HAEMOLYTIC HAEMOLYTIC ANAEMIAANAEMIAANAEMIA ANAEMIA

Dairion Gatot, Azmi S Kar.Divisi Hematologi-Onkologi MedikDepartemen Ilmu Penyakit Dalam FK-USU/RS H.Adam Malik, Medan 2007.

WHEN BY THEN

Hb 13 g% transfusion Hb 4 g%

WHEN BY THEN

No sign of bleedingNo sign of bleeding

HEMOLYTICHEMOLYTIC ??

DefinitionDefinition

•• Any situation in which there is a Any situation in which there is a reduction in RBC lifereduction in RBC life--span due tospan due toreduction in RBC lifereduction in RBC life span due to span due to increase RBC destruction. Failure of increase RBC destruction. Failure of compensatory marrow response compensatory marrow response p y pp y presults in anemia. Predominant site results in anemia. Predominant site of RBC destruction is red pulp of the of RBC destruction is red pulp of the

llspleen.spleen.

U d DU d DUsed Drug or Used Drug or traditional traditional medicinemedicine Hb Hb medicinemedicine decreaseddecreased

no sign of bleedingno sign of bleeding

Hemolytic ?Hemolytic ?

I f tiI f tiInfectionInfection

Anemia + Anemia + icterus (mild)icterus (mild) Hemolytic ?Hemolytic ?icterus (mild)icterus (mild)

NORMOCYTICANAEMIA

INTERPRETATIONLABORATORY TEST

PERIPHERAL SMEAR

POSITIVE NEGATIVE

INCREASED REDUCED

ANAEMIAPERIPHERAL SMEAR

RETICULOCYTE COUNT

BLOOD IN STOOL OR OTHER SOURCE OF BLEEDING IDENTIFIED

REPLACEMENT OF DECREASED HYPERCELLULAR HYPERCELLULAR

POSITIVE NEGATIVE NEGATIVE

BLEEDING IDENTIFIED

ANTIHUMAN GLOBULIN (COOMBS’TEST)

BONE MARROW AND

OTHER HAEMOLYTIC ANAEMIAS

AUTO IMMUNO HAEMOLYTIC

OTHER

Renal disease

MYELOPHTHISIC

Tumor

BLOOD LOSS

NORMAL MARROW ELEMENTS

CELLULARITYERYTHROID HYPERPLASIA

ERYTHROID HYPERPLASIA

BONE MARROW BIOPSY

DIAGNOSIS

Parasites

Hypersplenism

Microangiopathic

haemolysis

ANAEMIA

Erythroblastosis

foetalis

Transfusion

ti

Renal disease

Infection

Malnutrition

Aplastic

anaemia

Tumor

Myelofibrosis

Infection

Leukaemia

ANAEMIA

Hereditary

spherocytosis

Paroxysmal noctural

haemoglobinuria

E d fi i i

reaction

Collagen

vascular

disease

Radiation

Enzyme deficiencies

Drug or toxin

Haemoglobinopathies

normositic normochromic anemianormositic normochromic anemia• Diagnostic:Diagnostic:

– MCV 80-100 fL and– MCH > 27 pg or MCHC ³ 30 g/dLpg g

• Cause :– Distribution failure .– Lack of production,– Rate of RBC destruction

d d d ll lifreduced red-cell life span

Haemolytic anaemia

• Rate of RBC destruction

RBC production

Reticulocyte counts

ClassificationClassification of Hemolytic anemiasof Hemolytic anemias

I. I. Red cell abnormality (Intracorpuscular Red cell abnormality (Intracorpuscular factors)factors)factors)factors)

A. Hereditary A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis)1. Membrane defect (spherocytosis, elliptocytosis)2. Metabolic defect (Glucoze2. Metabolic defect (Glucoze--66--PhosphatePhosphate--Dehydrogenaze Dehydrogenaze

(G6PD) deficiency, Pyruvate kinase (PK) deficiency) (G6PD) deficiency, Pyruvate kinase (PK) deficiency) ( ) y, y ( ) y)( ) y, y ( ) y)3. Hemoglobinopathies (unstable hemoglobins, 3. Hemoglobinopathies (unstable hemoglobins,

thalassemias, sickle cell anemia )thalassemias, sickle cell anemia )

B. AcquiredB. Acquired1. Membrane abnormality1. Membrane abnormality--paroxysmal nocturnal paroxysmal nocturnal

hemoglobinuria (PNH) 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 warmcaused by warm--reactive antibodies reactive antibodies -- caused by coldcaused by cold--reactive antibodies reactive antibodies

2. Transfusion of incompatible blood2. Transfusion of incompatible blood2. Transfusion of incompatible blood 2. Transfusion of incompatible blood

B. Nonimmune hemolytic anemiasB. Nonimmune hemolytic anemias1 Ch i l1 Ch i l1. Chemicals 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), 2. Bacterial infections, parasitic infections (malaria),

venonsvenons3. Hemolysis due to physical trauma 3. Hemolysis due to physical trauma

-- hemolytic hemolytic -- uremic syndrome (HUS)uremic syndrome (HUS)-- thrombotic thrombocytopenic purpura (TTP)thrombotic thrombocytopenic purpura (TTP)thrombotic thrombocytopenic purpura (TTP)thrombotic thrombocytopenic purpura (TTP)-- prosthetic heart valvesprosthetic heart valves

4. Hypersplenism4. Hypersplenism

M h i f h l iM h i f h l iMechanisms of hemolysis:Mechanisms of hemolysis:

IIntravascularntravascular-- IIntravascularntravascular-- EExtravascularxtravascular

I l h l i (1)I l h l i (1)Inravascular hemolysis (1):Inravascular hemolysis (1):

red cells destruction occurs in vascular spacered cells destruction occurs in vascular space-- red cells destruction occurs in vascular space red cells destruction occurs in vascular space -- clinical states associated with Intravascular hemolysis:clinical states associated with Intravascular hemolysis:

acute hemolytic transfusion reactionsacute hemolytic transfusion reactionsacute hemolytic transfusion reactions acute hemolytic transfusion reactions severe and extensive burns severe and extensive burns paroxysmal nocturnal hemoglobinuriaparoxysmal nocturnal hemoglobinuriasevere microangiopathic hemolysis severe microangiopathic hemolysis physical trauma physical trauma bacterial infections and parasitic infections (sepsis)bacterial infections and parasitic infections (sepsis)

InravascularInravascular hemolysishemolysis (2):(2):InravascularInravascular hemolysishemolysis (2):(2):

l b f l h ll b f l h l-- laboratory signs of intravascular hemolysislaboratory signs of intravascular hemolysis::

indirect hyperbilirubinemia indirect hyperbilirubinemia ypyperythroid hyperplasia erythroid hyperplasia hemoglobinemiahemoglobinemiamethemoalbuminemiamethemoalbuminemiamethemoalbuminemiamethemoalbuminemiahemoglobinuriahemoglobinuriaabsence or reduced of free serum haptoglobin absence or reduced of free serum haptoglobin h idh id ii iihemosiderhemosideriinurianuria

INTRAVASCULAR HAEMOGLOBIN DEGRADATIONINTRAVASCULAR HAEMOGLOBIN DEGRADATION

Free Hb in blood

Haptoglobin (102 mg/dL)Haptoglobin (102 mg/dL)

Hb-haptoglobin liver (catabolism same as extravascular)

HbHb

in excess of haptoglobin

Methaemoglobinαβ dimers

globin amino acid pool

Heme

kidney

tubular reabsorption

Heme (Fe+++)

haemopexinhaemopexin-heme

Urine haemoglobin

Urine haemosiderin haemopexin heme

albuminmethemalbumin

albuminalbuminheme

RE cells in liver

ExtravascularExtravascular hemolysishemolysis ::

-- red cells destruction occurs in reticuloendothelial system red cells destruction occurs in reticuloendothelial system -- clinical states associated with extravascular hemolysis :clinical states associated with extravascular hemolysis :

i h l ii h l iautoimmune hemolysisautoimmune hemolysisdelayed hemolytic transfusion reactions delayed hemolytic transfusion reactions hemoglobinopathieshemoglobinopathiesg pg phereditary spherocytosis hereditary spherocytosis hypersplenismhypersplenismhemolysis with liver diseasehemolysis with liver diseasehemolysis with liver diseasehemolysis with liver disease

Extravascular hemolysis Extravascular hemolysis (2)(2)::

LLaboratory signs of extravascular hemolysis:aboratory signs of extravascular hemolysis:indirect hyperbilirubinemia indirect hyperbilirubinemia i d ti f bili bi b bili d ti f bili bi b bilincreased excretion of bilirubin by bileincreased excretion of bilirubin by bileerythroid hyperplasia erythroid hyperplasia hemosiderosishemosiderosis

EXTRAVASCULAREXTRAVASCULAR HAEMOGLOBINHAEMOGLOBIN DEGRADATIONDEGRADATION

plasma protein and

Macrophage

Haemoglobin Heme + globinplasma protein and amino acid pool

lungs

Biliverdin + CO + Fe transferrin + Fe Bone marrow

Bilirubin

plasma albumin

Bilirubin-Albumin (unconjugated)Bilirubin-Albumin (unconjugated)

liver

Bilirubin diglucuronide (conjugated)

bile duct to duodenum

Urobilinogen Bloodkidney

stool Urobilinogen (urine)y

Urobilinogen + stercobilinogen

Hemolytic anemia Hemolytic anemia -- clinical features:clinical features:

-- pallor pallor -- jaundice jaundice -- splenomegaly splenomegaly

Laboratory features:Laboratory features:yy

1. Laboratory features1. Laboratory featuresnormocytic/macrocytic hyperchromic anemianormocytic/macrocytic hyperchromic anemia-- normocytic/macrocytic, hyperchromic anemianormocytic/macrocytic, hyperchromic anemia

-- reticulocytosisreticulocytosis-- increased serum ironincreased serum iron-- antiglobulin Coombs’ test is positiveantiglobulin Coombs’ test is positive

2. Blood smear 2. Blood smear -- anisopoikilocytosis, spherocytesanisopoikilocytosis, spherocytes-- erythroblastserythroblasts

schistocytesschistocytes-- schistocytesschistocytes

3. Bone marrow smear3. Bone marrow smearh d h lh d h l-- erythroid hyperplasiaerythroid hyperplasia

LABORATORYLABORATORY

1.1. BLOOD FILMBLOOD FILM

• Microspherocyte : 1. Autoimmuno haemolytic anaemia

(AIHA)

2. Hereditary spherocytosis

3. Haemoglobinopathies : HbCg p

4. Hipersplenisme

MCV NMCV N

MCH N

MCHC

AIHASpherocyte

LABORATORY

• RBC abnormalities

Sel target : HbC

Fragmented RBC : schistocytesFragmented RBC : schistocytes

burr cells

h l t ll (MAHA)helmet cells (MAHA)

• Plasmodium

HbC Helmet cells Burr cellsP. falciparum

LABORATORY

2. BONE MARROW

Erythroid hyperplasia : rubrisit predominant

Iron stores : negative / or

DIAGNOSISDIAGNOSIS OF HEMOLYTIC ANAEMIADIAGNOSISDIAGNOSIS OF HEMOLYTIC ANAEMIA

Basic steps are :

1. Evaluation of clinical information from a review of the hi & h i l i ihistory & physical examination

2. Evaluation of the basic blood examination & specialized laboratory examinationlaboratory examination

3. Bone marrow examination

Diagnosis of hemolytic syndrome:Diagnosis of hemolytic syndrome:Diagnosis of hemolytic syndrome:Diagnosis of hemolytic syndrome:

1. Anemia1. Anemia2 R i l i2 R i l i2. Reticulocytosis2. Reticulocytosis3. Indirect hyperbilirubinemia 3. Indirect hyperbilirubinemia

Autoimmune hemolytic anemia caused byAutoimmune hemolytic anemia caused by warmwarm reactivereactiveAutoimmune hemolytic anemia caused by Autoimmune hemolytic anemia caused by warmwarm--reactive reactive antibodies:antibodies:

I. PrimaryI. Primary

II. SecondaryII. Secondaryyy1. acute1. acute-- viral infectionsviral infections

drugs (drugs ( αα Methyldopa Penicillin Quinine Quinidine)Methyldopa Penicillin Quinine Quinidine)-- drugs ( drugs ( αα--Methyldopa, Penicillin, Quinine, Quinidine)Methyldopa, Penicillin, Quinine, Quinidine)2. chronic 2. chronic -- rheumatoid arthritis, systemic lupus erythematosusrheumatoid arthritis, systemic lupus erythematosus-- lymphoproliferative disorderslymphoproliferative disorders(chronic lymphocytic leukemia, lymphomas, (chronic lymphocytic leukemia, lymphomas, WaldenstrÖm’s macroglobulinemia)WaldenstrÖm’s macroglobulinemia)g )g )

-- miscellaneous (thyroid disease, malignancy ) miscellaneous (thyroid disease, malignancy )

Autoimmune hemolytic anemia caused by Autoimmune hemolytic anemia caused by coldcold--reactive reactive antibodies:antibodies:antibodies:antibodies:

I. Primary cold agglutinin diseaseI. Primary cold agglutinin disease

II. Secondary hemolysis:II. Secondary hemolysis:-- mycoplasma infections mycoplasma infections -- viral infections viral infections -- lymphoproliferative disorders lymphoproliferative disorders

III. Paroxysmal cold hemoglobinuriaIII. Paroxysmal cold hemoglobinuria

Autoimmune hemolytic anemia Autoimmune hemolytic anemia --di idi idiagnosis diagnosis

i i C b ’i i C b ’-- positive Coombs’ testpositive Coombs’ test

ANTIGLOBULIN TESTS (COOMB’S TEST)

Direct antihuman globulin tests (DAT)

Indirect antihuman globulin tests (IDAT)

Kriteria Diagnosis AIHA• Direct Coombs test positif (C3b &/ anti IgG pada eritrosit).• Perexclusionem menyingkirkan kemungkinan AIHA sekunder:

A i b t b t lk h l b h ki i (O ti l – Anamnesis obat-obatan, alkohol, bahan kimia (Occupational disease), adakah keganasan ?,

– Pemeriksaan serologi virus dan bakteria misalnya Dengue, CMF, EBV, HIV, Rubella,P ik ACA t k t h i d Si d A ti F f li id – Pemeriksaan ACA untuk mengetahui adanya Sindroma Anti Fosfolipid (APS),

– Pemeriksaan Rematoserologi, C3 dan C4, ANA, Anti dsDNA (Penyakit Auto Immun),

– Pemeriksaan Coomb’s apakah ada IgG/IgM atau C3b pada eritrosit dan/atau antibodi terhadap eritrosit, jenis reaktifitas cold type jika bereaksi pada suhu ≤20oC

– Pemeriksaan sidikan hati limpa KGB mediastinum dan para aorta – Pemeriksaan sidikan hati, limpa, KGB mediastinum dan para aorta (Limfoma Non Hodgkin’s),

– Pemeriksaan Immunoelektroforesis protein (Penyakit proliferasi sel B limfosit atau plasma),BMP Aspirasi dan Biopsi untuk menilai adanya Penyakit limfoproliferasi – BMP Aspirasi dan Biopsi untuk menilai adanya Penyakit limfoproliferasi non sekretorik.

TreatmentTreatment::

steroidssteroids-- steroidssteroids-- splenectomysplenectomy-- immunosupressive agents immunosupressive agents -- transfusion transfusion

GG--6PD deficiency 6PD deficiency yyG6-PD activity

GG--6PD deficiency6PD deficiencyGG 6PD deficiency 6PD deficiency • X-linked disorders, heterozygote females only

l h f h lrarely have significant haemolysis

• Haemolysis cause by infection, acidosis, drugs & toxins

• Red blood cells membrane oxidation

• Precipitation of haemoglobin Heinz bodies

• PB smear bite cells

• In acute haemolytic episode G-6PD activityIn acute haemolytic episode G 6PD activity

maybe normal

DiagnosisDiagnosis :

Low level G-6PD concentration

Treatment :

1. Avoid of drugs exposure.1. Avoid of drugs exposure.2. Transfusion .2. Transfusion .3 No spesific treatment3 No spesific treatment3. No spesific treatment.3. No spesific treatment.4. Anti oksidan, ???.4. Anti oksidan, ???.

Drug exposure of hemolytic.Drug exposure of hemolytic.g p yg p y

A l d k• Asetanilid primakuin• Furazolidon sulfasetamid• Biru metilen sulfametoksazol• Biru metilen sulfametoksazol• Asam nalidixat sulfanilamid• Naftalen sulfapiridinN p• Nitrofurantoin biru toluidin• Fenazopirid trinitrotoluen• Fenilhidrazin jamu

Hereditary microspherocytosisHereditary microspherocytosis (1)(1)

1. Pathophysiology1. Pathophysiologyp gp g-- red cell membrane protein defects (spectrin deficiency) red cell membrane protein defects (spectrin deficiency)

resulting cytoskeleton instabilityresulting cytoskeleton instability2. Familly history2. Familly history3. Clinical features3. Clinical features

-- splenomegalysplenomegaly4. Laboratory features4. Laboratory features

h l ti ih l ti i-- hemolytic anemiahemolytic anemia-- blood smearblood smear--microspherocytes microspherocytes -- abnormal osmotic fragility test abnormal osmotic fragility test -- positive autohemolysis testpositive autohemolysis test-- positive autohemolysis test positive autohemolysis test -- prevention of increased autohemolysis by including glucose in prevention of increased autohemolysis by including glucose in

incubation medium incubation medium 5. Treatment 5. Treatment

-- splenectomysplenectomy

Osmotic fragility test

A : congenital non-spherocytic anaemiasA : congenital non spherocytic anaemias

B : spherocytosis

H dit i h t iH dit i h t i (2)(2)Hereditary microspherocytosisHereditary microspherocytosis (2)(2)

5. Treatment 5. Treatment ::SSplenectomyplenectomy

Paroxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuria (PNH).(PNH).y gy g ( )( )

1. Pathogenesis1. Pathogenesis

-- 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 cellsingle abnormal stem cell

l ll l h h id lh h id l i i l (GPI) h b lii i l (GPI) h b li-- glycosylglycosyl--phosphatidylphosphatidyl-- inositol (GPI) anchor abnormalityinositol (GPI) anchor abnormality-- deficiency of the GPI anchored membrane proteins deficiency of the GPI anchored membrane proteins (decay(decay--accelerating factor =CD55 and a membrane inhibitor accelerating factor =CD55 and a membrane inhibitor ( y( y ggof 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 hemolysisintravascular hemolysisintravascular hemolysis intravascular hemolysis

2. Symptoms2. Symptomsf d k b i i h if d k b i i h i-- passage of dark brown urine in the morningpassage of dark brown urine in the morning

3. PNH 3. PNH ––laboratory features:laboratory features:

-- pancytopeniapancytopeniap y pp y p-- chronic urinary iron loss chronic urinary iron loss -- serum iron concentration decreased serum iron concentration decreased

hemoglobinuriahemoglobinuria-- hemoglobinuriahemoglobinuria-- hemosiderinuriahemosiderinuria-- positive Ham’s test (acid hemolysis test)positive Ham’s test (acid hemolysis test)-- positive sugarpositive sugar--water test water test -- specific immunophenotype of erytrocytes (CD59, CD55)specific immunophenotype of erytrocytes (CD59, CD55)

HAMS & SUGAR WATER TEST

Paroxymal nocturnal haemoglobinuria (PNH)Paroxymal nocturnal haemoglobinuria (PNH)

• RBC in PNH are abnormally sensitive to

l sis t mpl m ntlysis to complement

• Diagnosis can be made by :

1. Abnormal lysis of RBC by acidic serum (Ham’s tests)

2 H i di l i (S )2. Hypotonic medium solution (Sugar water test)

4.4. TreatmentTreatment ::

-- washed RBC transfusionwashed RBC transfusion-- iron therapy iron therapy -- allogenic bone marrow transplantationallogenic bone marrow transplantationallogenic bone marrow transplantation allogenic bone marrow transplantation

Haemolytic crisisy

Increased rate of haemolysis

ReticulocytosisReticulocytosis

Painful crisis stasis blood vessel

l iauto splenectomia

priapism

retinopathy

necrosis papilla renalis

Abnormal HbAbnormal Hb•• ThalassemiasThalassemias:

– Often in people of Mediterranean or African-Often in people of Mediterranean or AfricanAmerican, an inherited impairment in production of either alpha or beta chains o the globin moleculeglobin molecule.

– Lab : hypochromic, microcytic anemia with basophilic stippling, elliptical cells, and target cellscells.

– Alpha thalassemia: at least two alpha genes exist, manifestation depend on number of

d l dgenes deleted.– Beta thalassemia: several different beta thal

genes exist. Disease due to absence or gmalfunction of beta-globin genes.

Basophilic stippling Target cell

THALASEMIATHALASEMIATHALASEMIATHALASEMIA

Azmi S.KarDi i i f H t l M di l O lDivision of Hematology-Medical Oncology

Departement of Internal MedicineFaculty of Medicine

S U U i iSumatera Utara University

TALASEMIATALASEMIA• Talasemia merupakan salah Talasemia merupakan salah

satu penyakit darah herediter yang ditandai herediter yang ditandai dengan berkurangnya atau tidak ada sama sekali s se l sintesa rantai globin dari hemoglobin.e l

Hemoglobin ManusiaHemoglobin Manusia

• Hemoglobin adalah suatu protein tetramerik, terdiri dari 4 rantai polipeptida. Pada manusia dewasa hemoglobin utama disebut HbA, terdiri dari 2 rantai α dan 2 rantai β (α2β2).terdiri dari 2 rantai α dan 2 rantai β (α2β2). Didampingi oleh hemoglobin minor yaitu HbA2.(α2δ2).

• Pada janin dan neonatus terdapat HbF, Hb Gowers 1, Hb Gowers 2 dan Hb Portland).

• HbF (α2γ2) bertahan sampai umur 20 mingguHbF (α2γ2) bertahan sampai umur 20 minggu post partum.

• HbF pada orang dewasa < 1%.

Hemoblobin manusia 2

• Tiap individu mengandung sepasang otosom maka individu normal mengandung 4 gen alfa yang menghasilkan jumlah protein yang sama.y g e g s ju p o e y g s

• Gen beta berbeda dengan gene alfa, dimana tiap kromosom hanya mengandung 1 gen beta.

Gen gen penentu rantai globin• 1.Kelompok α (Alpha like) : rantai alfa

dan rantai zeta, ditentukan oleh kelompok gen (gen cluster) yang terletakkelompok gen (gen cluster) yang terletak di kromosom 16.

• 2.Kelompok β (Beta like) : rantai beta, p β ( )gamma, delta dan epsilon, ditentukan oleh kelompok gen yang terletak di kromosom 11kromosom 11.

Talasemia BetaTalasemia Beta

• Terjadi gangguan produksi rantai beta.• 1.β°-talasemia : tidak terjadi sintesis rantai β

ok tidak ada mRNA rantai β• 2.β+-talasemia : sintesis rantai beta berkurang2.β+ talasemia : sintesis rantai beta berkurang

ok mRNA rantai beta berkurang atau tidak berfungsi.

• 3 HPFH hereditary persistence of fetal• 3.HPFH,hereditary persistence of fetal hemoglobin.

• 4.δβ-talasemia: gene rantai delta dan beta hilhilang.

• 5.Hb Lepore: gene rantai delta dan beta hilang sebagian.g

K K T BKlasifikasi Klinis Talasemia Beta

Klasifikasi Klinis

Genotip Fenotip

Thal Minor β/βt β/β+Thal Minor

Thal Intermedia

β/βt

βt/βt

β/β+

β/β°β+/β+

β /β°Intermedia

Thal Majorβt/βt

β+/β°β°/β°

Patogenesis Talasemia Beta Patogenesis Talasemia Beta Major.• 1.Menurunnya sintesis rantai β : β°, β+ dan

variannya.• 2.Kelebihan rantai-α menyebabkan terjadinya

presipitasi intraseluler dari rantai α yang tidakpresipitasi intraseluler dari rantai α yang tidak larut

• 3.Eritropoeisis meningkat tetapi tidak efektif dengan banyak sel prekursor eritrosit yang dihancurkan prematur yang berhubungan dengan kelebihan rantai α.dengan kelebihan rantai α.

• 4.Memendeknya masa hidup eritrosit dan terjadinya skwestrasi oleh limpa.

Akibatnya 1.

• 1. Sumsum tulang hiperplastik : expansi sumsum tulang dan penebalan cortex.

• 2. Meningkatnya absorbsi besi dan terjadi penumpukan besi menyebabkan:penumpukan besi menyebabkan:– a.sirosis hati– b.kelainan endokrin spt DM– c.pigmentasi kulit– d.hemosiderosis jantung dengan manifestasi

perikarditis, aritmia, kardiomegali,gagal jantung.

Akibatnya 2:

• 3.Hipersplenisme :– a. bertambahnya volume plasma.– b. memendeknya umur eritrosit baik darah

di i d i dsendiri maupun dari donor.– c. lekopenia.– d trombositopenia– d. trombositopenia.

Gambaran hematologi:Gambaran hematologi:

• 1.Anemia : hipokromik, mikrositik, MCV rendah.• 2.Retikulositosis.• 3.Lekopenia dan trombositopenia dapat terjadi.• 4.Darah tepi: sel target, eritrosit berinti, anisositosis, p g , , ,

polikromasia, basofilia berbintik, adanya normoblas.• 5.Umur eritrosit memendek.• 6.HbF meningkat, HbA2 normal.6.HbF meningkat, HbA2 normal.• 7.Sumsum tulang menunjukkan megaloblastik dan

hiperplasia eritroid.• 8 Fragilitas osmotik menurun• 8.Fragilitas osmotik menurun.• 9.Feritin serum meningkat.

G BGambaran Biokimiawi:

• 1. Bilirubin meningkat, terutama bilirubin indirek.

• 2. Adanya gangguan fungsi hati.3 Ad f i d k i• 3. Adanya gangguan fungsi endokrin :– Hipogonadisme– Diabetes Melitus.

G KGambaran Klinis.

• 1.anemia• 2.ikterus ringan, batu empedu.• 3.hepatosplenomegali, hipersplenisme.• 4.wajah yang abnormal.j y g

– Hair-on-end– Fraktur o.k expansi sumsum tulang dan struktur tulang

abnormal– Osteoporosis yang menyeluruh.

• 5.pertumbuhan terganggu.• 6.ulkus pada tungkai.6.ulkus pada tungkai.• 7.bila tidak diobati, 80% akan meninggal pada tahun

pertama.

Penatalaksanaan

• 1.hipertransfusi utk mempertahankan Hb antara 10.5-11.0 g/dl.g/dl.

• 2.terapi chelation• 3.splenektomi:

– Kebutuhan transfusi semakin meningkat 50% dariKebutuhan transfusi semakin meningkat 50% dari sebelumnya

– Kebutuhan PRC > 250 ml/kg/thn– Lekopenia atau trombositopenia makin berat

• 4.ulkus tungkai agak sulit diterapi• 5.tindakan suportif :

– Asam folat– Vaksinasi hepatitis– Digitalis dan diuretik kalau gagal jantung dll.

• 6.tindakan lanjutanO l h l i– Oral chelation

– Transplantasi sumsum tulang dsb.

T B IT B ITalasemia Beta IntermediaTalasemia Beta Intermedia

• Gambaran klinis:– 2-10% insidensi– Defek pada 2 beta globin gene– Secara klinis lebih ringanSecara klinis lebih ringan– Umumnya tidak memerlukan transfusi– Hepatosplenomegali yang nyata, gangguan

pertumbuhan hiperbilibrubinemia dan overloadpertumbuhan, hiperbilibrubinemia dan overload besi.

– Infeksi Parvovirus B19 merangsang untuk terjadinya krisis aplastikterjadinya krisis aplastik.

PPenatalaksanaan

• Asam folat • Diet: hindarkan makan daging (besi↑),zat

mengandung besi, minum teh setiap habis makanmakan

• Terapi chelation diberikan bila kadar feritin > 2000ng/ml

• Tansfusi jarang diperlukan, kecuali pada saat krisis aplastik atau infeksi akutK d k d l l kt i• Kadang-kadang perlu splenektomi.

TT ββ T TTalasemiaTalasemia-- ββ minor atau Traitminor atau Trait

• Gambaran klinis:– 1.asimptomatik:

• Ditemui saat pemeriksaan rutin: Hb rendah, stippling basofil,MCV rendah, RDW normal.

• Waktu pemeriksaan keluarga yang mempunyai riwayat talasemia

– 2.pemeriksaan fisik normal.

• Diagnosis:– Hb normal atau agak menurun

Hipokromik mikrositik target– Hipokromik,mikrositik,target sel,anisositosis,stippling basofil,MCV rendah, DRW normal.HbA2 meningkat (>4%) HbF sedikit meningkat– HbA2 meningkat (>4%), HbF sedikit meningkat pada 50% kasus.

D T BDasar gejala klinis Talasemia Beta.

• Kekurangan rantai beta menyebabkan anemia karena jumlah HbA yang rendah. Sebagai usaha kompensasi maka dibentuklah HbF dan HbA2, sehingga ciri khas dari Thal-β adalahHbA2, sehingga ciri khas dari Thal β adalah kenaikan HbF dan atau HbA2. Rantai alfa yang berlebih berbeda dengan rantai beta dan delta tidak dapat membent k tetramer dandelta tidak dapat membentuk tetramer dan mengendap membentuk Heinz bodies. Pengendapan rantai tsb dapat merusak membran dan menimbulkan bentuk eritrosit yang tidak normal (poikilositosis) yang menyebabkan eritrosit mudah dirusak danmenyebabkan eritrosit mudah dirusak dan memperberat anemianya.

T AT ATalasemia Alfa.Talasemia Alfa.

• 1. Tipe delesi (deletional α Thalassemia)• 2. Tipe non delesi ( non deletional α

Th l i )Thalassemia).

T Talasemia alfa tipe delesi

• Ditandai dengan delesi (hilangnya) gen alfa. Delesi gen lf d j di k il id kalfa dapat terjadi karena persilangan yang tidak

seimbang (unequal crossover) yang dapat menghilangkan satu atau dua gen alfa dengan haplotip α / dan /α-/ dan --/.

• Variasi-variasinya sbb:– Genotip Gambaran klinis

/ N l– αα/αα Normal– αα/α- α -Thal-2 (silent

carrier)α /α α Thal 1 (trans)– α-/α- α-Thal-1 (trans)

– αα/-- α-Thal-1 (cis)– α-/-- Penyakit HbH

/ H d f t li d Hb– --/-- Hydrops fetalis dg Hb Bart’s

T Talasemia alfa non delesi

• Tidak dijumpai delesi tetapi terjadi mutasi pada gen yang menyebabkan gangguan pada rantai globin alfa. Gen alfa abnormal yang g ob Ge b o y gmengganggu sintesis rantai globin alfa ditulis αT sehingga terdapat haplotip αT αT /,αT -/ dan ααT/ Gangguan yang menyebabkan timbulnyaααT/. Gangguan yang menyebabkan timbulnya gen αT

bervariasi, tetapi pada dasarnya dapat berupa p p y p pgangguan pada mRNA atau pada protein.

Dasar gejala klinis dari talasemia alfaDasar gejala klinis dari talasemia alfa.

• Gejala klinis tergantung pada gen alfa yang masih utuh.A i i b l k k d Hb l (HbA)• Anemia timbul karena kadar Hb normal (HbA) menurun akibat kurangnya rantai globin alfa.

• Kekurangan rantai globin alfa menyebabkan ketidak sesuaian dengan pasangannya yaitu rantai beta dansesuaian dengan pasangannya yaitu rantai beta dan rantai gamma. Rantai beta dan rantai gamma yang berlebih akan membentuk HbH ( β4) dan Hb Bart’s ( γ4). HbH dan Hb Bart’s walaupun dapat mengikat oksigen tetapi tidak mudah melepaskannya kembali, maka akan timbul hipoksia. Anemia juga timbul sebagai akibat destruksi eritrosit yang berlebihan.

Klinis Talasemia alfa

• 1.HbH.– Sering dijumpai di Asia Tenggara.– Terjadi delesi 3 gen alfa.– Anemia mikrositik,hipokrom,

anisopoikilositosis,fragmentosit– Splenomegali– Splenomegali– Hemolisa intravaskuler dan

hemosiderinuria.– Sumsum tulang hiperplasia– Perkembangan dan harapan hidupnya

lnormal.

Klinis

• 2. Hb Bart’s hydrops fetalis – Delesi 4 gen alfa.– Menyebabkan kematian bayi in utero atau

b b j d h l hibeberapa jam sesudah lahir.– Pada bayi dijumpai oedema dan

hepatosplenomegali .p p g– Hb yang utama adalah Hb Bart’s dengan

sedikit HbH dan Portland tanpa dijumpai HbA t HbFHbA ataupun HbF.

– Selalu menyebabkan toksemia dan PPH.