Hematological Disorders Outline PDF

1 Hematological Disorders 2 Anemia Basic principles Reduction in circulating red blood cell (RBC) mass Presents with signs and symptoms of hypoxia Hemoglobin (Hb), hematocrit (Hct) and RBC count are used as surrogates for RBC mass Classification of a...

1 Hematological Disorders 2 Anemia Basic principles Reduction in circulating red blood cell (RBC) mass Presents with signs and symptoms of hypoxia Hemoglobin (Hb), hematocrit (Hct) and RBC count are used as surrogates for RBC mass Classification of anemia based on mean corpuscular volume (MCV) Microcytic (MCV < 80 µm3) Macrocytic (MCV > 100 µm3) Normocytic (MCV = 80 - 100 µm3) 3 Anemia (cont’d) Basic principles Reticulocytes: Immature RBCs released from the bone marrow Used to identify bone marrow response to anemia Identified on blood smear as large cells with bluish cytoplasm (Residual DNA) Polychromasia: even younger RBCs Normal reticulocyte count (RC) is 1-2% RBC lifespan ~120 days; each day ~1-2% of RBCs are removed from circulation and replaced by reticulocytes Functional bone marrow responds to anemia by increasing the RC to ≧ 3% RC is falsely elevated in anemia RC is measured as % of total RBCs; decrease in total RBCs falsely elevates % of RC RC is corrected by multiplying RC by Hct/45 Corrected count ≧ 3% indicates good response -> peripheral destruction  Corrected count ≧ 3% indicates good response -> peripheral destruction Corrected count < 3% indicates poor response -> underproduction 4 5 Microcytic Anemia Basic principles Anemia with MCV < 80 µm3 Microcytic anemia are due to decreased production of Hb RBC progenitor cells in the bone marrow are large and normally divide multiple times to produce smaller mature cells Microcytic anemia is due to an “extra” division which occurs to maintain Hb concentration Hb = heme + globin; heme = iron and protoporphyrin. Decrease in component leads to microcytic anemia 6 Microcytic Anemia (cont’d) Types Iron deficiency anemia Anemia of chronic disease Thalassemia Sideroblastic anemia 7 Iron Deficiency Anemia Anemia due to decreased levels of iron ↓iron -> ↓heme -> ↓hemoglobin -> microcytic anemia Most common type of anemia Lack of iron is the most common nutritional deficiency in the world (~⅓ of world’s population) Iron is consumed in heme (meat derived) and non-heme (vegetable derived) forms Absorption occurs in the duodenum. Enterocytes have heme and non-heme (DMT1) transporters; the heme form is more readily absorbed Enterocytes transports iron across the cell membrane into blood via ferroportin Transferrin transports iron in the blood and delivers to liver and bone marrow  Absorption occurs in the duodenum. Enterocytes have heme and non-heme (DMT1) transporters; the heme form is more readily absorbed Enterocytes transports iron across the cell membrane into blood via ferroportin Transferrin transports iron in the blood and delivers to liver and bone marrow macrophages for storage Stored intracellular iron is bound to ferritin, which prevents iron from forming free radicals 8 Iron Deficiency Anemia (cont’d) Laboratory measurements of iron status Serum iron - measure of iron in the blood Total iron-binding capacity (TIBC) - measure of transferrin molecules in the blood % saturation - percentage of transferrin molecules that are bound by iron (normal is 33%) Serum ferritin - reflects iron stores in macrophages and liver 9 Iron Deficiency Anemia (cont’d) Causes: Typically dietary or blood loss Infants - prematurity, breastfeeding (human milk is low in iron), cow milk Children - poor diet Adults (20 - 50 yo) - peptic ulcer disease in men and menorrhagia or pregnancy in women Elderly - Colon polyps/carcinoma in the western world; hookworm (ancylostoma duodenale and necator americanus) in the developing world Other causes: malnutrition, malabsorption, gastrectomy (acid aids iron absorption) 10 Iron Deficiency Anemia (cont’d) Stages of iron deficiency Storage iron is depleted - ↓ferritin; ↑TIBC Serum iron is depleted - ↓serum iron; ↓% saturation Normocytic anemia in early stages - bone marrow makes fewer but normal sized, RBCs Microcytic hypochromic anemia in late stages - bone marrow makes smaller and fewer RBCs 11 Iron Deficiency Anemia (cont’d)  Microcytic hypochromic anemia in late stages - bone marrow makes smaller and fewer RBCs 11 Iron Deficiency Anemia (cont’d) Laboratory findings Microcytic, hypochromic RBCs with ↑ red cell distribution width (RDW) ↓serum iron; ↓ferritin; ↑TIBC; ↓% saturation 12 13 Anemia of Chronic Disease Anemia associated with chronic inflammation Endocarditis, autoimmune conditions, cancer etc Most common type of anemia in hospitalized patients Chronic disease results in production of acute phase reactants from the liver including hepcidin Hepcidin sequesters iron in storage sites by: Limiting iron transfer from macrophages to erythroid precursors Suppresses erythropoietin (EPO) production Aim is to prevent bacteria from accessing iron ↓available iron -> ↓heme -> ↓hemoglobin -> microcytic anemia 14 Anemia of Chronic Disease (cont’d) Laboratory findings ↓serum iron; ↑ferritin; ↓TIBC; ↓% saturation 15 Sideroblastic Anemia Anemia due to defective protoporphyrin synthesis ↓protoporphyrin -> ↓heme -> ↓hemoglobin -> microcytic anemia Protoporphyrin is synthesized via a series of reactions Succinyl CoA uses vitamin B6 as cofactor with aminolevulinic acid synthetase (ALAS) to create aminolevulinic acid (ALA) Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen Additional reactions convert porphobilinogen to protoporphyrin  Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen Additional reactions convert porphobilinogen to protoporphyrin Ferrochelatase attaches protoporphyrin to iron to make heme (occurs in mitochondria) Iron is transferred to erythroid precursors and enters the mitochondria to form heme. If protoporphyrin is deficient, iron stays in mitochondria 16 17 Sideroblastic Anemia (cont’d) Sideroblastic anemia can be congenital or acquired Congenital defect most commonly involves ALAS Acquired causes include: Alcoholism - mitochondrial poison Vitamin B6 deficiency - required cofactor for ALAS Lead poisoning - inhibits ALAD and ferrochelatase Laboratory findings: ↑serum iron, ↑ferritin, ↓TIBC, ↑% saturation 18 19 20 21 Thalassemia Anemia due to decreased synthesis of the globin chain of Hb ↓globin -> ↓hemoglobin -> microcytic anemia Inherited mutation; carriers are protected against plasmodium falciparum malaria Divided into ɑ- and β-thalassemia based on decreased production of alpha or beta hemoglobin chains Normal types of Hb are: HbA (ɑ2β2) >95% HbA2 (ɑ2δ2) 1-3% HbF (ɑ2γ2) ~1% 22 Thalassemia (cont’d)  HbF (ɑ2γ2) ~1% 22 Thalassemia (cont’d) ɑ-Thalassemia is usually due to gene deletion; normally chromosome 16 has 4 alpha genes One gene deleted - asymptomatic Two genes deleted - mild anemia with ↑RBC counts; cis deletion is associated with increased risk of severe thalassemia in offspring Cis deletion is when both deletions occurs on the same chromosome; seen in Asians Trans deletion is when one deletion occurs on each chromosome; seen in Africans and African Americans Three genes deleted - severe anemia; β chains form tetramers (HbH) that damages RBCs Four genes deleted - lethal in utero; γ chains form tetramers (Hb Barts) that damages RBCs 23 Thalassemia (cont’d) β-Thalassemia is usually due to gene deletion; two beta genes are present on chromosome 11 Mutations result in absent or diminished production of the β globin chain Seen in individuals of African and Mediterranean descent β-thalassemia minor is the mildest form of disease and is usually asymptomatic with an increased RBC count Microcytic, hypochromic RBCs Hemoglobin electrophoresis shows slightly decreased HbA (ɑ2β2) with increased HbA2 (ɑ2δ2) and HbF (ɑ2γ2) 24 Thalassemia (cont’d) β-thalassemia major is the most severe form of disease and presents with severe anemia a few months after birth; high HbF (ɑ2γ2) at birth is temporarily protective Unpaired ɑ chains precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis (spleen) Massive erythroid hyperplasia resulting in: Expansion of hematopoiesis into the skull and facial bones  Expansion of hematopoiesis into the skull and facial bones Extramedullary hematopoiesis with hepatosplenomegaly Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors Chronic transfusions are often necessary; leads to risk for secondary hemochromatosis Smear shows microcytic, hypochromic RBCs Hemoglobin electrophoresis HbA2 (ɑ2δ2) and HbF (ɑ2γ2) with little or no HbA (ɑ2β2) 25 Microcytic Anemia 26 Macrocytic Anemia Basic principles Anemia with MCV>100µm3 Most commonly due to folate or vitamin B12 deficiency (megaloblastic anemia) Folate and vitamin B12 are necessary for DNA precursor synthesis Lack of folate or vitamin B12 impairs synthesis of DNA precursors Impaired division and enlargement of RBC precursors leads to megaloblastic anemia Impaired division of granulocytic precursors leads to hypersegmented neutrophils Megaloblastic change is also seen in rapidly dividing epithelial cells 27 Macrocytic Anemia (cont’d) Folate deficiency Folate circulates in the serum as methyltetrahydrofolate (methyl THF); removal of the methyl group allows for participation in DNA precursors synthesis Methyl group is transferred to vitamin B12 (cobalamin) Vitamin B12 then transfers it to homocysteine, producing methionine Deficiency of vitamin B12 traps methyl THF in its circulating form, falsely increases the serum folic acid in 30% of cases Deficiency of folic acid and/or vitamin B12 increases plasma homocysteine Folic acid deficiency is the most common cause of increased serum homocysteine  Deficiency of folic acid and/or vitamin B12 increases plasma homocysteine Folic acid deficiency is the most common cause of increased serum homocysteine level in USA 28 Macrocytic Anemia (cont’d) Folate deficiency Dietary folate is obtained from green vegetables and some fruits Absorbed in jejunum (Polyglutamate vs monoglutamate) Folate deficiency develops within months, body stores are minimal Causes: Drugs (Intestinal conjugate) Poor absorption (OCD, alcohol, intestinal pathology) Folate antagonists (MTX, TMP, 5-FU) Clinical and lab findings: Macrocytic RBCs Glossitis ↓serum folate, ↑serum homocysteine, normal methylmalonic acid 29 Macrocytic Anemia (cont’d) Vitamin B12 deficiency Vitamin B12 is involved in odd-chain fatty acid metabolism, which explains the neurologic problems that’s unique to vitamin B12 deficiency Propionyl CoA is converted to methylmalonyl CoA and then to Succinyl CoA by methylmalonyl CoA mutase using vitamin B12 as cofactor When vitamin B12 is deficient, there’s an increase in propionyl CoA and methylmalonyl CoA and propionyl CoA causes demyelination in the spinal cord, brain and peripheral nerves 30 Macrocytic Anemia (cont’d) Vitamin B12 deficiency Dietary vitamin B12 is complexed to animal-derived proteins Salivary gland enzyme (ie amylase) release vitamin B12, which is then bound by R-binder (also from salivary gland) and carried through the stomach Pancreatic proteases in the duodenum detach vitamin B12 from R-binder  Dietary vitamin B12 is complexed to animal-derived proteins Salivary gland enzyme (ie amylase) release vitamin B12, which is then bound by R-binder (also from salivary gland) and carried through the stomach Pancreatic proteases in the duodenum detach vitamin B12 from R-binder Vitamin B12 deficiency is less common than folate deficiency and takes years to develop due to large hepatic stores of vitamin B12 Pernicious anemia is the most common cause of vitamin B12 deficiency Autoimmune destruction of parietal cells (body of stomach) leads to intrinsic factor deficiency Other causes: pancreatic insufficiency, damage to terminal ileum, dietary deficiency is rare (vegans) 31 Macrocytic Anemia (cont’d) Vitamin B12 deficiency Clinical and laboratory findings: Macrocytic RBCs with hypersegmented neutrophils Glossitis Subacute combined degeneration of spinal cord Poor proprioception and vibratory sensation and spastic paresis REVERSIBLE dementia ↓serum vitamin B12, ↑serum homocysteine, ↑methylmalonic acid 32 Macrocytic Anemia (cont’d) Vitamin B12 deficiency Schilling test Has been used in the past to demonstrate impaired absorption of vitamin B12 This is achieved indirectly by combining orally administered radioactive vitamin B12 with IF, or with pancreatic extract Followed by a 24-hour urine collection to measure radioactive vitamin B12 Lack of absorption of radioactive vitamin B12 excludes a potential cause of impaired absorption, whereas the presence of absorption confirms the cause of the impaired absorption 33 Normocytic Anemia  impaired absorption, whereas the presence of absorption confirms the cause of the impaired absorption 33 Normocytic Anemia Basic principles Anemia with normal-sized RBCs (MCV = 80 - 100µm3) Due to increased peripheral destruction or underproduction Reticulocyte count helps to distinguish between these two etiologies 34 Normocytic Anemia (cont’d) Anemia due to underproduction Basic principles Decreased production of RBCs by bone marrow; characterized by low corrected reticulocyte count Etiologies include: Early iron deficiency anemia or anemia of chronic disease Drugs (MCC) Infections (2nd MCC) Radiation or malignancy Renal failure - decreased production of EPO by peritubular interstitial cells Damage to bone marrow precursor cells (may result in anemia or pancytopenia) 35 Normocytic Anemia (cont’d) Anemia due to underproduction Infects progenitor red cells and temporarily halts erythropoiesis leads to significant anemia in the setting of preexisting marrow stress (e.g., sickle cell anemia) Treatment is supportive (infection is self-limited). 36 Normocytic Anemia (cont’d) Anemia due to underproduction Aplastic anemia Damage to hematopoietic stem cells, resulting in pancytopenia (anemia, thrombocytopenia, and leukopenia) with low reticulocyte count  Aplastic anemia Damage to hematopoietic stem cells, resulting in pancytopenia (anemia, thrombocytopenia, and leukopenia) with low reticulocyte count Etiologies include drugs or chemicals, viral infections, and autoimmune damage Treatment includes cessation of any causative drugs and supportive care with transfusions and marrow-stimulating factors (e.g., erythropoietin, GM-CSF, and G- CSF) Immunosuppression may be helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines May require bone marrow transplantation as a last resort Myelophthisic process Pathologic process (e.g., metastatic cancer) that replaces bone marrow; hematopoiesis is impaired, resulting in pancytopenia. 37 Normocytic Anemia (cont’d) Peripheral RBC destruction (hemolysis) Divided into extravascular and intravascular hemolysis Extravascular hemolysis involve reticuloendothelial system (macrophages of the spleen, liver and lymph nodes) Macrophages consume RBCs and breakdown Hb Globin broken down to amino acids Heme broken down to iron and protoporphyrin; iron is recycled Protoporphyrin is broken down into unconjugated bilirubin Clinical and laboratory finding include: Anemia with splenomegaly, jaundice Marrow hyperplasia with corrected reticulocyte >3% 38 Normocytic Anemia (cont’d) Peripheral RBC destruction (hemolysis) Divided into extravascular and intravascular hemolysis Intravascular hemolysis involve destruction of RBCs within vessels  Divided into extravascular and intravascular hemolysis Intravascular hemolysis involve destruction of RBCs within vessels Clinical and laboratory findings include: Hemoglobinemia Hemoglobinuria Hemosiderinuria ↓Haptoglobin 39 Normocytic Anemia (cont’d) Extravascular hemolysis Hereditary spherocytosis: inherited defect of RBC cytoskeleton-membrane tethering proteins Membrane blebs are formed and lost over time Loss of membrane renders cells round (spherocytes) instead of disc-shaped Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages Clinical and laboratory findings: Spherocytes with loss of central pallor ↑RDW and ↑mean corpuscular hemoglobin concentration (MCHC) Splenomegaly, jaundice with unconjugated bilirubin, and increased risk for bilirubin gallstones 40 41 Normocytic Anemia (cont’d) Extravascular hemolysis Sickle cell anemia: autosomal recessive mutation in Β chain of Hb Gene carried by 10% of individuals of African descent, likely due to protective role against falciparum malaria Sickle cell disease arise when 2 abnormal Β genes are present; results in >90% HbS in RBCs HbS polymerizes when deoxygenated; polymers aggregate into needle-like  against falciparum malaria Sickle cell disease arise when 2 abnormal Β genes are present; results in >90% HbS in RBCs HbS polymerizes when deoxygenated; polymers aggregate into needle-like structures (sickle) Increased risk of sickling occurs with hypoxemia, dehydration and acidosis HbF protest against sickling, high HbF at birth is protective for the first few months of life Cells continuously sickle and de-sickle while passing through the microcirculation -> complications Extravascular hemolysis Intravascular hemolysis 42 Normocytic Anemia (cont’d) Sickle cell anemia Extensive sickling leads to complication of vaco-occlusion Dactylitis - swollen hands and feet due to vaso-occlusive infarcts in bones Autosplenectomy - shrunken, fibrotic spleen Increased risk of infection with encapsulated organisms such as s. pneumoniae and H. influenzae (MCC of death in children) Increased risk of Salmonella paratyphi osteomyelitis Acute chest syndrome - vaso-occlusion in pulmonary microcirculation Presents with chest pain, SOB, lung infiltrate Often precipitated by pneumonia (MCC of death for adult) Pain crisis Renal papillary necrosis 43 Normocytic Anemia (cont’d) Sickle cell anemia Sickle cell traits is the presence of one mutated and one normal Β chain; results in