Brad LewisSan Francisco General Hospital

Blood alone moves the wheels of history.

Benito Mussolini

Blood will tell, but often it tells too much.

Don Marquis

Anemia in the Patient with HIV

Goals of this Talk• How to Approach the Anemic Patient• Anemias specific to HIV

– Evaluating hemolysis– Iron Deficiency and CDA– G6PD– B12 Deficiency– Marrow Dysfunction

Anemia in HIV (EuroSIDA)

Mocroft A, AIDS 1999; 13:943–50

AnemiaAn Approach to Anemia

Evaluating HemolysisThe Bucket with The Hole

Evaluating HemolysisThe Bucket with The Hole

Reticulocytes

Retic #=1/mmRetic %= 20%

Retic # = 1/mmRetic % = 30%

Corr Retic = Retic x hgb/nl hgb

RPI = corrected retic. count/Maturation time (Maturation time = 1 for Hct=45%, 1.5 for 35%, 2 for 25%, and

2.5 for 15%.)

Retic Hi Retic Low

AnemiaAn Approach to Anemia

Retic Hi Retic Low

Anemia

MCV HiMCV NlMCV Lo

An Approach to Anemia

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

IntrinsicExtrinsicSplenicMechanicalRecovery

TissueOn FloorOccult

Iron(Lead)ThalFrags

B12FolateLiverETOHThyroidToxicMDS

Chronic DiseaseRenalMixedMild/TreatedEarlyTransfusedEndocrineIntrinsic BMDilution

An Approach to Anemia

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

Intrinsic Hgb’opathy Enzymopathy Membrane

HSPNH

ExtrinsicSplenicMechanicalRecovery

TissueOn FloorOccult

An Approach to Anemia

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

IntrinsicExtrinsic AIHA

coldwarm

Drug/Toxins Sepsis BurnsSplenic/HepaticMechanical MAHA

TissueOn FloorOccultRecovery

Hemolysis Diagnosis

• Check the RETIC!• Confirmatory Testing

– LDH, Haptoglobin• 1% Population Ahaptoglobinemic

– Bilirubin

• Intravascular (massive)– Plasma Hgb– Urine Hemosiderin (Hemoglobinuria)

• The Hgb A1C of the hematologist

Specific Diagnostic Tests-High Retic

• Smear

• Coombs- Direct and Indirect– Does NOT diagnose hemolysis

• G6PD ASSAY (and Retic count)

• Hemoglobin Electropheresis???

What Else Could It Be?

• 56 yo Hawaiian male

• Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320, Ind. Bili 2.1– Fe studies nl, B12/Folate nl, Coombs 4+IgG

– Well!

What Else Could It Be?

• 56 yo Hawaiian male

• Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320, Ind. Bili 2.1– Fe studies nl, B12/Folate nl, Coombs 4+IgG

– Well!

• Given 12 mo prednisone without effect ---

What Else Could It Be?

• 56 yo Hawaiian male

• Hgb 7, WBC nl, MCV nl, Plt nl, LDH 320, Ind. Bili 2.1– Fe studies nl, B12/Folate nl, Coombs 4+IgG

– Well!

• Given 12 mo prednisone without effect ---

• Retic #20 (0.5%)

• BM with MDS, evolving AML– PNH

Microangiopathic Hemolysis

• DIC• TTP, HUS• Malignant Hypertension• Mechanical

– Vasculitis– Tumor– Cardiac Valve– SBE– TIPSS– AVM

Microangiopathic Hemolysis

MAHA-What Else Could It Be?

• MDS– Malignant– HIV

• B12

• Iron Deficiency

G6PD• X-linked, race variable• Unable to Reduce Glutathione

– Susceptible to oxidant damage• Drugs

– Sulfa– Methylene Blue– Anti-Malarial– Nitrates

• Infections• DKA• Fava Beans

G6PD DeficiencyA

vera

ge G

6PD

Act

.

Time in Circulation

“Italian” G6PD DeficiencyA

vera

ge G

6PD

Act

.

Time in Circulation

Normal

Nl mean

Severe G6PD Def.

“African” G6PD DeficiencyA

vera

ge G

6PD

Act

.

Time in Circulation

“African” G6PD DeficiencyA

vera

ge G

6PD

Act

.

Time in Circulation

G6PD in hemolysis

“African” G6PD Deficiencyhemolysing with oxidant stress

Ave

rage

G6P

D A

ct.

Time in Circulation

Hemolyzed

New Average G6PD Activity

Young Retics with more G6PD

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

B12FolateToxic AZT,DDC Chemo DilantinMDSHepaticETOHThyroidOther

Nuclear Maturation

Lipid Bilayer

Diagnostic Tests-Low Retic Macrocytic

• Repeat Retic• Smear (round vs. oval macrocytes, hypersegmented

PMN)• B12 and Folate (and Iron)• Hepatic• Toxic?

– AZT, DDC, Stavudine, Lamivudine

– Chemo, ETOH

• Cold Agglutinin• To BM or not to BM

B12 Hyperseg PMN

B12 Deficiency

• ??Diagnostic level (<300)– Role of Methylmalonic acid

• ??atrophic gastritis• Role of Schilling Test today• Anti-Intrinsic Factor Ab (specific and

sensitive for Pernicious Anemia) • Diagnostic/therapeutic trial• ??Multi-factorial etiology of B12 & Anemia

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

Iron(Lead)ThalassemiaFragmentationSideroblastic Anemia

acquiredcongenital

An Approach to Anemia

Diagnostic TestsLow Retic Microcytic

• Iron/TIBC vs. Ferritin• Hemoglobin Electropheresis

– Test Fe First• May mask B-Thal

– GENETIC SCREENING OF FAMILY– The “Normal” Electropheresis

• Nl Fe, Nl HPLC = Alpha Thal!

• Smear?• Value of MCV, RBC # and RDW• Lead?

Evaluating Iron

• Ferritin– Sensitive/specific

• Except increased in inflammation, liver disease, malignancy• Fe/TIBC (Transferrin) and Saturation

– Decreased in inflammation, malignancy– < 10% Sat suggests Iron Deficiency

• THEREFORE:– Iron Trial almost always safe– Serum (soluble) Transferrin Receptor

• Mediates iron transfer into cell• Increased in Fe-def, rapid cell production

– CHR-Retic Hemoglobin Concentration?• Follow-up GI Eval

– 10 -15% with malignancy– ?Only if ferritin <100?

Iron Metabolism

PlasmaFe-Tf

Hepcidin

Hepcidin

Hepcidin

Iron Signal?

Erythropoiesis Signalanemia, hypoxia

RBC

Bone MarrowDuodenum

Spleen

Tomas Ganz ASH 2006

InflammationIL-6

Hep

cidin

Dec. Hep

Inc. Hep

Treatment of Iron Deficiency

• Oral always preferred– ?low dose equally effective– ?role for Vitamin C

• When to use IV iron– Recent decreased risk of anaphylaxis– Poor compliance

• Side-effects, etc

– Poor Absorption• Jejeunal/duodenal disease• Sprue• “Chronic Disease”?• Anemia of Malignancy

Retic Hi Retic Low

Anemia

Destruction Loss MCV HiMCV NlMCV Lo

Early AnythingMild/Treated Transfused Chronic DiseaseRenalMixedEndocrineIntrinsic BM Aplastic Myeloma True Lymphoma Drug Infection Anorexia Malignancy Parvovirus

Myelosuppressive Drugs in HIV

• ACV, Ganciclovir, Foscarnet, Cidofovir

• Ampho

• Septra/Dapsone/ IV Pentamidine

• Pyrimethamine

• AZT, Zalcitabine

• Chemo

• Interferon

Intrinsic Marrow Involvement

• Infections– Fungal– AFB

• MAC and TB– Parvovirus

• Malignancy– DLCL– Hodgkins– Myeloma– Other (Castlemans, Hemophagocytosis, etc)

• Dysplasia

Parvovirus Infection

• Persistent/Relapsing anemia in immunocompromised– Neutropenia in 35%, Thrombocytopenia 20%

• Treatable with IVIG (repeated courses??)

• Diagnosis– Serology + 30%– PCR usually + (may be false “persistent” +)– Bone Marrow Bx Diagnostic (Cyto + Immuno)

Arch Path Lab Med. 2007 Nov;131(11):1697-9Morelli, P. Eur J Clin Mic Inf Dis 26:833, 2007

Bone Marrow Asp w/ Parvovirus

Parvovirus

Hgb and Quality of LifeQ

uali

ty o

f L

ife

(LA

SA

)

7 9 11 13Hgb

Crawford. Cancer 2002;95:888, Soignet. Semin Hematol. 2000

Risks of PRBC Tx vs. EPO

Erythropoietin RBC Transfusion