Transcript PK Anemia dr. Bastiana, SpPK
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Gangguan Eritrosit:
Anemia
dr. Bastiana SpPK
Gangguan Eritrosit Anemia Polisitemia
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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 LOGO
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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, angina) www.themegallery.com
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Anemia
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ANEMIA → symptoms / syndrome
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Hb ↓
PCV ↓
RBC ↓ Hypoxia → Otak , Otot Kompensasi : - heart rate ↑ → tachycardia → flow rate ↑ cardiomegaly → heart failure → † → blood flow priority (pallor) - RBC 2,3-DPG content ↑ → O2 dissoc.curve
shift to the right → O2 release to the tissues ↑ .
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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
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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 LOGO
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Anemia
LOGO Anemia berdasarkan morfologi
Anemia sec. morfologi eritrosit, dilihat dari: ukuran dan warna di bawah mikroskop atau indeks eritrosit (MCV, MCH, dan MCHC)
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Kriteria Ukuran (size): Normositik, Mikrositik, Makrositik Kriteria Warna (pucat): Normokromik, Hipokromik
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Cara Mengetahui Ukuran eritrosit : * membandingkan dengan inti sel limfosit kecil bawah mikroskop) : → ukuran sama = normositik lebih kecil = mikrositik lebih besar = makrositik (di LOGO * Menghitung MCV (Mean Cell Volume) MCV= PCV/Ery X 10 (fL) (1 fL=10 -12 L= 1 μm 3 ) N : dewasa = 80-100 fL , di bawah 1 thn = 76- 86 fL MCV : normositik , mikrositik, makrositik * Eritrosit dengan variasi ukuran yang abnormal
anisositosis
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Bandingkan ukuran sel eritrosit dengan inti limfosit LOGO
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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 LOGO
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Eritrosit dengan central palor (CP)
Bandingkan diameter CP dengan diameter sel eritrosit
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Warna, dapat diketahui juga dari MCH (Mean Cell Hb) MCH= Hb/RBC x 10 (pg) Dewasa: MCH=27-32 pg, Anak-anak: MCH=23-31 pg (1pg=10 -12 g=1 μμg) MCH normal → normokromik MCH < normal → hipokromik
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MCHC (Mean Cell Hb Concentration) : MCHC=Hb/PCV x 100 (g/dL) Normal: MCHC = 32-36 g/dL
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Klasifikasi Anemia secara morfologi
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Anemia Hipokromik-Mikrositik
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Anemia Normokromik Normositik
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Anemia Makrositik
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Anemia hipokromik mikrositik 1 Contoh: - Anemia defisiensi Fe - Thalasemia - Anemia akibat Penyakit Kronik - Anemia sideroblastik MCV <80 fl; MCH <27 pg Anemia normokromik normositik 2 Contoh: - Anemia pasca perdarahan akut - Anemia aplastik - Anemia hemolitik - Anemia akibat penyakit kronik - Anemia pada GGK - Anemia pada mielofibrosis - dll MCV 80 -95 fl MCH 27-34 pg Anemia makrositik 3 A. Megaloblastik, contoh: - Anemia defisiensi Folat, - Anemia defisiensi vitamin B12 B. Nonmegaloblastik contoh: - Anemia pd peny. Hati kronis - Anemia pd hipotiroid, dll MCV > 95 fl
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Hipokromik-Mikrositik
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Normokronik-normositik
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Makrositik
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makrosit-oval (Anemia megaloblastik ditandai oleh makrosit oval ini)
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Pendekatan diagnostik Anemia:
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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 fisik : 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)
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Pemeriksaan Laboratorium CBC (complete blood count )→ to confirm anemia (Hb, PCV, 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) .
PBS: Pheripheral blood smear
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Lanjutan …. Pendekatan Doagnostik…
LOGO - 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
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Anemia Hipokromik-Mikrositik
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Setiap kondisi yang menimbulkan gangguan sintesis Hb
gambaran hipokromik mikrositik Anemia Defisiensi Besi
penyebab tersering dari anemia Hipokromik-Mikrositik Perhatikan penyebab lain (DD=diff diagnosis) sebelum mendiagnosis Anemia def. besi, spt: - anemia akibat penyakit kronis - Thalasemia - anemia Sideroblastik, dll
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ANEMIA DEFISIENSI BESI LOGO
Definisi:
Anemia yang timbul akibat kosongnya cadangan besi tubuh
besi utk eritropoeisis
pembentukan Hb Anemia def. Fe, ditandai dgn: - anemia hipokromik mikrositik - besi serum - TIBC (Total Iron Binding Capacity) - Saturasi transferin - Feritin serum - Pengecatan Besi sumsum tulang negatif - Respon terhadap pengobatan dengan preparat Fe
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Faktor Penyebab (Etiologi)
LOGO I.
Keseimbangan negatif Fe (Negative Iron balance): - Asupan Fe ↓ -
(inadequate diet , impaired absorption)
Fe loss ↑
(GI bleeding, excessive menstrual flow,
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bleeding diathesis)
↑ demands
(infancy, pregnancy, lactation)
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Lanjutan ….Faktor Penyebab
II. Inadequate presentation to erythroid precursors: atransferrinemia - Anti TrfR Ab III. Abnormal Fe balance : Aceruloplasminemia - Autosomal dominant hemochromatosis ( mutations in ferroportin ) LOGO
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Patogenesis desifisiensi Fe
3 pathogenetic factors: - Impaired Hb synthesis reduced Fe supply) (consequence of 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 LOGO
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Status besi tubuh:
Serum Iron = SI Total Iron Binding Capacity (TIBC) % Transferrin Saturation = SI/TIBCx100% Simpanan besi (Iron storage): - Hemosiderin larut dalam →produk degradasi feritin yang tidak air → mayoritas tdd aggregat kristal ferric oxyhydroxide, FeOOH (di Hepar danSutul besi (prosedur invasif) → dideteksi dengan biopsi/aspirasi dan pengecatan LOGO - Ferritin → kompleks garam Fe3+dan apoferitin yang larut dalam air, dengan jumlah yang sangat kecil di serum. (dideteksi dengan metode imunoasai)
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LOGO
Kandungan besi tubuh = 35-50 mg/kgBB: ±80% - Fe fungsional, sebagai heme-Iron (65% Hb, myoglobin, enzim heme : cytochrom-C,A,A3,B, catalase , peroxidase) - Non-heme-Fe (sebagian kecil) 20% - simpanan besi / Iron storage (ferritin, hemosiderin) hanya ± 15% pada wanita 0.2% - circulating (terikat padaTransferrin)
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Iron Cycle in the body :
Fe diet → as heme-Fe (Hb, myoglobin, enzyme-Fe), 5-35% adsorbed from animal/meat sources , adsorbed easily .
→ as non-heme-Fe (vegetables , legumes), 90% of diet-Fe but only 2 20% of it absorbed → depends on the iron-status and the ratio of Enhancer:Inhibitor LOGO
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Enhancers (zat yang menstimulasi penyerapan (absorbsi) : Ascorbate, Cytrate, organic acids / other amino acids , by reducing Fe 3+ to Fe 2+ . LOGO Inhibitors (zat yang menghambat absorbsi) : Carbonate, Phytate, Tannins, Phosphate, Oxalat chelate Non-heme Fe → unabsorbable
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LOGO
Bahan makanan yang menghambat absorbsi besi non heme (Non-heme Iron) : - Phytate (dari legumes, sayuran) - Tannin & Polyphenol (dari teh, kopi, wine, coklat ) - Phosphate/phosphoprotein dari kuning telur - Minerals (Ca, Zn, Cd) - Tetracycline yang bereaksi dengan menghambat absorbsi Fe →
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Siklus Fe dalam tubuh
: LOGO Diet’s Iron → duodenum / proximal jejunum .
Iron from gut → released into circulation , bound to transferin → distributed to body’s organ / tissues( to bone marrow as a part of heme / Hb ) → circulate inside red blood cells with blood flow
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The development of IDA
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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 ↓ .
LOGO *IDA= Iron Deficiency Anemia
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* 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 LOGO
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Marrow Ferritin Transf-Sat sTrfR Retic Hb content Hb MCV Symptoms
Stage-1 (prelatent)
↓ ↓ N N N N N fatigue 40
Stage-2 (latent)
( - ) <12ug/L <16% ↑ ↓ N N fatigue
Stage-3 (IDA)
( - ) <12ug/L <16% ↑ ↓
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< < pallor
Symptoms Morphology SI - TIBC Ferritin LOGO
I D A Anemia Hypo – Micro SI ↓ TIBC ↑ ↓↓ A.C D Anemia Hypo – Micro SI ↓ TIBC ↓/N N/ ↑ 41
Pendekatan Diagnostik Anemia Defisiensi Fe LOGO 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)
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LOGO 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) - Endoscopy
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Normal I D A An.of Chronic Disease Fe Overload
S I
N (1/3 mol.Trsf) ↓ ↓ ↑↑
TIBC
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N ↑ N / ↓ N / ↑ 44
Pemeriksaan Lab. Anemia def. Fe
LOGO 1. CBC – confirm Anemia & find hypochromic microcytic picture from BSE and Red Cells Indices ( Hb, PCV ,MCV , MCH , MCHC) 2 . SI – Fe 2+ 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)
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% 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 )
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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 ) LOGO
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Anemia of Chronic In
fection
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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
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Penyebab menurunnya ‘circulating Fe’
LOGO 1. Impairment of Fe release from macrophage in competing with lactoferrin , phagocyte’s product , even storage-Fe is still enough . 2. Inadequate EPO Respons towards anemia (effects of cytokine production by macrophage) .
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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 .
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Anemia Sideroblastik
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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
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Sideroblast and Ringed Sideroblast ( in Sideroblastic Anemia ) LOGO
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Classification of Sideroblastic Anemia
1.
Hereditary
: X-linked, defect in heme synthesis enzyme pathway Fe absorption ↑ → % of Transferrin saturation and Ferritin level ↑
LOGO
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2. Acquired :
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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 .
LOGO
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LOGO -
Secondary;
Abnormal metabolism of Vit.B6 (alcoholism, malabsorption) , impairment of heme synthesis ( Pb intoxication) , Rhematoid Arthritis , or An.megaloblastik .
Usually related to myeloproliferative diseases ( AML, Myelofibrosis, Polycythemia or another types of MDS )
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Macrocytic Anemia
- Non-Megaloblastic Macrocytic Anemia :
Reticulocytosis
Liver disease / Alcoholism Myelodysplastic Syndrome
Erythroleukemia (FAB-M6) - Megaloblastic Macrocytic Anemia LOGO
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Megaloblastic Macrocytic Anemia
LOGO macrocyte = erythrocyte with MCV > normal .
macrocyte/microcyte depend on the balance between nuclei & cytoplasmic maturation .
(nuclear dividing stopped when intracellular Hb production reach a proper level ) .
If nuclear maturation delayed ( in DNA synthesis’s defect ) or cytoplasmic maturation ↑ ( increase of EPO’s activities ) → critical level of Hb achieved earlier → Macrocyte
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LOGO Megaloblast = bigger than normal normoblast .
Megaloblastic changes = increased size of hemopoietic precursor cells in bone marrow ( not only in normoblast !) Primary defect : Defect of DNA synthesis ( altered almost all active cells / organs i.e : hemopoietic tissue, epithelial cells , mucous cells, etc )
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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 Bili and LDH ↑.
→ total/indirect LOGO
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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) LOGO
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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) LOGO
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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 ) LOGO
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VITAMIN B12 ASAM FOLAT LOGO
-Food from animal products -Heat stabile -Storage : enough for 3 yrs -Relatively low needs (only 1% of folate requirements)
CAUSE OF DEFICIENCY
-Vegetarian (seldom) -Impaired Intrinsic Factor (pernicious anemia) -Gastrectomy -Atropic Gastritis -Anticonvulsant, alcoholism -Limited sources (vegetable , fruits) -Heat labile -Storage enough only for 3 mths -Higher folate needs
CAUSE OF DEFICIENCY
Nutrition (alcoholism, goat’s milk diet) -Prematurity -Hemodyalisis -Bowel resection -Pregnancy -Anticonvulsant , MTX 64
Pathogenesis of Megaloblastic Anemia
: LOGO
Megaloblastic changes
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 .
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B12 Metabolism LOGO
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 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)
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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 LOGO
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)
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Hematological pictures of Megaloblastic Anemia LOGO
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
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Megaloblastic Anemia LOGO
find oval-Macrocyte cell and hypersegmenteneutrophil .
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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) - Folate & Vit.B12 assay - Gastric juice analysis - Schilling Tests - Antibody Assay
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Anemia Hemolitik
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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).
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HEMOLYTIC ANEMIA
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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 (+) .
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Definition of Hemolytic Anemia
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anemia caused by shortened red cell’s survival as a result of excessive uncompensated destruction of red cells .
LOGO
Hemolytic process = every process of red cells destruction with still / without compensated by bone marrow → anemia is not always present .
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Compensation ability of bone marrow :
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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 (+).
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Diagnostic approach in Hemolytic Anemia
LOGO 1.
Confirm anemia (Hb/PCV/RBC) an acute case usually acquired , and chronic case is mostly hereditary . 2.
3.
4.
5.
To find the signs of hemolytic process .
Extra or Intravascular ?
Hereditary or acquired ?
The cause of hemolysis episodes .
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The signs of Hemolytic process :
LOGO 1. Increased of red cells destruction - Unconjug.bilirubin
hemolisys . 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
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LOGO
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2.Destruksi eritrosit
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Microspherocyte, Fragmentocyte, Poikilocyte Erythrocyte Osmotic Fragility ↑ Positive Autohemolysis test Shortened of red cells’ survival
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3. Tanda Peningkatan Eritropoisis: Reticulocytosis Normoblastosis Erythropoietic Hyperplasia in bone marrow
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LOGO
Hemolisis Ekstra vaskular
Hemolisis ekstravaskular lebih sering dijumpai dibandingkan hemolisis intravaskular
Hemolisis terjadi di sel makrofag dari sistem retikuloendothelial (RES) terutama pada Lien, hepar dan sutul karena sel ini mengandung enzim heme oksigenase
Lisis terjadi karena kerusakan membran eritrosit (misal Akibat reaksi Ag-Ab; presipitasi hb di sitoplasma, menurunnya fleksibilitas eri,dll) LOGO
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Klasifikasi Anemia Hemolitik
LOGO Dibagi atas 2 golongan besar, yaitu: 1. Anemia hemolitik karena faktor di dalam eritrosit sendiri (gangguan intra korpuskuler) 2. Anemia hemolitik karena faktor di luar eritrosit (gangguan ekstra korpuskular )
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lanjutan ….Klasifikasi anemia hemolitik :
LOGO 1.
Gangguan intra korpuskular (Hereditary Hemolytic Anemia ) - Membrane abnormality (hereditary spherocytosis , hereditary ovalocytosis ) - defect of globin chain (Thalassemia, Hb pathia) - enzyme defect ( G-6PD deficiency , PK deficiency)
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Hereditary Spherocytosis : LOGO
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Hereditary Ovalocytosis : LOGO
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Lanjutan ……klasifikasi anemia hemolitik
2. Gangguan ekstrakorpuskular (Acquired Hemolytic Anemia): - physical / chemical substances - infections (bacteria, parasites, viruses, fungi) - mechanical trauma (prostetic heart valves) - Immune mechanism (Alloimmune / Autoimmune / Drug-Induced HA)
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Hereditary Spherocytosis :
LOGO
autosomal dominant
Spherocytosis, decreased membrane surface area relative to cell volume → osmotic fragility test (OFT)↑ among the family member .
The primary lesion is caused by membrane protein defects (↓of spectrin) → cytoskeleton instability .
60% - chronic anemia , jaundice, splenomegaly, 20% without hemolysis / splenomegaly .
Bilirubin excretion ↑ ,causing bilestone in USG.
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Thalassemia :
Defect of 1 or more globin-chain synthesis (the amount = quantitatively) : LOGO - deficiency of α globin-chain → α-thalassemia - deficiency of β globin-chain → β-thalassemia - deficiency of δβ globin-chain → δβ-thalassemia the primary defects in Hb-pathia is in the globin amino acids structure (qualitatively)
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α-Thalassemia
LOGO
α-Thalassemia = is caused by the impairment of α-globin chain production/synthesis .
α-globin chain synthesis is directed by 2 pairs of α-gene (4 locus α-gen) → depending of the number of defected locus → 3 types of α-Thalassemia (α-thal trait , HbH Disease, and HbBart’s Hydrops Fetalis)
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Clinical consequences in α-Thalassemia
LOGO
Deficiency of α-globin chain → excess of β, γ chain since fetal life to form β4-tetramers (HbH) or γ4-tetramers (HbBart) .
Defect of 1-2 α-Gen = α-trait (clinically good)
Defect of 3 α-Gen = HbH disease ( Hb 10-11 g/dl) → excess of β-chain → to form β4 tetramers (HbH ) as intracellular inclusion → detected by BCB-stain .
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HbH-inclusion (β4) in HbH Disease as shown in BCB staining (compare with reticulocyte) LOGO
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LOGO
Defect of 4 α-gene (HbBarts’hydrops fetalis) → clinically severe , stillborn baby with hydrops fetalis ( severe hypoxia ) .
HbBarts = γ4-tetramers (excess of γ-chains that unable to form HbF ) .
HbBarts and HbH inclusions precipitated in red cell’s membrane → mechanical trapping in spleen → macrophagic phagocytosis → hemolysis .
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99
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- β-Thalassemia
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Clinically consequences in β-Thalassemia : - No problems during fetal life because HbF synthesis is normally produced (normal α and γ chains) - When HbA is dominantly needed , the clinically problems exist as incapability to synthesize HbA ( HbA2 α2β2) → excess of α-chain → compensated ↑ of δ and γ production → ↑ (in β-Thalassemia minor) and HbF ↑ (in β-Thalassemia mayor)
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Β-Thalassemia mayor :
LOGO severe anemia → repeated transfusion is oftenly needed → Fe↑↑ → hemochromatosis - chronic ineffective erythropoiesis medullary → hypertrophy in childhood → facial malformation: * Frontal bossing * Maxillary hypertrophy * Hypertelorism (mongoloid’s eye)
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β-chain deletion forms :
LOGO
β
0
-Thalassemia : no β-chain production.
β
+
Thalassemia : β-chain production << in heterozygous case : medium severe in homozygous : severe (Cooley’s
anemia)
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Laboratory Diagnosis in Thalassemia
1.
CBC, Peripheral Blood Smear LOGO 2.
Hb-Electrophoresis : in Celulose-Acetat (pH 8.4) for thalassemia and Hb-pathia screening Using hemolysate → formed bands of different types of Hb ( normal : bands A, F, and A2 , measured densitometrically)
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Lanjutan …..Lab diagnosis in thalasemia
LOGO 3 . HbA2 mesurement to diagnose β-Thalassemia trait using anion-exchange resin column chromatography in both HbELP and chromatography , HbC, HbE and HbO can interrupt the conclusion because of the same band location with HbA2 .
4. HbF determination : - Alkali Denaturation Test - Acid-elution (Kleihauer) test - RID or ELISA methods
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5. HbH Inclusion detection : - Supravital staining using Brilliant Cresyl Blue (BCB) or NewMethylene Blue (NMB) - HbH inclusion seen as dispersed blue green granules in red cells (compare with reticulocyte as a filament) - in HbH disease : HbH inclusion +++ - in Thalassemia α-trait : HbH inclusion + in 1: 10000 eritrosit .
LOGO
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Defisiensi G-6PD
LOGO Oxidant → produce H2O2 → oxidizing Hb’s free sulfhydryl → to form Sulf-Hb → aggregates that precipitated as Heinz Bodies → destructed in spleen .
- Oxidant / Sulf-Hb are controlled by Reduced Glutathione (GSH )
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- X-linked, ± 300 variants .
normal G-6PD genes : - type B (GdB) 1. GdA – (type A–) - type A (GdA) - Abnormal enzyme types : 2. Gd-Mediterranean (GdMed) 3. Gd-Canton : many in Asia - G-6PD deficient red cells are resistent to Plasmodium Falciparum .
LOGO
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Substances causing lysis in G-6PD deficiency : 1. Antimalaria 2. Sulfonamides 3. Vit.K, Vit.C
6. Fava beans 7. Naphtalene 8. Uremia 4. Lung Infection 9. Antibiotics (virus,bacteria) (Penicilline , 5. Antipyreticum streptomycine LOGO
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The highest G-6PD activity is in reticulocyte .
G-6PD screening test : Test’s principle : G-6PD G-6P + NADP 6-PG + NADPH UV LOGO (fluorescence)
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Acquired Hemolytic Anemia
: Secondary Hemolytic Anemia
caused by infection / systemic disorders
: LOGO
Malignancy – Autoimmune-reacted hemolysis , microangiopathy or hypersplenisme , appearing Anemia of chronic disease, bleeding tendencies, and marrow’s suppression
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LOGO
Disseminated Intravascular Coagulation (DIC): Systemic intravascular coagulation → fibrin deposit intravascularly / endothelial damage (microangiopathyi ) caused by sepsis → red cells destruction .
Chronic Liver Disease : hemolysis caused by hypersplenism .
Chronic Renal Disease: hemolysis caused by microangiopathy
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Immune Hemolytic Anemia
Red cell membrane-bound Ab hemolysis .
The speed & hemolysis location depend on IgG or IgM, and the ability to activate complement .
Optimal temperature to bind Ab : 37 0 C – Warm-IgG-Type <30 0 C – Cold-IgG-Type
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Lanjutan ….acquired hemolytic anemia
Cell+IgG → destructed by spleen Cell+IgM → enhance the activation of complement’s cascade → intravascular hemolysis
Immune destruction often cause minimally membrane damage → shape change into spherocyte .
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Immune Hemolytic Anemia classification : 1. Alloimmune : Transfusion Rx , Hemolytic
Disease of the Newborn (HDN)
LOGO 2. Autoimmune : Warm/Cold AIHA, Paroxysmal Cold Hb-uria (PCH) 3. Drug-induced HA : penicilline type, aldomet, and stibophen type .
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Hemolytic Disease of the Newborn (HDN) – Rh-neg mother , with Rh-Pos fetus , during I and second pregnancy LOGO
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Antiglobulin Tests (Coombs) :
Direct Coombs Test (Direct Antiglobulin Test/DAT) = Ab detection test (IgG and or C3d /complement-bound red cells) .
LOGO Indirect Coombs Test = test for serum free Ab .
DAT usually positive in AIHA (.
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Drug-Induced hemolytic anemia :
Penicilline type : drug as hapten binds red cell membrane → antigenic → stimulate Ab production against Drug in drug-red cell complex LOGO Phenacetin/Quinidin type : Drug (hapten) adsorbed protein → stimulated-Ab binds drug-protein complex → activate complement → red cell lysis.
Aldomet type : drug change red cell membrane’s structure → detected as foreign cell → Autoantibody production .
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Aplastic (Hypoplastic?) Anemia
Severe & fatal Anemia because of ↓ red cells/leucocytes/platelet production (pancytopenia) caused by Stem Cells impairment (radiation, chemicals, drugs, or genetic matters) LOGO
Marrow aplasia / hypoplasia-causing substances - radiation , benzene, cytostatics (6-MP, busulfan), arsen, chloramphenicol, anticonvulsant (phenytoin), analgetic (phenylbutazone) , DDT, etc
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fatigue, palpitation, infections, bleeding tendency
Lab : - pancytopenia - normochromic normocytic ‘dry-tap’ marrow , hypocellularity
Prognosis : bad especially for < 40 yrs old patients → marrow transplantation .
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-
Treatment for Aplastic Anemia :
1.
2.
3.
4.
5.
Avoid every toxic material Avoid infections / bleeding tendency Use Washed-Erythrocyte if transfusion is needed or Plat.Concentrate (PC) for any profuse bleeding ( give corticosteroid if bleeding is minimal) Marrow stimulants (androgenic hormon ) Marrow Transplantation LOGO
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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% ) LOGO
•
Klasifikasi : I. Primer (Otonomik) A. Polisitemia Vera B. Eritrositosis Murni (Eritremia) II. Sekunder A. Fisiologis (
Oksigenasi Jaringan
) B. Non-fisiologis (
Oksigenasi Jaringan N
) III. Eritrositosis Relatif
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ERYTHROCYTOSIS - DIAGNOSTIC TESTS
LOGO
• • • • • • • • • •
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. : LOGO Kategori A 1.Massa eritrosit: Lk > 36 ml / kgBB (PCV > 54%) Pr > 32 ml / kg BB (PCV > 51%) 2. Saturasi oksigen > 92% 3. Splenomegali
Kategori B 1. Trombositosis (> 400.000 / 2. Lekositosis (> 12.000 /
m
l)
m
l) 3. Skor LAP 4. B12 serum > 900 pg/ml
LOGO
+
atau
+
PRIMARY “PURE” ERYTHROCYTOSIS
LOGO
( 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
LOGO
• 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
LOGO
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C l i c k t o e d i t c o m p a n y s l o g a n .
SOAL LATIHAN :
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1. Nyonya Ana, usia 40 tahun, MRS (Masuk Rumah Sakit) dengan keluhan pusing, dan badan terasa lemah. Pemeriksaan fisik: KU lemah, Tensi: 100/60 mmHg, Nadi:90 x/menit, RR: 20 x/menit, suhu:37˚C. Kepala/Leher: anemia (+), tidak dijumpai ikterus, dyspnea dan sianosis, Thorak/Cor dan Abdomen :dalam batas normal (dbn). Extremitas: dbn. Hasil laboratorium: Hb 8 g/dl, RBC 3,20 x 10 12 /L, Hematokrit 24 %, MCV 75 fl, MCH 25 pg, MCHC 33 g/dl. Jika anda adalah dokter jaga di RS tersebut, dari data yang ada, kemungkinan diagnosis pasien tersebut adalah: A. Anemia normokromik-normositik B. Anemia hipokromik-mikrositik C. Anemia makrositik D. Anemia makrositik-megaloblastik E. Anemia makrositik-non megaloblastik www.themegallery.com
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Lanjutan …...soal latihan
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2. Dari kasus ny. Ana, 40 tahun tersebut, diagnosis diferensial untuk penyebab anemianya adalah: A. Anemia defisiensi folat, anemia defisiensi Vitamin B12, B. Anemia karena perdarahan akut, anemia aplastik C. Anemia defisiensi besi, thalasemia, anemia sideroblastik D. Anemia hemolitik, anemia pada penyakit mielofibrosis E. Anemia pada penyakit liver, anemia pada penyakit hipotiroid Company Logo www.themegallery.com
Lanjutan …...soal latihan
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3. Dari soal kasus Ny. Ana, 40 tahun tersebut, langkah pemeriksaan laboratorium selanjutnya yang perlu dilakukan untuk konfirmasi diagnosis adalah: A. pemeriksaan bilirubin, haptoglobin, hitung retikulosit B. Serum Iron, TIBC dan Feritin C. Pemeriksaan B12 dan asam folat dalam darah D. Pemeriksaan T3, T4 dan TSH E. Pemeriksaan Aspirasi sumsum tulang Company Logo www.themegallery.com
CLINICAL CASE
LOGO
A 35-year-old man complains of chronic physical fatigue, which began 3-4 weeks ago. He said he felt tired all of the time even through his occupation as a software developer was mentally but not physically demanding. He breathed comfortably at rest but, when he exerted himself, he experienced difficulty in breathing and had hard time catching his breath. He also complained of „more than usual” mental fatigue, confessing an increasing inability to concentrate and focus his attention on tasks at hands. Colleagues noticed his pallor and his inattentiveness at brainstorming sessions and suggested he reschedule his annual physical examination for an earlier date. He complained of vague abdominal pain and sense of abdominal fullness. His appetite was depressed, and he thought perhaps his physical and mental symptoms were caused by poor diet. However, attempts to increase eating resulted in nausea. His stools, he said, were sometimes loose and tarry. Eventually, increased heart palpitations and chest pain made him seek medical advice
Laboratory findings revealed the following:
Patient
RBC (red blood cell count) HCT (hematocrit ratio) 3.5 T/L 28%
LOGO
Normal
4.5-6.0 T/L 40-52% Hb (hemoglobin) 8.0g/dL 13-17g/dL MCV (mean corpuscular volume) MCH (mean corpuscular hemoglobin) MCHC (mean corpuscular hemoglobin concentration) 70fL 22.8pg
28% 78-95fL 29pg 34%
QUESTIONS
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2.
3.
4.
Case history questions: What general medical condition is suggested by the person’s symptoms?
What fundamental change in function of blood related to the red blood cells could simultaneously affect the function of several systems (cardiovascular, respiratory, gastrointestinal, and others)?
What specific diagnosis is supported by the laboratory findings?
How could the stool be related to the laboratory findings ?
ANSWER
LOGO 1.
2.
3.
4.
A reduction in oxygen-carrying capacity of the blood and thus a reduction in the delivery of oxygen to various body tissues An iron defficiency anemia Most cases of iron-defficiency anemia result from internal blood loss. Dark, tarry loose stools suggest bleeding from the gastrointestinal tract and warrant further tests to determine the exact cause
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C l i c k t o e d i t c o m p a n y s l o g a n .