Polycythemia

1
Polycythemia

• Victor Politi, M.D., FACP
• Medical Director, SVCMC, School of Allied Health
  Professions, Physician Assistant Program

2
Introduction

• Polycythemia vera is a chronic myeloproliferative
  disorder characterized by increased red blood
  cell mass (RCM), or erythrocytosis
• The resultant hyperviscosity of the blood
  predisposes such patients to thrombosis

3
Introduction

• Increased RCM 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.

4
Introduction

• Its etiology is not fully established, but
  hypersensitivity to interleukin-3 may play a role
  in the sustained erythrocytosis observed in this
  disease.

5
Introduction

• Polycythemia vera should be suspected in patients
  with elevated hemoglobin or hematocrit levels,
  splenomegaly, or portal venous thrombosis.

6
Introduction

• Secondary causes of increased red blood cell mass
  (e.g., heavy smoking, chronic pulmonary disease,
  renal disease) are more common than polycythemia
  vera and must be excluded

7
Introduction

• Patients may present with complaints of pruritus
  after bathing, burning pains in the distal
  extremities (erythromelalgia), gastrointestinal
  disturbances, or nonspecific complaints such as
  weakness, headaches, or dizziness.
• Other patients are diagnosed after an incidental
  finding of an elevated hemoglobin and/or
  hematocrit level on a complete blood count.

8
Introduction

• Diagnosis is made using criteria developed by the
  Polycythemia Vera Study Group major criteria
  include elevated red blood cell mass, normal
  oxygen saturation, and palpable splenomegaly.

9
Introduction

• Untreated patients may survive for six to 18
  months, whereas adequate treatment may extend
  life expectancy to more than 10 years.

10
Introduction

• Treatment includes phlebotomy with the possible
  addition of myelosuppressive agents based on a
  risk-stratified approach.
• Agents under investigation include interferon
  alfa-2b, anagrelide, and aspirin. Consultation
  with a hematologist is recommended.

11
Introduction

• Alternative Names
• Primary polycythemia
• Polycythemia rubra vera
• Myeloproliferative disorder
• Erythremia
• Splenomegalic polycythemia
• Vaquez's disease
• Osler's disease
• Polycythemia with chronic cyanosis
• Myelopathic polycythemia
• Erythrocytosis megalosplenica
• Cryptogenic polycythemia

12
Pathophysiology

• Normal stem cells are present in the bone marrow
  of patients with PV.
• Also present are abnormal clonal stem cells that
  interfere with or suppress normal stem cell
  growth and maturation.

13
Pathophysiology

• Evidence indicates that the etiology of
  panmyelosis is unregulated neoplastic
  proliferation.
• The origin of the stem cell transformation
  remains unknown

14
Polycythemia vera

• Bone marrow film at 100X magnification
  demonstrating hypercellularity and increased
  number of megakaryocytes

15
Pathophysiology

• Thromboses and bleeding are frequent in persons
  with PV and myeloproliferative disease (MPD), and
  they result from the disruption of hemostatic
  mechanisms because of
• an increased level of red blood cells
• an elevation of the platelet count

16
Pathophysiology

• Tissue factor is also synthesized by blood
  leukocytes, the level of which is increased in
  persons with MPD, which can contribute to
  thrombosis.

17
Pathophysiology

• Hyperhomocysteinemia is a risk factor for
  thrombosis and is also widely prevalent in
  patients with MPD (35 in controls, 56 in
  persons with PV).

18
Statistics

• Polycythemia vera is a rare disease
• The peak incidence of PV is age 50-70 years
• However, it occurs in persons of all age groups,
  including those in early adulthood and childhood,
  albeit rarely.
• The disease is slightly more common in males than
  in females.

19
History

• The disease usually develops slowly
• Symptoms are often insidious in onset
• They are often related to blood hyperviscosity
  secondary to a marked increase in the cellular
  elements of blood, which impairs
  microcirculation.

20
History

• Symptoms are related to hyperviscosity, sludging
  of blood flow, and thromboses, which lead to poor
  oxygen delivery and symptoms that include
• headache, dizziness, vertigo, tinnitus, visual
  disturbances, angina pectoris, or intermittent
  claudications

21
History

• Bleeding complications ,, include epistaxis, gum
  bleeding, ecchymoses, and GI bleeding.
• Thrombotic complications ,, include venous
  thrombosis or thromboembolism and an increased
  prevalence of stroke and other arterial
  thromboses.

22
History

• Abdominal pain due to peptic ulcer disease is
  present because PV is associated with increased
  histamine levels and gastric acidity or possible
  Budd-Chiari syndrome (hepatic portal vein
  thrombosis) or mesenteric vein thrombosis.

23
History

• Splenomegaly, when present, can cause early
  satiety because of
• gastric filling being impaired by the enlarged
  spleen or, rarely, symptoms of splenic
  infarction.
• Weight loss may result from early satiety or from
  the increased myeloproliferative activity of the
  abnormal clone.

24
History

• Pruritus results from increased histamine levels
  released from increased basophils and mast cells
  and can be exacerbated by a warm bath or shower.
• This occurs in up to 40 of patients.

25
Physical

• The following symptoms are due to the
  manifestations of myeloproliferative disorders
  with extramedullary hematopoiesis
• Splenomegaly - Present in 75 of patients at the
  time of diagnosis
• Hepatomegaly - Present in approximately 30 of
  patients with PV

26
Physical

• Hypertension is common in patients with PV. The
  red blood cell mass should differentiate PV from
  Gaisbock syndrome, which is hypertension and
  pseudopolycythemia (i.e., high hemoglobin levels
  due to low plasma volume).

27
Physical

• Polycythemia is characterized by increased cell
  counts in all cell lines in the myeloid series
  (i.e., red blood cells, white blood cells
  preferentially granulocytes, and platelets).

28
Physical

• However, if red blood cell levels are increased,
  several conditions must be excluded, including
• conditions that increase red blood cells
  secondary to systemic hypoxic conditions or an
  artificial condition stimulating EPO secretion in
  the kidneys
• granulocytosis from infections or mobilization by
  secondary causes, as in leukemoid reactions
• thrombocytosis from bleeding and iron deficiency.

29
Secondary Causes of Increased Red Cell Mass
(Erythrocytosis)

• Chronic pulmonary or cardiac disease
• Decreased 2,3-diphosphoglycerate
• High oxygen affinity hemoglobinopathy
• Increased carboxyhemoglobin (in smokers) and
  methemoglobin
• Residence at high altitude
• Adrenal cortical hypersecretion
• Hydronephrosis
• Tumors producing erythropoietin or anabolic
  steroids
• Relative (stress)
• Disorders associated with decreased plasma volume
  (e.g., diarrhea, emesis, renal diseases)

30
Diagnosis

• PV should be suspected when hemoglobin and/or
  hematocrit levels are elevated
• (gt than 18 g per dL 180 g per L in white men
  and gt than 16 g per dL 160 g per L in blacks
  and women)
• hematocrit level greater than 52 percent (0.52)
  in white men and 47 percent (0.47) in blacks and
  women

31
Diagnosis

• PV also should be suspected in patients with
  portal venous thrombosis and splenomegaly with or
  without thrombocytosis and leukocytosis.

32
Diagnosis Other Signs and Symptoms of
Polycythemia Vera

• More Common
• Hematocrit level gt52 percent (0.52) in white men,
  gt47 percent (0.47) in blacks and women
• Hemoglobin level gt18 g per dL (180 g per L) in
  white men, gt16 g per dL (160 g per L) in blacks
  and women)
• Plethora
• Pruritus after bathing
• Splenomegaly
• Weight loss
• Weakness
• Sweating

• Less Common
• Bruising/epistaxis
• Budd-Chiari syndrome
• Erythromelalgia
• Gout
• Hemorrhagic events
• Hepatomegaly
• Ischemic digits
• Thrombotic events
• Transient neurologic complaints (headache,
  tinnitus, dizziness, blurred vision,
  paresthesias)
• Atypical chest pain

33
(No Transcript)
34
Diagnosis

• In making the diagnosis of PV, once a secondary
  cause is ruled out, the diagnosis of PV is made
  using a combination of major and minor criteria
  defined by the Polycythemia Vera Study Group
  (PVSG).
• Although new diagnostic modalities have been
  developed, these criteria remain the standard
  method to diagnose PV

35

• A diagnosis of polycythemia vera is made when a
  patent fulfills
• all three of the major criteria
• Or
• any two major and any two minor criteria
• Major Criteria
• total RBC vol.
• Men gt or to 36 mL/kg
• Women gt or to 32 mL/kg
• arterial 02 saturation gt or to 92
• Splenomegaly
• Minor Criteria
• Thrombocytosis with platelet count gt 400,000/mL
• Leukocytosis with WBC gt 12,000/mL
• Increased leukocyte alkaline phosphatase LAP gt
  100U/L (no infection)
• Serum B12 gt 900 pg/mL or binding capacity UB12 BC
  gt 2200 pg/mL

36
Serum EPO assay

• EPO levels in patients with PV are often below
  the lower limit of normal compared with patients
  with secondary erythrocytosis and pseudo
  erythrocytosis
• but the levels for PV and secondary
  erythrocytosis or pseudo erythrocytosis overlap
  and are nonspecific for differentiating these
  conditions.

37
Bone marrow morphology and histology

• Overall hypercellularity with expansion of all
  cell lines with megakaryocytic proliferation and
  the presence of myelofibrosis can help diagnose
  PV and MPD
• PV patients may have normal bone marrow findings
• These results are nonspecific and may be observed
  in the other Philadelphia chromosomenegative
  MPDs.

38
Bone marrow findings for Polycythemia vera
include

• Moderate to marked hypercellularity
• trilineage hyperplasia
• megakaryocytes increased hyper lobulated
• dilated sinusoids with intravascular
  hematopoiesis
• decreased or absent iron stores
• increased reticulin (only in a minority of
  patients)

39
Labs

• Peripheral blood findings
• Increased hemoglobin hematocrit
• Normal red blood cell morphology, unless iron
  deficient or spent phase
• Normoblasts may be present
• Mild to moderate leukocytosis
• Mild neutrophilia and/or basophilia
• Thrombocytosis

40
Labs

• This disease may also alter the results of the
  following tests
• Lactate dehydrogenase
• u/a
• Serum uric acid
• T- WBC
• RBC count
• Platelet aggregation test
• Leukocyte alkaline phosphatase
• Hemoglobin
• ESR
• Erythropoietin

41
Labs

• Automated red blood cell counts and hematocrit
  values (including hemoglobin levels) may be
  deceptive with regard to the total red blood cell
  mass.
• Direct measurement of the red blood cell mass
  should show an increase with a normal or slightly
  decreased plasma volume.
• This is a nuclear medicine test that uses
  radiochromium-labeled red blood cells to measure
  actual red blood cell and plasma volume.
• However, patients with hemoglobin concentrations
  of at least 20 g/dL or hematocrit values of at
  least 60 in males and 56 in females always have
  an elevated red blood cell mass.

42
Labs

• The red blood cells in patients with PV are
  usually normochromic normocytic unless the
  patient has been bleeding from underlying peptic
  ulcer disease or phlebotomy treatment (wherein
  the cells may be hypochromic and microcytic,
  reflecting low iron stores).

43
Labs

• An elevated white blood cell count (gt12,000/µL)
  occurs in approximately 60 of patients. It is
  mainly composed of neutrophils with a left shift
  and a few immature cells.
• Mild basophilia occurs in 60 of patients.
• The leukocyte alkaline phosphatase score is
  elevated (gt100 U/L) in 70 of patients.
• This technique is only semiquantitative and is
  susceptible to laboratory errors unless it can be
  performed by flow cytometry, which is not
  routinely available

44
Labs

• The platelet count is elevated to
  400,000-800,000/mL in approximately 50 of
  patients.

45
Labs

• 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, while the true plasma potassium level in
  vivo is actually within the reference range, as
  shown by measuring plasma levels and the lack of
  ECG changes.

46
Labs

• Abnormal platelet function (as measured by
  platelet aggregation tests with epinephrine,
  adenosine diphosphate, or collagen) may be
  demonstrated, but bleeding time may be normal.
• Some patients' platelet-rich plasma aggregates
  spontaneously without the addition of any of the
  above substances.
• This indicates a propensity for thromboses

47
Labs

• Bone marrow studies are not necessary to
  establish the diagnosis but the findings of
• hypercellularity
• hyperplasia of the erythroid, granulocytic and
  megakaryocytic cell lines
• myelofibrosis
• support the diagnosis of a myeloproliferative
  process.

48
Labs

• Iron stores are decreased or absent because of
  the increased red blood cell mass, and
  macrophages may be masked in the myeloid
  hyperplasia that is present.

49
Labs

• Fibrosis is increased and detected early by
  silver stains for reticulin

50
Labs

• 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.

51
Labs

• Hyperuricemia occurs in 40 of patients and
  reflects the high turnover rate of bone marrow
  cells releasing DNA metabolites.

52
Imaging Studies

• An enlarged spleen is often palpable and does not
  require any imaging studies.
• In some patients with posteriorly enlarged
  spleens or in those who are obese,
  ultrasonography or CT scanning may be able to
  detect an enlargement missed during the physical
  examination.

53
Other Tests

• The serum EPO level should be decreased in nearly
  all patients with PV and no recent hemorrhage.
• This distinguishes polycythemia from secondary
  causes of polycythemia in which the serum EPO
  level is generally within the reference range or
  is elevated.
• Each lab has its own reference range for serum
  EPO level

54
Treatment

• The objective of treatment is to reduce the high
  blood viscosity (thickness of the blood) due to
  the increased red blood cell mass and to prevent
  hemorrhage and thrombosis.
• No single treatment is available for PV.
• Thrombosis accounts for the majority of morbidity
  and mortality. The major goal of treatment is to
  prevent thrombotic events.

55
Treatment

• Examples of thrombotic events include arterial
  and venous thrombosis, cerebrovascular accident,
  deep venous thrombosis, myocardial infarction,
  peripheral arterial occlusion, and pulmonary
  infarct

56
Treatment

• The mainstay of treatment for PV is phlebotomy,
  which is aimed at reducing hyperviscosity by
  decreasing the venous hematocrit level to less
  than 45 percent (0.45) in white men and 42
  percent (0.42) in blacks and women.
• The PVSG reported the best median survival, 12.6
  years, for this type of treatment.

57

• Phlebotomy is a simple procedure without many
  risks, except for the eventual development of
  iron deficiency

58
Treatment

• Patients with hematocrit values of less than 70
  may be bled twice a week to reduce the hematocrit
  to the range of 40.
• 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

59
Treatment

• 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

60
Treatment

• Because phlebotomy is the most efficient method
  of lowering the hemoglobin and hematocrit levels
  to the reference range, all new patients are
  initially phlebotomized to decrease the risk of
  complications.
• The presence of elevated platelet counts that may
  be exacerbated by the phlebotomy is an indication
  to use myelosuppressive agents to avoid
  thrombotic or hemorrhagic complications

61
Treatment

• Once the patient's hemoglobin and hematocrit
  values are reduced to within the reference range
  (i.e., lt45), implement a maintenance program
  either by inducing iron deficiency by continuous
  phlebotomies (frequency of the procedure depends
  on the rate of reaccumulation of red blood cells)
  or using a myelosuppressive agent.

62
Treatment

• The use of myelosuppressive agents such as
  radioactive phosphorus (32P), chlorambucil
  (Leukeran), busulfan (Myleran), pipobroman
  (Virocyte), and hydroxyurea (Hydrea) in
  conjunction with phlebotomy has been studied.
• Chlorambucil, busulfan, and pipobroman, all
  alkylating agents, have fallen out of favor
  because of concerns about rates of iatrogenic
  leukemia.
• The agent 32P remains in use with supplemental
  phlebotomy and has a reported median survival
  similar to that of phlebotomy alone-10.9 years
  according to PVSG data.

63
Treatment

• In patients treated with chlorambucil and 32P the
  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.

64
Treatment

• Hydroxyurea has been the mainstay therapy for PV
  after 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

65
Treatment

• Recombinant interferon alfa-2b reduces
  myeloproliferation and splenomegaly, and
  alleviates the symptom of pruritus.
• It has no established mutagenic potential, and
  thus may prove a valuable option for younger
  patients and those with significant splenomegaly.
  
• A small case series of 11 patients found that the
  patients' red cell indices could be normalized
  over six to 12 months with interferon therapy
  alone, and without evidence of thrombosis.
• However, many patients discontinue interferon
  because of side effects, and high cost of
  treatment.

66
Treatment

• splenectomy in patients with painful splenomegaly
  or repeated episodes of thrombosis causing
  splenic infarction

67
Treatment

• Occasionally, chemotherapy may be given to
  suppress the bone marrow.
• The use of anti-platelet therapy (such as
  aspirin) is controversial because it may cause
  gastric bleeding.
• Allopurinol is given for hyperuricemia (gout).

68
Treatment

• A risk-stratified approach to the management of
  PV is currently recommended
• Patients treated with phlebotomy alone benefit
  from low rates of malignancy but experience more
  thrombosis events during the first few years of
  treatment.
• Patients treated with myelosuppressive agents and
  supplemental phlebotomy avoid this early
  thrombotic risk but in turn have significant
  rates of malignant transformation after about six
  years of therapy

69
Treatment

• High-risk patients
• those 60 years or older
• or those with a history of thrombosis
• A myelosuppressive agent with supplemental
  phlebotomy is reasonable in this group
• This group's generally shorter life expectancy
  lessens the threat of eventual iatrogenic
  malignancy.
• Patients in this group stand to gain from the
  benefit of lower early thrombosis rates with
  myelosuppressive medications.

70
Treatment

• Indeterminate risk
• lt than age 60 and have no history of
  thrombocytosis, but do have cardiovascular or
  other risk factors
• Therapy in this group should be individualized,
  possibly with the addition of agents acting on
  platelet function or number.

71
Treatment

• low risk
• lt than 60 years and have no thrombosis-related
  risk factors
• Phlebotomy alone may be the treatment of choice
  with the goal of reducing the hematocrit level to
  less than 45 percent (0.45) or lower based on
  gender and race

72
Treatment

• Consultation with a hematologist is recommended
  to apply such strategies, and newer agents may be
  tailored to patients on an individualized basis.

73
Prognosis

• Polycythemia vera usually develops slowly, and
  most patients treated appropriately do not
  experience any problems related to the disease.
• However, the abnormal bone marrow cells may begin
  to grow uncontrollably leading to acute
  myelogenous leukemia.

74
Prognosis

• Patients with polycythemia vera also have an
  increased tendency to form blood clots that can
  result in strokes or heart attacks.
• Some patients may experience abnormal bleeding
  because their platelets are abnormal.

75
Prognosis

• PV is a chronic disease, and its natural history
  of 1.5-3 years of median survival in the absence
  of therapy has been extended to at least 10-20
  years because of new therapeutic tools.

76
Prognosis

• The major causes of morbidity and mortality are
  as follows
• Thrombosis
• Hemorrhagic complications
• Peptic ulcer disease
• Myelofibrosis and pancytopenia
• Acute leukemia or a myelodysplastic syndrome

77
Thrombosis

• reported in 15-60 of patients
• major cause of death in 10-40 of patients
• Venous and arterial thromboses have resulted in
  pulmonary emboli, renal failure from renal vein
  or artery thrombosis, intestinal ischemia from
  mesenteric vein thromboses, or peripheral
  arterial emboli.

78
Hemorrhagic complications

• occur in 15-35 of patients
• lead to death in 6-30 of these patients
• Bleeding is usually the consequence of vascular
  compromise resulting from ischemic changes from
  thrombosis or hyperviscosity.

79
Peptic ulcer disease

• Associated with PV at a 3 to 5 fold higher rate
  than that of the general population
• This has been attributed to increased histamine
  serum levels

80
Myelofibrosis and pancytopenia

• Occur in 3-10 of patients, usually late in the
  disease
• In these patients, infections and bleeding
  complications may be the most serious health
  threats
• red blood cell transfusions may be required to
  maintain adequate red blood cell counts and to
  improve fatigue and other anemia-related
  symptoms.

81
Acute leukemia or a myelodysplastic syndrome

• Develops in 1.5 of patients treated with
  phlebotomy alone
• The transformation risks
• increase to 13.5 within 5 years with treatment
  using chlorambucil
• And 10.2 within 6-10 years in patients treated
  with 32P
• At 15 years, the transformation risk for HU is
  5.9, which, although not statistically
  significant, is a worrisome trend

82

• Questions