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Anemias • Anemias of blood loss • Acute blood loss • Chronic blood loss • Hemolytic anemias • Hereditary spherocytosis (HS) • Hemolytic disease due to red cell enzyme defects: Glucose-6phosphate dehydrogenase deficiency • Sickle cell disease • Thalassemia syndromes • Paroxysmal nocturnal hemoglobinuria • Immunohemolytic anemia • Hemolytic anemia resulting from trauma to red cells – cardiac valve prostheses, microangiopathic disorders • Anemias of diminished erythropoiesis • Anemia = reduction of total circulating red cell mass below normal limits, reduces the O2 carrying capacity of the blood tissue hypoxia • Dx based on a reduction in Hct/Hgb, correlate with RBC mass, except when changes in plasma vol. caused by fluid retention or dehydration • Clinical – pale, weakness, malaise, fatigue, dyspnea • Microcytic hypochromatic: hemoglobin synthesis (iron deficiency) • Macrocytic: impaired maturation • Normocytic normochromatic: need smear Anemia of Blood Loss • Acute blood loss –effects due to loss of intravascular vol. shock • Significant bleeding – predictable changes in the blood involving WBCs & platelets as well as RBCs • Chronic blood loss – anemia only if rate of loss exceeds regenerative capacity of the marrow or iron stores are depleted • 5 days for CFU-E to release as reticulocytes • Leukocytosis w/ significant loss of blood • reticulocytes at 10-15% by 7 days • early recovery accompanied by thrombocytosis Hemolytic Anemias • Premature destruction of RBCs & shortened RBC life span below normal 120 days • Elevated EPO levels and compensatory in erythropoiesis • Accumulation of hemoglobin degradation products released by RBC breakdown derived from hemoglobin • Extravascular hemolysis is more common, generally from alterations that render RBC less deformable • Premature destruction also occurs in phagocytes • Hyperplasia of phagocytes leading to splenomegaly • Generally caused by alterations in RBCs that make them less deformable • Principal clinical features – anemia, splenomegaly, jaundice, often benefit from splenectomy, haptoglobin • Intravascular hemolysis • Caused by mechanical injury (valves), complement fixation, intracellular parasites, or exogenous toxic factors • Clinical – anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, jaundice, • no splenomegaly • Morphology regardless of type • increased erythroid precursors (normoblasts) in marrow • prominent reticulocytosis in the peripheral blood Hereditary Spherocytosis • Intrinsic defects in the RBC membrane skeleton that render cells spheroid, less deformable, vulnerable to splenic sequestration & destruction • avg RBC life span = 10-20 days (norm= 120) • Diverse mutations insufficiency of membrane skeletal components • Spectrin: chief protein component • Also: ankyrin, band 3, band 4.2 • Compound heterozygosity (2 defective) is worse • Deficiency of membrane skeleton stability of lipid bilayer, leading to loss of membrane fragments as red cells age in circulation • Spleen: premature demise of spherocytes, trapped in splenic cords & phagocytized, erthyrostasis • leading to decreased glucose and pH • Increased MCHC • dehydration because of loss of K+ and H2O • Anemia, Splenomegaly, jaundice, gall stones, aplastic crises, hemolytic crises • splenectomy is beneficial • Morphologic: sphere shaped, hyperchromic, lack central zone of pallor, cholelithiais, • clinical- splenomegaly, anemia, jaundice • Dx: abnormally sensitive to osmotic lysis, increased MCHC • Aplastic crisis: triggered by acute parvovirus infection • Rx- splenectomy (^ risk of sepsis) Glucose-6-phosphate Dehydrogenase Deficiency • Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves from oxidative injuries and leads to hemolysis • G6PD reduces NADP to NADPH which allows reduction of oxidized glutathione --> catalyzes breakdown of H2O2 • G6PD deficiency is a recessive X-linked trait (males high risk) • G6PD- (blacks) and G6PD Mediterranean most of clinically significant anemias • Protect against plasmodium falciparum malaria • Episodic hemolysis: exposures that generate oxidant stress • infections, drugs (sulfonamides, primaquine), foods (e.g. fava beans in mediterranean, antimalarials) • Both intravascular and extravascular hemolysis • Heinz bodies: membrane bound precipitates • removed by macrophages in spleen • bite cells in peripheral smear • Can cause intravascular hemolysis by damaging membrane • Acute intravascular hemolysis marked by Anemia, hemoglobinemia, hemoglobinuria; 2-3 days following exposure to oxidant • Self-limited usually -- Older cells more at risk Sickle Cell disease • Common hereditary hemoglobinopathy that occurs primarily in individuals of African descent, 8-10% of African Americans have HbS trait (heterozygotes) • Point mutation in the 6th codon of Beta-globin that leads to replacement of glutamate with valine leading to the HbS molecule undergoing polymerization when deoxygenated, sickle shape • Manifestations • Chronic hemolysis • microvascular occlusions • tissue damage • Variables affecting the rate and degree of sickling • Interaction of HbS with other types of hemoglobin in the cell • HbA normal, HbF inhibits polymerization even more so infants not symptomatic • HbC causes dehydration and worsens sickling • MCHC increased • reduced pH lowers oxygen affinity and worsens • Slow transit time of red cells through the microvascular beds worsens • Inflamed vascular beds, spleen • Peripheral blood • variable numbers of irreversibly sickled cells • Correlates with severity of hemolysis • Reticulocytosis • target cell • Howell-Jolly bodies: small nuclear remnants in cells due to asplenia • Increased breakdown of hemoglobin • pigment gallstones • Hyperbilirubinemia • Autosplenectomy • Chronic erythrostasis -> splenic infarction, fibrosis, shrinking • infarctions in Bones, brain, kidney, liver, retina • X-ray: secondary new bone formation • Prominent cheekbones • Crew cut skull • Increased susceptibility to infections due to poor spleen function • H. influenzae and pneumococcus • Crises • Vaso-oclusive =pain crises • MC sites are bones, lungs, liver, brain, spleen, penis • Children bone crises difficult to distinguish from osteomyelitis • Acute chest syndrome • Fever, cough, chest pain, pulmonary infiltrates • Worsening pulmonary ->systemic hypoxia and vasoocclusion • Sequestration crises: occur in children with intact spleens • Splenic enlargement, hypovolemia, shock • Aplastic crises • Parvovirus B19 • Rx: hydroxyurea • increases HbF • unexplained anti-inflammatory effect Thalassemia Syndromes • Heterogenous group of disorders caused by inherited mutations that decrease the synthesis of adult hemoglobin, HbA • Alpha-globin genes on chromosome 16 • Beta-globin gene on chromosome 11 • Named by deficienct synthesis of Chain Beta-Thalassemias • Mutations that synthesis of β-globin chains • β0 mutations – absent β-globin synthesis • MC cause- Chain terminator mutations: new stop codon in exon • β+ mutations – β-globin synthesis • MC cause- Splicing mutations: ectopic splice site in intron • Promoter region mutations: reduce transcription • 2 mechanisms leading to anemia • Hypochromic, microcytic anemia w/ O2 transport capacity • Diminished survival of red cells & precursors • Membrane damage • Ineffective erythropoiesis • Extravascular hemolysis • Extramedullary hematopoiesis • Excessive absorption of iron • Unpaired α-chains precipitate in RBC and form insoluble includions that cause membrane damage • Leads to ineffective erythropoiesis • Excessive absorption of dietary iron • Suppress circulating hepcidin • Iron overload iron-laden liver • Prone to splenic sequestration & extravascular hemolysis • Clinical syndromes • β-thalassemia major (β+/β+, β+/β0 or β0/β0) • Severe, transfusion dependent • 2 thalessemia allelles • Microcytotic hypochromatic poikilocytosis anemia • β-thalassemia minor or trait (β+/β or β0/β) • Heterozygous carriers of allele • Mild asymptomatic microcytic anemia • Increase in HbA2 • more common • β-thalassemia intermedia (almost anything) • Severe but no transfusions • May have α-thalessemia that lessens mismatch • Morphology: • anisocytosis, poikilocytosis, microcytosis, hypochromia • enlargement of bones of face and skull • crew-cut appearance on X-ray • splenomegaly α-Thalassemias • Inherited deletions that result in reduced or absent synthesis of α-globin chains • Normally there are 4 α-globin genes • Clinical syndromes – determined & classified by the number of αglobin genes that are deleted • Silent carrier – deletion of one gene • α-thalassemia trait – deletion of 2 genes • Hemoglobin H disease – deletion of 3 genes • Severe: resembles β-thalessemia intermedia • MC in asians • High affinity for oxygen not good for O2 delivery • Hydrops fetalis – deletion of all 4 genes • Lethal in utero w/o transfusions • Survive early due to l2y2 Hb tetramer but distress by 3rd trimest • May be cured by bone marrow transplant • life-long dependence on transfusion iron overload Paroxysmal Nocturnal Hemoglobinuria • Acquired mutations in the phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for the synthesis of certain cell surface proteins • GPI-linked proteins are deficient • Causes dysfunction of platelets • Only hemolytic anemia caused by acquired genetic defect • Intravascular hemolysis caused by the C5b-C9 membrane attack complex • 25% at night due to in blood pH which activity of complement • Thrombosis = leading cause of dz-related death bc of platelet dysfunction • 5-10% develop AML or myelodysplastic syndromes • Diagnosed flow cytometry: RBC missing CD59 • Bone marrow transplantation can cure Immunohemolytic Anemia • Caused by antibodies that bind to RBCs premature destruction • Can be caused by ingested drug • Often against Rh blood group • Direct Coombs antiglobulin test • Detection of antibodies and or complement on red cells • pts RBC mixed w/ sera containing antibodies to human IG or complement • If present on subject RBC agglutination (clumping) • Indirect Coombs antiglobulin test • Characterize antigen target and temperature dependence of antibody in sera • Patient sera tested to agglutinate commercially available RBC w/ particular antigens on it • Classification • Warm Antibody type: IgG antibodies > 37 degrees • Idiopathic (MC immunohemolytic anemia) • Autoimmune (lupus) • Drugs (penicillin and cephalosporins, α-methyldopa) • Cold agglutinin type: IgM antibodies <37 degrees • Acute: mycoplasmal infection, mono • Chronic • Raynaud phenomenon • Cold hemolysin type: IgG antibodies <37 degrees • Rare, in children after virus infection • Paroxysmal cold hemoglobinuria Megaloblastic Anemias • Caused by impairment of DNA synthesis that leads to distinctive morphologic changes (abnormally large erythroid precursors & red cells) • Macrocytic oval cells is highly characteristic • hypersegmented neutrophils • giant metamyelocytes & band forms • increased levels of growth factors (EPO) Folate Deficiency • 3 major causes • Decreased intake – chronic alcoholics, elderly, indigent • In foods is usually folylpolyglutamates (sensitive to heat) • Increased requirements – pregnancy, infancy • Impaired utilization – folic acid antagonists (methotrexate) • Dietary deficiency in chronic alcoholics, indigent, or very elderly • Diagnosis • folate levels • Increased homocysteine but normal methylmalonate • No neurologic symptoms • Must excluse B12 deficiency first since the anemia will respond with folate supplementation but neurological symptoms will remain Vitamin B12 (cobalamin) Deficiency • B12 needed to synthesize thymidine a base of DNA • Folic acid is “trapped” as n5-methyl FH4 • Lack of folate is the proximate cause of the anemia • diets with animal products usually have sufficient B12 • Pernicious anemia • Autoimmune gastritis leading to failure of intrinsic factor production by parietal cells leading to vitamin B12 deficiency • 3 types of autoantibodies • Type I: block binding B12 to intrinsic factor • Type II: prevent complex binding to ileal recepetor • Type III: interrupt gastric proton pump on parietal cell • Morphology- Atrophy of the fundic glands, intestinalization (glandcular lining epithelium replaced by goblet cells), atrophic glossitis, demyelination of dorsal and lateral tracts • CNS – demyelination of dorsal & lateral tracts leading to spastic paraparesis, sensory ataxia, severe paresthesias in lower limbs • Not improved by folate • dz of older adults • Diagnosis • homocysteine & methylmalonic acid • Megaloblastic anemia • Leukopenia w/ hypersegmented ganulocytes • Low serum B12 Iron Deficiency anemia • MC nutritional disorder in the world • Iron in body is recycled extensively between functional & storage pools • Transferrin: transports in plasma, synthesized in liver • Ferritin: protein-iron complex storage form • Shells aggregate into hemosiderin granules • Seen w/ prussian blue stain • Correlates with body iron stores • Iron balance is maintained largely by regulating the absorption of dietary iron in the proximal duodenum • No excretion pathway • Absorption: luminal nonheme ferric (Fe3+) reduced to ferrous (Fe2+) state • Hepcidin: regulates iron absorption • Inhibits iron transfer from enterocyte to plasma by binding ferriportin • High hepcidin levels trapping iron in duodenal cells and lost when cells sloughed • Causes • Dietary lack • Infants, impoverished, elderly, teenagers • Impaired absorption • 1 mg of iron must be absorbed a day • 10-15% ingested is absorbed • Increased requirements • Chronic blood loss • MC cause in the Western world • GI bleed until proven otherwise in adult men & post menopausal women • Risk of missing occult GI cancer • Hypochromic, microcytic anemia • Low serum iron and ferritin • Elevated TIBC • Disappearance of stainable iron in the macrophages of the bone marrow • Clinical- pica, Plummer-Vinson Syndrome (esophageal webs, microytic hypochromic anemia, and atrophic glossitis) Anemias of Diminshed Erythropoiesis • Megaloblastic anemias • Iron deficiency anemia • Anemia of chronic disease • Aplastic anemia • Pure red cell aplasia • Other forms of marrow failure Anemia of Chronic Disease • 3 Categories • Chronic microbial infections, such as osteomyelitis, endocarditis, lung abscess • Chronic immune disorders, such as RA • Neoplasms, lung and breast, non-Hodgkin lymphomas • Increased IL-6 -> increase hepcidin production • Iron sequestration • Keep iron away from bacteria that need it • Erythropoieten levels low for level of anemia • Hepcidin may suppress this • Increase iron in marrow macrophages, high ferritin, decreased TIBC • anemia is usually mild, normocytic, normochromic Aplastic Anemias • Chronic primary hematopoietic failure & attendant pancytopenia • Hypocellular marrow dry tap • No splenomegaly • Reticulocytopenia is the rule • Congenital anomalies • Hypoplasia of kidneys & spleen, defects of thumbs or radii • Major causes • MC- Idiopathic: stem cell defects, immune • Chemical agents: benzene, arsenicals, alkylating agents • idiosyncratic: chloramphenical, carbamazapine, gold salts • Physical agents: whole body irradiation • Viral: hepatitis, CMV, EBV, Herpes zoster • Inherited • fanconi anemia: defects in multiprotein complex required for DNA repair • telomerase defects: adult onset • premature stem cell exhaustion • morphology • hypocellular bone marrow- ‘dry tap’ • Pure red cell aplasia • Only erythroid progenitors are suppressed • Most likely autoimmune • Parvovirus B19: symptoms clear in 1-2 weeks • Other forms – myelophthisic anemia, chronic renal failure, hepatocellular liver disease, endocrine disorders (hypothyroidism) Polycythemias • Abnormally high RBC count • Relative • Dehydration (reduced plasma volume) • Gaisbock syndrome: • “stressed” usually hypertensive, obsese, anxious patients • Absolute • Primary (low erythropoietin) • Polycythemia vera: erythropoietin independent myeloproliferative disorder • MC cause of polycythemia • Inherited erythropoietin receptor mutations • Secondary (high erythropoietin) • Compensatory: lung disease, high altitude, cyanotic heart disease • Paraneoplastic: erythropoietin secreting tumors • Hemoglobin mutants with high 02 affinity • Inherited defects that stabilize HIF-1a (stimulates transcription of erythropoietin gene • Chuvash polycythemia • Prolyl hydroxylase mutations Bleeding Disorders • Excessive bleeding results from • Increased fragility of the vessels • Platelet deficiency or dysfunction • Derangement of coagulation • Prothrombin time (PT) • Test extrinsic and common coagulation pathway • Prolonged from dysfunction of Factor V, VII, X, prothrombin, fibrinogen • Partial thromboplastin time (PTT) • Test intrinsic and common path • Prolonged from dysfunction of Factor V, 8-12, prothrombin, fibrinogen Bleeding Disorders: Hemorrhagic Diatheses • Bleeding disorders caused by vessel wall abnormalities • Bleeding related to platelet number: thrombocytopenia • Chronic immune thrombocytopenia purpura • Acute immune thrombocytopenia purpura • Drug-induced thrombocytopenia • HIV-associated thrombocytopenia • Thrombotic microangiopathies • Thrombotic thrombocytopenic purpura (TTP) & hemolytic uremia syndrome (HUS) • Bleeding disorders related to defective platelet functions • Hemorrhagic Diatheses related to abnormalities in clotting factors • The factor VIII-vWF complex • Von Willebrand disease • Hemophilia A (factor VIII deficiency) • Hemophilia B (Christmas disease, Factor IX deficiency) • Disseminated intravascular coagulation Vessel Wall Abnormalities • Nonthrombocytopenic purpuras • Platelet count, bleeding time, PT, PTT normal results • Causes • Infections • meningococcemia • Drug reactions • deposit immune complexes • Scurvy, Ehlers-Danlos, Cushing • Defects in vessel walls -> microvascular bleeding • Henoch-schonlein purpura • Rash, colicky abdominal pain, polyarthralgia, acute glomerulonephritis due to deposition of circulating immune complexes • Hereditary hemorrhagic telangiestasia (Weber-Osler-Rendu) • Dilated, tortuous vessels that bleed easily commonly in nose & tongue • Perivascular amyloidosis • Often amyloid light chain (AL) amyloidosis • Manifests as mucocutaneous petechiae Thrombocytopenia • Thrombocytopenia: platelet count <100,000 • <20,000 = spontaneous bleeding • Most feared site is intracranial bleeding • Causes • Decreased production = bone marrow issue • Drugs, alcohol, HIV • Decreased platelet survival • Immunologic: antibodies against platelets • Nonimmunologic: DIC, thrombotic microangiopathies, mechanical injury • Sequestration • hypersplenism • Dilution • transfusions Chronic Immune Thrombocytopenic Purpura (ITP) • Cause – autoantibodies to platelets act as opsonins • Mostly against platelet membrane glycoproteins IIb-IIIa or Ib-IX, IgG class • primary (diagnosis of exclusion) • secondary (SLE, HIV, B-cell neoplasms) • Splenectomy helps • site of removal of opsonized platelets, site of plasma cells that produce autoantibodies • Findings • Megakaryocytes increased number and size in marrow • Abnormally large platelets in blood • Spleen normal size though • Clinical- women 40+, petechiae echymoses, risk of intracranial bleeds • Dx made by exclusion of other causes of thrombocytopenia • Most response to glucocorticoids Other Causes of Thrombocytopenia • Acute ITP • Autoantibodies to platelets • Children • following a viral illness • usually self-limited • Drug-induced: quinine, quinidine, vancomycin, gold salts • heparin-induced (HIT) • Type 1 thrombocytopenia: goes away after therapy • Due to platelet aggregating effect of heparin • Type 2 thrombocytopenia: 5-14 days after therapy starts • Paradoxical thrombosis, even in setting of low platelets • HIV-associated • megakarocytes infected, prone to apoptosis • B cell hyperplasia predispose to autoantibody development Thrombotic Microangiopathies • Caused by insults that lead to excessive activation of platelets, which deposit as thrombi in microcirculatory beds • Pentad of • microangiopathic hemolytic anemia • Transient neurologic deficits • Renal failure • thrombocytopenia • Thrombotic thrombocytopenic purpura (TTP) • Deficiency of ADAMTS13 = “vWF metalloprotease” • Tend to decrease vWF platelet aggregation • HUS: absence of neuro symptoms • E. Coli 0157:H7 endothelial damage by shiga-like toxin • Alternative complement pathway inhibitor deficiency • Factor H, CD46, Factor 1 • Cyclosporine, radiation, HIV, autoimmune conditions • Differentiate from DIC because PT and PTT usually normal Defective Platelet Dysfunctions • Defects of adhesion • Bernard-Soulier syndrome • inherited deficiency of platelet membrane glycoprotein complex Ib-IX (receptor for vWF) • Defective platelet aggregation • Glanzmann thrombasthenia • AR deficiency or dysfunction of glycoprotein IIb-IIIa (integrin that participates in “bridge formation” btwn platelets) • Defects of platelet secretion • “storage pool” disorders • Not able to release thromboxanes and granule bound ADP • Acquired • aspirin and other NSAIDs: block TXA2 • Uremia: complex defects in adhesion, granule secretion and aggregation Abnormalities in Clotting Factors • Most commonly manifest as large post-traumatic ecchymoses or hematomas or prolonged bleeding after a laceration or surgical procedure • Hereditary – usually single clotting factor • Hemophilia A: factor VIII • Hemophilia B: Factor IX • Von Willebrand disease • Acquired – usually multiple factors simultaneously • vit K deficiency: impair synthesis factor II, VII< IX, X, protein C • DIC: inhibitory autoantibodies Von Willebrand Disease • Most important job of vWF is to promote adhesion of platelets to subendothelial matrix • Attach to glycoprotein Ib-IX and collagen • MC inherited bleeding disorder of humans ( 1% of adults in US) • Testing: ristocetin agglutination test • 20 variants • Type 1 (mild) and Type 3 (severe AR disorder) • reduced quantity of circulating vWF • Type 2 • qualitative defects in vWF • Subtype 2A MC (AD) • Defects in platelet function despite a normal platelet count • 2 abnormalities in platelet adhesion and clot formation • 2 decrease in factor VIII levels • Clinically – Epistaxis, excessive bleeding from wounds, menorrhagia • Can give desmopressin to stimulate vWF release for surgery Hemophilia A (Factor VIII Deficiency) • MC hereditary disease associated with life-threatening bleeding • X-linked recessive (effects mainly males) • Clinical severity correlates well with level of factor VIII activity • Symptoms • Petechiae are characteristically absent • Easy bruising, massive hemorrhage after trauma • Hemoarthroses: bleeding in joints • Prolonged PTT, normal PT • Abnormality of intrinsic coagulation pathway Hemophilia B (Christmas Disease, Factor IX Deficiency) • Clinically indistinguishable from hemophilia A – factors VIII and IX function together to activate factor X • Inherited X linked recessive trait • PTT is prolonged and PT normal Disseminated Intravascular Coagulation (DIC) • Acute, subacute, or chronic thrombohemorrhagic disorder characterized by the excessive activation of coagulation, which leads to the formation of thrombi in the microvasculature of the body • Consumption of platelets, fibrin, & coagulation factors & activation of fibrinolysis • Not a 1 disease • 2 major mechanisms trigger DIC • Release of tissue factor or thromboplastic substances into circulation • Widespread injury to endothelial cells • Most likely associated with: • Obstetric complications: thromboplastins enter circulation from fetus/placenta • Malignant neoplasms: acute promyelocytic leukemia and adenocarcinoma of lung • Sepsis: endotoxins or production of TNF • Major trauma: release of thromboplastins • Possible consequences • Widespread deposition of fibrin – ischemia, microangiopathic hemolytic anemia • Hemorrhagic diathesis: from consumption of platelets and factors • Clinical Features • Microangiopathic hemolytic anemia • Dyspnea, cyanosis, respiratory failure • Convulsions & coma • Oliguria & renal failure • Shock • Waterhouse friderichsen syndrome: adrenal hemorrhage • Sheehan postpartum pituitary necrosis • Only definitive treatment is to remove or treat the inciting cause • Chronic DIC: thrombotic complications • Acute DIC: bleeding diathesis