Hematolymphoid Pathology Flashcards
What are red blood cells (RBCs)?
Main function is to carry oxygen around in the blood from the lungs to other organs/ tissues and to carry CO2 in the reverse direction. This is accomplished by binding ox oxygen/ CO2 to hemoglobin, which is by far the most common protein found in RBCs.
What is Anemia?
A reduction in the oxygen-transporting capacity of blood, resulting from a decrease in circulating red cell mass, below normal limits. Too few RBCs. *most common.
-Measure by looking at the hemoglobin concentration in the blood (reflects oxygen-transporting capacity.
How can anemia be classified?
Based on the underlying mechanism or based on the morphological appearance
What are the classifications of anemia, based on underlying mechanisms (pathophysiological classification)
- Anemia can stem from decreased red blood cell (RBC) production (bone marrow is at fault)
- Blood loss (problem lies outside the bone marrow, in the circulation - peripheral problem)
- Increased destruction (hemolytic anemias - peripheral problem)
- Disturbed erythroid proliferation (diminished erythropoiesis)
Describe anemia resulting from decreased red blood cell (RBC) production
-Defect in early stem cells (e.g. aplastic anemia, pure red cell aplasia)
-Defective cell division in maturing precursors (e.g. vitamins B12/folate deficiency; myelodysplasia)
-Defective hemoglobin synthesis in maturing precursors (e.g. iron deficiency; hereditary thalassemias)
-Bone marrow replacement (by tumour, etc.)
Describe anemia resulting from blood loss
-Acute (e.g. trauma or hemorrhage)
-Chronic (e.g. gastrointestinal tract lesions, gynecologic disturbances, reproductive female, slow-bleeding mucosal tumours)
Describe anemia resulting from increased destruction (hemolytic anemias)
- Intrinsic (intracorpuscular) abnormalities (RBCs are abnormal):
-hereditary (usually): 1. membrane abnormalities/defects (e.g. hereditary spherocytosis), 2. enzyme deficiencies/defect (e.g. glucose-6-phosphate dehydrogenase deficiency), 3. disorders of hemoglobin synthesis - structurally abnormal globin synthesis (hemoglobinopathies, e.g. sickle cell anemia, thalassemia syndromes)
-acquired: membrane defect: paroxysmal nocturnal hemoglobinuria (hereditary but develops later in life due to stimulus) - Extrinsic (extracorpuscular) abnormalities (extracellular defect affecting normal RBCs):
-antibody-mediated (immune mediated damage): 1.alloantibodies (e.g. transfusion reactions), 2.autoantibodies (e.g. idiopathic autoimmune diseases)
-mechanical trauma to red cells (nonimmune damage): 1. microangiopathic hemolytic anemias (e.g. disseminated intravascular coagulation (DIC), 2. defective cardiac valves, 3. infections (e.g. malaria)
Describe anemia resulting from disturbed erythroid proliferation (diminished erythropoiesis)
- Disturbed proliferation and differentiation of stem cells (aplastic anemia, pure red cell aplasia)
- Disturbed proliferation and maturation of erythroblasts: 1.defective DNA synthesis (deficiency or impaired use of B12 and folic acid, megaloblastic anemias), 2. anemia of renal failure (erythropoietin deficiency), 3. anemia of chronic, 4. anemia of endocrine disorders, 5. defective hemoglobin synthesis (deficient heme syntheis - iron deficiency, deficient globin synthesis (thalassemias)
- Marrow replacement (e.g. by primary hematopoietic neoplasms such as acute leukemia)
- Marrow infiltration (myophthisis anemia - e.g. metastatic neoplasms, granulomatous disease
How is anemia classified based on morphology
Using peripheral blood counts and smears (stained), the morphological classification of anemia is based on:
- size RBC is either normocytic, microcytic or macrocytic, measured by MCV (mean cell volume)
-degree of hemoglobinization - colour “redness”: RBC is either normochromic or hypochromic, measured on the hemogram by the MCHC (mean corpuscular/cell hemoglobin concentration)
-shape
What are the classifications of anemia based on morphology
- Normochromic, normocytic = normal, pink colour, normal size e.g. acute blood loss, many chronic diseases and malignancies
- Hypochromic, microcytic = too pale (low MCH), too small (low MCV) e.g. iron deficiency anemia, thalassemias (hereditary disorders with decreased production of Hb due to Hb gene deletions)
- Macrocytic = too big (high MCV), always normochromic, e.g. vitamin B12/folate deficiency, liver disease, myelodysplasia
- Abnormally shaped e.g. sickle cell anemia
What is the clinical presentation of anemia?
-decreased oxygen delivery to organs/tissues
-symptoms: generalized weakness, malaise (unwell feeling), headaches, easily tired, fainting spells, shiny tongue, fragile and concave fingernails
-signs: compensatory physiological cardiovascular and respiratory changes, trying to increase oxygen delivery to tissues (increased heart rate, increased cardiac stroke volume, decreased peripheral vascular resistance, increased respiratory rate, shortness of breath (SOB) on exertion)
-late signs of anemia: pale mucous membranes, heart murmur, heart failure (peripheral edema, worsening shortness of breath)
Describe further the anemia of blood loss (hemorrhage)
Can be due to:
1. Acute bleeding (hemorrhage):
-effects are mainly due to loss of intravascular volume, which if massive can lead to cardiovascular collapse, shock and death
-if blood loss is >20% of blood volume, immediate threat is hypovolemic shock rather than anemia
-if patients survives, hemodilution begins and maximizes in 2 to 3 days, when the full extend of RBC loss is seen
-normocytic and normochromic. recovery occurs via a compensatory rise in erythropoietin levels, stimulating increased bone marrow RBC production and reticulocytosis
2. Slow chronic blood loss:
-iron stores are gradually depleted when blood loss is occurring to outside the body e.g. mucosal bleeding. iron is essential for hemoglobin synthesis and erythropoiesis, and its deficiency leads to chronic anemia of underproduction i.e. iron deficiency anemia.
What are hemolytic anemias?
All causes have in common accelerated red cell destruction (hemolysis). Red cell life span is shortened to less than the normal 120 days. Regardless of cause, low tissue O2 levels trigger increased erythropoietin from the kidney, which in turn stimulates erythroid hyperplasia in the bone marrow and increased release of reticulocytes into the blood - hallmarks of all hemolytic anemias. In severe hemolytic anemias, the erythropoietic drive may be so pronounced that extra-medullary hematopoiesis appears in the liver, spleen and lymph nodes.
How are hemolytic anemias organized?
- One approach groups them according to pathogenesis - whether the RBC defect is intrinsic to the RBCs (intracorpuscular) or extrinsic to them (extracorpuscular)
- A second more clinical approach classifies hemolytic anemias according to whether the hemolysis is primarily occurring extravascular (most) or intravascular.
Describe extravascular hemolysis
Caused by defects that increase the destruction of either partly damaged or antibody-coated RBCs by phagocytosis in the spleen. Extreme alterations of shape are necessary for red cells to navigate the sluggish blood flow through splenic sinusoids and any reduction in red cell deformability makes this passage difficult; abnormal RBCs become recognized and phagocytosed by resident splenic macrophages. Findings that are relatively specific for extravascular hemolysis (compared to intravascular):
1. Hyperbilirubinemia and jaundice, from degradation of hemoglobin in macrophages
2. Enlarged spleen (spenomegaly) due to “work hyperplasia” of phagocytes in the spleen
3. Formation of bilirubin-rich gallstones (pigment stones) and increased risk of choleithiasis
Describe intravascular hemolysis
Characterized by such severe injuries that RBCs literally burst within the circulation. May be due to mechanical forces (e.g. turbulence over a defective heart valve), biochemical or physical agents that severely damage the red cell membrane (e.g. complement fixation, bacterial toxins, intracellular parasites like malaria, or heat). Findings that distinguish intravascular hemolysis from extravascular hemolysis include:
1. Hemoglobinemia, hemoglobinuria, and hemosiderinuria (hemoglbin released into the circulation is small enough to filter into the urinary space, is partly processed into hemosiderin, then lost in the urine)
2. Loss of iron may lead to iron deficiency if hemolysis is persisten
3. Decreased serum levels of haptoglobin, a plasma protein that binds free hemoglobin before it is removed from the circulation.
List causes of anemia
- Hereditary spherocytosis
- Sickle cell anemia
- Thalassemia
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Immune hemolytic anemias
Describe hereditary spherocytosis
Autosomal dominant, caused by mutations affecting RBC membrane skeleton, leading to loss of membrane and eventual conversion of red cells to spherocytes, which are phagocytosed and removed in the spleen. Clinically present as anemia with spenomegaly.
Describe sickle cell anemia
Autosomal recessive, abnormal hemoglobin resulting from a B-globin mutation that causes deoxygenated hemoglobin to self-associate into long polymers that distort the red cell, producing a sickle shape. Blockage of vessels by sickled cells causes pain crises and tissue infarction, particularly of the marrow and spleen. RBC damage caused by repeated bouts of sickling results in moderate to severe hemolytic anemia. Patients are at a high risk for bacterial infections and strokes.
Describe Thalassemia
Autosomal codominant disorders caused by mutations/deletions in a- or B-globin that reduce hemoglobin synthesis, resulting in microcytic, hypochromic anemia. A relative excess of the unpaired globin chains results in formation of aggregates that damage red cell precursors to further impair erythropoiesis, and also result in some degree of extravascular hemolysis.
Describe Glucose-6-phosphate dehydrogenase (G6PD) deficiency
X-linked disorder caused by mutations that destabilize G6PD, affecting the hexose monophosphate shunt (glutathione) metabolic pathway. G6PD deficiency makes red cells susceptible to oxidant damage.
What are anemias of diminished erythropoiesis?
-include anemia caused by inadequate dietary supply of nutrients, especially iron (needed for hemoglobin), folic acid, and vitamin B12 (needed for DNA synthesis in nucleated erythroid precursors)
-other anemias of this type are associated with bone marrow failure (aplastic anemia), systemic inflammation/tumor (anemia of chronic disease), or direct bone marrow infiltration by tumour or inflammatory cells (myelophthisic anemia).
List the common and important causes of anemias of diminished erythropoiesis
- Iron deficiency anemia
- Anemia of chronic inflammation (anemia of chronic disease)
- Megaloblastic anemia
- Aplastic anemia
- Myelophthisic anemia
Describe iron deficiency anemia
Caused by chronic bleeding or inadequate iron intake; reduced iron results in insufficient hemoglobin synthesis which results in hypochromic, microcytic anemia
Describe anemia of chronic inflammation (anemia of chronic disease)
Caused by inflammatory cytokines, which increase hepcidin levels (secreted from liver) and thereby sequester iron in macrophages; cytokines also suppress erythropoietin production.
