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

FLOW CHART ANEMIA NORMOSITIK NORMOKROM

Anemia MCV 80-100 fL and MCHC 30 g/dL or MCH > 27 pg/dL

Indeks retikulosit <10

Indeks retikulosit 10-15

Indeks retikulosit >15

Abnormal Hambatan Produksi/Pematangan

Normal Anemia hemolitik/def.Fe dalam terapi ? Periksa ACTH Infiltrasi Keganasan Hipoplasia SSTL Cincin sideroblastik ?

BMP

Kehilangan/Penghancuran Berlebihan Periksa: Bilirubin indirek, LDH

Normal Perdarahan ?
Tidak Ya

Tinggi
Anemia Hemolitik Periksa urin

Negatif

Tes coombs, C3/C4 Anti dsDNA

Hemolisis Ekstravaskular Defect Extra corpuscular Mekanik, Toksin, Infeksi

Positif Hb/ hemosiderin

Positif AIHA Primer or Secunder Negatif Defect Intra corpuscular

Hemolisis Intravaskular

FLOW CHART ANEMIA MIKROSITIK HIPOKROM

Anemia MCV<80fl & MCHC<30g/dL or MCH 27 pg/dL

Indeks retikulosit <10

Indeks retikulosit 10-15

Indeks retikulosit >15

SI/IBC, Transferin, Feritin

Elektroforesis hemoglobin

Normal/Tinggi

Defisiensi Fe

Normal
Dalam terapi Fe ?

Abnormal Hemoglobinopati Thalasemia

BMP

Pasokan, Absorpsi ? Hemolitik ? Gangguan metabolisme Fe Mielodisplasia (MDS) Anemia of Chronic Diseases (ACD)

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

II. Extracorpuscular factors

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

B. Nonimmune hemolytic anemias

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

Hemolysis - RBC destruction

Extravascular Hemolysis
Ingested by RE cell (spleen & liver) Heme Globin

Intravascular Hemolysis
Hgb liberated in blood vessel Hgb + haptoglobin Serum haptoglobin + hemalbumin & plasma Hgb + hemoglobinuria & hemosidenuria

Iron

Reutilized Protoporphyrin

Hgb + albumin
Hgb excreted in urine

Reutilized

bilirubin

Mechanisms of hemolysis / pathogenesis:

- Intravascular - Extravascular

Inravascular hemolysis :
- Red cells destruction occurs in vascular space - Clinical states associated with Intravascular hemolysis: Acute hemolytic transfusion reactions Severe and extensive burns Paroxysmal nocturnal hemoglobinuria (PNH) Severe microangiopathic hemolysis Physical trauma Bacterial infections and parasitic infections (sepsis)

- Laboratory

signs of intravascular hemolysis:

Indirect hyperbilirubinemia Erythroid hyperplasia Hemoglobinemia Methemoalbuminemia Hemoglobinuria Absence or reduced of free serum haptoglobin Hemosiderynuria

Extravascular hemolysis :
- Red cells destruction occurs in reticuloendothelial system (RES) - Clinical states associated with extravascular hemolysis : Autoimmune hemolysis Delayed hemolytic transfusion reactions Hemoglobinopathies Hereditary spherocytosis Hypersplenism Hemolysis with liver disease

- Laboratory signs of extravascular hemolysis: Indirect hyperbilirubinemia Increased excretion of bilirubin by bile Erythroid hyperplasia Hemosiderosis

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:
Hematology test

1. Laboratory features - Normocytic/macrocytic, hyperchromic anemia - Reticulocytosis - Increased serum iron - Antiglobulin Coombs test is positive

2. Blood smear - Anisopoikilocytosis, spherocytes - Erythroblasts - Schistocytes

3. Bone marrow smear - Erythroid hyperplasia

Extra corpuscular Factor Autoimmune Hemolytic Anemia (AIHA) * warm-reactive antibodies:

I. Primary II. Secondary 1.Acute - viral infections - drugs ( -Methyldopa, Penicillin, Quinine, Quinidine) 2. Chronic - rheumatoid arthritis, systemic lupus erythematosus - lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas, Waldenstrms macroglobulinemia) - miscellaneous (thyroid disease, malignancy )

* cold-reactive antibodies:
I. Primary cold agglutinin disease II. Secondary hemolysis: - Mycoplasma infections - Viral infections - Lymphoproliferative disorders III. Paroxysmal cold hemoglobinuria

Diagnosis
- positive Coombs test (DAT)

Treatment:
- steroids - splenectomy - immunosupressive agents - transfusion

Intracorpuscular FACTOR: Accquired : Paroxysmal Nocturnal Hemoglobinuria (PNH)

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

3. PNH laboratory features: - pancytopenia - chronic urinary iron loss - serum iron concentration decreased - hemoglobinuria - hemosiderinuria - positive Hams test (acid hemolysis test) - positive sugar-water test - specific immunophenotype of erytrocytes (CD59, CD55) 4. Treatment : - washed RBC transfusion - iron therapy - 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 Andayani Hematology 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-Jollyes bodies Cabots 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
Fanconis 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 Fanconis 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

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

Definition
ACD 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 - Hodgkins disease and Non-Hodgkins 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 )

ACD
Infection and inflammation Interleukin-1 (IL-1) Other Cytokines

Stored iron in reticuloendothelial system

[Leukocytes (granulocytes)]

Lactoferrin Plasma iron

Lactoferrin iron

Decreased circulating plasma iron

ACD infection Inflammation Immune response Macrophage activity

Increased phagocytosis - Decreased RBC survival Reticulo endothelial system Increased ferritin synthesis - Increased stored iron Increased membrane receptors - Increased avidity for RBCs and iron-binding proteins

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 features sFe TS TIBC sFerritin Sideroblasts sTR Iron deficiency without iron deficiency <10% <10g/L <10% >10% , N >200g/L, N 10-20% N ACD with iron deficiency <10% N, <30g/L, N <10%

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) (ET)

2. Essential thombocytosis 3. 4.

Myelofibrosis with myeloid metaplasia (MMM) 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 etiology median age

: : :

2 per 100,000 unknown 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 Bartters 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 - Risk to transform to acute leukemia spent phase ( Spent phase 40% 1.5 % 10-25%

: normalization of red cell mass asso. with

cytopenia , increasing splenomegaly (extramed.hemat.) & collagen fibrosis of BM ) -BMP : hipersellarity

WHO criteria for diagnosis of Polycythemia Vera

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

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 polycythemia

Finding
Splenomegaly Leukocytosis Thrombocytosis RBC volume arterial O2 sat B12 level LAP Bone Marrow EPO level Endogenous CFU-E growth

PV
+ + + increased normal increased increased
Panhyperplasia decreased +

2nd Polycythemia
normal normal normal normal normal normal -

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 Intermediate risk

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

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