Hematology Lecture Notes PDF

Hematology Lec5&6 Dr Sura Al Shamma Pathology department  Sickle cell disease Sickle cell disease is a group of haemoglobin disorders resulting from the inheritance of the sickle β‐globin gene. The sickle β‐globin abnormality is caused by substitution of valine for glutamic acid...

Hematology Lec5&6 Dr Sura Al Shamma Pathology department  Sickle cell disease Sickle cell disease is a group of haemoglobin disorders resulting from the inheritance of the sickle β‐globin gene. The sickle β‐globin abnormality is caused by substitution of valine for glutamic acid in position 6 in the β chain. The homozygous state (HbSS or sickle cell anaemia) is the most common form of sickle cell disease. but interaction of HbS with thalassaemia and certain variant haemoglobins also leads to sickling. The term sickle cell disease (SCD) is used to denote all entities associated with sickling of haemoglobin within red cells. Pathophysiology. Deoxygenation of HbS leads to a conformational change that triggers the formation of large polymers. The red cell shows a characteristic shape change because of polymer formation and becomes distorted and rigid ,the so called sickle cell. Sickling‐induced membrane fragmentation and complement‐ mediated lysis cause intravascular destruction of red cells. Membrane damage also leads to extravascular haemolysis through entrapment of poorly deformable cells or uptake by macrophages. ( SCD is characterized by chronic intravascular and extravascular hemolysis  In addition intracellular polymers leads to red cell membrane changes ,generation of oxidant substances ,and abnormal adherence of red cells to vascular endothelium, leading to vascular occlusion enhanced by increased blood viscosity owing to the presence of deformed blood Factors affecting Hb polymerization The polymerization of HbS in the circulating red cells is influenced by the oxygenation status the intracellular haemoglobin S concentration and the presence of non‐sickle haemoglobins (HbF) Sickle Cell Disease, Animation – YouTube  Deoxygenation of SS erythrocytes leads to intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology. OXY-STATE DEOXY-STATE Red Blood Cells from Sickle Cell Anemia Clinical feature The physiological changes result in a disease with the following cardinal signs: (1) Hemolytic anemia (2) Crisis, Vaso occlusive, aplastic or haemolytic (3) multiple organ damage with microinfarcts, including heart, skeleton, spleen, and central nervous system. Clinical features are of a severe haemolytic anaemia exaugurated by crises. The symptoms of anaemia are often mild in relation to the severity of the anaemia because Hb S gives up oxygen (O2 ) to tissues relatively easily compared with Hb A. The clinical expression of Hb SS is very variable, some patients having an almost normal life, free of crises, but others develop severe crises even as infants and may die in early childhood or as young adults. Clinical feature Effects of chronic hemolysis -Anemia. Patients with more severe anaemia at baseline have a greater probability of developing stroke and renal dysfunction. On the other hand, a higher haemoglobin level is associated with higher incidence of painful episodes, avascular necrosis and acute chest syndrome. Jaundice, due to rapid heme turnover and subsequent generation of bilirubin Cholelithiasis.(gall bladder stones) due to red cell destruction and excess bilirubin secretion into the hepatobiliary tree. Crises 1. Vaso occlusive Painful crises  The most frequent crises.  They may be sporadic and unpredictable or precipitated by infection, acidosis, dehydration or deoxygenation  severe pain occur in the bones (hips, shoulders and vertebrae are commonly affected). The ‘hand– foot’ syndrome (painful dactylitis caused by infarcts of the small bones) is frequently the first presentation of the disease and may lead to digits of varying lengths Visceral crises  acute sickle chest syndrome- most common cause of death  Hepatic and girdle sequestration  Splenic sequestration is typically seen in infants and presents with an enlarging spleen, falling haemoglobin and abdominal pain.  Priapism and liver and kidney damage due to repeated small infarcts are other complications 2. Aplastic crisis usually due to parvovirus B19 infection. With a normal erythrocyte life span of 120 days, no anemia results from an unnoticed marrow shut‐down of a few days. However, the sickle cell patients, with their markedly shortened RBC life span, can have a precipitous fall in hematocrit and retic count. This may be life‐threatening. 3. Hemolytic crisis. Most sickle cell patients establish a stable, tonic level of hemolysis. Rarely, for obscure reasons, they experience a catastrophic fall in hematocrit, increasing intensity of jaundice, and increasing reticulocyte count. This is called a "hemolytic crisis." Other organ damage The most serious is of the brain (a stroke occurs in 7% of all patients) or spinal cord. Up to a third of children have had a silent cerebral infarct by the age of 6 years Leg ulcers. Deep , nonhealing ulcers of skin and tela subcutanea (classically around the medial malleolus) may be the only clinical manifestation of sickle cell disease in an otherwise well-compensated patient. Autosplenectomy.. In childhood, the spleen is enlarged due to excess activity in destruction of the sickled erythrocytes. Gradually, the spleen infarcts itself down to a fibrous nubbin Pulmonary hypertension Infections Early loss of splenic function from recurrent vaso‐occlusion and the inability to make specific immunoglobulin G (IgG) antibodies to polysaccharide antigens increases the risk of fulminant sepsis Pneumonia, urinary tract infections and Gram‐negative septicaemia are common. Osteomyelitis may also occur, usually from Salmonella s Pregnancy haemoglobin level falls in SCD Painful episodes become more common in the last trimester incidence of pre‐eclampsia is higher Risk to the fetus is also increased.  Growth and development Children with SCD are born with normal weight but fall behind other children by the end of the first year Lab findings 1. The haemoglobin is usually 6–9 g/dL – low in comparison to mild or no symptoms of anaemia. 2. Sickle cells and target cells occur in the blood. Features of splenic atrophy (e.g. Howell–Jolly bodies) may also be present. 3. Screening tests for sickling are positive when the blood is deoxygenated (e.g. with dithionate and Na2 HPO4 ). 4. HPLC or haemoglobin electrophoresis : in Hb SS, no Hb A is detected. The amount of Hb F is variable and is usually 5–15%, larger amounts are usually associated with a milder disorder. Therapy Routine health care (avoid precipitation factors ,folic acid prophylaxis,good hydration and nutrition) Transfusion therapy Hydroxyurea (to increase HbF) Pain management Bone marrow transplantation New therapeutic modalities Gene therapy Sickle cell trait This is a benign condition with no anaemia and normal appearance of red cells in a blood film. Haematuria is the most common symptom and is thought to be caused by minor infarcts of the renal papillae. Hb S varies from 25–45% of the total haemoglobin Care must be taken with anaesthesia, pregnancy and at high altitudes  Haemolytic anaemias Hemolytic anemia Hereditary hemolytic anemia Acquired hemolytic anemia Defective Metabolic (enzyme) Membrane defect Hemoglobin defect Immune Non immune HS, PNH Synthesis G6PD HbS, Thal, Classification of acquired Hemolytic anemia Immune haemolytic anaemias Acquired haemolytic anaemias Immune haemolytic anaemias Antibody mediated hemolysis is an important cause of acquired hemolytic anemia. Antibodies may be:  autoantibodies produced by the patient’s own immune system & directed against his own red cell antigens, or they may be alloantibodies produced by the patient & directed against antigens not present on his own red cells but introduced either by transfusion or secondarily acquired as in drug induced hemolysis. The immune hemolytic anemias are characterized by a positive direct Coomb’s test  Direct Coombs test(direct antiglobulin test‐ DAT) Negative –hereditary hemolytic anemia Positive –Acquired hemolytic anemia Acquired haemolytic anaemias Immune haemolytic anaemias 1. Autoimmune haemolytic anaemias Autoimmune haemolytic anaemias (AIHAs) are caused by antibody production by the body against its own red cells. They are characterized by a positive direct antiglobulin test (DAT), also known as the Coombs’ test , and divided into ‘warm’ and ‘cold’ types according to whether the antibody reacts more strongly with red cells at 37°C or 4°C. a) Warm autoimmune hemolytic anemia The autoantibodies are : polyclonal IgG in type They react best at 37 C. Red cells coated with IgG are taken up by macrophages especially in the spleen. Part of the coated membrane is lost so the cell becomes progressively more spherical to maintain its volume & is ultimately prematurely destroyed predominantly in the spleen. Clinical features: Present at any age in both sexes. Hemolytic anemia of variable severity. The spleen is often enlarged. It is classified as:  Idiopathic  Secondary to: autoimmune disorders, lymphoma, CLL, drugs  Laboratory findings: Features of hemolytic anemia: Anemia ,Blood film shows Spherocytes polychromasia & nucleated red cells Reticulocytosis Increase bilirubin and LDH. Direct Coomb’s test is positive. b) Cold autoimmune hemolytic anemia:  The cold autoantibody attaches to red cells mainly in the peripheral circulation where blood temperature is cooled.  The antibody is usually IgM & binds to red cells best at 4 C It is either monoclonal, as in primary cold haemagglutinin syndrome or associated with lymphoproliferative (CLL,Lmphoma )disorders, or may be a transient polyclonal response following infections such as infectious mononucleosis or Mycoplasma pneumonia.  The antibody cause agglutination of the RBC (clumping) then detaches from red cells when they pass to the warmer central circulation & if the complement sequence is completed on the red cell surface; intravascular hemolysis will result  Etiology: types of cold autoimmune hemolytic anemia are: ‐Idiopathic (cold hemagglutinin disease): monoclonal antibody. ‐Secondary to lymphoproliferative disease: monoclonal antibody. ‐Secondary to infection (Mycoplasma pneumoniae or infectious mononucleosis): polyclonal antibody. Clinical feature The patient has a chronic haemolytic anaemia aggravated by the cold and often associated with intravascular haemolysis. Mild jaundice and splenomegaly may be present. The patient may develop acrocyanosis (purplish skin discoloration) at the tip of the nose, ears, fingers and toes caused by the agglutination of red cells in small vessels.  Laboratory findings are similar to those of warm AIHA except that spherocytosis is less marked, red cells agglutinate in the cold the DAT(Direct coombs test) is positive , reveals complement (C3d) only on the red cell surface. 2. Alloimmune haemolytic anaemias In these anaemias, antibody produced by one individual reacts with red cells of another. Two important situations are transfusion of ABO‐incompatible blood and Rh disease of the newborn Drug‐induced immune haemolytic anaemias Non –Immune hemolytic anemia Red cell fragmentation syndromes (non immune hemolysis) These arise through physical damage to red cells either on abnormal surfaces (e.g. artificial heart valves or arterial grafts), arteriovenous malformations or as a microangiopathic haemolytic anaemia. This is caused by red cells passing through abnormal small vessels. The latter may be caused by deposition of fibrin strands, often associated with disseminated intravascular hemolysis (DIC) The peripheral blood contains many deeply staining red cell fragments Aplastic anemia Aplastic anemia is defined as pancytopenia (anemia+ leucopenia+ thrombocytopenia) resulting from aplasia of the bone marrow Etiology: Primary: Congenital e.g. Fanconi’s anemia Idiopathic Secondary: to one of the following  Ionizing radiation  Chemicals: benzene & other organic solvents, insecticides, hair dyes  Drugs: Which regularly cause marrow depression e.g. busulphan, cyclophosphamide. Which rarely cause marrow depression e.g. chloramphenicol, sulphonamides.  Infection: viral hepatitis (non‐A non‐B) Pathogenesis: the underlying defect in all cases appears to be substantial reduction in the number of stem cells & a fault in the remaining stem cells or an immune reaction against them. This makes them unable to divide & differentiate sufficiently to populate the bone marrow. Clinical features: The onset is at any age with a peak incidence around 30 years & a slight male predominance. It can be insidious or acute with symptoms & signs resulting from anemia, neutropenia or thrombocytopenia. Infections, particularly of the mouth & throat, are common. Generalized infections are frequently life threatening. Bruising, bleeding gums, epistaxis & menorrhagia are the most frequent hemorrhagic manifestations & the usual presenting features. Symptoms of anemia. The lymph nodes, liver& spleen are not enlarged Laboratory findings 1. Anemia is normochromic normocytic or macrocytic. 2. The reticulocyte count is reduced (