ANEMIA Your company information anemia • • • Anemia adalah suatu sindroma klnik yang disebabkan oleh penurunan kapasits angkut oksigen darah Keadaan klinik yng ditandai oleh penuruna kadar hemoglogin , hmatokrit atau hitung eritrosit . Angka normal ketiga parameter itu ditentukan oleh umur jenis kelamin dan keadaan fisiologi Pada dasarnya anemia terjadi karena : – – Proses eritropoesis yang tidak normal Masa hidup eritrosit memendek , karena ; • • 1. hemolisis 2 kehilangan darah (bleeding ) baik secara akut maupun krinik eritropoesis • Untuk terjadi eritropoisis yang baik maka diperlukan – Sel induk – Bahan pembentuk eritrosiit – Lingkungan mikro sumsum tulang yang baik – Mekanisme regulasi Sel induk limfoid Sel induk Mieloid Sel induk Pluripoten Sel induk mieloid BFU - E CFU – E Pronormoblast Normoblast Basofilik Normoblast polikromatofilik Retikulosit eritrosit • 2 Proses utam dalam eritropoiesis: – Pembentukan Inti ( DNA) – Pembentukan hemoglobin Pembentukan Inti • Mula mula terjadi pembentukan DNA sebagai bhan penyusun yang berguna dalam mitosis SEL. Bahan Pembentukan utama DNA (asam folat atau vitamin B12). Apabila terjadi defisiensi asam folat maka akan menghambat mitosis Pembentukan Hemoglobin • Pembentukan hemoglobin merupakan proses terpenting dalam sitoplasma eritrosit (Heme dan Globin). • Pembentukan heme terjadi dalam mitokondria yang memerlukan protoporfirin , Gangguan pembentukan Protoporfirin menimbulkan anemia sideroblastic Definition of anemia: Anaemia is defined as a reduced haemoglobin level in the peripheral blood. The principal effect is decreased oxygen-carrying capacity of the blood. Mild Moderate Severe Normal Hb: Hb 10-12 g/dl (M) Hb 9-11 g/dl (F) Hb 8-10 g/dl (M) Hb 7-9g/dl (F) Hb concentrations are below this level 13.5-17.5 g/dl (M) 11.5-15.5 g/dl (F) Normal Blood Count: adult values Hb 13.5-17.5 g/dl (M); 11.5-15.5 g/dl (F) RBC 4.5-6.5 x 1012/l (M); 3.9-5.6 x 1012/l (F) PCV (haematocrit) 40-52% (M); 36-48% (F) MCV 80-95 fl MCH 27-34 pg MCHC 30-35g/dl Reticulocytes 0.5-2.0% Platelets 150-400x109/l WBC (total) 4.0-11.0 x109/l Neutrophils 2.5-7.5 x109/l Lymphocytes 1.5-3.5 x109/l Monocytes 0.2-0.8 x109/l Eosinophils 0.04-0.44 x109/l Basophils 0.01-0.1 x109/l • Hct, Hb, RBC: determine degree of anemia • Red cell indices (MCV, MCH, MCHC): determine normocytic, macrocytic, microcytic, normochromic, hypochromic. • RDW: measure aniscytosis. • Reticulocyte count or index: estimate marrow response • Blood film: determine red cell shape, Hb content, red cell inclusion, abnormalities white cells and platelet. Hct, hematocrit; Hb, hemoglobin, RBC, red blood cell; RDW, red distribution width Cardiovascular Exertional dyspnea, tachycardia, and palpitations, orthopnea, angina. Respiratory cardiomegaly, murmurs, vascular bruits, ↑respiratory rate. Neurologic Skin Headaches, tinnitus, dizziness, faintness, loss of concentration, fatigue, cold sensitivity. Pallor of skin, mucous membranes, nailbeds, and palms. Gastrointestina Anorexia, nausea, constipation, diarrhea. l Genitourinary Menstrual irregularity, amenorrhea, menorrhagia, loss of libido or potency. • Anemia Hipokromik mikrositer (MCV < 80, MCH <27 pg) – Anemia defisiensi besi – Thalasemia – Anemia oleh Penyakit Kronis – Anemia Sideroblastik • Anemia Normokromik normositer ( MCV 80-95, MCH 27 – 34 ) – Anemia pasca perdarahan akut – Anemia aplastic – Anemia hemolitik tertentu – Anemia mieloplastik – Anemia gagal ginjal kronik – Anemia leukemia akut • Anemia Makrositer ( MCV > 95 fl): – Anemia Megaloblastik • Anemia defisiiensi asam folat • Anemia defisiensi vitamin B12 – Anemia non megaloblastic • anemia pada penyakit hati kronik • Anemia pada hipotiroidi • Anemia pada sindroma mielodislastik ANEMIA MAKROSITIK HIPOKROMIK Included : 1. Iron deficiency anaemia 2. Thalassaemic syndromes 3. Sideroblastic anaemia 4. Anaemia of chronic disease (some cases) The causes of a hypochromic, microcytic anaemia. These include lack of iron (iron deficiency) or of iron release from macrophages to serum (anemia of chronic inflammation or malignancy), failure of protoporphyrin synthesis (sideroblastic anaemia) or of globin synthesis (α- or β- thalassemia) Developmental Stages of Iron Deficiency Iron depletion storage iron decreased or absent Iron deficiency storage iron decreased or absent low serum iron low transferrin saturation Iron-deficiency anemia storage iron decreased or absent serum iron low transferrin saturation low hemoglobin level The development of iron deficiency anaemia. Reticuloendothelial (macrophage) stores are lost completely before anaemia develops. MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume Causes of Iron Deficiency Chronic blood loss Pregnancy, lactation Inadequate dietary intake of iron Malabsorption of iron Red blood cells: • Anisocytosis, RDW • Mild ovalocytosis, target cells • Hypochromia (low MCHC), microcytosis (low MCV) • Reticulocyte N or Leukocytes: • Differential WBC normal, a small number leukopenia Platelets: • Thrombocytosis or thrombocytopenia Profil iron: • SI concentration: , in mild IDA low-normal • TIBC: , in mild IDA high-normal • Saturation transferin (iron/TIBC) is often <15% not specific, may occur in inflamation (e.g. arthritis) • Serum transferrin receptor (sTfR): when serum ferritin levels are borderline low, its elevation early stage IDA SI, serum iron; TIBC, total iron binding capacity; IDA, iron deficiency anemia sTfR: to evaluate suspected IDA in patients who have inflammation, infection or chronic d Serum Ferritin: • Levels < 10 μg/L, characteristic of IDA • Levels 10 to 20 μg/L: presumptive (not diagnostic) • May be ↑with concomitant inflammatory disease (e.g., rheumatoid arthritis), chronic renal disease, malignancy, hepatitis, or iron administration. • IDA can be suspected in RA or other severe inflammatory states if the ferritin < 60 μg/L. IDA, iron deficiency anemia; RA, rheumatoid arthritis Blood Count in Iron Deficiency: example Hb RBC PCV 7.5 g/dl 4.05 x 1012/l 26% MCV MCH Reticulocytes 64 fl 18.5 pg 2.6% WBC differential Platelets 7.5x109/l Normal 530x109/l • Diagnosis: Hb, MCV, MCH, Blood film (cell pencil), Ferritin, sTfR • If the diagnosis is established, search for a source of blood loss if unapparent • GI loss is the most prevalent of blood loss in men, uterine/menstrual loss in women. GI, gastrointestinal Serum Fe TIBC Saturatio n Ferritin BM Stores Sideroblast s Iron deficiency ↓ ↑ ↓ ↓↓ absent ↓ Chronic disease ↓ N or ↓ ↓ N or ↑ N or ↑ ↓ Sideroblasti c anaemia N or ↑ N N or ↑ ↑ ↑ ↑ ring sideroblasts Thalassaem ia N or ↑ N N or ↑ ↑ ↑ ↑ Haemochro matosis ↑ N ↑ ↑↑↑ ↑↑↑ N or ↑ • 150-200 mg elemental iron in 3 to 4 doses, 1 hour before meals (65 mg of elemental iron is contained in 325mg of ferrous sulfate USP, or in 200 mg dried ferrous sulfate) • Do not give with meals or antacids or with inhibitors of acid production. • A few patients may complain of GI intolerance to pills, pyrosis, constipation, diarrhea, and/or metalic taste and require daily dose, change of oral iron preparation. Macrocytic Anemia • Macrocytic anemia: RBC abnormally large (MCV>95fL). • Macrocytic anemia: 1. Anemia megaloblastic 2. Anemia non-megaloblastic • A group of anemia in which erythroblast in BM show abnormality-maturation of the nucleus (delayed relative to cytoplasma), due to defective DNA synthesis, caused by deficiency of vit. B12 or folate. BM, bone marrow • Found in food of animal origin: liver, meat, fish • Absorbtion: distal ileum • Vit B12 – glycoprotein IF (synthesized by gastric parietal cells) bind to cubilin (receptor for IF) direct endocytosis the cubilin IF-B12 complex in the distal ileum, where B12 is absorbed and IF destroyed. • Transport: transcobalamins, which delivers B12 to BM BM, bone marrow, IF, intrinsic factor Causes of severe vitamin B12 deficiency Nutritional Vegan Malabsorption Congenital lack or abnormality of intrinsic factor (IF) Total or partial gastrectomy Intestinal causes Ileal resection Crohn’s disease Causes of Folate Deficiency Nutritional Old age Proverty Malabsorbtion Pregnancy, lactation, Hemolytic anemias Myelofibrosis Liver disease Inflammatory disease: Crohn’s disease TBC Rheumatoid arthritis Psoriasis Exfoliative dermatitis Malignant disease: Carcinoma myeloma lymphoma The absorption of dietary vitamin B12 after combination with intrinsic factor (IF), through the ileum. Folate absorption occurs through the duodenum and jejunum after conversion of all dietary forms to methyltethrahydrofolate (methyl THF). TC, transcobalamin. • • • • • • Signs of anemia Jaundice (mild) the excess breakdown Hb (ineffective erythropoiesis in BM) Glossitis, angular stomatitis Mild symptoms of malabsorbtion (loss of weight) Purpura (thrombocytopenia) Many asymptomatic patients are diagnosed when a blood count has been perormed for another reason (reveal macrocytosis). Vit. B12 deficiency Folate deficiency Compound Hydroxycobalamin Folic acid Route Intramuscular Oral Dose 1.000 ug 5mg Initial 6x 1.000ug over 2-3 weeks Daily for 4 month Maintenance 1.000 ug every 3 months Life long therapy in: chronic inherited hemolytic anemias, myelofibrosis, renal dialysis Prophylactic Total gastrectomy Ileal resection Pregnancy, severe hemolytic anemias, dialysis, prematurity. Hemolytic anemia • • • Anemia that results from an increase in the rate of RBC destruction. The normal adult marrow, is able to produce red cells at 6-8 times the normal rate. It leads to a marked reticulocytosis Warm type Autoimmune Idiopathic Secondary SLE, other autoimmune disease CLL, lymphomas Drugs (e.g. Methyldopa) Alloimmune Induced by red cell antigens Hemolytic transfusion reaction Cold type Idiopathic Secondary Infections: Mycoplasma pneumonia, infectious mononucleosis Lymphoma • AIHA cause by antibody production by the body against its own red cells. • Characterized by a positive DAT (Coombs’ test) • Antibody reacts more strongly with RBC at 370C (warm type) or 40C (cold type) AIHA, autoimmune hemolytic anemia; DAT, direct antiglobulin test • The RBC coated with IgG alone or with complement, taken up by macrophages (have receptor for IgFc fragment) • Part of the coated membrane is loss the cell becomes spherical (sperocyte) prematurely destroyed, predominantly in the spleen. Some of the more frequent variations in size (anisocytosis) and shape (poikilocytosis) that may be found in different anaemias. DIC, disseminated intravascular coagulopathy; G6PD, glucose6-phosphate dehydrogenase; HUS, haemolytic uraemic syndrome; TTP, thrombotic thrombocytopenic purpura. • • • • • • Pallor Jaundice Splenomegaly Urine dark (excess urobilinogen) The disease tends to remit and relapse When associated with ITP: Evan’s syndrome ITP, immune thrombocytopenic purpura • Remove the underlying cause • Corticosteroids • Immunosuppressive: azathioprine, cyclophosphamide, ciclosporin, mycophenolate mofetyl • Folic acid • High-dose immunoglobulin • The autoantibody: monoclonal or polyclonal attach to RBC where the blood temperature is cooled. • Antibody (IgM), binds to RBC best on 40C. • IgM Abs are highly efficient fixing complement extra- and intra-vascular hemolysis. • A chronic hemolytic anemia aggravated by the cold • Often associated with intravascular hemolysis • Mild jaundice • Splenomegaly • Acrocyanosis (purplish skin discoloration at the tip of nose, ears, fingers and toes, caused by agglutination of RBC in small vessels • Keeping the patient warm • Treating the underlying cause • Chlorambucyl Aplastic Anemia Aplastic Anemia (AA) (Panmyelopathy, Panmyelophtysis) Definition: a group of pathogenitically heterogenous bone marrow (BM) failure. Bi- or tricytopenia (anemia, granulocytopenie, thrombocytopenia) due to hypoplasia or aplasia of the BM. Incidence: in Europe 2-3/1.000.000/year. Age distribution between 10-25 years and over 60 years Classification: o Moderate AA or non severe AA (MAA or nSAA) o Severe AA (SAA) o Very severe AA (vSAA) Classification of aplastic Anemia (two out of three criteria must be fullfilled) nSAA Neutrophils <1.0 Platelets <50 Reticulocytes <2.0 SAA <0.5 <20 <2.0 vSAA <0.2 <20 <2.0 Classification based on the presumed etiology: Idiopathic: > 80% Drug-induced: <20% Post-infectious (after hepatitis): <5% Hereditary forms : <1% Clinical presentation o o o o Anemia Neutropenic infection: oral cavity and pharyngeal ulcers) necrotizing gingivitis or tonsilitis Pneumonia phlegmon Bleeding due to thrombocytopenia Diagnosis Parameter Discription Comments Differential blood count Bi- or tri-cytopenia • Anemia N,N/ moderately macrocytic • Leukocytopenia resulting from granulocytopenia and monocytopenia. • Absence giant platelet in blood smear Bone Marrow • • BMA and BMB are mandatory • Biopsy length at least 15mm • • Aplasia or hypoplasia, cellularity <25% No infiltration of neoplastic cells Without fibrosis N,N, normochrom-normocyter; BMA, bone marrow aspiration, BMB, bone marrow biopsy Differential diagnostics and diagnosis by exclusion Hypoplastic acute leukemia Myelodisplatic syndrome Hairy cell leukemia and other lymphoma BM infiltration by solid tumors Hypersplenism Aplasia after chemotherapy or radiation therapy Therapy Object of therapy: Induction of “remission” Prevention bleeding and neutropenic infections Prevention of chronic transfusion requirement (iron overload, allosensitization) Therapy AA Age < 40-50 years: HLA Identical sibling donor: BMT No HLA Identical sibling donor o ATG/CsA Age ≥50 years: o ATG/CsA or CSA ATG, anti thymocyte globulin CsA, Cyclosporin A BMT, bone marrow transplant Supportive Therapy • • • • • • Infection prophylaxis: Reverse isolation Air filtration Prophylactic antibiotics and antimycotics Bleeding prophylaxis: Avoid platelet aggregation inhibitor Tranexamic acid Platelet transfusion Transfusion Leukocyte-depleted blood products: mandatory in AA patients Erythrocyte concentrates: in case of signs hypoxic anemia. Platelet-transfused prophylactically: 1. Stable out-patients without risks (fever, infections): <5.000/μl with regular blood count at least once a week 2. Fever (>380C), infections, signs of bleeding, history severe hemorrhages (WHO grade 3 or 4) transfusion trigger <20.000/μl Iron chelation: Patients with regular transfusion become a persistent requirement when serum ferritin >1.000ng/ml
