Pathology chapter 13 notes
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- What is anemia
- Reduction in blood oxygen transport capacity, usally due to reduced circulating red blood cell mass. Reflected by low hematocrit and hemoglobin concentration
- In most anemia, what does increased erythropoietin production induce
- Erythroid marrow hyperplasia
- What does anemia from acute blood loss reflect
- Loss of blood volume (may lead to shock and death). After 4-5 days increased erythropeoietin leads to compensatory increases in marrow production (reticulocytosis)
- What does anemia from chronic blood loss reflect
- Results when iron reserves are depleted-iron deficiency anemia. With iron replenishment, increased marrow production (reticulocytosis) appears in several days
- What are hemolytic anemias characterized by
- Premature red blood cell destruction, accumulation of hemoglobin catabolites (bilirubin), and markedly increased erythropoieses with asociated reticulocytosis
- What is intravascular hemolysis
- Red blood cells are damaged by mechanical injury (microangiopathic hemolytic anemia) or complement (mismatched blood transfusion). Patients exhibit hemoglobinemia; hemoglobinuria; hemosiderinuria; jaundice; reduced serum haptoglobin
- What is extravascular hemolysis
- Occurs in mononuclear phagocytes of spleen. Predisposing factors include red blood cell membrane injury, reduced deformability, or opsonization. Manifestations are similar to intravascular hemolysis but without hemoglobinemia and hemoglobinuria
- What is hereditary spherocytosis
- Autosomal dominant disorder in which red blood cell cytoskeletal membrane protein defects render reythrocytes spheroidal, less deformable, and vulnerable to splenic sequestration and destruction
- What is the pathophysiology of spherocytosis
- Defects in several different membrane skeletal proteins can cause HS; leads to deficiencies in spectrin.
- What are the characteristics of spectrin-deficient red blood cells
- They have unstable membranes and lose fragments. They have diminished membrane flezibility and are trapped and destroyed in the splenic cords
- What is the morphology of Hereditary spherocytosis
- Spherocytic red blood cells appear small and lack central pallor. Marked congestion and prominent erythrophagocytosis in the splenic cords of Billroth. Bone marrow exhibits normoblastic hyperplasia
- What are the clinical features of hereditary spherocytosis
- Anemia, moderate splenomegaly, and jaundice are characteristic. Infections can trigger hemolytic crisis (massice hemolysis) or aplastic crisis (suppression of erythropoiesis by parvovirus). Gallstones develop from chronic byperbilirubinemia. Mean cell hemoglobin concentration is increased
- What is glucose-6-phosphate dehydrogenase (G6PD)
- An enzyme in the hexose monophosphate shunt that produces reduced glutathione, which protects the red blood cells from oxidative injury
- In G6PD deficient red blood cells, what does the altered hemoglobin precipitate as
- Heinz bodies, which attach to the inner cell membrane, reduce deformability, and increase susceptibility to splenic macrophage destruction. Cause both intravascular and extravascular hemolysis
- Which G6PD deficiencies lead to clinically significant hemolysis
- G6PD A- (10% American blacks) and G6PD Mediterranean
- What is sickle cell disease
- A hereditary hemoglobinopathy resulting from substitution of valine for glutamic acid, transforming Hemoglobin A to mutant S. 8% of American blacks are heterozygous
- What is the sickling phenomenon
- Deoxygenated HbS undergoes aggregation and polymerization into long, stiff chains that deform red blood cells
- What factors influence sickling of red blood cells in Sickle Cell disease
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The amount of HbS and its interaction with other hemoglobin chains in the cells. Beta-globin chains like HbF (weak interaction with HbS) and HbC (strong interaction with HbS) also influence sickling
The mean corpuscular hemoglobin concentration (MCHC). Dehydration increases MCHC, facilitating sickling
Capillary bed transit times. Usually significant deoxygenation cannot occur - What are the consequences of sickling in sickle cell disease
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Chronic hemolysis--membranes become irreversibly damaged
Microvascular occlusion--hypoxia and infarction result - What is the morphology in sickle cell disease
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Spleen is enlarged in early childhood. Progressive scarring and shrinkage of spleen (autosplenectomy)
Bone marrow shows normoblastic hyperplasia
Microvascular occlusions - What are the clinical features of sickle cell disease
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Chronic hemolytic anemia (with chronic hyperbilirubinemia and gallstones)
Vaso-occlusive crises that present as painful episodes of ischemic necrosis
Apastic crisis due to transient suppression of erythropoiese triggered by parvovirus infection. Folate deficiency due to increased requirements
Progressive splenic fibrosis and impairment of the alternate complement pathway - What are Thalassemia syndrome
- A heterogenous group of mendelian disorders characterized by defects that lead to reduced synthesis of alpha or Beta globin chains. Beta by one gene on 11, alpha by two on 16
- How are beta thalassemias classified
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Beta0 total absence of beta globin chains
Beta+ reduced Beta globin sysnthesis - What do the consequences of diminished synthesis of one globin chain in Thalassemia derive from
- Low intracellular hemoglobin (hypochromia) and a relative excess of the other chain
- What is the pathophysiology of Beta Thalassemia
- Decreased Beta globin synthesis leads to excess unbound alpha chains which form aggregates that damage the cell membrane. Precursors are destroyed in the marrow or red blood cells are removed in the spleen. Marked compensatory expansion of the erythropoietic marrow. Excessive absorption of dietary iron
- What is the pathophysiology of alpha thalassemia
- Imbalanced synthesis ofalpha and non alpha chains. Free Beta chains for unstable tetramers that damage red blood cells and their precursors
- How is Beta Thalassemia classified
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Major: Homozygotes have severe, transfusion dependent anemia. Marked anisocytosis. Affects Mediterranean, Africa, Southeast Asia
Minor: Heterozygotes are asyptomatic
Intermedia: Features and severity and between the other two forms - How is alpha Thalessemia classified
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Related to the number of genes deleted
Silent carrier: Single deletion, asymptomatic
Alpha-Thalassemia trait: Two gene deletions. Comparable to Beta Thalassemia minor
Hemoglobin H disease: Deletion of three alpha genes. Resembles Beta Thalassemia intermedia
Hydrops fetalis: Deletion of all four genes. Not compatible with life - What is paroxysmal nocturnal hemoglobinuria
- Rare disorder characterized by chronic intravascular hemolysis. Acquired (not inherited) membrane defect. Increased sensitivity to complement-mediated lysis of RBCs. Deficiency of GPI. RBCs are hypersensitive to complement, Granulocytes, and platelet GPI proteins are predisposed to thrombosis
- What is hemolysis in immunohemolytic anemias due to
- Anti-red cell antibodies. Direct Coombs test is used
- What is warm antibody hemolytic anemia
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Idiopathic 60%. IgG anti-red blood cell coats the RBCs. Do not fix complement, but act as opsonins. Splenomegaly is characteristic.
Two models: Hapten (Antibody with drug) and Autoantibody (Drugs produce antibodies) - What is cold agglutinin immune hemolytic anemia
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Anemia is caused by IgM antibodies that agglutinate red blood cells at low temperatures
Acute hemolysis occurs after infection from Mycoplasm pneumonia and Epstein Barr virus
Chronic hemolysis occurs with lymphoproliferative disorders or is idiopathic. RBC agglutiion and complement fixation below 30C - What is cold hemolysin hemolytic anemia
- Occurs in paroxysmal cold hemoglobinuria and manifests as acute intermittent massive intravascular hemolysis after exposure to cold. IgG autoantibodies (Donath-Lansteiner) against P blood group antigen. Complement fixation and low temperatures, hemolysis upon rewarming. Mainly after infections from Mycoplasma pneumonia, measles, mumps, influenza
- What results from significant trauma to red blood cells
- Fragmentation and intravascular hemolysis. Can be from Prosthetic heart valves with turbulen flow and shear forces, or diffuse narrowing of the microvasculature owing to fibrin deposistion (DIC)
- What my impaired red blood cell production be due to
- Various disorders, including deficiency of a vital nutrient (Iron, vitamin B12, folate) or stem cell failure
- What are megaloblastic anemias commonly due to
- Deficiency of vitamin B12 or folate
- What is the morphology of megaloblastic anemia
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Abnormally large erythroid precursors (megaloblasts) in which nuclear maturation lags behind cytoplasmic maturation
Ineffective erythropoiesis with compensatory megaloblastic hyperplasia
Prominent anisocytosis
Abnormal granulopoiesis with giant metamyelocytes - What is the pathophysiology of Megaloblastic anemia
- Deficiency of vitamin B12 or folate resulting in deranged or inadequate DNA synthesis, but normal RNA and protein synthesis. Cytoplasmic maturation is ahead of nuclear maturation. B12 and folate deficiency affects all rapidly dividing cells
- What is the mechanism of B12 absorption
- B12 ultimately comes from dietary animal products. Peptidic digestion releases B12, where it is bound by R binders. B12 is released in the duodenum and binds to Intrinsic Factor (IF). IF-B12 binds to receptors in the ileum. B12 complexes with transcobalamin II and is transported to tissue
- What are several causes of impaired absorption of B12
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Achlorhydria (elderly people): impairs vitamin B12 release from the R protein bound form
Gastrectomy
Pernicious anemia
Resection of the distal ileum
Increased requirements - What is pernicious anemia likely due to
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Autoimmune response to gastric parietal cells resulting in chronic atropic gastritis and deficient IF production.
Type I antibodies block binding of B12 to IF
Type II prevent IF-B12 from binding to the ileal receptor - What is the morphology of pernicious anemia
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Bone marrow: megaloblastic erythroid hyperplasia
Alimentary canal: atrophic glossitis (shiny tongue); absence of parietal cells
CNS: Lesions found in 75%, demyelination of doral and lateral cord tracts - What are the clinical features of pernicious anemia
- Insidious, symptoms apear at 40-60 due to anemia and posterolateral spinal tract involvement
- What are the characteristics of Anemia of Folate deficiency
- Folate deficiency induces a megaloblastic anemia clinicall and hematologically indistinguishable from that seen with B12 deficiency, except that gastric atrophy and neurologic changes do not occur. Deficiency can result from inadequate intake, malabsorption syndrome, increased demand, and administration of folate antagonists
- What are some general characteristics of iron metabolism
- Duodenum is the primary site of absorption. Heme iron is directly absorbed, non-heme iron must be reduce to ferrous iron by cytochrome B and transported in by DMT1. Basolateral transport involves ferriportin, plasma transport involves transferrin. Excess iron is bound to ferritin and excreted in the feces
- What is the etiology of iron defeficient anemia
- Negative iron balance and consequent anemia can result from low dietary intake, malabsorption, excessive demand, and chronic blood loss
- What is the most important cause of iron deficiency anemia in the Western world
- Chronic blood loss
- What are the clincal features of iron deficient anemia
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Peripheral blood: Red blood cells are pale, small and cariable in shape
Marrow: Mild hyperplasia of normoblasts, but loss of sideroblasts and stainable iron in marrow macrophages
Other organs: Plummer-Vinson triad of hypochromic microcytic aemia, atrophic glossitis, esophageal webs - Describe anemia of chronic disease
- Anemia is common in the setting of diverse chronic inflmmatory mediactors (TNF-alpha and IL-1), which increases the release of hepcidin from the liver Hepcidin blocks ferroportin activity on macrophages, so iron is sequestered away from erythroid progenators. Serum iron is low, but ferritin levels are high. Inflammatory mediators also reduce erythropoietin production. Anemia is normocytic/normochromic or microcytic/hypochromic
- How is aplastic anemia characterized
- Failure or suppression of multipotent myeloid stem cells. Neutrophenia, anemai, and thrombocytopenia result
- What is the etiology of Aplastic anemia
- Idiopathic 65%; Myelotoxic drugs or chemicals; dose related (benzene, alkylating agents, vincristine or busulfan); idiosyncratic (chloramphenicol, chlorpromazine, streptomycin); Hepatitis (non A, B, C, G)
- What is the pathogenesis of aplastic anemia
- Stem cell alterations may be due to environmental insults, drug exposure, or infections. Idiopathic may be due to primary defect in the number or function of stem cells, or suppression of altered stem cells by T cell mediated mechanisms
- What is the morphology of Aplastic anemia
- Hypocellular marrow (replacement by fat cells), with secondary effects due to granulocytopenia (infections) and thrombocytopenia
- What are the clinical features of aplastic anemia
- Insidious with symptoms related to loss of red blood cells, neutrophils, and platelets. Splenomegaly is absent. Bone marrow transplantation or immunosuppression is required
- What is pure red blood cell aplasia
- A form of marrow failure due to absence of red blood cell precursors. May appear acutely and transiently in chronic hemolytic states due to parvovirus infection (aplastic crisis)
- What is myelophthisic anemia
- Space-occupying lesions that destroy or distort the marrow architecture depress productive capacity; associated with pancytopenia and white and red blood cell precursors in peripheral blood. Metastatic cancer is the most common cause
- What is anemia of diffuse liver disease primarily due to
- Bone marrow failure, exacerbated by variceal bleeding or folated deficiency
- What is polycythemia
- Relative or absolute increase in the concentration of red blood cells in the peripheral blood. Relative may be due to decreased plasma volumes. Absolute may be due to primary (myeloid neoplasm polycythemia vera) or secondary (increased erythropoietin for physiologic or pathophysiologic sources)
- What are some cuases of hemorrhagic diatheses
- Increased blood vessel fragility, platelet disorders, coagulation defects, or some combo.
- What are some characteristics of increased vascular fragility in bleeding disorders
- Relatively common but usually do not cause serious bleeding. Petechial and purpuric hemorrhages. Caused by infections, drug reactions, poor vascular support (Ehlers-Danlos or scurvy), and Henoch Schonlein purpura (systemic hypersensitibity reaction of unknown cause)
- What is thrombocytopenia
- Decrease in platelet number characterized principally by petechial bleeding, most often from small vessels of skin and mucous membranes. Must be severe before bleeding become clinically evident
- What are the main causes of Thrombocytopenia
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Decreased production: ineffective megakaryopoiesis or generalized marrow disease
Decreased survival: immune-mediated platelet destruction with marrow hyperplasia. Drug induced (quinine, heparin) or consumption (DIC hemolytic uremic syndrome)
Sequestration: Retained in red pulp of spleen
Dilution: Massive whole blood transfusions
HIV - What is immune thrombocytopenia purpura
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Two forms of antibody mediated platelet destruction
Acute: Self limited after viral infection of rubella, cytomegalovirus, hepatitis, monomucleosis
Chronic: Platelet autoantibodies against IIb/IIIA or Ib/IX. Splenectomy benefits 75-80% - What are the clinical features of immune thrombocytopenia purpura
- Women of childbearing age; long history of bruising or nosebleeds, but can be sudden onset. Subarachnoid or intracerebral hemorrhage is rare but serious
- What is the morphology of immune thrombocytopenia purpura
- Spleen is normal size but shows sinusoidal congestion and prominent germinal centers. Bone marrow megakaryocyte numbers are increased
- What are the characteristics of drug-induced thrombocytopenia
- Many drugs can act as hapten or participatin in the formation of immune complexes that deposit on platelet membranes. Drug induced antibodies cause removal of platelets via the reticuloendothelial system and result in bleedin gsymptoms. Withdrawal of the offending drug leads to clinical improvement
- What are the characteristics of Thrombotic Thrombocytopenic purpura and hemolytic uremic syndrome
- Related disorders within the spectrum of thrombotic microangiopathies characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, transient neurological deficits (TTP), or renal failure (HUS). Usually due to widespread hyaline microthrombi in arterioles and capillaries composed of platelets and fibrin
- What is the pathophysiology of Thrombotic thrombocytopenic purpura
- Deficiencies in ADAMTS13, a serum metalloprotease that limits the size of von Willebrand factor. In its absence, high molecular weight vWF promotes platelet aggregation throughout the microcirculation
- What is the pathophysiology of Hemolytic Uremic Syndrome
- Follows gastrointestinal infections with verotoxin-producing E. coli. Injures endothelial cells and promotes dysregulated platelet activation and aggregation
- What is the epidemiology of Thrombotic thrombocyopenic purpura and hemolytic uremic syndrome
- TTP affects women; HUS affects children and the elderly during food poisoning outbreaks
- How are hemorrhagic disorders related to defective platelet function characterized
- Prolonged bleeding time in association with normal platelet count
- What are common congenital disorders of hemorrhagic disorders related to defective platelet functions
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Defective platelet adhesion: Bernard-Soulier syndrome caused by deficient GbIb/IX, the receptor for vWF
Defective platelet aggregation: Thrombasthenia caused by deficient GpIIb/GpIIIa, which is involved in binding fibrinogen
Disorders of platelet secretion: Initial aggregation with collage or ADP is normal, but subsequent platelet responses are impaired (secretion of prostaglandins and granule-bound ADP) - What acquired disorders are clinically significant in hemorrhagic disorders related to defective platelet functions
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Aspirin ingestion: Suppresses the synthesis of thromboxane A2, necessary for platelet aggregation
Uremia: Defects in platelet function - How does bleeding in patients with clotting factor abnormalities differ from that encountered in patients with platelet deficiencies
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Spontaneous appearance of petechiae or purpura is uncommon; instead, there will be large ecchymoses or hematomas after injury or prolonged bleeding after laceration or surgery
Bleeding into gastrointestinal and urinary tracts and weight-bearing joints is common - What are acquired deficiencies of clotting abnormalities associated with
- Multiple clotting abnormalities. Vitamin K deficiency causes depresses synthesis of factors II, VII, IX, and X and protein C. Parenchymal liver disease causes hemorrhagic disease
- What do hereditary deficiencies of clotting abnormalities typically affect
- A single clotting factor. The most common factors are Hemophilia and von Willebrand disease
- What is one component required for factor X activation in the intrinsic coagulation pathway
- Factor VIII procoagulant protein. Deficiency causes classic hemophilia A
- What are the categories of von Willebrand disease
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Type 1 and 3: reduced levels of vWF. 1 is dominant and most common, quite mild. 3 is severe but uncommon recessive
Type 2: dominant caused by reduced amount of the intermediate and large vWF multimers - Why are levels of factor VIII often reduced in von Willebrand disease
- vWF stabilizes factor VIII in circulation. Reflected by prolonged bleeding time despite normal platelet numbers and prolonged partial thromboplastin time
- How does von Willebrand disease most often present
- Spontaneous bleeding from mucous membrane, excessive bleeding from wounds, and menorrhagia. Except for type 3, factor VIII levels are only modestly depressed. Symptoms of hemophilia, such as bleeding into the joints, are uncommon
- What is factor VIII deficiency
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Hemophilia A. X-linked recessive, reduced amount of active factor VIII. Clinical features only seen in severe deficiency. Post traumatic bleeding may be excessive. Associated with:
Massive hemorrhage after trauma
Spontaneous hemorrhages in joints
Absence of petechiae
Prolonged partial thromboplastin time and normal bleeding time. Treat with replacement therapy - What is Factor IX deficiency
- Hemophilia B or Christmas disease, X-linked recessive. Clinically indistinguishable from Hemophilia A
- What is Disseminated intravascular coagulation
- Acute, subacute, or chronic thrombohemorrhagic disorder occuring as a secondary complication in a variety of diseases. Characterized by activatino of the coagulation sequence, leading to microthrombi throughout the microcirculation. Consumption of platelets, fibrin, and coagulation factors, leading to activation of fibrinolytic mechanisms
- How may Disseminated intravascular coagualtion present
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Signs and symptoms relating to infarction caused by microthrombi
Hemorrhagic diathesis result from activation of fibrinolytic mechanisms and depletion of elements required for hemostasis - What is the pathogenesis of Disseminated intravascular coagulation
- Triggered by release of tissue factor or thromboplastic substances into the circulation, and widespread endothelial circulation
- What sources can tissue factor or thromboplastic substances released into the circulation be derived from in DIC
- Placenta, granules of leukemic cells, mucus release from adenocarcinomas, bacterial endotoxins activating release of IL-1 and TNF-alpha
- How does endothelial injury initiate DIC
- It causes tissue factor release from endothelial cells, promoting platelet aggregation, and by activating the intrinsic coagulatino pathway by exposing subendothelial connective tissue
- What is the morphology of DIC
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Microthrombi, with infarctions and hemorrhages, found in:
Kidneys, Lungs, Brain, Adrenals, and Placenta - What are the clinical features of DIC
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50% in obstetric patients, 30% with carcinomatosis. Sepsis and trauma for the rest. Onset can be fulminant or insidious.
Microangiopathic hemolytic anemia resulting from widespread microvascular occlusion
Respiratory symptoms
Neurologic signs and symptoms, including convulsions and coma
Oliguria and acute renal failure
Circulatory failure and shock