PK Anemia dr. Bastiana, SpPK

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Gangguan Eritrosit:

Anemia dr. Bastiana SpPK

  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, angina)

ANEMIA → symptoms / syndrome

   Hb ↓

   PCV ↓ Hypoxia → Otak , Otot

   RBC ↓ 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 ↑ .

Klasifikasi Anemia Berdasarkan patofisiologi:

   Anemia Aplastik

   Anemia Megaloblastik

   C. Gangguan sintesis Hemoglobin (Hb) 

   Anemia Defisiensi Besi, Thalasemia

   D. Gangguan sintesis eritropoetin 

   Anemia karena GGK

  Lanjutan…..anemia berdasarkan patofisiologi

    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 MCHC)

  

  Kriteria Ukuran (size): Normositik, Mikrositik, Makrositik

  

  Kriteria Warna (pucat): Normokromik, Hipokromik

• * membandingkan dengan inti sel limfosit kecil (di bawah mikroskop) : → ukuran sama = normositik lebih kecil = mikrositik lebih besar = makrositik * Menghitung MCV (Mean Cell Volume) MCV= PCV/Ery X 10 (fL) (1 fL=10
• ^-12 L= 1μm
³ ) N : dewasa = 80-100 fL , di bawah 1 thn = 76- 86 fL MCV : normositik , mikrositik, makrositi
• * 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)

  MCH= Hb/RBC x 10 (pg) 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) : MCHC=Hb/PCV x 100 (g/dL) Normal: MCHC = 32-36 g/dL

  Klasifikasi Anemia secara morfologi 1. Anemia Hipokromik-Mikrositik .

  Normositik 3. Anemia Makrositik

• _- 2 _{Contoh: Anemia pasca}
• _- perdarahan akut

  _{Anemia aplastik}

  _-

  _{Anemia hemolitik}

  _-

  _{Anemia akibat}

  penyakit kronik
• _{- Anemia pada GGK -} Anemia pada _{mielofibrosis - dll}

  3 _{A. Megaloblastik, contoh:}

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

  B. Nonmegaloblastik _{contoh: - Anemia pd peny.}

  Hati kronis _{- 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}

  Hipokromik-Mikrositik

   makrosit-oval

(Anemia megaloblastik ditandai oleh makrosit oval ini)

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 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)

  

Pemeriksaan Laboratorium

• - CBC (complete blood count )→ to confirm

   anemia (Hb, PCV, RBC) & the type of anemia (MCV; MCH; MCHC), RDW reflects marrow’s responses .

• - 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 Hipokromik-Mikrositik

  

  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

   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

I. Keseimbangan negatif Fe (Negative Iron

  balance): - Asupan Fe ↓ (inadequate diet , impaired absorption)

• - Fe loss ↑ (GI bleeding, excessive menstrual flow, bleeding diathesis) - ↑ demands (infancy, pregnancy, lactation)
Lanjutan….Faktor Penyebab

  II. Inadequate presentation to erythroid precursors:

• - atransferrinemia - Anti TrfR Ab

  III. Abnormal Fe balance :

  Aceruloplasminemia - - Autosomal dominant hemochromatosis ( mutations in ferroportin )

Patogenesis desifisiensi Fe

   3 pathogenetic factors: (consequence of - Impaired Hb synthesis 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)

   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)

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

  Enhancers (zat yang menstimulasi

   penyerapan (absorbsi) :

  Ascorbate, Cytrate, organic acids / other _{3+ 2+} amino acids , by reducing Fe to Fe .

  Inhibitors (zat yang menghambat absorbsi) :

  Carbonate, Phytate, Tannins, Phosphate, Oxalat chelate Non-heme-Fe → unabsorbable

  

  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 Fe → menghambat absorbsi

   Siklus Fe dalam tubuh : 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

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

  Stage-1 Stage-2 Stage-3 (prelatent) (latent) (IDA) Marrow ↓ ( - ) ( - ) Ferritin ↓ <12ug/L <12ug/L Transf-Sat N <16% <16% sTrfR N ↑ ↑ Retic Hb N ↓ ↓ content Hb N N < MCV N N < Symptoms fatigue fatigue pallor

  Symptoms Morphology SI - TIBC Ferritin Anemia

  I D A Hypo – SI↓ - ↓↓ Micro TIBC ↑ Anemia

  A.C D Hypo – N/ ↑ SI - ↓ Micro

  TIBC / ↓ N

  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. 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

S I TIBC Normal

  N N

(1/3 mol.Trsf)

  I D A ↑ ↓

  An.of Chronic N / ↓ ↓

  Disease Fe Overload

↑↑

N /

  ↑

  1. CBC – confirm Anemia & find hypochromic microcytic picture from BSE and Red Cells Indices ( Hb, PCV ,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%

   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

  :

  1. Impairment of Fe release from macrophage in competing with

  

, phagocyte’s product

   lactoferrin , even storage-Fe is still enough .

  2. Inadequate EPO Respons towards anemia (effects of cytokine production by macrophage) .

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 )

  

Classification of Sideroblastic Anemia

  synthesis enzyme pathway Fe absorption ↑ → % of Transferrin saturation and Ferritin level ↑

• - 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 .

• - 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 )

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 . 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

  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 )

  

  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 )
• 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

  

  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 .

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 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 &

  Bone Marrow Aspiration:

  megaloblastic 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 (+).

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 :

  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

  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)

Klasifikasi Anemia Hemolitik

  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 )

   lanjutan….Klasifikasi anemia hemolitik :

  Hemolytic Anemia ) - Membrane abnormality (hereditary spherocytosis , hereditary ovalocytosis ) - defect of globin chain (Thalassemia, Hb- pathia) - enzyme defect ( G-6PD deficiency , PK- deficiency)

  Hereditary Ovalocytosis : 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)

Hereditary Spherocytosis : -

   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.

Thalassemia :

   Defect of 1 or more globin-chain synthesis (the amount = quantitatively) : - 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)

  α-Thalassemia 

  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)

Clinical consequences in α-Thalassemia

  

  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 .

  in BCB staining (compare with reticulocyte)

  

  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 .

• - β-Thalassemia

  

  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 (α2β2) → excess of α-chain → compensated ↑ of δ and γ production → HbA2 ↑ (in β-Thalassemia minor) and HbF ↑ (in β-Thalassemia mayor)

  Β-Thalassemia mayor :

• - 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)
• - β-chain deletion forms :

  

  β -Thalassemia : no β-chain production.

  

  β Thalassemia : β-chain production

• + << in heterozygous case : medium severe in homozygous : severe (Cooley’s

  anemia)

Laboratory Diagnosis in Thalassemia

  1. CBC, Peripheral Blood Smear

  

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)

  Lanjutan…..Lab diagnosis in thalasemia 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 .
• - 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 .
• - 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 )

   - X-linked, ± 300 variants .

   normal G-6PD genes : - type B (GdB) - type A (GdA) - Abnormal enzyme types :

  1. GdA– (type A–)

  2. Gd-Mediterranean (GdMed)

  3. Gd-Canton : many in Asia - G-6PD deficient red cells are resistent to Plasmodium Falciparum .

• - Substances causing lysis in G-6PD

  deficiency :

  1. Antimalaria

  6. Fava beans

  2. Sulfonamides

  7. Naphtalene

   3. Vit.K, Vit.C

   8. Uremia

  4. Lung Infection 9. Antibiotics (virus,bacteria) (Penicilline ,

  5. Antipyreticum streptomycine

  

  The highest G-6PD activity is in reticulocyte .

  

  G-6PD screening test : Test’s principle : G-6PD G-6P + NADP 6-PG + NADPH UV (fluorescence)

   : Acquired Hemolytic Anemia

Secondary Hemolytic Anemia caused by - infection / systemic disorders :

  

  Malignancy – Autoimmune-reacted hemolysis , microangiopathy or hypersplenisme , appearing Anemia of chronic disease, bleeding tendencies, and marrow’s suppression

  

  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

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 C – Warm-IgG-Type <30 C – Cold-IgG-Type 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 .

  

  Immune Hemolytic Anemia classification :

  1. Alloimmune : Transfusion Rx , Hemolytic

   Disease of the Newborn (HDN)

  2. Autoimmune : Warm/Cold AIHA, Paroxysmal Cold Hb-uria (PCH)

  3. Drug-induced HA : penicilline type, aldomet, and stibophen type .

  Rh-neg mother , with Rh-Pos fetus , during I and second pregnancy

Antiglobulin Tests (Coombs) :

  

  Direct Coombs Test (Direct Antiglobulin Test/ DAT) = Ab detection test (IgG and or C3d /complement-bound red cells) . Indirect Coombs Test = test for serum free Ab .

   DAT usually positive in AIHA (.

Drug-Induced hemolytic anemia :

   Penicilline type : drug as hapten binds red cell membrane → antigenic → stimulate Ab production against Drug in drug-red cell complex 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 .

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)

  

  Marrow aplasia / hypoplasia-causing substances - radiation , benzene, cytostatics (6-MP, busulfan), arsen, chloramphenicol, anticonvulsant (phenytoin), analgetic (phenylbutazone) , DDT, etc

  Symptoms & Lab.appearance of Aplastic Anemia  fatigue, palpitation, infections, bleeding tendency

   Lab : - pancytopenia - normochromic normocytic - ‘dry-tap’ marrow , hypocellularity

   Prognosis :

• - bad especially for < 40 yrs old patients →

  marrow transplantation .
• - Treatment for Aplastic Anemia :

  1. Avoid every toxic material

  2. Avoid infections / bleeding tendency

  3. Use Washed-Erythrocyte if transfusion is

  needed or Plat.Concentrate (PC) for any profuse bleeding ( give corticosteroid if bleeding is minimal)

  4. Marrow stimulants (androgenic hormon )

  5. Marrow Transplantation

  (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

   1.Massa eritrosit: Lk &gt; 36 ml / kgBB (PCV &gt; 54%) Pr &gt; 32 ml / kg BB (PCV &gt; 51%)

   2. Saturasi oksigen &gt; 92%

   3. Splenomegali

  Kategori B

  1. Trombositosis (&gt; 400.000 / ml)

  2. Lekositosis (&gt; 12.000 / ml)

  3. Skor LAP ­

  4. B12 serum &gt; 900 pg/ml Diagnosis PV bila :

  A1 + A2 + A3 atau

  A1 + A2 + dan 2 dari kategori B

• + + +

  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

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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 ₁₂ g/dl, RBC 3,20 x 10 /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

Lanjutan …...soal latihan

  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

  3. Dari soal kasus Ny. Ana, 40 tahun tersebut, langkah pemeriksaan laboratorium selanjutnya yang perlu dilakukan untuk konfirmasi diagnosis adalah: