Departemen Ilmu Patologi Klinik

  Gangguan Eritrosit:

Anemia

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

  

Departemen Ilmu Patologi Klinik

Fakultas Kedokteran dan Ilmu Kesehatan

Universitas Tadulako

  

Gangguan Eritrosit

Anemia Polisitemia

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  Penurunan di bawah normal kadar Hb, hitung eritrosit, dan hematokrit

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%),

Anemia

  Hb 7g/dl  symptom (+) Akut: hipovolumia (pucat, ggn penglihatan, syncope, tachycardia) ; Kronis : tissue hypoxia (fatique, dyspnea, Headache)

  Klasifikasi Anemia

  Berdasarkan patofisiologi:

  I. Kegagalan produksi sel darah merah:

  A. Gangguan sel induk hematopoesis

  Anemia Aplastik 

  B. Gangguan sintesis DNA

   Anemia Megaloblastik

  C. Gangguan sintesis Hemoglobin (Hb)

   Anemia Defisiensi Besi, Thalasemia

  D. Gangguan sintesis eritropoetin

   Anemia karena GGK

  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 karena perdarahan akut

  

Anemia

  Anemia berdasarkan morfologi

• Anemia sec. morfologi eritrosit, dilihat dari:
• ukuran dan warna di bawah mikroskop atau
• indeks eritrosit (MCV, MCH, dan M
• Kriteria Ukuran (size): Normositik, Mikrositik, Makrositik

  Warna (pucat): Normokromik,

• Kriteria Hipokromik

  Cara Mengetahui Ukuran eritrosit:

• membandingkan dengan inti sel limfosit kecil (di bawah mikroskop) : → ukuran sama = normositik lebih kecil = mikrositik lebih besar = makrositik

  MCV (Mean Cell Volume) *

  N : dewasa = 80-100 fL , di bawah 1 thn = 76- 86 fL MCV : normositik , mikrositik, makrositik

• Eritrosit dengan variasi ukuran yang abnormal

  anisositosis

  Bandingkan ukuran sel eritrosit dengan inti limfosit

  : 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 CP> ½ Ø Eri = hipokromik Eritrosit dengan central palor (CP) Bandingkan diameter CP dengan diameter sel eritrosit

• Warna, dapat diketahui juga dari MCH (Mean Cell Hb)

  Dewasa: MCH=27-32 pg, Anak-anak: MCH=23-31 pg _-12 (1pg=10 g=1μμg)

  MCH normal → normokromik MCH < normal → hipokromik

• MCHC (Mean Cell Hb Concentration) :

  Normal: MCHC = 32-36 g/dL

  

Klasifikasi Anemia secara

morfologi

  Anemia Normositik Normokromik 3. Anemia Makrositik

  1 Contoh:

  2 Contoh:

• _-

  Anemia pasca

  perdarahan akut

  _- Anemia aplastik _- Anemia hemolitik _- Anemia akibat

  penyakit kronik

  _-

  Anemia pada

• Anemia defisiensi Fe _- Thalasemia _- Anemia akibat Penyakit Kronik _- Anemia sideroblastik
• Anemia defisiensi Folat,
• Anemia defisiensi vitamin B12

  GGK _-

Anemia pada

  3 A. Megaloblastik,

  contoh:

  B. Nonmegaloblastik contoh:

• Anemia pd peny.

  Hati kronis

• _- mielofibrosis dll
• Anemia pd hipotiroid, dll

  MCV <80 fl; MCH <27 pg

MCV 80 -95 fl

MCH 27-34 pg

  MCV > 95 fl Anemia hipokromik- mikrositik Anemia normokromik- normositik

  Anemia makrositik Miikrositiik Hipoikromiik

Normokronik-normositik

   makrosit-oval (Anemia megaloblastik ditandai oleh makrosit oval)

  Makrositik

  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 ,

petechiae , liver & spleen , lymphenodes ,rectal /

vaginal toucher , feet (ulcer,arthritis)

• Pemeriksaan Laboratorium

  to confirm blood count )→ anemia (Hb, PCV/HCT, RBC) & the type of anemia (MCV; MCH; MCHC), RDW reflects marrow’s responses .

• CBC (complete
• Reticulocyte count →

   to look for the RBCs’ shape and any abnormalities of

• PBS :

   RBCs besides the other blood cell lines ( Serum Iron ,TIBC, % Transferrin

• Iron status

  saturation , Iron storage ) ( direct/total bilirubin,LDH

• Blood chemistry and stool examination for occult blood test , etc) .

  PBS: Pheripheral blood smear

  Lanjutan…. Pendekatan Doagnostik …

• 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 Sideroblastik, dll

  ANEMIA DEFISIENSI BESI

• Definisi: Anemia yang timbul akibat kosongnya cadangan besi tubuh  besi utk eritropoeisis pembentukan Hb • Anemia def. Fe, ditandai dgn:
• anemia MH
• besi serum
• TIBC (Total Iron Binding Capacity)
• Saturasi transferin
• Feritin serum
• Pengecatan Besi sumsum tulang negatif
• Respon terhadap pengobatan dengan preparat Fe

  Faktor Penyebab (Etiologi) I.

  Keseimbangan negatif Fe (Negative Iron balance):

  Asupan Fe ↓ - (inadequate diet , impaired absorption)

• Fe loss ↑

  (GI bleeding, excessive menstrual flow)

• ↑ demands

  (infancy, pregnancy, lactation)

Lanjutan….Faktor Penyebab

  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

  membrane → RBC deformability ↓ → RBC viability ↓→ RBC destruction ↑ especially in spleen → reduced RBC survival

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. (dideteksi dengan metode imunoasai)
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 ↓ .
• IDA= Iron Deficiency Anemia
• * Stage-2 (latent Fe-deficient)

• Exhaustion of storage-Fe , RBC production is still normal , Ferritin ↓↓
• Circulating-Fe (SI) begin ↓ , Transf- Receptor ↑ .
• * Stage-3 (Fe-Deficiency Anemia)
• Stadium of Iron Deficiency Anemia

  storage iron depletion Functional iron depletion (iron deficiency anemia) Transport iron depletion Iron depletion Std.1/prelatent Std.2/latent Std.3/IDA Iron storage compartment Iron transport compartment Functional Iron compartment Normal iron status Lab.test values Hb N N N 

  SI N N  

  TIBC N N  

  Feritin N   

  Symptoms Morphology SI - TIBC Ferritin

  Anemia

  I D A Hypo – SI↓ - ↓↓ Micro TIBC ↑

  Anemia

  A.C D Hypo – N/ ↑ SI - ↓ TIBC / ↓ Micro

  N

Pendekatan Diagnostik Anemia Defisiensi Fe

  1. Anamnesis – pola menstruasi, kehamilan /

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

  2. Pemeriksaan fisik – sistematik dari seluruh permukaan

  tubuh sampai ke organ dalam ( hati, limpa, kelenjar getah bening (lymphnodes)

  3. DL Hapusan Laboratorium- Hema ( , LED,

  darah tepi , Retikulosit)

• Serum (SI,TIBC,Ferritin, Bilirubin)
• BMA (Bone Marrow Aspiration)
• Pemeriksaan Urine dan tinja

  4. Penunjang - Radiology (EKG, USG)

• Endoscopy

S I TIBC Normal

  N N

(1/3 mol.Trsf)

  I D A ↑ ↓

  An.of Chronic N / ↓ ↓

  Disease Fe Overload ↑↑ N / ↑

Pemeriksaan Lab. Anemia def. Fe

  1. CBC – confirm Anemia & find hypochromic microcytic picture from BSE and Red Cells Indices ( Hb, HCT ,MCV , MCH , MCHC)

  2+ .

  2 SI – Fe released from Transferrin + ferrozine (chromagen) → measured colored complex

  TIBC – serum + excess FeCl2 → to fill all Transferrin- binding sites → the excess Fe is fixed by Mg- carbonate → Fe-saturated Transferrin is measured with Ferrozine (= TIBC)

  % 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), hemolysis, inflammation / infection / malignancy ( Ferritin = acute-phase

   protein )

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

  5. Bone Marrow’s Aspirate evaluation : ( using Perls or Prussian Blue stain )

Anemia of Chronic Infection

• 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 Tissues / RES

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

differentiated by sTfR exam (serum transferrin

receptor) that ↑ in IDA but normal in ACD .

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 bisa dijumpai secara normal di sutul

  Sideroblast and Ringed Sideroblast ( in Sideroblastic Anemia )

• - Primary :

  Stem cell clonal mutations(MDS = MyeloDysplastic Syndromes , RA-RS) Normochromic-macrocytic anemia .

  Marrow : erythroid hyperplasia with dysplastic or megaloblastic appearance

• ringed sideroblast in normoblast .

  

Macrocytic Anemia

• - Non-Megaloblastic Macrocytic Anemia :
• Reticulocytosis • Liver disease / Alcoholism • Myelodysplastic Syndrome • Erythroleukemia (FAB-M6)
• - Megaloblastic Macrocytic Anemia

  Megaloblastic Macrocytic Anemia 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 dysharmony between nuclei & cytoplasm (delayed nuclei maturation) → increased cels (megaloblastic changes) → marrow’s ineffective erythropoiesis → intramedullary hemolysis → total/indirect Bili and LDH ↑.
• Deficiency of Folic acid:

• Inadequate diet (intake < / demand ↑ in pregnancy - lactation , child’s growth / malabsorption in tropical sprue / bowel resection / small intestine inflammation )
• Drug’s effect (anti-epilepsi)
• FA loss ↑ (dialysis)

• Deficiency of Folic acid:
• Inadequate diet (intake < / demand ↑ in pregnancy - lactation , child’s growth / malabsorption in tropical sprue / bowel resection / small intestine inflammation )
• Drug’s effect (anti-epilepsi)
• FA loss ↑ (dialysis)

• Deficiency of Vit.B12:
• Inadequate diet : Intake < in vegetarians , demand ↑ , impaired absorption caused by decreased Intrinsic Factor ( gastrectomy , pernicious anemia ) Malabsorption (bowel infection , worms / blind loop syndr )

  VITAMIN B12 ASAM FOLAT

• Food from animal products
• Heat stabile
• Storage : enough for 3 yrs
• Relatively low needs (only 1% of folate requireme
• Limited sources (vegetable , fruits)
• Heat labile
• Storage enough only for 3 mths
• Higher folate needs
>Vegetarian (seldom)
• Impaired Intrinsic Factor (pernicious anemia)
• Gastrectomy
• Atropic Gastritis -Anticonvulsant, alcoho>Nutrition (alcoholism, goat’s milk diet)
• Prematurity
• Hemodyalisis
• Bowel resection
• Pregnancy
• Anticonvulsant , MTX

  : 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)
• FA defic → hyperhomocysteinemia → thrombosis and vascular occlusion .

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 B1
• Vit.

  B12 content in the daily diet is 5-3ug , daily requirement of B12 is 1-3 ug, and B12 body’s storage is 2-5 mg (enough for 3 yrs)

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)

• Pernicious Anemia = autoimmune disease → auto-Ab to parietal cells (Anti-IF or Anti-Parietal)

Hematological pictures of Megaloblastic Anemia

• Bone Marrow :
• megaloblastosis
• ineffective erythropoiesis
• Peripheral blood :
• Oval macrocytosis
• Hypersegmented neutrophil ( five 5-lobed

   cells or one 6-lobed cell) or the mean lobes of 100 neutrophils is > 3.4 Megaloblastic Anemia  find oval-Macrocyte cell and hypersegmenteneutrophil .

Diagnosis of Megaloblastic Anemia

• Screening :
• CBC , Neutrophil’s lobe count
• Serum Indirect Bilirubin , LDH (lactate dehydrogenase)
• Spesific tests :
• megaloblastosis & megaloblastic

  Bone Marrow Aspiration: changes, erythropoietic activitiy ↑ ( ineffective erythropoiesis)

• Folate & Vit.B12 assay
• Gastric juice analysis
• Schilling Tests - Antibody Assay

  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)

• Hemolisis dapat terjadi di dalam pembuluh darah

  (hemolisis intravaskular) dan di luar pembuluh darah (hemolisis ekstravaskular).

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 (–) .
• If the destruction is acute or chronic with very shortened life of red cells , there will no compensation → anemia (+) .

Definition of Hemolytic Anemia :

• anemia caused by shortened red cell’s survival as a result of excessive uncompensated destruction of red cells .
• Hemolytic process = every process of red cells destruction with still / without compensated by bone marrow → anemia is not always present .

  Compensation 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 .
• If red cells live only 20 days → anemia (+).

Diagnostic 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 ? 5. The cause of hemolysis episodes .

The signs of Hemolytic process :

• 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 - Erythropoietic Hyperplasia in bone marrow

POLISITEMIA (ERITROSITOSIS)

• Peningkatan patologis massa eritrosit
• massa eritrosit normal : (sea level)
• - o : 26 - 32 ml / kg BB - o : 23 - 29 ml / kg BB
• eritrositosis : massa eritrosit > normal

   ( PCV : o >51% ; o >48% )

• Klasifikasi :

  A. Polisitemia Vera

  B. Eritrositosis Murni (Eritremia)

  A. Fisiologis ( Oksigenasi Jaringan )

  B. Non-fisiologis ( Oksigenasi Jaringan N )

  

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
• Erythroid progenitor assay
• Sleep apnea evaluation

POLISITEMIA VERA

  Proliferasi klonal neoplastik sel

• progenitor hematopoitik pluripoten

  Kriteria diagnosis P.V. :
• Kategori A

  

Lk &gt; 36 ml / kgBB (PCV &gt; 54%)

Pr &gt; 32 ml / kg BB (PCV &gt; 51%)

   2. Saturasi oksigen &gt; 92%

   3. Splenomegali

  

PRIMARY “PURE” ERYTHROCYTOSIS

( ERYTHREMIA )

peningkatan massa eritrosit murni

• tidak ada penyebab eritrositosis sekunder
• kadar eritropoitin normal atau rendah
• mungkin akibat mutasi gene reseptor

• eritropoitin ® progenitor eritroid jadi lebih

  sensitif terhadap eritropoitin.

II. ERITROSITOSIS SEKUNDER

  Merupakan respons terhadap keadaan lain

• yang bersifat :
• fisiologis : akibat oksigenasi jaringan yang ¯

• - non fisiologis : tanpa penurunan oksigenasi

  jaringan

III.ERITROSITOSIS RELATIF

• Sindroma Gaisbock •

  Stress erythrocytosis

• Pseudo erythrocytosis

• Massa eritrosit tinggi normal
• Volume plasma rendah

  Click to edit company slogan . www.themegallery.com Thank You !

  ANEMIA → symptoms / syndrome

• Hb

  ↓

• PCV ↓ Hypoxia → Otak , Otot • RBC

  ↓ Kompensasi :

• heart rate ↑ → tachycardia → flow rate ↑ →

  cardiomegaly → heart failure → †