Departemen Ilmu Patologi Klinik

Gangguan Eritrosit:

Anemia

Rosa Dwi Wahyuni, MD, M.Kes, Sp.PK

Departemen Ilmu Patologi Klinik

Gangguan Eritrosit

Anemia

ANEMIA

Definisi Anemia:

 Sindroma klinis yang disebabkan penurunan massa eritrosit total dalam tubuh.

 Keadaan dimana massa eritrosit dan atau massa hemoglobin tidak dapat memenuhi fungsinya untuk menyediakan oksigen bagi jaringan tubuh

ANEMIA

Penurunan Hb dan Hct :

< batas bawah 95% interval referens dari kelompok usia, jenis kelamin

dan lokasi geografis (ketinggian)

Hb12-14 g/dl ; (Hct 36-41%),

Hb7g/dl  symptom (+)

Akut: hipovolumia (pucat,

ggn penglihatan, syncope, tachycardia) ;

Kronis: tissue hypoxia (fatique, dyspnea, Headache)

Klasifikasi Anemia

Berdasarkan patofisiologi:

Lanjutan…..anemia berdasarkan patofisiologi

E. Gangguan karena mekanisme lain:  Anemia karena penyakit kronis,

 anemia sideroblastik

 Anemia karena infiltrasi sumsum tulang

II. Peningkatan destruksi sel darah merah:  Anemia Hemolitik

III. Kehilangan darah (Blood Loss)

Anemia

Anemia berdasarkan morfologi

• Anemia sec. morfologi eritrosit, dilihat dari:

- ukuran dan warna di bawah mikroskop atau - indeks eritrosit (MCV, MCH, dan MCHC)

- Kriteria Ukuran (size): Normositik, Mikrositik, Makrositik

Cara Mengetahui Ukuran eritrosit: MCV : normositik , mikrositik, makrositik

* Eritrosit dengan variasi ukuran yang abnormal

Perhatikan Warna sel eritrosit

:

- Bandingkan diameter central pallor(CP)

dengan diameter sel eritrosit tersebut .

- Normal, bentuk sel eritrosit adalah seperti cakram bikonkaf (biconcave disk) →

pada hapusan darah tepi terlihat bulat, Ø 7-8 μ dengan area central pallor di bagian tengah

CP≤ 1/3 Ø Eri = normokromik

Eritrosit dengan

central palor (CP)

- Warna, dapat diketahui juga dari MCH (Mean Cell Hb) Dewasa: MCH=27-32 pg, Anak-anak: MCH=23-31 pg

(1pg=10-12g=1μμg)

MCH normal → normokromik

MCH < normal → hipokromik

Klasifikasi Anemia secara

morfologi

1.

Anemia Mikrositik Hipokromik

2.

Anemia Normositik _Normokromik

1

Contoh: - Anemia defisiensi Fe

- _Thalasemia - _{Anemia akibat}

Penyakit Kronik

- _Anemia

sideroblastik

2

Contoh:

- Anemia pasca

perdarahan akut

- Anemia aplastik - Anemia hemolitik - Anemia akibat

penyakit kronik

 makrosit-oval

(Anemia megaloblastik ditandai oleh makrosit oval)

Pendekatan diagnostik Anemia

:

• _Anamnesis

_:

onset /bleeding tendency / routine medicinal /

occupation / hobby / travel history / family / diet / GI symptoms / menstruation cycle / history of

previous pregnancy-delivery / alcohol consumption , etc

•

_{Pemeriksaan fsik}

_:

conjunctiva & lips (pallor) / mouth (cheilosis) /

tongue (glossitis) / gum / nails (koilonychia) , hair (signa de bandera, alopecia) , jaundice ,

• _{Pemeriksaan Laboratorium}

-

CBC (complete

blood count

)→

to confirm

anemia (Hb, PCV/HCT, RBC) & the type of anemia (MCV; MCH; MCHC), RDW

-

Reticulocyte count

→

reflects marrow’s responses .

-

PBS :

to look for the RBCs’ shape and any abnormalities of RBCs besides the other blood cell lines

-

Iron status

( Serum Iron ,TIBC, % Transferrin saturation , Iron storage )

-

Blood chemistry

( direct/total bilirubin,LDH and stool examination for occult blood test , etc) .

-

Radiological examinations

( Chest X-ray,

USG , MRI )

-

Cardiological examinations

(EKG,Treadmill,

Echocardiography)

Notes !

:

-

First confirm

Anemia (

Hb , PCV , RBC

)

-

Classify the anemia (MCV, MCH, MCHC)

-

Causes of anemia

Anemia Mikrositik Hipokromik

- Setiap kondisi yang menimbulkan gangguan sintesis Hb

 gambaran hipokromik mikrositik

- Anemia Defisiensi Besi penyebab tersering dari anemia MH

- Perhatikan penyebab lain (DD=diff diagnosis) sebelum mendiagnosis Anemia def. besi, spt:

- anemia akibat penyakit kronis - Thalasemia

ANEMIA DEFISIENSI

BESI

• Definisi:

Anemia yang timbul akibat kosongnya cadangan besi tubuh

besi utk eritropoeisis  pembentukan Hb • Anemia def. Fe, ditandai dgn:

- anemia MH

Faktor Penyebab (Etiologi)

I.

Keseimbangan negatif Fe (

Negative Iron

balance)

:

-

Asupan Fe ↓

(inadequate diet , impaired absorption)

- Fe loss ↑

(GI bleeding, excessive menstrual flow)

- ↑ demands

II. Abnormal Fe balance : - Aceruloplasminemia

- Autosomal dominant hemochromatosis ( mutations in ferroportin )

Patogenesis desifsiensi Fe

• _{3 pathogenetic factors:}

- Impaired Hb synthesis (consequence of reduced Fe supply)

Transferin saturation< 16% inadequate Fe-supply to marrow → Hb contents of RBC ↓ → hypochromic & microcytosis

- Generalized defect in cellular proliferation

- Fe-deficient → oxidative damage to the red cell’s

Status besi tubuh:

• Serum Iron = SI

• Total Iron Binding Capacity (TIBC)

• % Transferrin Saturation = SI/TIBCx100% • Simpanan besi (Iron storage):

- Hemosiderin →produk degradasi feritin yang tidak larut dalam air → mayoritas tdd aggregat kristal ferric oxyhydroxide, FeOOH (di Hepar danSutul→ dideteksi dengan biopsi/aspirasi dan pengecatan besi (prosedur invasif)

- Ferritin → kompleks garam Fe3+dan apoferitin yang larut dalam air, dengan jumlah yang sangat kecil di

serum.

The development of IDA

• Stage-1 (prelatent Fe-deficient): - progressive loss of storage-Fe

- body’s Fe reserve is still sufficient to

maintain both the transport and functional compartment , so RBC development is still normal .

- peripheral blood picture is normal , no symptoms of anemia , but ferritin is ↓ .

* Stage-2 (latent Fe-deficient)

- Exhaustion of storage-Fe , RBC

production is still normal , Ferritin ↓↓

- Circulating-Fe (SI) begin ↓ , Receptor ↑ .

* Stage-3 (Fe-Deficiency Anemia)

storage iron depletion

Symptoms Morphology SI - TIBC Ferritin

I D A

Anemia

Hypo –

Micro

TIBC ↑

SI↓ -

↓↓

A.C D

Anemia

Hypo –

Micro

TIBC /

SI

↓

-

↓

N

Pendekatan Diagnostik

Anemia Defisiensi Fe

1. Anamnesis – pola menstruasi, kehamilan /

persalinan, tendensi perdarahan, penyakit kronis, diet, pekerjaan, riwayat bepergian

3. Laboratorium-

Hema (

DL

, LED,

Hapusan darah tepi

, Retikulosit)

- Serum (SI,TIBC,Ferritin, Bilirubin)

- BMA (Bone Marrow Aspiration)

- Pemeriksaan Urine dan tinja

4.

Penunjang

- Radiology (EKG, USG)

S I

TIBC

Normal

_N

(1/3 mol.Trsf)

N

I D A

↓

_↑

An.of Chronic

Disease

↓

N /

↓

% Saturasi Transferrin = SI/TIBC X 100%

Erythropoeisis impaired when % Tf.Sat < 15%

3. Ferritin Serum :

Serum Ferritin level ~ Fe-storage

Ferritin <15 ug/L → Definitive Fe-Deficient

N/↑ Ferritin in IDA , if :

- impaired liver function ( damaged hepatocyte),

4. Transferrin Serum :

measured by immunodiffusion methode Normal value : 2-4 g/L

Anemia of Chronic In

_fection

• Gejala klinis miripdengan anemia def.Fe

• Gambaran lab. hematologi = Anemia def. Fe

(An.Hypo-Micro, MCV↓, MCH↓, SI↓) , tapi TIBC N/ ↓ and Ferritin N/↑)

• _{Pathogenesis :}

Fe → storage // Transferrin

Diagnosis Anemia akibat penyakit kronis:

• lab hematologi:

- Anemia hipokromik mikrositik - SI ↓ , TIBC ↓/N , Ferritin N/↑ ( jika Ferritin ↓, An. Def.Fe ) - Inflamasi / infeksi (+) :

CRP and LED ↑

Problem

: IDA with inflammation → ferritin ↑

(falsely diagnosed as ACD) ; it can be

Anemia Sideroblastik

• Defek pada sintesis Heme → akumulasi Fe di

mitochondria → degenerasi Fe → granula Fe di sekitar inti normoblast, membentuk struktur spt cincin {paling jelas terlihat dengan pengecatan Perl (Perls’ stain) } →

Ringed Sideroblast (karakteristik anemia Sideroblastik)

Sideroblast and Ringed Sideroblast ( in

2

.

Acquired

:

-

Primary

:

Stem cell clonal mutations(MDS = MyeloDysplastic Syndromes , RA-RS)

Normochromic-macrocytic anemia . Marrow : erythroid hyperplasia with

Macrocytic Anemia

- Non-Megaloblastic Macrocytic Anemia :

• Reticulocytosis

• Liver disease / Alcoholism

• Myelodysplastic Syndrome

• _{Erythroleukemia (FAB-M6)}

macrocyte = erythrocyte with MCV > normal . Megaloblast = bigger than normal normoblast .

Megaloblastic changes = increased size of hemopoietic precursor cells in bone marrow ( not only in normoblast !)

• Etiology of DNA synthesis defect :

deficiency of vit.B12 and folic acid → maturation

•

_{Deficiency of Folic acid}

_:

- Inadequate diet

(intake < / demand ↑ in pregnancy

lactation , child’s growth / malabsorption in tropical sprue / bowel resection / small intestine inflammation )

•

_{Deficiency of Folic acid}

_:

- Inadequate diet

(intake < / demand ↑ in pregnancy

lactation , child’s growth / malabsorption in tropical sprue / bowel resection / small intestine inflammation )

•

_{Deficiency of Vit.B12:}

- Inadequate diet :

Intake < in vegetarians , demand ↑ , impaired absorption caused by

decreased Intrinsic Factor

( gastrectomy , pernicious anemia )

VITAMIN B12 ASAM FOLAT

-Food from animal products -Heat stabile

-Storage : enough for 3 yrs -Relatively low needs (only 1% of folate requirements)

-Limited sources (vegetable ,

fruits)

-Heat labile

-Storage enough only for 3 mths

-Higher folate needs

CAUSE OF DEFICIENCY CAUSE OF DEFICIENCY

-Vegetarian (seldom)

-Impaired Intrinsic Factor (pernicious anemia)

-Gastrectomy

-Atropic Gastritis

-Anticonvulsant, alcoholism

-Nutrition (alcoholism, goat’s milk diet)

Pathogenesis of Megaloblastic Anemia

:

• atrophy of tongue papilla & mucosal GI → glossitis , gastritis, nausea , constipation.

• B12 defic → demyelinisation of spinal cord & peripheral nerve → loss of foot’s balance / sensory (Neuropatia)

B12 Metabolism

•

Vit.B12 → purine & pyrimidin synthesis →

synthesis DNA & RNA → mitosis and

maturation

• Vit.B12 made from microbiological source

because plants do not produce B12 ( meat ,

liver, eggs and milk are rich of Vit B12 ).

Vit.B12 absorption

• B12 diet → in gaster bind by IF (Intrinsic Factor)

produced by parietal cells → IF-B12 complex → ileum : B12 absorbed , IF freed into the lumen

• impaired IF : gastrectomy/gastritis/ Auto-Ab-antiIF or Auto-Ab-antiparietal) → no absorption of B12 →

impaired DNA synthesis → (Pernicious Anemia

with Achlorhydria)

Hematological pictures of

Megaloblastic Anemia

• Bone Marrow :

- megaloblastosis

- ineffective erythropoiesis

• Peripheral blood :

- Oval macrocytosis

Megaloblastic Anemia

Diagnosis of Megaloblastic Anemia

•

Screening :

- CBC , Neutrophil’s lobe count

- Serum Indirect Bilirubin , LDH (lactate

dehydrogenase)

•

Spesific tests :

-

Bone Marrow Aspiration:

megaloblastosis & megaloblastic changes, erythropoietic activitiy ↑ ( ineffective erythropoiesis)

Anemia Hemolitik

• Anemia hemolitik: anemia yang disebabkan oleh proses hemolitik.

• Hemolisis: pemecahan eritrosit sebelum waktunya (sebelum masa hidup rerata eritrosit, yaitu 120 hari). (Proses pemecahan eri karena sdh waktunya

senescence=penuaan)

HEMOLYTIC ANEMIA

• Normal red cell’s survival = 110-120 days → destructed by macrophage in marrow and spleen .

When the survival are shortened → EPO production is stimulated (compensated) → no Hb changes → anemia (–) .

Definition of

Hemolytic Anemia

_:

• anemia caused by shortened red cell’s survival as a result of excessive uncompensated destruction of red cells .

-

C

ompensation ability of bone marrow

:

• Ability to ↑ red cells production ( 6-8 x normal ) : - survival shorten ½ → production ↑ 2x

- survival shorten ¼ → production ↑ 4x - survival shorten 1/6 → production ↑ 6x - survival shorten 1/8 → production ↑ 8x ↑ of production 6-8 x is maksimum .

D

iagnostic approach in Hemolytic Anemia

:

1. Confirm anemia (Hb/PCV/RBC)

an acute case usually acquired , and chronic case is mostly hereditary .

2. To find the signs of hemolytic process . 3. Extra or Intravascular ?

4. Hereditary or acquired ?

The signs of Hemolytic process :

1. Increased of red cells destruction

- Unconjug.bilirubin serum ↑ → jaundice - Urobilinogenuria

- Hb-uria → sign of intravascular hemolysis

- Abdom.pain → splenomegaly, spleen infarction - Leg’s Ulcer → intrinsic defect of erythrocyte - Haptoglobin serum ↓↓/neg → intravascular hemolisys .

2.Destruksi eritrosit

:

- Microspherocyte, Fragmentocyte, Poikilocyte

- Erythrocyte Osmotic Fragility ↑

- Positive Autohemolysis test

- Shortened of red cells’ survival

3. Tanda Peningkatan Eritropoisis

:

- Reticulocytosis

- Normoblastosis

POLISITEMIA

(ERITROSITOSIS)

• Peningkatan patologis massa eritrosit • _{massa eritrosit normal : (sea level)}

- o : 26 - 32 ml / kg BB - o : 23 - 29 ml / kg BB

•

_{Klasifikasi :}

I. Primer (Otonomik)

A. Polisitemia Vera

B. Eritrositosis Murni (Eritremia)

II. Sekunder

A. Fisiologis (

Oksigenasi Jaringan

)

ERYTHROCYTOSIS - DIAGNOSTIC TESTS

•

_{Complete Blood Count}

• _{Bone Marrow examination} • _{Arterial Blood Gas analysis}

• _{Leukocyte Alkaline Phosphatase} • P_5O

• _{IVP or renal ultrasound}

• _{Liver ultrasound or CT scan} • _{Erythropoietin level}

POLISITEMIA VERA

•

Proliferasi klonal neoplastik sel

progenitor hematopoitik pluripoten

•

_{Kriteria diagnosis P.V. :}

Kategori A

1.Massa eritrosit:

Lk > 36 ml / kgBB (PCV > 54%)

PRIMARY “PURE” ERYTHROCYTOSIS

( ERYTHREMIA

)

•

peningkatan massa eritrosit murni

•

_{tidak ada penyebab eritrositosis sekunder}

•

_{kadar eritropoitin normal atau rendah}

•

_{mungkin akibat mutasi gene reseptor}

II. ERITROSITOSIS SEKUNDER

•

_{Merupakan respons terhadap keadaan lain}

yang bersifat :

- fisiologis : akibat oksigenasi jaringan yang

¯

III.ERITROSITOSIS RELATIF

•

_{Sindroma Gaisbock}

•

_{Stress erythrocytosis}

•

Pseudo erythrocytosis

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ANEMIA

→ symptoms / syndrome

- blood flow priority (pallor)

- RBC 2,3-DPG content ↑→ O2 dissoc.curve shift to the right → O2 release to the