1

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

PRV POLYCYTHEMIA RUBRA VERA

Is an acquired myeloproliferative disorder that causes over production of all

three hematopiotic cell lines, most prominent red blood cells.

HCT is elevated ˃54% male, ˃ 51%Female

When HCT increased, red blood cell mass should be measured to check whether

primary (( where it is increased )) or secondary (( where it is normal)).

RED CELL MASS 26----34 ml/kg MEN

21----29 ml/kg WOMEN

If RCM INCREASED , DETERMINE WHETHER 1RY OR 2RY.

Polycythemia rubra vera “PRV”:

Polycythemia vera (PV) is a stem cell disorder characterized as a

panhyperplastic, malignant, and neoplastic marrow disorder. Its most

prominent feature is an elevated absolute red blood cell mass because of

uncontrolled red blood cell production. This is accompanied by increased

white blood cell (myeloid) and platelet (megakaryocytic) production, which

is due to an abnormal clone of the hematopoietic stem cells with increased

sensitivity to the different growth factors for maturation Autonomus over production of erythroid cells

Independent of erythropiotein as the S .Erythropiotein is low

Median age 60 year , rare les than 40 year

It is a relatively common disorder

Pathophysiology

A. Excessive Red Blood Cell production (erythrocytosis) B. Results in increased blood viscosity and Blood Volume C. Ultimately results in thrombosis

Epidemiology

Frequency

United States Polycythemia vera (PV) is relatively rare, occurring in 0.6-1.6 persons per million population.

2

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

Race

Originally, Jewish persons were thought to have a higher predilection for polycythemia vera than members of other ethnic groups. Subsequently, however, many studies have shown that this condition occurs in all ethnic groups.

Sex

Polycythemia vera has no sex predilection, although the Polycythemia Vera Study Group (PVSG) found that slightly more males than females are affected.

Age

The peak incidence of polycythemia vera is age 50-70 years. However, this condition occurs in persons of all age groups, including early adulthood and childhood, albeit rarely.

CLINICAL FEATURES:

Triad of HYPERVISCOSITY, HYPERVOLEMIA, HYPERMETABOLISM.

Characterized by:

HTN ----1/3 of cases

Gout

Peptic ulceration --- 5-10%

DVT

Symptoms of polycythemia vera (PV) are often insidious in onset, and they

are often related to blood hyperviscosity secondary to a marked increase in the

cellular elements of blood. Subsequent sludging of blood flow and thrombosis

lead to poor oxygen delivery with symptoms of ischemia of central nervous

system , cardiovascular system and peripheral symptoms. A. Most patients present with symptoms related to expanded ( RBC &

PLASMA ) blood volume and increased blood viscosity.

Common complaints ---Cerebral Circulation Impairment and coronary:

1. Headache 2. Tinnitus 3. Dizziness 4. Visual disturbance

3

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

5. Transient Ischemic Attack symptoms 6. Paresthesias 7. Angina pectoris 8. Intermittent claudication

B. Generalized pruritis ; especially following a warm shower or bath ;may be

striking symptom with dyspnea and night sweats. It is a classical symptom.

Itching is present in approximately 40% of patients with polycythemia vera

Cause ----histamine release from increase number of basophil and mast

cells or prostaglandin production.

B. Patients may also initially complain of bleeding ----- seen in approximately

1% of patients with PV, include epistaxis, gum bleeding, ecchymoses, and

gastrointestinal (GI) bleeding. Cause of Epistaxis ----engorgement of mucosal blood vessels AND

abnormal hemostasis due to qualitative abnormalities in platelet function.

C. Thrombosis – Patients with polycythemia vera are prone to the development of blood

clots (thrombosis). A major thrombotic complication (e.g. heart

attack, stroke, deep venous thrombosis, or Budd-Chiari syndrome) may

sometimes be the first symptom or indication that a person has

polycythemia vera . This occurs at a rate of (1%) including venous

thrombosis or thromboembolism and an increased prevalence of stroke

and other arterial thromboses.

It is the most common complication of PRV(major cause of morbidity

&death) and it Appears to be related to increase viscosity and abnormal

platelet.

Uncontrolled platelet leads to very high incidence of thrombotic

complication of surgery. Those cases need to be treated first.

1. Arterial -------------- cardiac, cerebral, peripheral

2. Venous ---------------leg veins, portal veins, hepatic veins, cerebral veins

D. There is a high incidence of peptic ulcer disease as well as GIT bleeding. Abdominal pain due to peptic ulcer disease may be present because PV is

associated with increased histamine levels and gastric acidity or may be

related to an increased susceptibility to infection with the ulcer-causing

4

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

bacterium H. pylori. Or possible Budd-Chiari syndrome (hepatic portal vein

thrombosis) or mesenteric vein thrombosis. Early satiety can occur in

patients with splenomegaly, because of gastric filling being impaired by the

enlarged spleen or, rarely, as a symptom of splenic infarction. Weight loss

may result from early satiety or from the increased myeloproliferative

activity of the abnormal clone.

E. Over production of uric acid leads to gout.

Gouty arthritis may be present in up to 20% of patients

F. A rare but classic

symptom of

polycythemia vera

(and the related

myeloproliferative

diseaseessential

thrombocythemia)

is erythromelalgia.

This is a sudden,

severe burning pain in

the hands or feet,

usually accompanied

by a reddish

or bluish coloration of

the skin.

Erythromelalgia is

caused by an increased

platelet count or

increased platelet

"stickiness"

(aggregation), resulting

in the formation of tiny

blood clots in the

vessels of the

extremity; it responds

rapidly to treatment

with aspirin .

5

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

IN SUMMARY;

C/F

1. BLEEDING 2.THROMBOSIS

Peptic ulcer Headache

GIT bleeding Dizziness

Epistaxis Tinnitus,blurred vision

Vertigo

3. PRURITIS 4.GOUT

PHYSICAL EXAMINATION:

Physical findings in patients with polycythemia vera (PV) are due to the

myeloproliferative process and excess concentrations of the cellular elements of

blood with extramedullary hematopoiesis.

1. Plethora, red face , Conjunctival suffusion

Plethora or a ruddy complexion is

characteristic of PV and results

from the marked increase in total

red blood cell mass. This

manifests in the face, palms,

nailbeds, mucosa, and conjunctiva

2. Engorged retinal veins

on fundoscopy

3. Spleen ---enlarged in 75% of cases, always present when imaged.

4. Hepatomegaly is present in approximately 30% of patients.

Hypertension is common in patients with PV. Measurement of

the red blood cell mass should differentiate this condition from

Gaisbock syndrome, which is hypertension and

6

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

pseudopolycythemia (ie, high hemoglobin levels due to low

plasma volume)

DIFFERENTIAL DIAGNOSIS OF POLYCYTHEMIA:

A. Spurious polycythemia (relative )

Increased HCT and hemoglobin ----- due to reduction of plasma volume

Dehydration ,Diuretic ,Stress.

Middle aged men, overweight , HTN , HCT always ˂ 60%

B. Secondary polycythemia :

Hypoxia—COPD , lung fibrosis , bronchiectasis ,pulmonary HTN

Hypoxia --- 2RY to cyanotic congenital heart disease

Renal lesions---- polycystic kidney disease , hypernephroma

Hepatic lesions--- cyst, hepatoma.

Causes (( genetic basics )) NEW:

1RY----The causes of polycythemia vera (PV) are unknown, but a number of approaches are now being studied to define the molecular lesion or lesions. The JAK2 V617F mutation can give rise to a turned-on cytokine receptor, leading to pancytosis similar to the PV phenotype. This is similar to the biologic properties of theBCR/ABL abnormality in that they both mimic cytokine signaling.

Clonality studies using a rare polymorphism in the G6PD gene demonstrate predominant expression of a single allele in all blood cell lines. X-chromosome inactivation studies have played a pivotal role in establishing current concepts of many hematologic malignancies. Approximately 90% of patients with PV show a skewed pattern of X inactivation in all their blood cell lines, indicating support for the concept of a transformed multipotential stem cell.

Cytogenetic studies show the presence of an abnormal karyotype in the hematopoietic progenitor cells in approximately 34% of patients with PV, depending on which stage of the disease the study was performed at. Approximately 20% of patients have cytogenetic abnormalities at diagnosis, increasing to more than 80% for those with more than 10 years of follow-up care.

The following genetic abnormalities, which are similar to the abnormal karyotypes observed in patients with myelodysplastic syndromes and other MPDs, have been observed in patients with PV:

Deletion of 20q (8.4%) Deletion of 13q (3%) Trisomy 8 (7%) Trisomy 9 (7%) Trisomy of 1q (4%) Deletion of 5q or monosomy 5 (3%) Deletion of 7q or monosomy 7 (1%)

7

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

2RY----The main reasons for higher than normal Epo are chronic hypoxia , poor oxygen delivery due to abnormal red blood cell structure, and tumors releasing inappropriately high amounts of Epo.

Some of the common conditions that can result in elevated erythropoietin due to chronic hypoxia or poor oxygen supply include:

1. COPD, emphysema, chronic bronchitis 2. Pulmonary hypertension 3. Hypoventilation syndrome 4. Congestive heart failure. 5. Obstructive sleep apnea. 6. Poor blood flow to the kidneys. 7. Living in high altitudes.

2,3-BPG deficiency is a condition in which the hemoglobin molecule in the red blood cells has an abnormal structure. In this condition, hemoglobin has a higher affinity to hold on to oxygen and is less likely to release it to the tissues. This results in more red blood cells being produced in response to what the tissues in the body perceive as an inadequate oxygen level. The outcome is more circulating red blood cells.

Certain tumors have a tendency to secrete inappropriately high amounts of Epo, leading to polycythemia. The common Epo-releasing tumors are:

1. Liver cancer (hepatocellular carcinoma). 2. Kidney cancer (renal cell carcinoma). 3. Adrenal adenoma or adenocarcinoma. 4. Uterine cancer.

There also are more benign conditions that may cause increase Epo secretion, such as kidney cysts and kidney obstruction.

Chronic carbon monoxide exposure can also lead to polycythemia. Hemoglobin naturally has a higher affinity for carbon monoxide than for oxygen. Therefore, when carbon monoxide molecules attach to hemoglobin, polycythemia may occur in order to compensate for the poor oxygen delivery by the existing hemoglobin molecules. A similar scenario can also occur with carbon dioxide in long-termcigarette smoking.

Polycythemia in newborns (neonatal polycythemia) is often caused by transfer of maternal blood from the placenta or blood transfusions. Prolonged poor oxygen delivery to the fetus (intrauterine hypoxia) due to insufficiency of the placenta can also lead to neonatal polycythemia

8

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

LABORATORY:

Polycythemia is characterized by increased cell counts in all cell lines in the myeloid series (ie, red blood cells, white blood cells [preferentially granulocytes], and platelets). Thus, if red blood cell levels are increased, several conditions must be excluded, including the following:

A. Conditions that increase red blood cells secondary to systemic hypoxia or an artificial condition stimulating erythropoietin secretion in the kidneys

B. Granulocytosis from infections or mobilization by secondary causes, as in leukemoid reactions

C. Thrombocytosis from bleeding and iron deficiency

A. Red Blood Cell related increases 1. Elevated Hemoglobin And Hematocrit

a. White men: Hemoglobin >18 mg/dl (Hematocrit >52%) b. Black men: Hemoglobin >16 mg/dl (Hematocrit >47%) c. Women: >16 mg/dl (Hematocrit >47%)

2. Elevated Red Blood Bell count 8 - 9 million & occasionally 11 million erythrocytes / cubic ml of blood.

B. Proliferation of all cell lines (50% of patients) 1. Thrombocytosis 2. Leukocytosis

FOR DIAGNOSIS OF PRV

The Polycythemia Vera Study Group (PVSG) was the first to set rigorous criteria for the diagnosis of polycythemia vera (PV) in the 1970s. With the establishment of polymerase chain reaction (PCR)–based methods for detecting the JAK2 V617F mutation, this may become the first molecular diagnostic marker for PV, similar toBCR/ABL for chronic myelogenous leukemia (CML). However, because of a paucity of centers doing red blood cell mass measurements, demonstrating an elevated red blood cell mass continues to become more difficult.

The diagnostic criteria set by the PVSG are organized into two categories, A and B. The diagnosis of PV is established if all three category A criteria are present, or if criteria A1 plus A2 plus any two criteria from category B are present.

A. Exclude secondary causes of increased RBC Count B. Criteria

1. Major Criteria A (first two required) a. Increased Red Blood Cell mass

i. Men: >36 ml/kg ii. Women: >32 ml/kg

b. Normal arterial Oxygen Saturation (>92%)

9

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

c. Splenomegaly (or two minor criteria below) 2. Minor Criteria B (two required if no Splenomegaly)

a. Platelet Count >400 x10^3/uL b. Leukocyte count >12 x10^3/uL c. Alkaline Phosphatase >100 U/L d. Serum Vitamin B12 >900 pg/ml or binding capacity > 2200

pg/mL C. Experimental diagnostic tools

1. Endogenous erythroid colony growth in EPO-free medium 2. Bone Marrow Biopsy: Polycythemia-specific finding 3. Serum Erythropoietin low

a. Test Sensitivity: 70% b. Test Specificity: 90%

D. Diagnostic criteria for PV as per the 2008 revised World Health Organization (WHO) guidelines include both major and minor criteria. Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria.

Major WHO criteria are as follows:

1. Hemoglobin > 18.5 g/dL in men and > 16.5 g/dL in women, or other evidence of increased red blood cell volume.

2. Presence of JAK2617V F or other functionally similar mutation, such asJAK2 exon 12 mutation.

Minor WHO criteria are as follows:

1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation

2. Serum erythropoietin level below the reference range for normal 3. Endogenous erythroid colony formation in vitro

E. Once an MPD (Philadelphia chromosome negative [Ph–]) is documented, it

must be differentiated from the following conditions, which have manifestations that overlap with polycythemia vera (PV):

1. Essential thrombocytosis (ET) 2. Chronic myelogenous leukemia (CML) 3. Agnogenic myeloid metaplasia (AMM)

NEW CONCEPT FOR DAIGNOSIS OF PRV:

The major diagnostic issue related to PV is distinguishing it from other forms of erythrocytosis, which are more common than PV. JAK2 V617F mutation and erythropoietin (Epo) level are key in the diagnosis of erythrocytosis. If the JAK2V617F

10

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

mutation is positive and Epo level is low, then it confirms the diagnosis of PV (JAK2 V617F mutation is positive in 97% of PV patients).

If the JAK2 V617F mutation is absent but the Epo level is low, then testing forJAK2 exon 12 and 13 mutations would be helpful is making a diagnosis of PV in the 2-3% of PV patients who are negative for JAK2 V617F mutation. Patients who are negative for JAK2 mutations and have a normal or high Epo level have secondary erythrocytosis.

Total blood volume= plasma + red cell mass

1.HCT: The hall mark of PRV is HCT above normal ˃ 60%

Bleeding may lower HCT to normal range or lower.

Red cell mass is ˃ 30% of

predicted volume.

2.Red cell morphology is normal.

3.WBC is characteristically

increased 10000---20000/ml (60%

of patient)

It is mainly composed of

neutrophils with a left shift and a

few immature cells. Mild

basophilia occurs in 60% of

patients.

4.Platelet morphology is usually

normal but large hypogranular

Platelets seen.

Count is elevated, some times,

1000000/ ml. The platelet count is

elevated to 400,000-800,000/µL in

approximately 50% of patients.

The release of potassium into the

serum caused by the increased

number of platelets during in vitro

coagulation may cause a

pseudohyperkalemia in the serum,

whereas the true plasma

potassium level in vivo is actually

within the reference range, as

shown by measuring plasma

11

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

levels and by the lack of electrocardiography (ECG) changes. Morphologic

abnormalities in platelets include macrothrombocytes and granule-

deficient platelets.

Abnormal platelet function (as measured by platelet aggregation tests with

epinephrine, adenosine diphosphate [ADP], or collagen) may be

demonstrated, but bleeding time may be normal. Some patients' platelet-

rich plasma spontaneously aggregates without the addition of any of the

above substances. This indicates a propensity for thromboses. 5.Bone marrow -----

Are not necessary to

establish the diagnosis

of polycythemia vera.

The finding

of Hypercellular

,panhyperplasia of all

hemaopoietc cells

To differentiate

primary from

secondary.

Characteristic

finding------

increased

megakaryocytes

6. Routine coagulation

test results are normal,

with a high turnover

rate for fibrinogen. The

prothrombin time (PT) and

activated partial

thromboplastin (aPTT) time

may be artifactually prolonged,

however, because the

erythrocytosis results in the

collection of a low amount of

plasma in relation to the

anticoagulant in the test tube.

Thus, the volume of the ratio

of anticoagulant to blood must

be modified when drawing

blood for coagulation tests in

12

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

patients who are polycythemic.

6.Iron stores-------------usually absent from bone marrow

They are transferred to increase red cell mass

It May result from chronic GIT blood loss

7.VITAMIN B12 ---are increased due to increased level of transcobalamin II

((WBC))

Vitamin B-12 levels are elevated to more than 900 pg/mL in approximately

30% of patients, and 75% of patients show an elevation in the unbound

vitamin B-12 binding capacity greater than 2200 pg/mL. This is because of

increased transcobalamin-III, a binding protein found in white blood cells,

and it reflects the total white blood cell counts in the peripheral blood and

bone marrow.

8.ALKALINE PHOSPHATASE---increased as a marker of qualitative

abnormality in myeloid line. The leukocyte alkaline phosphatase (LAP)

score is elevated (>100 U/L) in 70% of patients. This technique is only

semiquantitative and is susceptible to interobserver and laboratory errors

unless it can be performed by flow cytometry, which is not routinely

available.

9.URIC ACID-----------------------may be increased.

Hyperuricemia occurs in 40% of patients and reflects the high turnover rate

of bone marrow cells releasing DNA metabolites.

10.RBC morphology-----may show -hypochromic microcytic &

poikilocytosis due to decrease Fe.

There may be elliptocytosis due to hypersplenism in peripheral blood film.

11.ARTERIAL BLOOD GASE--- looking for O2 saturation

1ry ------------ more than 90%

2ry ------------ low in cyanotic CHD and chronic lung disease.

Measuring arterial oxygen saturation (SaO2) and carboxyhemoglobin (COHb) levels is important to rule out hypoxia as a secondary cause for erythrocytosis. Pulse oximetry is the most convenient method for measuring SaO2; however, in people who smoke cigarettes, the COHb must be determined directly and subtracted to give an accurate SaO2 value. A value below 92% indicates a causal relationship with erythrocytosis. If the fall is due to increased COHb, this is less likely to cause erythrocytosis.

Nocturnal oxygen desaturation due to sleep apnea is observed in 20% of patients

12.URINE ROUTINE EXAMINATION:

Should be examined in all patients with polycythemia.

13

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

Hematuria is caused by renal carcinoma and polycystic kidney disease

with increased level of erythropoietin leading to increased level of red cell

mass.

MORE INVESTIGATIONS :

Cytogenetics of the bone marrow cells show a clonal abnormality in 30% of patients who are not treated and in 50% of patients who are treated with alkylating or myelosuppressive agents. These chromosomal abnormalities include deletions of the long arm of chromosome 5 or 20 (5q-, 20q-) and trisomy 8 (+8) or 9 (+9). Leukemic transformation is usually associated with multiple or complex abnormalities.

Measuring spontaneous growth of erythroid progenitors in cultures (burst-forming unit, erythroid [BFU-E]) in the absence of Epo is a very sensitive test for polycythemia vera (PV) or familial erythrocytosis. However, it is not routinely available for clinical use.

The hemoglobin-oxygen dissociation curve may be useful in rare cases to detect a congenital hemoglobinopathy with increased oxygen affinity. This condition can occur in families.

Complications

A. Accelerated atherosclerotic and thrombotic disease 1. Cerebrovascular Accident 2. Myocardial Infarction 3. Peripheral Vascular Disease 4. Other rarely affected vessels

a. Mesenteric thrombosis b. Hepatic vein thrombosis or Portal Vein Thrombosis

B. Hemorrhage 1. Epistaxis 2. Acute GI Bleed

C. Progression to other hematologic disorder 1. Myelofibrosis (20% of patients) 2. Leukemia (5% of patients)

TREATMENT: Myelosuppression

Patients can be risk-stratified for their risk of thrombosis according to their age and history of thrombosis. Patients older than 60 years or with a previous history of thrombosis are considered to be high risk. Patients younger than 60 years and with no prior history of thrombosis are considered low risk.

14

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

SUMMARY OF TREATMENT

A. Goal: Keep Hematocrit below threshold 1. White men: Hematocrit <45% 2. Black patients and all women: Hematocrit <42%

B. Age Under 60 years 1. Low or intermediate risk patients

a. Repeated phlebotomy b. Interferon alfa-2b c. Low dose Aspirin (Platelet Count <150 x10^3/uL)

2. High risk patients a. Low or Intermediate Risk Management options (above) b. Hydroxyurea c. Bisulfan

C. High risk patients over age 60 years 1. Repeated phlebotomy 2. Low dose Aspirin 3. Hydroxyurea 4. Busulfan

D. Women of child bearing age 1. Low or intermediate risk patients

a. Repeated phlebotomy b. Low dose Aspirin (Platelet Count <150 x10^3/uL)

2. High risk patients a. Low or Intermediate Risk Management options (above) b. Interferon alfa-2b c. Bisulfan

Prognosis: Median survival in symptomatic patients

A. Survival without treatment: 6-18 months B. Survival with treatment: >10 years

As the condition cannot be cured, treatment focuses on treating symptoms

and reducing thrombotic complications by reducing the erythrocyte levels.

All patients with PV should undergo phlebotomy to keep their hematocrit

below 45% and should take aspirin, 81 mg daily. In addition, if a patient is

at high risk for thrombosis, cytoreductive therapy is added to the

management plan. Hydroxyurea at a starting dose of 500 mg twice daily is

the most commonly used cytoreductive agent. It can be titrated on the

basis of blood counts. In patients who are refractory to or intolerant of

hydroxyurea, interferon-alpha can be used as an alternative. Busulfan is

also an option for patients older than 65 years.

15

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

DETAILED APPROACH TO TREATMENT:

A. The treatment of choice is phlebotomy (venesection )

Phlebotomy (bloodletting) has long been the mainstay of therapy for

polycythemia vera (PV). The object is to remove excess cellular

elements, mainly red blood cells, to improve the circulation of blood

by lowering the blood viscosity. Because phlebotomy is the most

efficient method of lowering the hemoglobin and hematocrit levels to

the reference range, all newly diagnosed patients are initially

phlebotomized to decrease the risk of complications. Phlebotomy is

one form of treatment, which often may be combined with other

therapies. The removal of blood from the body reduces the blood

volume and brings down the hematocrit levels; in patients with

polycythemia vera, this reduces the risk of blood clots

To maintain HCT ˂ 45% in men and 42% in female by repeated

phlebotomy.

Patients can be phlebotomized once or twice a week to reduce the

hematocrit to the range of less than 45%. 500 ml can be taken daily for 2 days then every alternate days until

PCV˂0.5

OR one unit of blood is removed weekly.

Patients with severe plethora who have altered mentation or

associated vascular compromise can be bled more vigorously, with

daily removal of 500 mL of whole blood. Maintain HCT at normal level has been shown to decrease

thrombosis.

There is no need for iron supplementation or restriction.

Elderly patients with some cardiovascular compromise or cerebral

vascular complications should have the volume replaced with saline

solution after each procedure to avoid postural hypotension. The

presence of elevated platelet counts, which may be exacerbated by

phlebotomy, is an indication to use myelosuppressive agents to

avoid thrombotic or hemorrhagic complications.

B. Maintenance therapy

Once the patient's hemoglobin and hematocrit values are reduced to within the reference range, implement a maintenance program either by inducing iron deficiency by continuous phlebotomies (the frequency of the procedure depends on the rate of reaccumulation of the red blood cells) or by using a myelosuppressive agent. The choice depends on the risks of secondary leukemias and the rate of thrombosis or bleeding. Patients must be cautioned to not take iron supplements

16

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

C. Myelosuppresion is indicated for:

1. High phlebotomy required—

2. Maintenance

3. Marked thrombocytosis ˂ platelet 700000/ml

4. Intractable pruritis

The risks for secondary leukemia depend on the type of therapy (eg, phlebotomy, radioactive phosphorus-32 [32 P], chlorambucil) or the type of myelosuppressive agents (eg, hydroxyurea [HU], anagrelide, interferon alfa) and duration of therapy.

The Polycythemia Vera Study Group (PVSG) demonstrated a decreased survival rate and increased mortality rate from acute leukemia in the first 5 years, and a total of 17% of patients had leukemia after 15 years with chlorambucil and with32P. An increased incidence of thrombotic complications occurred in the phlebotomy arm. This indicates that phlebotomy is not ideal for patients with elevated platelet counts and previous thrombosis, as are observed in patients who are older. In this situation, using HydroxyUrea has decreased these complications.

Drugs----Alkalyting agents and radioactive phosphorus

This will Increase the risk of leukemia .It is better to be avoided

Hydroxyurea----cytoreductive agent ,Widely used and not leukemogenic.

Hydroxyurea has been the mainstay therapy for PV since the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation. In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone; the PVSG recommended that HU should be the drug of choice for patients older than 40 years.

The role of HU in leukemic transformation is not clear. Several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with the long-term use of HU in patients with essential thrombocythemia (from 0% to 5.5%) and in patients with PV (from 2.1% to 10%).

D. Busulphan and Interferon

Interferon alfa has been demonstrated in small anecdotal studies to

possibly be useful in patients who have relapsed or progressed to

agnogenic myeloid metaplasia (AMM) or severe hepatosplenomegaly.

However, only low doses are tolerated and significant adverse effects from

long-term use may limit its usefulness

17

DETAILED APPROACH TO POLYCYTHEMIA 2014 DR MAGDI AWAD SASI

E. High dose aspirin (325/8hr/day) // Dipyridamole (25mg/8hr/day)

Low-dose aspirin suppresses thromboxane biosynthesis by platelets,

which is increased in PV and essential thrombocythemia. The European

Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) found

that low doses of aspirin (40 mg/d) were effective for preventing

thrombosis and controlling microvascular painful symptoms

(erythromelalgia), which result from spontaneous platelet aggregation, in

patients with PV and essential thrombocythemia, without creating a

bleeding diathesis.

Once aspirin daily may be affective in patient with history of thrombosis .

Others ,This will increase the GIT bleeding.

F. Allopurinol for hyperuricemia

G. For pruritis---

Aspirins

NSAIDS

H2 receptor antagonist--- cimetidine

Diphenlydramine

Ultraviolet light

H. Ruxolitinib

In November 2011, the JAK1/JAK2 inhibitor, ruxolitinib (Jakafi), became the first US Food and Drug Administration (FDA)–approved drug for patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-PV myelofibrosis, and post–essential thrombocythemia myelofibrosis.

I. In cases where secondary thrombocytosis (high platelet count) is

present, anagrelide may be prescribed.

J. Bone marrow transplants are rarely undertaken in polycythemia patients;

since this condition is non-fatal if treated and monitored, the benefits rarely

outweigh the risks involved in such a procedure.

K. There are indications that with certain genetic markers, erlotinib may be an

additional treatment option for this condition.

COURSE:

10% of patient as terminal event-------------acute myeloid leukemia

This is attributed to phosphorus and alkalyting agent

Indolent disease with survival ----- 11 to 15 years.