Polycythemia Vera(lots of red cells - for real)

• An uncommon disorder - distinguish from other causes of erythrocytosis

• Diagnosis depends on knowledge of erythropoeisis

• Complications most commonly from thrombosis and vascular incidents

• Long natural history with treatment

Definition of Erythrocytosis

• Normal hematocrit at FMLH:– Male 47 5 percent– Female 42 5 percent

• Normal hemoglobin at FMLH:– Male 15 2 gm/dl– Female 13.5 1.5 gm/dl

Absolute vs. Relative Erythrocytosis

Normal Spurious Polycythemia

Plasma Vol

RBC

RBC Mass - 51Chromium Assay

RBC Plasma TotalBlood Vol

Female 25 ml/kg> 32 ml/kg

35 ml/kg 60 ml/kg

Male 28 ml/kg> 36 ml/kg

33 ml/kg 61 ml/kg

Pathophysiology of Polycythemia

Secondary Polycythemia

• Appropriate EPO (tissue/kidney hypoxia)– pulmonary disease– high altitude– congenital heart disease– abnormal hemoglobin

• high affinity

• carboxyhemoglobin

Secondary Polycythemia

• Inappropriate EPO (ectopic production)– Tumors (hepatoma, renal carcinoma, leiomyoma,

hamartoma)– Renal disorders (transplantation, cysts)– hemangiomas– Androgen abuse– EPO abuse– Familial polycythemia

Polycythemia Vera

• P. vera is a rare disease

• Median age 60 - 65 years

• Clinical features– Attributed to increased blood viscosity and poor

oxygen delivery to organs (brain)

– Poor O2 delivery leads to ischemia and thrombosis

– Expanded blood volume and viscosity leads to increased cardiac work load

Oxygen delivery vs. Hematocrit

0

20

40

60

80

100

120

140

160

180

0 20 40 60 80

Hct

Oxy

gen

Tra

nsp

ort

J Clin Invest 1963;42:1150

P. Vera - Symptoms & Signs

• Symptoms– Headache

– Weakness

– Pruritis (aquagenic)

– Dizziness

– Diaphoresis

– Visual disturbance

– Weight loss

• Signs– Splenomegaly 70%

– Skin plethora 67%

– Hepatomegaly 40%

– Conjunctival plethora 59%

– Systolic Hypertension 72%

P. Vera - Diagnosis (PVSG criteria)

• Criteria– RBC mass elevated

– SaO2 > 92%

– Splenomegaly (or)• thrombocytosis

• Leukocytosis

• high LAP

• high B12

• Significance– True vs. spurious

– R/O most 2 causes

– Evidence for MPD

• False Positive 0.5%– smokers, drinkers

P. vera - Bone Marrow Biopsy

P. Vera - Natural History

PVSG GISPThrombosis/embolism 31% 30%AML 19% 15%Other cancer 15% 16%Hemorrhage 6% 3%Myelofibrosis 4% 3%Other 25% 35%

Treatment - PVSG

• Founded 1967

• Protocol 01– Phlebotomy vs. Chlorambucil vs. 32P

• Protocol 05– Phlebotomy with ASA, dipyridamole vs. 32P

• Protocol 08– Phlebotomy vs. Hydroxyurea

Risk of Thrombosis from Treatment(PVSG 01)

Treatment 3 years Overall

Phlebotomy 23% 38%*

Chlorambucil 10% 30%

32P 13% 34%

* p = 0.015

Types of Thrombosis(PVSG 01)

Event Percent

CVA 35%

Venous 26%

MI 12%

P. arterial 9%

Pulm. Infarct 6%

Risk of Cancer from Treatment(PVSG 01)

Treatment 7 years 14 years

Phlebotomy 1.29 1.49

Chlorambucil 2.00* 2.38*

32P 1.88* 1.86*

* p < 0.01

PVSG 08 - Hydroxyurea

Treatment Thrombosis Leukemia

Hydroxyurea(n = 51)

22% 6%

Phlebotomy(n = 134)

37% 2%

Treatment Options - Phlebotomy

• Advantages– quick, easy

– less trips to clinic

– low risk of cancer

– no medication need

– compliance

• Disadvantages– thrombosis risk

– symptoms of iron deficiency

– perhaps faster to “spent phase”

– vascular access

– cardiovascular effects

– no effect on spleen

– no effect on platelets

Treatment Options - 32P

• Advantages– quick and effective

– thrombosis risk low

– no medication

– follow-up need minimal

– compliance easier

– reduces spleen size

– lowers all counts

– few side-effects

• Disadvantages– risk of leukemia

– uncontrolled effects

– childbearing risk

– radiation issues

Treatment Options - Hydroxyurea

• Advantages– quick and effective

– thrombosis risk low

– reduces spleen size

– lowers all counts

– leukemia risk low

– few side-effects

• Disadvantages– close monitoring

– childbearing risk

– compliance (daily medication)

– GI toxicity (rare)

– leukemia risk (?)

Treatment Options - Summary

A g e > 7 0H yd roxyu rea

3 2 P ?

A g e 5 0 - 7 0H yd roxyu reaP h leb o tom y

A g e < 5 0P h leb o tom yH yd roxyu rea

P . V eraP h leb o tom ize to H C T < 4 5