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Robbins Pathology Chapter 14 RBCs
Robbins Pathology Chapter 14 RBCs
Anemia
Intravascular Hemolysis
-caused by mechanical injury, complement fixation, intracellular parasites (malaria), exogenous toxic factors (clostridial sepsis)
-Sx: anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, jaundice (or pigment gallstones); decreased serum haptoglobin (complexes are phagocytosed)
-increased erythropoietin -> normoblasts -> reticulocytes
Pathogenesis of β-Thalassemia
-hallmark = aggregates of unpaired α-globulin chains (not seen on blood smears)
β-Thalassemia syndromes
β-Thalassemia Major (β0-β0,β+-β0,β+-β+) - elevated HbF, severe transfusion-dependent
anemia 6-9 months after birth; anisocytosis, poikilocytosis, microcytosis,
hypochromia, reticulocytosis, "crew cut" xray, iron overload
β-Thalassemia Minor (trait) (β0-β, β+-β) - mild asymptomatic microcytic anemia
β-Thalassemia Intermedia - severe non-transfusion dependent anemia
Clinical Features of β-Thalassemia
-growth retardation and early death in untreated children
-cardiac disease from iron overload and secondary hemochromatosis (from transfusions) -tx with
iron chelators
-Tx: bone marrow transplant
α-Thalassemia
-inherited deletions that result in reduced or absent synthesis of α-globulin chains
-anema from lack of adequate hemoglobin and excess unpaired non-α-chains (β,γ,δ)-> Hemoglobin Barts and HbH
α-Thalassemia Syndromes
severity depends on number of defective genes (there are 4 α-globulin genes)
carrier=1: asymptomatic, no RBC abnormality
trait=2: asymptomatic, microcytic anemia
HbH disease=3: severe, non-transfusion-dependent anemia
hydrops fetalis=4: lethal in utero w/o transfusions; b/c hemoglobin Barts doesn't release O2
Paroxysmal Nocturnal Hemoglobinuria
-acquired (X-linked lyonized) mutation in PIGA gene (enzyme for cell surface protein synthesis)
-blood cells are deficient in GPI-linked proteins that regulate complement activity: CD55, CD59 (C3 convertase inhibitor that prevents spontaneous complement
activation), CD8
-intravascular hemolysis at night when blood pH is lower -> hemosiderinuria -> iron deficiency
-thrombosis is leading cause of death (dysfunctional platelets)
-dx: flow cytometry tx: bone marrow transplant
Immunohemolytic anemia
-caused by antibodies against RBCs -> premature destruction
-sometimes caused by a drug
-dx: direct and indirect Coombs test
-Warm antibody type, cold agglutinin type, cold hemolysin type
Clinical Features
-features of general anemia
-iron depletion in cells causes: koilonychia (spoon nails), alopecia, atrophic changes to tongue (glossitis) and gastric mucosa, and intestinal malabsorption, depletion of
iron from CNS may cause pica
-Plummer-Vinson Syndrome – triad: esophageal webs, microcytic hypochromic anemia, atrophic glossitis
-Dx: decreased H&H, microcytosis, hypochromia, poikolocytosis, serum iron and ferritin are low, total plasma iron-binding capacity (increased trasferrin levels) is
high, hepcidin levels are low
-in uncomplicated iron-deficiency anemia tx is iron supplements, reticulocytes appear in 5-7 days
Aplastic anemia
-syndrome of chronic primary hematopoietic failure and attendant pancytopenia (anemia, neutropenia, thrombocytopenia)
-Idiopathic: usually autoimmune, can be acquired or inherited defects of hematopoietic stem cells
-Etiology – most cases follow exposure to chemicals and drugs (chemotherapy, benzene) that cause marrow suppression, sometimes drugs not related to marrow
suppression (chloramphenicol, gold salts)
-persistant marrow aplasia can appear after viral infections (hepatitis - non-A,B,C,E,G; CMV, EBV, HZV)
-whole body irradiation (dose-dependent)
-inherited defects (Fanconi anemia – rare AR disorder with defects in multiprotein complex that is required for DNA repair); inherited defects in telomerase
-Pathogenesis – 1. Extrinsic, immune-mediated suppression of marrow progenitors, 2. Intrinsic abnormality of stem cells
-Clinical Features – -pancytopenia: Anemia: weakness, pallor, dyspnea; Thrombocytopenia (petechiae, ecchymosis), Neutropenia (minor infections, chills, fever,
prostration); splenomegaly is ABSENT, RBCs are normochromic and slightly macrocytic; RETICULOCYTOPENIA is the RULE; Dx: bone marrow aspirate
(distinguish from other causes of aplastic anemia that have same presentation); Tx: bone marrow transplant
Bleeding disorders caused by vessel wall abnormalities – “nonthrombocytopenic purpuras”; most often induce small hemorrhages (petichiae and purpura) on skin
and mucous membranes (esp gingiva), more significant bleeds can occur in joints, muscles, subperiosteal locations, menorrhagia, epistaxis, GI bleeds, hematuria;
platelet count, bleeding time, PT/PTT are usually normal
Infections: cause petichiae/purpura; menignococcemia, septicemia, infective endocarditis, rickettsioses; mechanism: microbial damage to the
microvasculature (vasculitis) and DIC
Drug Reactions: cause cutaneous petichiae/purpura w/o thrombocytopenia; deposition of drug-induced immune complexes in vessel walls which leads to
hypersensitivity (leukocytoclastic) vasculitis
Scurvy, Ehlers-Danlos Syndrome, Cushing syndrome: microvascular bleeding; defects in collagen weakens vessel walls
Henoch-Schönlein Purpura: characterized by purpuric rash, colicky abdominal pain, polyarthralgia, acute glomerulonephritis; caused by deposition of
circulating antibody-antigen complexes within vessels and glomerular mesangial regions
Hereditary hemorrhagic telangiectasia (Weber-Osler-Rendu): AD disorder characterized by dilated, tortuous vessels with thin walls that bleed easily (oral
cavity, GI tract); serious bleeding is possible
Perivascular amyloidosis: weakens blood vessel walls and causes bleeding; mucocutaneous petichiae
Thrombocytopenia - <100,000 platelets/μL; NORMAL PT/PTT; spontaneous bleeding usually associated with small vessels; bleeding in skin, mucous membranes,
GI and GU tracts, serious intracranial bleeds
-Causes of thrombocytopenia:
Decreased platelet production: conditions that depress marrow output generally or affect megakaryocytes selectively
o Drugs, infections (HIV), B12/folate deficiency, aplastic anemia, leukemia, disseminated cancer, granulomatous disease, myelodysplastic
syndromes
Decreased platelet survival: immune thrombocytopenia platelet destruction is caused by antibodies to platelets or immune complexes that deposit on
platelets; IgG antibodies from mother can cause thrombocytopenia in the fetus
o Autoimmune (primary and secondary), alloimmune (posttransfusion/neonatal), drugs, infections (HIV, EBV), DIC, thrombotic
microangiopathies, giant hemangiomas, mechanical injury (prosthetic heart valves)
Sequestration: in spleen, normally sequesters 30-35% of platelets, can be as high as 80-90% with splenomegaly (hypersplenism)
Dilution: massive transfusions; platelets decrease in stored blood
Drug-induced Thrombocytopenia - direct effect of drug on platelets or immunologically-mediated platelet destruction; drugs: gold salts (unknown mech) vancomycin,
quinidine, quinine (bind to platelet glycoproteins or create antigenic determinants that are recognized by autoantibodies), common consequence of platelet inhibitory
drugs that bind to glycoprotein IIb-IIIa (conformational changes -> antigenic epitope)
Heparin-induced thrombocytopenia: 5% of pts receiving heparin, most develop type I thrombocytopenia (little clinical importance, most likely from
platelet aggregation), type II occurs 5-14 days after therapy begins, leads to life-threatening venous and arterial thrombosis (caused by antibodies that
recognized factor V-heparin complexes, binding of antibody to these complexes activates platelets and promotes thrombosis (even in thrombocytopenia),
unless therapy is stopped clots in large arteries can lead to vascular insufficiency and limb loss, and emboli from DVTs can cause PE; risk of severe HIT is
lower in low-molecular weight heparin
HIV-associated Thrombocytopenia - One of the most common hematologic complications of HIV; both impaired production and increased destruction contribute (CD4
and CXCR4 are on megakaryocytes and allow them to be infected with HIV); HIV-infected megakaryocytes are prone to apoptosis and their ability to produce platelets
is impaired; HIV also causes B-cell hyperplasia and dysregulation (predisposes to development of autoantibodies –sometimes against Gp IIb-IIIa complexes),
autoantibodies opsoninize platelets (they are destroyed by mononuclear phagocytes in the spleen and elsewhere
Thrombotic Thrombocytopenic Purpura (TTP) – thrombotic microangiopathy; PENTAD: fever, thrombocytopenia, microangiopathic hemolytic anemia, transient
neurological deficits, renal failure; caused by increased activation of platelets which deposit as thrombi in microcirculatory beds; usually associated with deficiency
(acquired or inherited) of plasma enzyme ADAMTS13 (vWF metalloprotease) which causes multimers of vWF to accumulate in the plasma and promote platelet
activation and aggregation; delay in diagnosis can be fatal; tx with plasmapheresis (removes autoantibodies and provides functional ADAMTS13); PT/PTT normal
Hemolytic Uremic Syndrome (HUS) - thrombotic microangiopathy; Characterized by: microangiopathic hemolytic anemia, thrombocytopenia, no neurological
symptoms, acute renal failure; usually seen in children; caused by increased activation of platelets which deposit as thrombi in microcirculatory beds; strongly
associated with E. coli O157:H7 (Shiga toxin); results in platelet activation and aggregation; children and elderly at highest risk; presentation is bloody diarrhea
followed by HUS; irreversible renal damage and death can occur
Non-endemic “atypical” HUS: associated with inherited defects or acquired autoantibodies to complement factor H, membrane cofactor protein (CD46) or
factor I (three proteins normally act to prevent excessive activation of alternative complement pathway); relapsing and remitting course; mechanism unclear;
PT/PTT normal
Hematologic diatheses related to abnormalities in clotting factors: isolated coagulation factor deficiencies; usually manifest as large post-traumatic ecchymoses or
hematomas, or prolonged bleeding after surgery or laceration; bleeding in the GI and urinary tracts and weight bearing joints (hemarthroses) is common; hereditary
disorders usually affect one factor, acquired deficiencies affect multiple factors and can be based on decreased protein synthesis or shortened half-life (vit K deficiency
causes impaired synthesis of factors II, VII, IX, X and protein C); DIC
Factor VII-vWF Complex: once factor VIII reaches circulation it binds to vWF (which stabilizes it), most important function of vWF is to promote platelet adhesion to
subendothelial matrix; factor VIII function is assessed by coagulation assays with mixtures of patient plasma and factor VIII-deficient plasma; vWF is assessed using
ristocetin agglutination test
Von Willebrand Disease: most common inherited bleeding disorder (1% of US); most common symptoms: spontaneous bleeding from mucous membranes (epistaxis),
excessive bleeding from wounds, menorrhagia, prolonged bleeding time with normal platelet count, secondary decrease in gp IIb-IIIa reflected as prolonged PTT (in
types 1 and 3), hemarthroses not seen; treat patients facing hemostatic challenges (dental work, surgery) with desmopressin (stimulates vWF release) or infusions of
plasma concentrates containing factor VIII and vWF
Type 1: associated with reduced quantity of circulating vWF; type 1 is autosomal dominant, mild deficiency, 70% of cases
Type 3: associated with reduced quantity of circulating vWF; autosomal recessive, extremely low levels of functional vWF and corresponding severe
symptoms (bleeding resembles hemophilia because vWF stabilizes gp IIb-IIIa)
Type 2: qualitative defects in vWF; 25% of cases; many subtypes: 2A (most common, autosomal dominant, normal amounts of vWF but missense mutations
cause defective multimer assembly, mild-moderate bleeding)
Hemophilia A (Factor VIII deficiency): most common hereditary disease associated with life-threatening bleeding; caused by mutations in factor VIII; X-linked (males
and homozygous females); inadequate coagulation (fibrinogenesis) and inappropriate clot removal (fibrinolysis) contribute to bleeding; wide range of clinical severity
that correlates with level of factor VIII activity (not levels, protein may be created, but inactive); symptoms: easy bruising and massive hemorrhage after trauma or
surgery, hemarthroses (if recurrent may lead to crippling deformities), petichiae are absent; LAB: prolonged PTT, normal PT (abnormality of intrinsic pathway), factor
VIII assays required for dx; Tx: infusions of recombinant factor VIII, about 15% of pts develop antibodies to factor VIII (therapeutic challenge); many hemophiliacs
contracted AIDS from concentrates
Hemophilia B (Christmas Disease, Factor IX deficiency): severe factor IX deficiency; clinically indistinguishable from hemophilia A; X-linked; variable clinical
severity; 15% of pts have present but non-functioning factor IX; LAB: PTT is prolonged, PT is normal (intrinsic pathway abnormality); Dx: assay of factor IX; Tx:
infusions of recombinant factor IX
Disseminated Intravascular Coagulation (DIC): acute, subacute, or chronic thrombohemorrhagic disorder characterized by excessive activation of coagulation,
which leads to formation of thrombi in microvasculature in the body, secondary complication to many disorders; consumption of platelets, fibrin, coagulation factors,
secondary activation of fibrinolysis; presents with signs and symptoms of hypoxia and infarction from thrombi and hemorrhage due to depletion of factors required for
hemostasis and activation of fibrinolysis, or both.
Pathogenesis: pathologic activation of extrinsic and/or intrinsic pathways of coagulation (more common) or the impairment of clot-inhibiting mechanisms
(less common)
o Mechanisms:
Release of tissue factor or thromboplastic substances into circulation a from variety of sources:
Obstetric complications: thromboplastins derived from placenta, dead retained fetus, or amniotic fluid that enters
circulation
Cancers
o Cytoplasmic granules of acute promyelocytic leukemia cells
o Mucus from certain adenocarcinomas (lung, colon, pancreas, stomach): can directly activate factor X
independent of factor VII
Widespread injury to endothelial cells:
Endothelial cell injury and necrosis causes exposure of the subendothelial matrix leading to activation of platelets and both
arms of the coagulation pathway;
TNF (implicated in DIC in sepsis) induces endothelial cells to express tissue factor on their surfaces and decreases
expression of thrombomodulin (shifting hemostasis towards coagulation), TNF also regulates expression of adhesion
molecules on endothelial cells (promoting adhesion of leukocytes which can cause further damage by ROS)
Deposition of antigen-antibody complexes (SLE)
Temperature extremes (heat stroke, burns)
Sepsis: Microorganisms (meningococci, rickettsiae); injury to endothelial cells from endotoxins
Major trauma/surgery/burns: major trigger is release of thromboplastins
Hypoxia/acidosis/shock: can cause endothelial injury, further complicated by supervening infections
o Possible consequences
Widespread deposition of fibrin in microcirculation, leads to ischemia and microangiopathic hemolytic anemia
Consumption of platelets and coagulation factors and the activation of plasminogen leads to hemorrhagic diatheses
Morphology: thrombi are most often seen in brain, heart, lungs, kidneys, adrenals, spleen and liver (decreasing frequency), any tissue can be affected
o Waterhouse-Friedrichsen syndrome: massive adrenal hemorrhages probably caused by fibrin thrombi in microcirculation of adrenal cortex,
associated with menigococcemia
o Sheehan syndrome: pituitary post-partum necrosis, form of DIC
o Toxemia of pregnancy: placenta has widspread microthrombi causing premature atrophy of the cytotrophoblast and syncytiotrophoblast
o Giant hemangiomas: thrombi form within the neoplasm because of stasis and recurrent trauma to blood vessels
Clinical features: onset can be fulminant (as in endotoxic shoc or amniotic fluid embolism), or insidious and chronic (carcinomatosis or retention of dead
fetus); 50% are obstetric patients (tends to reverse with delivery); 33% have carcinomatosis; clinical presentations vary
o Common patterns: microangiopathic hemolytic anemia; dyspnea, cyanosis and respiratory failure; convulsions and coma; oliguria and acute renal
failure; sudden or progressive circulatory failure and shock
Acute DIC (associated with obstetric complications and trauma) is dominated by bleeding diatheses
Chronic DIC (cancer patients) tends to present as thrombotic complications
o Diagnosis: clinical observation, lab studies (fibrinogen levels, PT/PTT, fibrin degradation products)
o Prognosis: highly variable, depends on underlying disorder
o Treatment: remove and treat inciting cause, management requires balance between hemorrhage and thrombosis (sometimes administration of
anticoagulants or procoagulants is indicated)