Anemia

Anemia

Dr . Yenny Dian Andayani SpPD -KHOM

Divition Hematologic Oncologi Medic Dept Internal Medicine Moh HoesinGeneral Hospital

Palembang Faculty of Medicine Sriwijaya University Palembang

Morphological classification of anemias

• microcytic, hypochromic anemia – (decreased MCV)

• normocytic, normochromic anemia – (normal MCV)

• macrocytic, normochromic anemia – (increased MCV)

Normochrome normocyter anemia

• MCH normal

• MCHC normal

• MCV normal

MICROCYTIC HYPOCHROME anemia

• MCV MCH MCHC • microcytic, hypochromic RBC in the

peripheral blood

• MCV < 80fl

• MCH < 27pg

MACROCYTIC anemia

• MCV • MCH • MCHC

NormalAnemia hemolitik/def.Fe

dalam terapi ?Periksa ACTH

Infiltrasi Keganasan

Hipoplasia SSTL Cincin sideroblastik ?

AbnormalHambatan

Produksi/PematanganBMP

Indeks retikulosit <10‰ Indeks retikulosit 10-15‰

Tidak

PositifAIHA Primer or Secunder

NegatifDefect Intra corpuscular

Tes coombs, C3/C4Anti dsDNA

HemolisisEkstravaskular

Negatif

Defect Extra corpuscularMekanik, Toksin, Infeksi

HemolisisIntravaskular

Positif Hb/hemosiderin

Periksa urin

Kehilangan/Penghancuran BerlebihanPeriksa: Bilirubin indirek, LDH

Indeks retikulosit >15‰

AnemiaMCV 80-100 fL and MCHC 30 g/dL or MCH 27 pg/dL

FLOW CHART ANEMIA NORMOSITIK NORMOKROM

Normal Tinggi

Perdarahan ?

Ya

Anemia Hemolitik

Gangguan metabolisme Fe

Mielodisplasia (MDS)

Anemia of Chronic Diseases (ACD)

BMP

Normal/Tinggi

Pasokan, Absorpsi ?

Defisiensi Fe

SI/IBC, Transferin, Feritin

Indeks retikulosit <10‰ Indeks retikulosit 10-15‰

Dalam terapi Fe ?

Hemolitik ?

Normal

Hemoglobinopati

Thalasemia

Abnormal

Elektroforesis hemoglobin

Indeks retikulosit >15‰

AnemiaMCV<80fl & MCHC<30g/dL or MCH ≤ 27 pg/dL

FLOW CHART ANEMIA MIKROSITIK FLOW CHART ANEMIA MIKROSITIK HIPOKROMHIPOKROM

HEMOLYTIC ANEMIAS

Yenny Dian Andayani

Hematology Oncology Medic Division Dept.Internal Medicine Moh Hoesin General Hospital Faculty of

Medicine /Sriwijaya University Palembang

HEMOLYTIC ANEMIA

• Anemia of increased destruction– Normochromic, normochromic anemia– Shortened RBC survival– Reticulocytosis - Response to increased RBC

destruction– Increased indirect bilirubin– Increased LDH

Classification of Hemolytic Anemia

• Intracorpuscular factor

• Extracorpuscular factor

1.1. Intracorpuscular factor Intracorpuscular factor Red cell abnormality Red cell abnormality A. Hereditary A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis)1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) 2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) deficiency, Pyruvate kinase (PK) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) thalassemias, sickle cell anemia )

B. AcquiredB. Acquired 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH) 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH)

II. Extracorpuscular factorsII. Extracorpuscular factors

A. Immune hemolytic anemias A. Immune hemolytic anemias 1. Autoimmune hemolytic anemia 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood 2. Transfusion of incompatible blood

B. Nonimmune hemolytic anemiasB. Nonimmune hemolytic anemias 1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), venons 2. Bacterial infections, parasitic infections (malaria), venons 3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves - prosthetic heart valves 4. Hypersplenism 4. Hypersplenism

Hemolysis - RBC destruction

Extravascular Hemolysis

Ingested by RE cell (spleen & liver)

Heme Globin

Iron Protoporphyrin

Reutilized

bilirubinReutilized

Intravascular Hemolysis

Hgb liberated in blood vessel

Hgb + haptoglobin

Hgb + albumin

Hgb excreted in urine

Serum haptoglobin

+ hemalbumin & plasma Hgb

+ hemoglobinuria & hemosidenuria

Mechanisms of hemolysisMechanisms of hemolysis / pathogenesis / pathogenesis::

- - IIntravascularntravascular - - EExtravascularxtravascular

Inravascular hemolysis :Inravascular hemolysis :

- - RRed cells destruction occurs in vascular space ed cells destruction occurs in vascular space

- - CClinical states associated with Intravascular hemolysis:linical states associated with Intravascular hemolysis:

A Acute hemolytic transfusion reactions cute hemolytic transfusion reactions

SSevere and extensive burns evere and extensive burns

P Paroxysmal nocturnal hemoglobinuriaaroxysmal nocturnal hemoglobinuria (PNH) (PNH)

S Severe microangiopathic hemolysis evere microangiopathic hemolysis

P Physical trauma hysical trauma

B Bacterial infections and parasitic infections (sepsis)acterial infections and parasitic infections (sepsis)

- - LLaboratory signs of intravascular hemolysisaboratory signs of intravascular hemolysis:: IIndirect hyperbilirubinemia ndirect hyperbilirubinemia E Erythroid hyperplasia rythroid hyperplasia H Hemoglobinemiaemoglobinemia M Methemoalbuminemiaethemoalbuminemia H Hemoglobinuriaemoglobinuria A Absence or reduced of free serum haptoglobin bsence or reduced of free serum haptoglobin H Hemosiderynuriaemosiderynuria

Extravascular hemolysis :Extravascular hemolysis :

- - RRed cells destruction occurs in reticuloendothelial system ed cells destruction occurs in reticuloendothelial system (RES)(RES)- - CClinical states associated with extravascular hemolysis :linical states associated with extravascular hemolysis : A Autoimmune hemolysisutoimmune hemolysis D Delayed hemolytic transfusion reactions elayed hemolytic transfusion reactions H Hemoglobinopathiesemoglobinopathies H Hereditary spherocytosis ereditary spherocytosis H Hypersplenismypersplenism H Hemolysis with liver diseaseemolysis with liver disease

- - LLaboratory signs of extravascular hemolysis:aboratory signs of extravascular hemolysis: IIndirect hyperbilirubinemia ndirect hyperbilirubinemia IIncreased excretion of bilirubin by bilencreased excretion of bilirubin by bile E Erythroid hyperplasia rythroid hyperplasia H Hemosiderosisemosiderosis

Anamnesa

• Fatigue • Pallor• Shortness of Breath • Bleeding/petechiae• Joint symptoms• Rash-eg malar• Family History• Medications

Physical Exam Findings

• Tachycardia

• Tachypnea

• Jaundice

• Splenomegaly

• Signs of congestive heart failure in rapidly progressive anemia

Laboratory features:Laboratory features:

Hematology testHematology test1. Laboratory features1. Laboratory features - - NNormocytic/macrocytic, hyperchromic anemiaormocytic/macrocytic, hyperchromic anemia - - RReticulocytosiseticulocytosis - - IIncreased serum ironncreased serum iron - - AAntiglobulin Coombs’ test is positiventiglobulin Coombs’ test is positive

2. Blood smear 2. Blood smear - - AAnisopoikilocytosis, spherocytesnisopoikilocytosis, spherocytes - - EErythroblastsrythroblasts - - SSchistocyteschistocytes

3. Bone marrow smear3. Bone marrow smear - - EErythroid hyperplasiarythroid hyperplasia

Extra corpuscular FactorExtra corpuscular FactorAutoimmune Autoimmune HHemolytic emolytic AAnemia nemia (AIHA) (AIHA) * * warm-reactive antibodies: warm-reactive antibodies:

I. PrimaryI. Primary II. Secondary II. Secondary 1.1.AAcutecute - viral infections- viral infections - drugs ( - drugs ( -Methyldopa, Penicillin, Quinine, Quinidine)-Methyldopa, Penicillin, Quinine, Quinidine) 2. 2. CChronic hronic - rheumatoid arthritis, systemic lupus erythematosus- rheumatoid arthritis, systemic lupus erythematosus - lymphoproliferative disorders- lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas, (chronic lymphocytic leukemia, lymphomas, WaldenstrWaldenstrÖÖm’s macroglobulinemia)m’s macroglobulinemia) - miscellaneous (thyroid disease, malignancy )- miscellaneous (thyroid disease, malignancy )

* * cold-reactive antibodies:cold-reactive antibodies:

I. Primary cold agglutinin diseaseI. Primary cold agglutinin disease II. Secondary hemolysis:II. Secondary hemolysis: - - MMycoplasma infections ycoplasma infections - - VViral infections iral infections - - LLymphoproliferative disorders ymphoproliferative disorders III. Paroxysmal cold hemoglobinuriaIII. Paroxysmal cold hemoglobinuria

DDiagnosis iagnosis

- positive Coombs’ test- positive Coombs’ test (DAT) (DAT)

Treatment:Treatment: - steroids- steroids - splenectomy- splenectomy - immunosupressive agents - immunosupressive agents - transfusion- transfusion

Intracorpuscular FACTOR:Intracorpuscular FACTOR:Accquired :Accquired : Paroxysmal Paroxysmal NNocturnal octurnal HHemoglobinuriaemoglobinuria (PNH)(PNH)

1. 1. PPathogenesisathogenesis - an acquired clonal disease, arising from a somatic mutation in a - an acquired clonal disease, arising from a somatic mutation in a

single abnormal stem cell single abnormal stem cell - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - deficiency of the GPI anchored membrane proteins - deficiency of the GPI anchored membrane proteins (decay-accelerating factor =CD55 and a membrane inhibitor (decay-accelerating factor =CD55 and a membrane inhibitor of reactive lysis =CD59) of reactive lysis =CD59) - red cells are more sensitive to the lytic effect of complement - red cells are more sensitive to the lytic effect of complement - intravascular hemolysis - intravascular hemolysis 2. Symptoms2. Symptoms - passage of dark brown urine in the morning - passage of dark brown urine in the morning

3. PNH –laboratory features:3. PNH –laboratory features: - pancytopenia - pancytopenia - chronic urinary iron loss - chronic urinary iron loss - serum iron concentration decreased - serum iron concentration decreased - hemoglobinuria - hemoglobinuria - hemosiderinuria - hemosiderinuria - positive Ham’s test (acid hemolysis test)- positive Ham’s test (acid hemolysis test) - positive sugar-water test - positive sugar-water test - specific immunophenotype of erytrocytes (CD59, CD55)- specific immunophenotype of erytrocytes (CD59, CD55)

4. 4. Treatment Treatment :: - washed RBC transfusion- washed RBC transfusion - iron therapy - iron therapy - allogenic bone marrow transplantation - allogenic bone marrow transplantation

Intracorpuscular Factor Herediter ( defect)

• Hemoglobinopathies– Sickle Cell Disease, Sickle cell trait, Hemoglobin SC– Thallasemias

• Unstable RBC Membrane– Hereditary spherocytosis

• Metabolic Machinery– G6PD deficiency– Pyruvate kinase deficiency

G6PD deficiency

• Most frequently encountered abnormality of red cell metabolism

• Over 200 million people worldwide

• ? Survival advantage with malaria infection

• X chromosome

• Extensive polymorphism

Macrocytic Anemia

Yenny Dian AndayaniHematology Oncology Medic Division Dept.Internal Medicine Moh.Hoesin General Hospital /Faculty of

Medicine Sriwijaya University Palembang

Megaloblastic anemia/Macrocytic anemia

• fault in DNA synthesis

• 95% of cases of megaloblastic anemia are– deficiency of vitamin B12– deficiency of folic acid

• macrocytic blood picture

• megaloblastic erythropoesis.

Vitamin B12 deficiency

• inadequate diet (no animal products!)

• malabsorption

• pernicious anemia (PA)

• partial or total gastrectomy

• blind loop syndrome

• fish tapeworm

Folate deficiency

• Reduced intake ( nutritional & malabsorpsi)

• increased utilisation (pregnancy, malignancy, hyperthytoidsm)

• Defective utilisation : drugs (anticonvulsant, oral contraceptive), alcoholism.

• Reduced hepatic stores

alcohosm, hepatoma

Clinical Feature

Sympton and sign Vit B12 Def :

• Severe : anemia, neuropathy

• Other symptom : sore mouth,loss of taste, atropy mucosa of the tongue.

• Disorder of the central nervous system : paresthesias of the hands & feet, unsteadiness of gait, memory loss etc.

Syptom & sign folic acid def

• Often go undiagnosed, especially alcoholic who have a very poor diet and maintain blood alcohol levels above 100 mg/dl→ enteropatic cycle of folate supply to the intestine and tissues impared.

• Diagnosis is made difficult → clinician must be suspicious of the possibility of folate def. in the alcoholic.

The peripheral blood smear in Macrocytic Anemia

• oval macrocytes• anisocytosis• poikilocytosis.• hypersegmental neutrophils (>5% with more than five nuclear

lobes)• platelets bizarre in shape and size (giant platelets)• neutropenia• thrombocytopenia (not as severe as in AA)• low reticulocytosis• The bone marrow shows a megaloblastic erythropoesis

Bone marrow smear in MA

• megaloblastic erythropoesis

• bone marrow rich in cells,

• giant metamyeolcytes

• giant bands

• many Howell-Jolly’es bodies

• Cabot’s rings

Biochemical findings in MA

• serum indirect (unconjugated) bilirubin • serum LDH (principally LDH-1)

• serum iron – (unless the anemia is complicated with iron

deficiency)

• vitamin B12 concentration ↓

• folic acid concentration ↓

The diagnosis of megaloblastic anemia

• serum vitamin B12 concentration

• serum folic acid concentration

• if vitamin B12 and folate assays are within normal limits, then the bone marrow examination is performed (before blood transfusion or vitaminB12, folate administration).

• Schilling test

Diagnosis

• Establised based on laboratory test.

• DD : Macrocytosis in patients : dysplastic anemias, liver disease, hemolysis, exposure to the chemotherapeutic agents.

Treatment

• Folic Acid and Vit B12 ( etiology must known well)

• Severe with anemias : PRC transfusion

APLASTIC /HYPOPLASTIC ANEMIA

Yenny Dian Andayani

Hematologic Oncology Medic Division Dept Internal Medicine Moh.Hoesin General Hospital Faculty of

medicine Sriwijaya University Palembang

Aplastic anemia

• Aplastic anemia is a severe, life threatening syndrome in which production of erythrocytes, WBCs, and platelets has failed.

• Aplastic anemia may occur in all age groups and both genders.

• The disease is characterized by peripheral pancytopenia and accompanied by a hypocellular bone marrow.

Hypocellular bone marrow in aplastic anemia

Aplastic anemia

• Etiology– Acquired

» Most cases of aplastic anemia are idiopathic and there is no history of exposure to substances known to be causative agents of the disease

» Exposure to ionizing radiation – hematopoietic cells are especially susceptible to ionizing radiation. Whole body radiation of 300-500 rads can completely wipe out the bone marrow. With sublethal doses, the bone marrow eventually recovers.

» Chemical agents – include chemical agents with a benzene ring, chemotherapeutic agents, and certain insecticides.

» Idiosyncratic reactions to some commonly used drugs such as chloramphenicol or quinacrine.

Aplastic anemia

» Infections – viral and bacterial infections such as infectious mononucleosis, infectious hepatitis, cytomegalovirus infections, and miliary tuberculosis occasionally lead to aplastic anemia

» Pregnancy (rare)

» Paroxysmal nocturnal hemoglobinuria – this is a stem cell disease in which the membranes of RBCs, WBCs and platlets have an abnormality making them susceptible to complement mediated lysis.

» Other diseases – preleukemia and carcinoma

Aplastic anemia

– Congenital disorders» Fanconi’s anemia – the disorder usually becomes symptomatic

~ 5 years of age and is associated with progressive bone marrow hypoplasia. Congenital defects such as skin hyperpigmentation and small stature are also seen in affected individuals.

» Familial aplastic anemia – a subset of Fanconi’s anemia in which the congenital defects are absent.

Clinical features

• Fatique

• Heart palpitation

• Palor

• Infections

• Ptchiae

• Mucosal bleeding/gum bleeding

Aplastic anemia

• Pathophysiology:– The primary defect is a reduction in or depletion of

hematopoietic precursor stem cells with decreased production of all cell lines. This is what leads to the peripheral pancytopenia.

• This may be due to quantitative or qualitative damage to the pluripotential stem cell.

• In rare instances it is the result of abnormal hormonal stimulation of stem cell proliferation

• or the result of a defective bone marrow microenvironment • or from cellular or humoral immunosuppression of hematopoiesis.

Aplastic anemia

– Lab findings

» Severe pancytopenia with relative lymphocytosis (lymphocytes live a long time)

» Normochromic, normocytic RBCs (may be slightly macrocytic)

» Mild to moderate anisocytosis and poikilocytosis

» Decreased reticulocyte count

» Hypocellular bone marrow with > 70% yellow marrow

Differential Diagnosis of pancytopenia and hypoplastic marrow

• 1. Aplastic anemia• 2. Hypoplastic myelodysplastic syndrome or• hypoplastis AML• 3. PNH• 4. Hypoplastic antecedent phase of acute• lymphocytic leukemia• 5.Hypoplastic antecedent of hairy cell leukemia• 6. Idiopathic myelofibrosis• 7. Pure red cell aplasia• 8. Agranulocytosis.

Diagnosis Criteria for Severe AA

• At least two of following

- Absolute neutrophil count < 0,5 x 10 9 /L

- Platelet count < 20 x 10 9/L

- Anemia with corrected reticulocyte

count < 1 %.• One of the following

- Bone marrow cellularity <25 %

- Bone Marrow cellularity < 50 % with fewer the

30 % the neutrophil cell

Treatment• Marrow tranplantation isI curative for < 40 years.• Only one –third of patients have suitable donor.• Immunosuppressive therapy : not curative -ATG -Cyclosporin -Androgen - Corticosteroids

A

Anemia of chronic disease =Anemia of chronic disorders

(ACD)

Yenny Dian Andayani Division Hematology Oncology Medic

Dept.Internal Medicine RSMH/Faculty of medicine Sriwijaya University Palembang

DefinitionACD is a common type of anemia that

occurs in patients with infectious, inflammatory, or neoplastic diseases that persist for more than 1 or 2 months.

It does not include anemias caused by marrow replacement, blood loss, hemolysis, renal insufficiency, hepatic disease, or endocrinopathy, even when these disorders are chronic.

Epidemiology• ACD is more common that any anemia syndrome other

than blood loss with consequent iron deficiency• ACD is the most common cause of anemia in

hospitalized patients• After patients with bleeding, hemolysis, or known

hematologic malignancy were excluded, 52% of anemic patients met laboratory criteria for the anemia of chronic disorders

• ACD is observed in 27% of outpatients with rheumatoid arthritis .

Disorders Associated with the Anemia of Chronic Disease

• Chronic infections- Pulmonary infections: abscesses, emphysema,

tuberculosis, pneumonia - Subacute bacterial endocarditis ,Pelvic inflammatory disease

- Chronic urinary tract infections, Chronic fungal disease- HIVinfections, Osteomyelitis

• Chronic, noninfectious inflammations- Rheumatoid arthritis- LES (Systemic lupus erythematosus)- Sever trauma, thermal injury, Vasculitis

• Malignant diseases- Cancer

- Hodgkin’s disease and Non-Hodgkin’s Lympmhomas

- Leukemias

- Multiple myeloma

• Miscellanous - Alcoholic liver disease

- Thrombophlebitis

- Ischemic heart disease

• Idiopathic ACD

Pathogenesis

• Shortened red cell life span, moderately 20-30%

(from 120 to 60-90 days)

• Relative bone marrow (erythropoiesis) failure

- Cytokines released from inflammatory cells (TNF-,

IL-1, IFN-) affects erythropoiesis by inhibiting the

growth of erythroid progenitors

- Serum erythropoietin levels in patiens with ACD are

normal when compared to healthy subjects but much

lower than levels in non-ACD anemic patients

Pathogenesis

ABNORMAL IRON METABOLISM

• Activation of the reticuloendothelial system with increased iron retention and storage within it

• impaired release of iron from macrophages to circulating transferrin (impaired reutilization of iron)

• Reduced concentration of transferrin

(decreased production, increase sequestration in the spleen and in the foci of inflammation, increase loss )

Infection and inflammation

Interleukin-1 (IL-1)Other Cytokines Stored iron in

reticuloendothelial system

[Leukocytes (granulocytes)]

Lactoferrin Lactoferrin iron

Plasma iron

Decreased circulating plasma iron

ACD

ACD

infection

Inflammation

Immune response

Macrophage activity

Increased phagocytosis- Decreased RBC survival

Increased ferritin synthesis- Increased stored iron

Increased membrane receptors- Increased avidity for RBCs and iron-binding proteins

Reticulo endothelial

system

IL-1

Granulocytes

Acute-phase reactants

Lactoferrin

Circulating plasma iron (Lactoferrin-iron complex)

Decreased plasma iron (hypoferremia)

Symptoms and Sign

• Symptoms of the underlying disease

( malignancy or chronic inflammatory disease) : weight loss, anorexia, fever,chills,myalgias and artralgia.

• Symptoms of the anemia

Laboratory features

• The anemia is usually mild or moderate ( Hb 7-11g/dl)

- lower values are observed in 20-30% of patients

• The anemia is most often normochromic and normocytic (MCHC and MCV are normal)

- MCV 70-80 fl in 5-40% of patients with ACD

- MCHC 26-32 g/dl in 40-70%

• Erythrocyte sedimentation rate (ESR) - usually rapid

• Retikulocytes - most often normal or slightly decreased number, increased count is rarely

Laboratory features

• Iron metabolism

1. Serum Iron - decreased (it is necessary for the diagnosis of ACD)

2. TIBC - reduced or low-normal (N)

3. Saturation index is decreased and is often < 15 %.

4. Serum Ferritin-increased or normal

5. Serum Transferrin Receptor (sTR)-Normal

6. Sideroblasts in the bone marrow-reduced (5-20%)

Differential diagnosis

Laboratory Iron deficiency ACD

features without iron with iron

deficiency deficiency .

sFe

TS <10% >10% <10%

TIBC , N N,

sFerritin <10g/L >200g/L, N <30g/L, N

Sideroblasts <10% 10-20% <10%

sTR N

Therapy

1. Treatment of the underlying disorder

2. Iron supplementation (IS)

- for patients with ACD with chronic infection

or malignancy IS should be strictly avoided

- IS benefit patients with ACD associated with

auto-immune or rheumatic disorders.

- when ACD is complicated by iron deficiency

(about 27% patients).

3. Transfusion demand (about 30% ) patients who have low Hb and are symptomatic

4. Recombinant erythropoietin 10.000 units 3 times a week i.v. or s.c. 2-3tg, in the absence of response 20000j, If there is still no respose, the treatment should be discontinued. (in 40% of patients it reduces number of transfusions)

5. Sequential administration of erythropoietin and iron (48h later)

5. Iron chelation with deferoxamine - in some patients therapy was associated with a rise in hemoglobin level

6. In future anti-TNF-antibodies

POYCYTHEMIA

Yenny Dian Andayani

Hematology Oncology Medic Dept.of Internal Medicine Moh Hoesin General Hospital

/Faculty of Medicine University Sriwijaya Palembang.

Myeloproliferative disease

arise from precursors of the "myeloid" lineage in the bone marrow

1. Polycythemia vera (PV)

2. Essential thombocytosis (ET)

3. Myelofibrosis with myeloid metaplasia (MMM)

4. Chronic Myelomonocytic leukemia (CMML)

Polycythemia vera

1892 : 1st described by Vaquez

1900 : Phlebotomy as treatment by Osler 1951 : Dameshek classified PV as a MPD

1967 : Wesserman defined of PV and treatment

incidence : 2 per 100,000

etiology : unknown median age : 60 yrs. ( male )

Classfication of Polycythemia

• I. Primary (autonomous)

Polycythemia Vera

• II. Secondary Polycythemia

A. Physiologically appropriate (

decreased tissue oxygenation)

B. Physiologycally in appropriate

(normal tissue oxygenation ).

Physiologycally inappropriate EPO Overproduction

- Tumors ; renal , brain , hepatoma , uterine fibroid , pheochromocytoma

Renal artery stenosis Adrenal cortical hypersecretion Exogenous androgens NS

Bartter’s syndrome

Renal cyst , hydronephrosis

Physiologycally approprite (decreased tissue oxygenation) EPO Production secondary to hypoxia

- Lung disease

High altitude

Smoking

Cyanotic Heart disease

Methemoglobinemia

High O2 affinity hemoglobin

Cobalt

Clinical Features

- Head ache- Thrombosis common cause of death- Pruritis ( aggravated by bathing ) 50% - Erythromelagia- Digital ischemia ( palpable pulse )- Joint pain- Weight loss- Headache , vertigo- Visual disturbance- Conjunctival plethora- Palpable splenomegaly 70%

Clinical Features

- Lab : elevated leukocyte alkaline phosphatase ( LAP ) 70%

elevated serum B12 40%

- Risk to transform to acute leukemia 1.5 %

spent phase 10-25%

( Spent phase : normalization of red cell mass asso. with

cytopenia , increasing splenomegaly (extramed.hemat.) &

collagen fibrosis of BM )-BMP : hipersellarity

A1. elevated RBC mass > 25% above mean normal predicted value,or Hb > 18.5g/dL ( Male ) Hb > 16.5 g/dL (female )

A2. No cause of 2nd erythrocytosis,including: Absence of familial erythrocytosis No elevation of EPO from - hypoxia ( PaO2 92 % )

- high O2 affinity Hb. - truncated EPO receptor

- inappropiated EPO production by tumor A3. Splenomegaly

A4. Clonal genetic abnormality other than Ph chromosome or BCR/ABL fusion gene in marrow cells

A5. Endogenous erythroid colony formation in vitro

WHO criteria for diagnosis of Polycythemia Vera

B1. Thrombocytosis > 400,000 B2. WBC > 12,000 B3. BM Biopsy showing panmyelosis with prominent erythroid

& megakaryocytic proliferation B4. Low serum EPO levels

WHO criteria for diagnosis of Polycythemia Vera

Diagnosis : A1+A2 and any other of cathegory. A or A1+A2 and any 2 of cathegory. B or > 99th percentile of method specific reference range of age ,gender,altitude of residence

Criteria Polycythemia Vera study group

• Category A

1.total red cell mass Male ≥36 ml/kg

Female ≥32 ml/kg

2.Arterial oxygen saturation ≥ 92 %

3. Splenomegaly

• Category B

1. Thrombocytosis > 400 x 10 3/ul

2. Leukocytosis 12x 103/ul

3. Increased leukocyte alkaline

phosphatase (LAP)

4. Serum B12 > 900 pg/ml or B12

binding capacity > 2200 pg/ml

Pv Diagnosis : when A1+A+2+A3 and any 2 from category B are present.

PV & Secondary polycythemiaPV & Secondary polycythemia

Finding PV 2nd Polycythemia

Splenomegaly Leukocytosis Thrombocytosis RBC volume arterial O2 sat

B12 level

LAP Bone Marrow EPO level Endogenous CFU-E growth

++ ++

++

increasedincreased

normalnormal

increasedincreased

increasedincreasedPanhyperplasiPanhyperplasiaa

decreaseddecreased

++

- - - normalnormal

normalnormal

normalnormal

normalnormal

normalnormal

normalnormal

--

Staging & Prognosis

Hct. > 45% risk to thrombosis Death

age > 70 yrs. & previous history of thrombosis

; important predictor of recurrent thrombotic events

Treatment

aim ; - reduce thrombotic risk & slow leukemic transformation

- based on risk of thrombosis

Low risk

-age < 60yr.-no Hx thrombosis-Plt. < 1,500,000-no CVD risk

High risk

-age > 60yr.-Previous Hx. thrombosis-CVD risk(smoking, )

Intermediate risk

Treatment

Treatment of choice is “ Phlebotomy “

Hct. < 45 % in men , < 42% in women

“ Hydroxyurea “ is supplemented to decreased Hct.

“ IFN –alfa “ use for cytoreduction in younger

( decreased risk to leukemic transformation of hydroxyurea )

Treatment

Busulfan or P-32 in elderly pt. with hydroxyurea intolerated

Low dose ASA ( 40 mg ) ; alleviate of microvascular sequelae

( headache, vertigo,visual disturbance , erythromelalgia )

Anagrelide ; used in all MPD to lowering platelet count