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Pathology 7 - RBC disorders
Review for Pathology Block 1 - RBC disorders. All information is from class notes, Pathoma, and Goljan's Rapid Review Pathology.
Terms in this set (79)
Myeloid Stem Cell
Can differentiate into RBCs, platelets, granulocytes and monocytes.
Lymphoid Stem Cell
Can differentiate in lymphocytes (B and T cells and NK cells).
Microcytic anemia - Differential Dx
Iron deficiency anemia, anemia of chronic disease, thalassemia.
Iron Deficiency Anemia - Causes
Dietary lack of Iron, impaired absorption, increased requirement (as in pregnancy), or chronic blood loss (menstruation, bleeding from GI tract).
FYI, if a person >50 y.o. has iron deficiency anemia, your first assumption should be gastrointestinal carcinoma, so get a colonoscopy!
Iron Deficiency Anemia - Physical Exam Findings
Pallor, Koilonychia (spooning nail beds), Mucosal atrophy (GI tract), intestinal malabsorption, Esophageal webs, Decreased immune response
Iron Deficiency Anemia - Hematology findings
Hypochromic RBCs (decreased MCH), microcytic RBCs (decrease MCV), Elliptocytes, Poikilocytes, Increased RDW. Normal or increased platelet count. No stainable hemosiderin in bone marrow.
Iron Deficiency Anemia - Chemistries
Decreased serum iron
Decreased serum ferritin
Decreased transferrin saturation
Iron Deficiency Anemia - Treatment
Iron replacement. Patients over 50 require a colonoscopy to exclude colon carcinoma.
Anemia of Chronic Disease - Pathophysiology
Cytokines produced in malignancy or chronic infection increase hepcidin and decreased iron absorption in the duodenum. Iron is taken up by bone marrow macrophages.
Anemia of Chronic Disease - Hematological Findings
Normocytic, occasionally microcytic RBCs (normal or decreased MCV), stainable iron in bone marrow - Prussian Blue stain.
Anemia of Chronic Disease - Chemistries
Decreased serum iron, normal to increased ferritin levels, decreased TIBC, increased transferrin saturation.
Increased free erythrocyte protoporphyrin (FEP), since there is no iron for protoporphyrin to bind to.
Anemia of Chronic Disease - Treatment
Control of the underlying disease. Iron therapy is not indicated.
Megaloblastic anemia - Two deficiencies
B12 or Folate
B12 Deficiency - Causes
increased requirement (pregnancy, growth),
defective absorption (decreased intrinsic factor, gastric atrophy, infection, etc.),
partial gastrectomy (removal of antrum with parietal cells),
defective transport (decreased transcobalamin),
disorders of metabolism.
Also, fish tapeworm Diphyllobothrium latum can cause a decreased absorption.
Folate deficiency - Causes
Inadequate intake (alcohol and drug addiction),
increased requirement (pregnancy, growth and development),
defective absorption (defective jejunal mucosa),
disorders of metabolism (inhibition of enzymes).
Pernicious Anemia - Cause
A specific form of megaloblastic anemia caused by autoimmune gastritis with a failure in intrinsic factor production leading to B12 deficiency.
Pernicious Anemia - Clinical Findings
Insidious in onset, but may be severe at presentation.
Deficiency takes years to develop, as the body has B12 stores.
Hair is classically white/gray and skin is lemon yellow.
Chronic atrophic gastritis present.
B12 and Folate deficiency - Reactions of B12 and Folate
1. Tetra Hydro Folate (THF) is methylated in the body.
2. MTHFR is required to transfer the methyl group from THF to B12. THF is then used for DNA synthesis.
3. The methyl group is transferred from B12 to homocysteine, creating methionine.
B12 deficiency - Pathogenesis
1.Reduced availability of THF causes reduced DNA synthesis.
2. Anemia develops due to intramedullary destruction of RBCs
3. Anemia stimulates EPO production, producing erythroid hyperplasia and further erythroblast destruction.
4. Increased homocysteine can be damaging to blood vessels as it promotes atherosclerosis.
5. Increased homocysteine levels cause increased methylmalonic acid, which leads to demyelination of neurons, particularly in dorsal and lateral cell columns.
B12 deficiency - Treatment
Treatment with Folate alone will improve anemia, but will not prevent neurological damage! Vitamin B12 injections are preferred treatment, oral is not used in the case of pernicious anemia due to lack of intrinsic factor.
B12 deficiency - Blood Smear findings
Macrocytic anemia (increased MCV), pancytopenia, Howell-Jolly Bodies, hypersegmented neutrophils (A very important sign in B12 deficiency!)
Aplastic anemia - Definition
Pancytopenia due to failure or suppression of myeloid stem cells.
Aplastic anemia - Hematologic findings
Normocytic and normochromic anemia
Low reticulocyte count
Bone marrow biopsy shows stem cells replaced by fat or fibrous tissue --> "Dry tap" during biopsy.
Aplastic anemia - Causes
Majority of cases are acquired, but can be inherited (Fanconi's anemia).
Idiopathic - unknown cause
Secondary - bone marrow injury due to drugs, radiation, hypersensitivity, viral infection (viral hepatitis or parvovirus B19).
Aplastic anemia - Treatment
Platelet and RBC transfusions, Broad Spectrum antibiotics, anti-lymphocyte globulin, Bone marrow transplant.
I want to abbreviate "broad spectrum" as BS, but that kinda looks weird. Just take some BS antibiotics.
Hereditary Spherocytosis - Clinical Presentation
Anemia, splenomegaly, intermittent jaundice. Symptoms can be variable. Increased risk of bilirubin gallstones.
With infections, there may be a hemolytic crisis (infectious mono) or aplastic crisis (parvovirus).
Hereditary Spherocytosis - Pathogenesis
Most commonly, there are mutations in ankyrin, band 3, spectrin, or band 4 - all proteins that stabilize RBC membranes. Unstable membranes cause lipids to release, decreasing surface area and eventually producing spherocytes, which are eaten up by splenic macrophages.
Hereditary Spherocytosis - Inheritance
Usually autosomal dominant, prevalent in northern Europe.
Hereditary Spherocytosis - Hematological Findings
Anemia with Increased MCHC (mean corpuscular hemoglobin concentration), hyperbilirubinemia.
Hereditary spherocytosis (and hereditary elliptocytosis, basically the same thing) are the only two anemias with an increased MCHC!
Hereditary Spherocytosis - Diagnosis
Spherocytes in peripheral smear, osmotic fragility test (Spherocytes lyse easily in hypotonic solutions).
Hereditary Spherocytosis - Clinical Management
RBC transfusions, splenectomy, post splenectomy management.
Glucose-6-Phosphate Dehydrogenase Deficiency - Pathogenesis
G6PD produces NADPH, which reduces glutathione. Reduced glutathione is an antioxidant.
Oxidants that build up denature Hb and precipitates to form Heinz bodies. The Heinz bodies can be removed from the RBCs by splenic macrophages, causing "bite cells".
Glucose-6-Phosphate Dehydrogenase Deficiency - Clinical Episodes
Self-limited hemolysis 2 to 3 days after exposure to an oxidant: food, drugs or infection.
Sulfonamides, nitrofurantoins, and anti-malarials are important drugs in this disorder. Fava beans also create oxidants, no word if chianti has any effect.
Glucose-6-Phosphate Dehydrogenase Deficiency - Diagnosis
Quantitative assay of G6PD. You have to wait until the clinical episode is over, though.
Sickle Cell Anemia - Pathogenesis
Point mutation in the Hb gene substituting a glutamic acid with a valine on the beta chain. Polymerization of HbS occurs upon deoxygenation forming tactoids - deform the RBC.
Sickle Cell Anemia - Consequences of Sickling
Chronic hemolytic anemia - Sickled cells are susceptible to destruction by splenic macrophages.
Ischemic tissue damage due to occlusion of small vessels - Sickled cells are rigid, get stuck.
Sickle Cell Anemia - Peripheral Blood Smear
Sickle-shape RBCs, normochromic and normocytic anemia, normoblasts, target cells, Howell-Jolly Bodies.
Sickle Cell Anemia - Consequences
Dactylitis, sequestration crisis, autosplenectomy, renal papillary necrosis, vaso-occlusive crises (pain crises), aplastic crises, bilirubin gallstones.
Pain crises caused by hypoxic injury and infarction to an affected area.
Sickle Cell Anemia - Treatment
1. Painful Crises - require analgesics and hydration.
2. Hypertransfusion - replacement of patient's RBCs with healthy RBCs.
3. Hydroxyurea - Increases the concentration of HbF, which inhibits HbS from polymerizing.
Alpha Thalassemia - Pathogenesis
Reduced synthesis of alpha globin chains occurs when 1, 2, or 3 alpha globin genes are deleted, or no synthesis if all four genes are deleted. Anemia occurs due to decreased Hb production from excess unpaired non-alpha chains.
Alpha Thalassemia - Silent Carrier
Deletion of a single alpha globin gene. Asymptomatic. Affects 30% of African Americans.
Alpha Thalassemia - alpha thalassemia trait
Deletion of two alpha globin genes.
Often clinically normal with minimal or no anemia.
Hemoglobin H disease
Three alpha hemoglobin genes are deleted, and synthesis of alpha chains is markedly decreased. Tetramers of excess B-globin are formed, called HbH. HbH has a high oxygen affinity and is not useful for oxygen exchange - severe anemia that is disproportionate to the level of Hb.
Splenic macrophages remove old RBCs with oxidized HbH, causing splenomegaly.
Occurs mainly in Asians.
Deletion of all four alpha-globin genes (--/--). In the fetus, excess y-globin forms tetramers - Hb Barts, which has a very high oxygen affinity and can't deliver O2 to the tissues. Without transfusion, this leads to fetal death.
The fetus shows severe pallor, generalized edema, and massive hepatosplenomegaly.
Beta Thalassemia - Pathogenesis
Occurs due to point mutations in the Beta-globin gene leading to reduced or completely absent Beta-globin chains. Free alpha chains precipitate in RBC precursors leading to destruction in bone marrow or in spleen - extravascular hemolysis.
Beta Thalassemia - Clinical Findings
Massive Erythropoiesis - invades the bony cortex, you can see it on a head X-ray.
Secondary hemochromatosis due to excessive iron absorption and repeated blood transfusions.
Beta Thalassemia - Laboratory findings
High total RBCs, low MCV, normal RDW. Reticulocyte count elevated.
Serum iron is normal or elevated, ferritin normal or elevated - depends on transfusion history.
Beta Thalassemia - Peripheral Smear
Target cells, microcytes, tear drop cells, nucleated red cells.
Paroxysmal Nocturnal Hemoglobinuria - Pathogenesis
Somatic mutations in PIG-A gene leading to red cells, platelets, and granulocytes deficient in GPI-linked factors, namely DAF (CD55) and Membrane inhibitor of reactive lysis (CD59). Causes an intravascular hemolysis due to complement activation (DAF usually protects against complement).
Remember CD55 and CD59.
Paroxysmal Nocturnal Hemoglobinuria - Clinical Findings
Iron is lost in the urine (hemosiderinuria), so there is a secondary iron deficiency. May produce a brown-colored urine seen usually 3-4 days after the onset of hemolytic conditions.
May cause thrombosis of hepatic (Budd-Chiari syndrome), portal, and cerebral veins.
Granulocytopenia and abnormal leukocytes can cause infection.
Intravascular hemolysis, but may not be nocturnal and may not cause hemoglobinuria.
Paroxysmal Nocturnal Hemoglobinuria - Diagnosis
Flow cytometry detects RBC populations with a lack of CD55 and 59.
Paroxysmal Nocturnal Hemoglobinuria - Treatment
Immunosuppression, bone marrow transplantation.
Extravascular hemolysis - Definition
RBCs destroyed by reticuloendothelial system: Macrophages in spleen, liver, and bone marrow.
Intravascular hemolysis - Definition
RBCs are destroyed within blood vessels due to mechanical injury, complement fixation, infection, or toxins.
Hemolysis - Clinical Presentation
Anemia and jaundice, elevated reticulocyte count.
Hemolysis - Laboratory Findings
Positive Direct Coombs test (if Ab-mediated)
Increased indirect (unconjugated) bilirubin with jaundice.
Immunohemolytic anemia - Warm antibody type - Pathogenesis
Most common immunohemolytic anemia. IgG Abs fix to RBCs at 37 degrees C, causing extravascular hemolysis.
Can be idiopathic, or secondary to autoimmune disorder (SLE), drugs, lymphoid neoplasms.
Immunohemolytic anemia - Cold agglutinin type - Pathogenesis
Less common immunohemolytic anemia. Often preceded by infection, may have underlying B cell lymphoma.
IgM Abs fix complement to RBCs in peripheral (cool) body parts. Re-warming of blood leads to removal of IgM, but residual C3b remains on RBC surface, leading to extravascular hemolysis.
Immunohemolytic anemia - Cold hemolysin type - Pathogenesis
Rare, usually found in children following viral infection.
IgG Abs form against P blood group antigen. Hemolysis may be severe, but is usually self-limiting.
Clinically termed paroxysmal cold hemoglobinuria.
Immunohemolytic anemia - Warm antibody type - Treatment
Remove initiating agent, use immunosuppressive drugs, splenectomy.
Immunohemolytic anemia - Cold agglutinin type - Treatment
Difficult to treat. Avoid chilling, may advise moving to warm climates.
Immunohemolytic anemia - Cold hemolysin type - Treatment
Supportive treatment, the disease is usually self-limited.
Microangiopathic Hemolytic Anemia - Types
Disseminated Intravascular Coagulation (DIC)
Thrombotic Thrombocytopenia Purpura (TTP)
Hemolytic Uremic Syndrome (HUS)
Idiopathic Thrombocytopenia Purpura - Pathogenesis
Anti-platelet autoantibodies cause platelets to be destroyed in the spleen.
Chronic form may be associated with autoimmune diseases or AIDS, after viral infections, drugs.
IgG Abs most often form against platelet membrane receptors Gp IIb/IIIa or Ib-IX.
Gp IIb/IIIa is the protein that allows platelets to bind together.
Chronic Idiopathic Thrombocytopenia Purpura - Clinical Findings
Symptoms are due to thrombocytopenia: Epistaxis, mucous membrane bleeding, petechiae, ecchymoses.
Chronic Idiopathic Thrombocytopenia Purpura - Laboratory Findings
Megathrombocytes in peripheral blood
Megakaryocytic hyperplasia in bone marrow
Normal RBC and WBC morphology
Chronic Idiopathic Thrombocytopenia Purpura - Treatment
Splenectomy if relapse on steroid treatment
Acute Idiopathic Thrombocytopenia Purpura - Clinical Findings
Affects children usually.
Abrupt onset approximately 2 weeks after a viral infection.
Diagnosis of exclusion (process of elimination)
Acute Idiopathic Thrombocytopenia Purpura - Laboratory Findings
Thrombocytopenia, Normal RBC and WBC morphology, antiplatelet antibodies.
Acute Idiopathic Thrombocytopenia Purpura - Treatment
Usually a self-limited disease, resolving spontaneously.
Steroid therapy is indicated if thrombocytopenia is severe.
May progress to chronic ITP.
Thrombotic Thrombocytopenia Purpura - Pathogenesis
Widespread formation of hyaline thrombi composed of platelet aggregates. Consumption of platelets gives rise to thrombocytopenia.
Deficiency in ADAM-TS 13 - normally used to degrade high molecular weight vW multimers. The very large multimers cause platelet activation and aggregation.
Thrombotic Thrombocytopenia Purpura - Laboratory Findings
Thrombocytopenia with schistocytes in peripheral blood.
Normal PT and aPTT - coagulation system is not usually affected.
Low ADAM-TS 13.
Thrombotic Thrombocytopenia Purpura - Clinical Findings
Mnemonic: FAT RN -
Thrombotic Thrombocytopenia Purpura - Treatment
Urgent plasma exchange by plasmapheresis - FFP provides ADAM-TS 13 enzyme activity.
Hemolytic Uremic Syndrome - Pathogenesis
E. coli strain 0157:H7 causes gastroenteritis in children and the elderly, producing a Shiga-like toxin absorbed from GI mucosa, damaging endothelium. Damage is especially prominent in the kidney glomeruli. Endothelial damage leads to platelet activation.
TL;DR - E. coli 0157:H7 causes endothelium which causes platelet buildup which damages glomeruli.
Hemolytic Uremic Syndrome - Clinical Presentation
Bloody diarrhea is followed a few days later with microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.
Hemolytic Uremic Syndrome - Laboratory Findings
Schistocytes in peripheral blood.
Normal ADAM-TS 13 enzyme levels.
PT and aPTT normal.
Hemolytic Uremic Syndrome - Treatment
With children, treatment is usually supportive, results usually in complete recovery.
With adults, prognosis is guarded, as HUS usually develops in chronic life-threatening conditions.
Atypical Hemolytic Uremic Syndrome
Defect in complement factor H, 1 membrane cofactor protein (CD46) or factor I, leading to excessive activation of complement pathway.
Pathophysiology not well understood.
May be inherited or acquired, as in TTP.
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