFECTIVE HEMATOPOIESIS

HYPERCELLULAR, DYSPOIETIC MARROW RESULTING IN INTRAMEDULLARY CELL DEATH AND PERIPHERAL CYTOPENIAS

MACROCYTIC

TENDENCY TO PROGRESS TO ACUTE MYELOID LEUKEMIA

MDS

ABNORMAL MATURATION (dysplastic) OF HEMATOPOIETIC PRECURSORS IN BM

DETECTED MORPH AND FUNC

ALL 3 CELL LINES OF BM INVOLVED, BUT SEVERITY OF EACH IS VARIABLE, AND INDIVIDUAL CLASSIFICATION IS REQUIRED

• REACTIVE:
• --TRANSIENT
• --WBC <30k
• --HETEROGENEOUS
• --POLYCLONAL
• --KNOWN CAUSE

• NEOPLASTIC:
• --SUSTAINED
• --WBC > 30k
• --MONOMORPHIC
• --CLONAL
• --UNKNOWN IN MANY CASES

CD 19, 20, Ig kappa / lambda

CD 3, 4, 5, 7, 8

CD 5 CAN BE PRESENT ON B-CELLS

TARTRATE RESISTANT ACID PHOSPHATASE (TRAP) STAIN

• MONOCLONAL B-CELLS
• --STRONG SIg
• --CD11c, CD25, CD103

• FIBROSIS FROM BM BIOPSY -- DRY TAP
• --FRIED EGG APPEARANCE

SPLENOMEGALY w/o LYMPHADENOPATHY

PANCYTOPENIA NOT LEUKOCYTOSIS

t(14;18)(q32,q21)

FOLLICULAR LYMPHOMA

t(8;14)(q24;q32)

BURKITT LYMPHOMA

t(11;18)(q21,q21)

MALT LYMPHOMA

t(11;14)(q13;q32)

MANTLE CELL LYMPHOMA

MOST COMMON INDOLENT NHL IN US (20-40%)

50-60 yrs

MALES = FEMALES

• MORPHOLOGY
• --RESEMBLES nL GERM CENTER
• --EFFACEMENT OF NODAL ARCH
• --NODULAR GROWTH PATTERN (may be diffuse)
• --MIXED CENTROCYTES (small cleaved) AND CENTROBLASTS (LARGE NON-CLEAVED)
• --LACK APAPTOSIS/TINGIBLE BODY MACROs AND ZONATION

• IMMUNOPHENOTYPE
• --B CELL CD 19, 20, 10
• --MONOCLONAL (kappa or lambda LC)
• --BCL-2 PROT

• GENOTYPE
• --t(14;18)(q32,q21)
• --BCL-2 REARRANGE

MOST Pts PRESENT IN ADVANCED STAGE (75-85% stage iv)

MEAN SURVIVAL 7-9 yrs

NO CURE

MOST COMMON NHL 30-40%

• HETEROGENEOUS GROUP OF TUMORS
• --PREDOM LARGE LYMPHOCYTES

30% HAVE TRANSLOCATIONS INV BCL-6 (3q27) OR MUTATION OF ITS PROMOTOR

SOME FROM LOWER GRADE LYMPHOMAS (ex follicular)

• SUBSET IN HIV Pts
• --EBV + DLBCL

• CLINICALLY
• --RAPID GROWING MASS IN LYMPH OR EXTRANODAL (40-50%)
• --INTERMEDIATE IN MOST
• --HIGH GRADE ALSO

AGGRRESSIVE BUT MAY BE CURABLE

PRIMARILY AFFECTS LYMPHOID TISSUES

• INDISTINGUISHABLE FROM CLL EXCEPT
• --CLL ORIGIN IN BM AND PERIPH BLD
• --SLL ORIGIN IN LYMPHOID TISSUE

• MORPH:
• --DIFFUSE (not follicular) EFFACEMENT BY MONOTONOUS INFILTRATE OF SMALL LYMPHs
• --SMALL LYMPHs NOT CLEAVED
• --PSEUDO GROWTH CENTERS

• FEATURES OF LOW GRADE LYMPHOMA
• --LOW MIT
• --ABSENT NECROSIS

• GENETICS:
• DEL OF 11q, 13q14.3, AND 17p
• --TRISOMY 12q
• --NO CD10

• PROG:
• --LOW GRADE INDOLENT IN MOST
• --DEL 11q AND 17p WORST
• --5-10% RICHTERs TRANS TO LARGE CELL LYMPHOMA
• --15-30% PROLYMPHOCYTIC TRANS IN BLD

30% OF KID NHL

SUBSET IN HIV Pts

MOST TUMORS MANIFEST IN EXTRANODAL SITES

• AFRICAN (ENDEMIC)
• --TROPICAL EQUATORIAL & NEW GUINEA
• --MEAN AGE 7 yrs
• --MAXILLA, MANDIBLE, OVARIES, KIDNEYS

• NON-AFRICAN (SPORADIC)
• --NON ENDEMIC AREAS
• --11 yrs
• --ILEOCECUM, PERITONEUM

• MORPH
• --LOSS OF nL ARCH
• --DIFFUSE LYMPHOID INFILT
• --MEDIUM SIZE CELLS
• --ROUND NUC (small noncleaved cells)
• --MOD BLUE CYTOPLASM
• --TINGIBLE BODY MACROs AND HIGH MIT ACT, STARRY SKY APPEARENCE

• IMMUNOPHENOTYPE
• --B CELL CD 19, 20
• --MONOCLONAL (kappa or lambda)
• --CD 10
• --BCL-2 NEG (follicular is +)

• PATHOGENESIS
• -- C-MYC (8q24) TRANS
• --t(8;14), (8;22), or (8;2)
• --EBV RELATED (95% in african, 15% in non-african)

• CLINICAL
• --AGGRESSIVE HIGH GRADE TUMOR
• --CURABLE

• MARGINAL ZONE LYMPHOMA
• --HETEROGENEOUS
• --SPLEEN, LYMPH, EXTRALYMPH

• ASSOC w CHRONIC INFLAM DISORDERS RELATED TO INFECTION OR AUTOIMMUNE
• --HELICOBACTER PYLORI
• --SJOGREN, HASHIMOTO THYROIDITIS

• CLINICAL PRESENTATION EXTRANODAL
• --STOMACH MOST COMMON
• --SALIVARY, LUNG, ORBIT, SKIN

• MORPHOLOGY
• --INFILTRATE OF CENTROCYTE-LIKE CELLS, MONOCYTOID B-CELLS, PLASMA CELLS (MIXED)
• --REACTIVE BENIGN GERMINAL CENTERS
• --LYMPHOEPITHELIAL LESIONS (infiltrate destroy epi of crypts, ducts, and glands)

• IMMUNOPHENOTYPE
• --B CELL CD 19, 20
• --MONOCLONAL SIg
• --NEG CD 5 & 10

• GRADE
• --LOW
• --LOCALIZED, STAGE I or II

• ETIOLOGY
• --GASTRIC MALToma
• --ASSOC w HELICOBACTER INF

• CLINICAL COURSE
• --INDOLENT
• --POSS CURE WITH ANTIBIOTICS
• --IF GENETIC ABN (ex t(11;18)), NO LONGER CURE w ANTIBIOTICS

MATURE T-CELL LYMPHOMA ARISING IN SKIN

• CLINICAL FEATURES
• --MOST COMMIN CUTANEOUS T-CELL LYMPHOMA
• --INDOLENT WAXING AND WANING, 8-9 yrs
• --PROGRESSIVE SKIN LESIONS FROM RASH TO PLAQUES, TO TUMOR
• --SEZARY SYND: PERIPH BLD INVOLVEMENT

• MORPH
• --LYMPHOID INFILTRATE
• --SMALL & LARGE CELLS w CEREBRIFORM NUC IN EPI
• --PAUTRIER'S MICRO ABSCESSED

• IMMUNOPHENOTYPE
• --MATURE HELPER T-CELLS
• --CD 4, 3