Abordaje de la anemia

Abordaje de las anemias

Anemia normo-normo

Anemia microcítca

Anemia macrocítica

Anemia hemolítica

Dra. Gabriela Granados Brenes Anemia Hemolítica Dra. Gabriela Granados Brenes

Anemia hemolítica Hemólisis Lisis (Destrucción de glóbulos rojos) Destrucción o eliminación de glóbulos rojos del torrente sanguínea, antes de que cumplan su vida media de 120 días.

Anemia hemolítica Hallazgos de laboratorio Reticulocitosis Anemia aguda o crónica Bilirrubina indirecta aumentada Deshidrogenasa láctica aumentada Haptoglobina disminuida Alteraciones en la morfología de los glóbulos rojos

Patofisiología Mecanismos Intravascular Destrucción de células rojas con liberación del contenido celular en el plasma. Trauma producido por el endotelio dañado . Fijación y activación del complemento Agentes infecciosos que causas destrucción y degradación de la membrana celular.

Patofisiología Extravascular Destrucción y eliminación de células con alteraciones de la membrana por macrófagos del bazo e hígado

Patofisiología Los glóbulos rojos normales de 8 micras, pueden deformarse y pasar por sinusoides de hasta 3 micras

Historia clínica y examen físico Disnea y fatiga Ictericia o palidez Taquicardia de reposo Soplo funcional Colelitiasis Ulceras maleolares Causas crónicas (Drepanocitosis) Orina oscura, dolor lumbar (intravascular) Linfadenopatías o visceromegalias Desorden linfoproliferativo o destrucción por el bazo

Exámenes de laboratorio Anemia macrocítica Reticulocitosis Bilirrubina indirecta aumentada Deshidrogenasa láctica aumentada Haptoglobina disminuida Alteraciones en la morfología de los glóbulos rojos Hemosiderinuria positiva

Anemia hemolítica inmune Mediada por anticuerpos dirigidos contra antígenos presentes en la superficie del glóbulo rojo. Autoinmune Aloinmune Medicamentosa

Anemia hemolítica autoinmune Por anticuerpos calientes IgG (37 °C) Por anticuerpos fríos Ig M (0-4°C) Activan el complemento Unión de C3 a la superficie del eritrocito

Esferocitos en anemia hemolítica autoinmune por IgG

Prueba del Coombs directo Demuestra la presencia de anticuerpos o complemento en la superficie del glóbulo rojo.

Anemia hemolítica autoinmune La mayoría de los casos son por causa idiopática. Enfermedades linfoproliferativas y el VIH pueden ser por IgG o anti C3 IgG ( calientes) enfermedades autoinmunes (LES) Anti C3. Asociado a infecciones Mycoplasma pneumoniae

Tratamiento AHAI IgG Esplenectomía para casos refractarios Corticoesteroides Gamaglobulina intravenosa Plasmaferesis Citotóxicos Danazol Esplenectomía para casos refractarios IgM evitar el frío

Tratamiento AHAI Transfusión de glóbulos rojos empacados Siempre en caso de isquemia miocárdica o cerebral.

Anemia hemolítica inducida por drogas

Anemia hemolítica aloinmune Hemólisis post transfusión Incompatibilidad ABO Puede ser inmediata o tardía (Hasta 10 días después) Tratamiento de soporte

Anemia hemolítica microangiopática MAHA o hemólisis por fragmentación Disrupción mecánica de la membrana en la circulación Esquistocitos en sangre periférica

Anemia hemolítica microangiopática Púrpura trombótica trombocitopénica Coagulación intravascular diseminada Síndrome Urémico Hemolítico Preeclampsia Válvulas protésicas

Infección Mycoplasma pneumoniae Malaria Babesia Bruselosis Septicemia Clostridium perfringens Aborto séptico

Desórdenes Hereditarios Membranopatías Enzimopatías Hemoglobinopatías

Enzimopatías Déficit de G-6PD Hemólisis ocurre 2-4 días después de la exposición a un precipitante No tratamiento específico

Membranopatías Esferocitosis Enfermedad autosómica dominante Mutación en las proteínas de membrana de los glóbulos rojos Anemia hemolítica crónica Tratamiento : esplenectomía en mayores de 6 años. Diagnóstico Fragilidad osmótica

Hemoglobinopatías Causadas por desórdenes en la síntesis de hemoglobina Talasemia Drepanocitosis

Talasemia Grupo heterogéneo de anemias hereditarias Defecto en la síntesis de la cadena alfa o beta de la hemoglobina Disminución global de la hemoglobina Precipitación intracelular de la cadena anómala Diagnóstico: Electroforesis de hemoglobina Aumento de hemoglobina A2 : B talasemia

Talasemias Mundialmente , 15 millones de personas tienen la enfermedad clínica1 La severidad clínica varía desde pacientes asintomáticos hasta incompatibilidad con la vida The thalassemias comprise a group of inherited disorders of hemoglobin (Hb) synthesis. The two main types are α- and β-thalassemia, caused by an imbalance in the production of α- and β-globin chains. Data suggest that, worldwide, 15 million people have clinically apparent thalassemic disorders.1 The highest prevalence occurs where malaria was, or still is, endemic. This is because less severe forms of the disease (eg β-thalassemia minor, α-thalassemia trait) provide protection against malaria, in particular the frequently fatal cerebral malaria, caused by Plasmodium falciparum infection. Hence, the possession of the allele has conferred a selective advantage to populations in these areas. Clinical severity of the thalassemias varies from asymptomatic to death at birth. Reference Yaish HM. 2005. http://www.emedicine.com/ped/topic2229.htm. 1Yaish HM 2005. http://www.emedicine.com/ped/topic2229.htm

Talasemias, anemia del mediterráneo

Patofisiología de la β-talasemia Excess free α-globin chains Formation of heme and hemichromes Denaturation Degradation Iron-mediated toxicity Hemolysis Ineffective erythropoiesis Membrane binding of IgG and C3 Splenomegaly Removal of damaged red cells Anemia The figure shows the primary disease processes (in orange) generated as a result of the excess free α-globin chains in β-thalassemia and the compensatory mechanisms (in blue).1 The excess unbound α-globin chains and their subsequent degradation in red-cell precursors cause defective cell maturation and ineffective erythropoiesis. This, together with subsequent hemolysis, causes the anemia that is associated with thalassemia. Synthesis of erythropoietin is stimulated by the anemia and leads to marrow expansion up to 30 times the normal level and the skeletal deformities and the growth and metabolic disorders characteristic of thalassemia. Bone marrow hyperplasia leads to increased iron absorption and deposition in tissues. Splenomegaly results from accumulation of abnormal red blood cells in the spleen and this further exacerbates the anemia. Reference Olivieri N. N Engl J Med 1999;341:99–109. Increased erythropoietin synthesis Reduced tissue oxygenation Erythroid marrow expansion Skeletal deformities, osteopenia Iron overload Increased iron absorption Olivieri N. N Engl J Med 1999;341:99–109

Complicaciones de la Talasemia Bone expansion (‘hair on end’) Infection via transfusion Hypopituitarism Venous thrombosis Hypothyroidism / Hypoparathyroidism Pulmonary hypertension and embolism Cardiomyopathy Excessive melanin skin pigmentation (‘bronze diabetes’) This slide shows complications and therapeutic approaches for β-thalassemia.1 The β-thalassemias are associated with ineffective erythropoiesis and anemia that may be severe. Bone marrow expansion as a result of these disease processes causes skeletal deformities and growth and metabolic abnormalities, osteopenia, and stimulates intestinal iron absorption. Splenomegaly results from accumulation of abnormal red cells in the spleen. This further exacerbates the primary anemia. There may be extramedullary hematopoiesis in the liver, spleen and other loci such as paravertebral masses. Transfusion therapy is the mainstay of treatment suppressing the ineffective erythropoiesis and enabling growth and development to proceed normally. Iron overload is an inevitable consequence of the transfusion therapy in addition to the increased intestinal iron uptake associated with the underlying disease. If untreated with chelation therapy, excess iron accumulates in the liver, heart and endocrine organs resulting in severe damage and mortality. In some patients, bone marrow transplantation can afford a cure for thalassemia. Other treatments that are under investigation include fetal Hb modifiers and erythropoietin and gene therapy. Reference Rund D & Rachmilewitz E. N Engl J Med 2005;353:1135–1146. Arthropathy Hemosiderosis and cirrhosis of liver Extramedullary hematopoiesis Splenomegaly Diabetes mellitus Osteoporosis Delayed puberty and delayed secondary sexual characteristics Testicular or ovarian failure Short stature Rund D & Rachmilewitz E. N Engl J Med 2005;353:1135–1146

Tratamiento de la talasemia Trasplante de células madre Médula ósea Cordon umbilical donador no relacionado Non-mieloablativo Terapia de soporte Transfusion Leucorreducción Test virales Terapia quelante de hierro Deferoxamine (DFO) Deferiprone Deferasirox Endocrinopatías Reemplazo hormonal Osteoporosis Osteoclast replacement Vitamin D Terapia experimental Eritropoyenina Fetal Hb modicadores hidroxiurea, butirato Antioxidantes This slide shows complications and therapeutic approaches for β-thalassemia.1 The β-thalassemias are associated with ineffective erythropoiesis and anemia that may be severe. Bone marrow expansion as a result of these disease processes causes skeletal deformities and growth and metabolic abnormalities, osteopenia, and stimulates intestinal iron absorption. Splenomegaly results from accumulation of abnormal red cells in the spleen. This further exacerbates the primary anemia. There may be extramedullary hematopoiesis in the liver, spleen and other loci such as paravertebral masses. Transfusion therapy is the mainstay of treatment suppressing the ineffective erythropoiesis and enabling growth and development to proceed normally. Iron overload is an inevitable consequence of the transfusion therapy in addition to the increased intestinal iron uptake associated with the underlying disease. If untreated with chelation therapy, excess iron accumulates in the liver, heart and endocrine organs resulting in severe damage and mortality. In some patients, bone marrow transplantation can afford a cure for thalassemia. Other treatments that are under investigation include fetal Hb modifiers and erythropoietin and gene therapy. Reference Rund D & Rachmilewitz E. N Engl J Med 2005;353:1135–1146. Terapia futura Terapia génica Rund D & Rachmilewitz E. N Engl J Med 2005;353:1135–1146

Drepanocitosis Mutación puntual en la cadena β de la hemoglobina Hemoglobina S Menos soluble y precipita. Trastorno autosómico recesivo Puede existir Portadores Hb AS Enfermos Hb SS Crisis de hemólisis, cirisis de dolor

Patrón de herencia

Anemia drepanocítica Sickle cell disease Desorden hereditario de la síntesis de ADN Más frecuente en la población de raza negra Mayor prevalencia en áreas endémicas de malaria Los eritrocitos drepanocíticos tienen una hemoglobina mutada: Cambio Glu→Val en la posición 6 de cadena β de la globina Hb S resulta en un cambio de forma de los ertrocitos usualmente deformables a rígidos1 La morfologia irregular de los eritrocitos conduce a : Episodios de oclusipon vascular y crisis de dolor Daño orgánico múltiple1 Sickle cell disease (SCD) comprises a group of inherited disorders affecting hemoglobin (Hb) synthesis and is characterized by chronic hemolytic anemia. A single point sickle mutation in the gene encoding the β-globin chain of Hb leads to an amino acid substitution of glutamic acid to valine. This results in the formation of sickle Hb: HbS (α2 βs2). Erythrocytes with HbS have irregular morphology. Under low oxygen conditions these polymerize and have a tendency to become distorted and lose their elasticity. The irregular shape and lack of elasticity makes them less able to pass through narrow capillaries. This leads to vascular occlusion and associated symptoms – severe pain and progressive organ damage.1 SCD is inherited in an autologous recessive manner: Homozygous individuals (two mutant β-globin chains) have full disease phenotype Heterozygous individuals (one mutant β-globin chain) are normally asymptomatic but may exhibit symptoms under some conditions (eg at low oxygen levels such as high altitudes, or when severely dehydrated). Most severe forms have a significant impact on morbidity and mortality. Reference Claster S & Vichinsky EP. Br Med J 2003;327:1151–1155. Claster S & Vichinsky EP. Br Med J 2003;327:1151–1155

Patofisiología de la drepanocitosis HbS (α2βS2) Baja presión de oxígeno +O2 -O2 Polimerización dela HBS desoxigenadad Anemia hemolítica Irreversibilidad de células Drepanocíticas HbS is much less soluble than normal Hb when deoxygenated. Polymerization of HbS leads to the formation of the irreversibly ‘sickled’ cells. The pathogenesis of SCD relates to the shortened life span of the sickled erythrocytes (16–20 days in contrast to a lifespan of 120 days for normal erythrocytes) and adhesion of the sickled erythrocytes to the microvascular endothelium. Factors that increase the intracellular concentration of Hb (eg red blood cell dehydration), the time spent in the microcirculation or deoxygenation, all contribute to greater HbS polymerization. Exercise, fever and dehydration may all have deleterious effects in SCD. Although polymerization of HbS is critical, the irreversibly sickled red cells alone are not sufficient for initiating or maintaining the vaso-occlusion that underlies all the complications of SCD. Vaso-occlusion is also dependent on factors extrinsic to the cell, such as the state of the vascular endothelium, vascular tone and activation of platelets and white blood cells involving cytokines and adhesion molecules (α4 β1 and CD36). The anemia seen in SCD is primarily hemolytic, a consequence of the shortened survival of the damaged sickled red cells. Vaso-oclusion Obstrucción microvascular Episodios dolorosos isquémicos agudos Daño orgánico crónico progresivo Secuestro de eritrocitos en capilares Courtesy of Professor SL Thein, King's College Hospital, King's College London, London

Manifestaciones clínicas y complicaciones de la drepanocitosis

Eventos cerebrovasculares en drepancocitosis Causas importante de morbilidad y mortalidad en niños con anemia drepanocítica. Evidencia clínica 11% de los pacientes a los 20 años Incidenccia : 1.02% por 100 pacientes años entre 2 y 5 años Usualmente isquémicos en niños y ; hemorrágicos en adultos >50% de los pacientes experimentan una recurrencia Factores de riesgo : Leucocitos altos, anemia, STA recurrente Stroke is a major complication in SCD, affecting 11% of patients with SCD by the age of 20 years.1 Almost 10% of deaths in patients with SCD are due to stroke.2 Strokes are predominantly ischemic in pediatric patients and hemorrhagic in adult patients with SCD.1 Patients who have experienced a stroke have a high risk of recurrence.1,3 A number of highlighted genes have been proposed to increase the risk of specific types of stroke.4 References Ohene-Frempong K et al. Blood 1998;91:288–294. Manci EA et al. Br J Haematol 2003;123:359–365. Pegelow CH et al. J Pediatr 1995;126:896–899. Hoppe C et al. Blood 2004;103:2391–2396. Hoppe C et al. Blood 2004;103:2391–2396; Ohene-Frempong K et al. Blood 1998;91:288–294; Pegelow CH et al. J Pediatr 1995;126:896–899

Manejo y tratamiento de la drepanocitosis Seguimiento Monitoreo de daño orgánico Hydroxiurea (HU)1 Pued dar bbeneficio clínico, pero no todos los pacientes reponden. EL objetivo es disminuir la Hb S a < 30% Analgesia para dolor crónico y agudo Uno de los principales objetivos Transfusiones Según la clínica del paciente Trasplante de médula ósea La única cura posible’ Transfusion therapy increases the Hb level and therefore the oxygen-carrying capacity of blood, and decreases the proportion of sickle cells in the circulation. It provides effective treatment for many of the complications of SCD. The aim is to reduce HbS levels to <30% of total Hb, while ensuring Hb levels do not exceed 11 g/dL (or packed cell volume of 0.35) as this may result in complications from increased viscosity.1 Bone marrow transplantation offers the only cure. However, the availability of suitable human leukocyte antigen-matched donors is a severe limitation. Non-myeloablative conditioning regimens, cord blood transplantation and transplantation from unrelated stem cell donors may make this treatment more widely available. Elevated HbF is known to protect against the clinical sequelae of SCD.2 HbF has a high affinity for oxygen, therefore does not polymerize as HbS (polymerization of deoxygenated HbS accounts for the pathologic changes in SCD).2 Hydroxyurea (HU) is a ribonuclease reductase inhibitor that selectively kills cells in the bone marrow, thereby increasing the number of HbF-producing nucleated red cells (erythroblasts). The introduction of HU represented a major advance in therapy for the disease. References NIH Publication No 02-2117. NIH, Bethesda, MD, USA, http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf. Coleman E & Inusa B. Clin Pediatr 2007;46:386–391. 1Coleman E & Inusa B. Clin Pediatr 2007;46:386–391; 2Zimmerman SA et al. Blood 2007;110:1043–1047

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