RBC path Flashcards
Anemia
reduction of total circulating red cell mass below normal limits
Major mechanisms of anemia
blood loss, increased red cell destruction, decreased red cell production
Most useful lab values for anemia eval
mean cell volume, mean cell hgb, mean cell hgb concentration, RDW
Common clinical findings in anemia
pale, weakness, malaise, easy fatigability, dyspnea, SOB; chronic hypoxia can lead to fatty change in liver, myocardium, and kidney
What does HCT measure?
relative concentration of red cells, not the total red cell mass
How quickly are reticulocytes produced
5 days
Common features of hemolytic anemia
shortened red cell life span, elevated EPO levels and compensatory increase in EPO, accumulation of hgb degradation products
Where are senescent RBC destroyed?
macrophages in spleen, liver, bone marrow
Extravascular hemolysis
caused by alterations that render red cell less deformable, makes it more difficult for cells to go through spleen
Sxs of extravascular hemolysis
anemia, splenomegaly, jaundice
Intravascular hemolysis
caused by mechanical injury, complement fixation, intracellular parasites, exogenous toxic factors
Manifestations of intravascular hemolysis
anemia, hemoglobinemia, hemoglobinuria, hemosidonuria, jaundice
Role of haptoglobin
binds free hemoglobin, produces a complex that is cleared by phagocytes
Is bilirubin in uncomplicated hemolytic anemias conjugate or unconjugated?
unconjugated
Hereditary Spherocytosis
inherited disorder caused by intrinsic defects in red cell membrane skeleton that render red cells spheroid, less deformable, and vulnerable to splenic sequestration and destruction
Inheritance pattern of HS
autosomal dominant
Potential proteins affected by HS
spectrin a or b, ankyrin, band 3, protein 4.1 and band 4.2
G6PD deficiency
abnormalities reduce the ability of red cells to protect themselves from oxidative injury
What may cause episodic hemolysis characteristic of G60D?
infections such as viral hepatitis, pneumonia, typhoid fever; drugs; foods
Heinz bodies
denatured globin chains that appear as dark inclusions within red cells stained with crystal violet; will be plucked out by macrophages and produce bite cells
When will acute hemolysis begin following exposure of G6PD-deficient individuals to oxidants?
2 to 3 days
Most prominent form of Hgb in adults
A (alpha 2, beta 2)
Most prominent form of Hgb in newborns
HbF
Genetic aberration in sickle cell disease
point mutation in B globin, resulting in red cell distortion; glutamate replaced by valine
Vaso-occlusive crises
episodes of hypoxic injury and infarction that often cause severe pain
Acute chest syndrome
fever, cough, chest pain, pulmonary infiltrates and inflammation
Priapism
affects males after puberty and may lead to hypoxic damage and erectile dysfunction
Sequestration crises
entrapment of sickled red cells leading to rapid splenic enlargement, hypovolemia, shock
hyposthenuria
inability to concentrate urine
What types of organisms are children with sickle cell at increased susceptibility for?
encapsulated - S. pneumoniae, H. influenzae meningitis and septicemia
Thalassemia syndromes
group of disorders caused by inherited mutations that decrease synthesis of alpha or beta globin chains leading to anemia, tissue hypoxia, and red cell hemolysis
What chromosome codes for alpha globin
Chromosome 16
What chromosome codes for beta globin
chromosome 11
What do globin defects in thalassemia cause?
anemia via decreased red cell production and decreased red cell lifespan
Types of B-Thalassemia mutations
B0 mutation (absent synthesis), B+ mutations (reduced synthesis)
Two ways B-thalassemia causes anemia
deficit in HbA synthesis produces hypochromic, microcytic red cell; diminished survival of red cells and their precursors
Hemolysis in B-thalassemia and cause
extravascular hemolysis due to membrane damage from imbalance of alpha and beta globin chains
Which areas is B-thalassemia major most common in?
Mediterranean countries, parts of Africa, and Southeast Asia
Predominant type of Hb in B-thalassemia major individuals
HbF
Clinical course of B-thalassemia major
brief unless blood transfusions are given, growth retardation, bony prominences, hepatosplenomegaly; cardiac disease resulting from progressive iron overload and secondary hemochromatosis
Morphology of B-Thalassemia major
marked variation in size and shape, microcytosis, hypochromia
B-thalassemia minor
patients typically asymptomatic but may experience mild anemia
B-thalassemia minor blood smear
red cell abnormalities including hypochromia, microcytosis, basophilic stippling and target cells
HbF levels in B-thalassemia minor
normal or slightly increased
Why is it important to recognize B-thalassemia minor
superficially resembles hypochromic microcytic anemia of iron deficiency, important for genetic counseling
alpha thalassemia caused by…
inherited deletions that result in reduced or absent synthesis of a-globin chains
hemoglobin Barts
excess unpaired gamma globin chains that form gamma tetramers, seen in newborns with a-thalassemia
HbH
excess B-globin chains form tetramers, seen in older children and adults with a-thalassemia
Clinical syndromes of a-thalassemia
silent carrier state, a-thalassemia trait, HbH disease, hydrops fetalis
Paroxysmal nocturnal hemoglobinuria
acquired mutations in PIGA gene, essential for membrane associated complement regulatory proteins
What type of hemolysis is manifested in PNH?
intravascular hemolysis
Leading cause of death in PNH patients
thrombosis
CAs developed by PNH syndrome
acute myeloid leukemia, myelodysplastic syndrome
What GPI-linked proteins are deficient in patients with PNH?
CD55 (decay-accelerating factor), CD59 (membrane inhibitor of reactive lysis), C8 binding protein
Immunohemolytic anemias
caused by abs that bind to red cells leading to premature destruction
Warm antibody type immunohemolytic anemia
most common form, idiopathic or caused by drugs; IgG abs active at 37C
Cold agglutinin type immunohemolytic anemia
IgM abs bind below 37C, appear following an acute infection (Mycoplasma pneumoniae, EBV, CMV, influenza, HIV) or may be chronic
Clinical manifestations of cold agglutinin immunohemolytic anemia
pallor, cyanosis, Raynaud phenomenon
Cold hemolysin type immunohemolytic anemia
IgG abs bind below 37C, occurs in children following viral infections
Direct Coombs antiglobulin test
patient’s red cells mixed with sera containing abs specific for human immunoglobulin or complement, abs will cause agglutination if immunoglobulin or complement is present
Indirect Coombs antiglobulin test
patient’s serum tested for ability to agglutinate commercially available red cells bearing defined ags, used to characterize ag target and temp dependence of ab
Most significant hemolysis caused by trauma to red cells is in seen in individuals with…
cardiac valve prostheses, microangiopathic disorders, shear forces produced by turbulent blood flow and pressure gradients
Megaloblastic anemia
impairment of DNA synthesis leading to ineffective hematopoiesis
Macrocytic changes/morphology
peripheral blood has pokilocytic red cells, macrocytic red cells, hypersegmented polys, MCHC “normal,” low reticulocyte count; bone marrow is hypercellular with bands and dysplastic metamyelocytes
Neurologic complications of B12 deficiency
spastic paraparesis, sensory ataxia, severe paresthesias of lower limb.
Pernicious anemia
form of megaloblastic anemia caused by autoimmune gastritis that impairs production of IF, required for vitamin B12 uptake
Diagnostic values of pernicious anemia
moderate to severe megaloblastic anemia, autoantibodies to IF, leukopenia with hypersegmented granulocytes, low serum B12, elevated serum levels of homocysteine and methylmalonic acid
Primary cause of gastric pathology in pernicious anemia
autoreactive T-cell response initiates gastric mucosal injury and triggers formation of autoantibodies
B12 deficiency due to loss of pepsin secretion and achlorydria
vitamin B12 not released from proteins in food
Vitamin B 12 deficiency due to loss of exocrine pancreatic function
Vitamin B12 not released from haptocorrin-vitaminB12 complexes
Folic acid deficiency
megaloblastic anemia due to suppressed DNA synthesis
Homocysteine and MMA levels in folate deficiency
homocysteine elevated, MMA normal
Homocysteine and MMA levels in vitamin B12 deficiency
homocysteine and MMA elevated
Porphyrins
pigments involved in formation of heme
Clinical manifestation of porphyria
abnormal reactions to sunlight, staining of teeth, nervous system issues such as referred pain, seizures, hallucinations, and general psychosis
Most common nutritional disorder in the world
iron deficiency anemia
Most common populations to develop IDA
toddlers, adolescent girls, women of child bearing age
What protein transports iron throughout the body?
transferrin
What protein stores iron?
ferritin
Most functional iron in humans is found in what protein?
hemoglobin
Ferritin levels in IDA
<12ug/L
Ferritin levels in iron overload
5000 ug/L
What molecule regulates iron absorption
hepcidin
Most common cause of iron deficiency in the western world
chronic blood loss, like a GI bleed
Plummer-Vinson syndrome
esophageal webs, microcytic hypochromic anemia, atrophic glossitis
Anemia of chronic disease
impaired red cell production associated with chronic diseases that produce systemic inflammation
How does chronic inflammation suppress erythropoiesis?
stimulating hepcidin
Ferritin and TIBC in IDA
low ferritin, high TIBC
Ferritin and TIBC in anemia of chronic disease
high ferritin, low TIBC
Aplastic anemia
exhibits pancytopenia and can be acquired, inherited or triggered by chemical or physical agents
Two major etiologies of aplastic anemia
extrinsic, immune-mediated suppression of marrow precursors, stem-cell abnormalities
Aplastic anemia morphology
hypocellular bone marrow, fat cells, fibrous stroma, scattered lymphocytes, plasma cells
Clinical features of aplastic anemia
pancytopenia, weakness, pallor, dyspnea, thrombocytopenia, neutropenia, reticulopenia
Pure red cell aplasia
marrow disorder, only red cell precursors are affected
Etiology of pure red cell aplasia
thymoma, large, granular lymphocytic leukemia, drugs, autoimmune disorders, parvovirus infection
Myelophthisic anemia
form of marrow failure in which space-occupying lesions replace normal marrow elements most often due to metastatic CAs
Polycythemia
abnormally high red cell count, increased Hgb
Causes of relative polycythemia
dehydration, Gaisböck syndrome
Absolute polycythemia
primary when it results from intrinsic abnormality, secondary when progenitors are responding to a high level of EPO
Three main causes of excessive bleeding
increased fragility of vessels, platelet deficiency or dysfunction, derangement of coagulation
Primary pathway for initiation of coagulation
extrinsic (TF) pathway
Partial thromboplastin time
utilized for detecting abnormalities of blood clotting and to monitor treatment effect of heparin; tests intrinsic and extrinsic pathways; look at factors V, VIII, IX, X, XI, XII, prothrombin, fibrinogen
Prothrombin time
tests extrinsic and common clotting pathways; coumadin therapy; look at factors V, VII, X, prothrombin, fibrinogen
Bleeding disorders caused by vessel wall abnormalities usually present as….
small hemorrhages in skin and mucous membranes
Clinical conditions that cause abnormalities in vessel walls
infections, drug reactions, scurvy and ehlers-danlos, Henoch Schönlein purpura, hereditary hemorrhagic telangiectasia, perivascular amyloidosis
Thrombocytopenia
count <100,000/uL, <20,000 associated with spontaneous bleeding
PT and PTT in thrombocytopenia
normal, pathways remain intact
Thrombocytopenia due to decreased platelet production
results from conditions that depress marrow output or affect megakaryocytes
Thrombocytopenia due to decreased platelet survival
destruction caused by deposition of abs or immune complexes on platelets, may also occur via mechanical injury
Thrombocytopenia due to sequestration
if spleen is enlarged, it can harbor 80-90% of platelets
Thrombocytopenia due to dilution
result from massive transfusions, prolonged blood storage decreases the number of viable platelets
Chronic immune thrombocytopenic purpura
caused by autoab mediated destruction of platelets, can be idiopathic or secondary
Chronic ITP autoantibodies
directed against platelet membrane glycoproteins, typically IgG abs
Major site of platelet removal
spleen
Morphological characteristics of chronic ITP
spleen is of normal size, marrow has increased megakaryocytes, abnormally large platelets in peripheral blood
Clinical features of Chronic ITP
adult women <40 yo, bleeding into skin and mucosal surfaces, history of easy bruising or nosebleeds, hemorrages into soft tissues; may first present as melena, hematuria ,excessive menstrual flow, subarachnoid hemorrhage, intracerebral hemorrhage
Lab findings of chronic ITP
low platelet count, normal or increased megakaryocytes, large platelets in peripheral blood, PT and PTT normal
Acute ITP
mainly a disease of childhood, appear abruptly 1-2 weeks after a self-limited viral illness; most will self resolve
Drug-induced thrombocytopenia
most common drugs to cause platelet destruction are quinine, quinidine, and vancomycin
Type I heparin-induced thrombocytopenia
occurs rapidly after initiation of therapy and generally resolves
Type II heparin-induced thrombocytopenia
less common, begins 5-14 days after initiation of therapy; results in severe, sometimes life-threatening venous and arterial thromboses
HIV-associated thrombocytopenia
common manifestation of HIV, HIV-infected megakaryocytes (due to CD4 and CXCR4) making them prone to apoptosis, production of autoantibodies also occurs due to B cell hyperplasia
Thrombotic microangiopathy
caused by insults that lead to excessive platelet activation and cause the deposition of thrombi in small blood vessels
Thrombocytopenic purpura presentation
fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro deficits and renal failure
Hemolytic-Uremic syndrome presentation
microangiopathic hemolytic anemia and thrombocytopenia, NO neuro sxs, acute renal failure, frequently occurs in children
PT and PTT in thrombotic microangiopathies
normal
Typical cause of HUS
E. coli strain O157:H7
Atypical causes of HUS
alternative complement pathway inhibitor deficiencies
Genetic aberration in TTP
deficiency of ADAMTS13
Categories of inherited platelet disorders
defects of adhesion, aggregation, secretion
Bernard-Soulier syndrome
deficiency of glycoprotein complex Ib-IX, cannot attach to vWF
Glanzmann thronbasthenia
failure of platelets to aggregate due to dysfx of glycoprotein IIb-IIIa
Causes of disorders of platelet secretion
defective release of certain mediators, storage pool disorders
Acquired defects of platelet function
ingestion of aspirin and other NSAIDs, uremia
Common bleeding patterns that occur due to coagulation deficiencies
GI and GU tracts, hemarthrosis
Hemophilia A deficiency
Factor VIII
Hemophilia B deficiency
Factor IX
Vitamin K deficiency results in the impaired synthesis of which factors?
II, VII, IX, X, and protein C
Major source of factor VIII
sinusoidal endothelial cells and kupfer cells
Most common inherited bleeding disorder of humans
von Willebrand disease
Type 1 vW disease
autosomal dominant disorder, spectrum of presentations but often mild symptoms
Type 2 vW disease
autosomal dominant disorder, qualitative defects in vWF, normal number but missense mutations make it defective
Type 3 vW disease
autosomal recessive disorder, low levels of vWF and severe clinical manifestations
PTT in Type 1 and Type 3 vW disease
prolonged
Inheritance pattern of hemophilia A
X-linked recessive
Genetic aberration of most severe hemophilia A
inversion involve X csome that completely abolishes synthesis of factor VIII
Hemophilia A symptoms
easy bruising and massive hemorrhage after trauma or operative procedures, hemarthroses, prolonged PTT and normal PT
PTT and PT in Hemophilia B
prolonged PTT, normal PT
Disseminated Intravascular Coagulation
acute, subacute, or chronic thrombohemorrhagic disorder characterized by excessive activation of coagulation and formation of thrombi in microvasculature of the body
Two major mechanisms that trigger DIC
release of tissue factor, widespread injury to endothelial cells
Clinical features of DIC
most are obstetric patients, microangiopathic hemolytic anemia, dyspnea, cyanosis, respiratory failure, convulsions, coma, oliguria, acute renal failure
Sugar residue on A blood antigen
N-acetylgalactosamine
Sugar residue on B blood antigen
galactose
Febrile nonhemolytic reaction
fever and chills, mild dyspnea, often occurs within 6 hours of a transfusion
Allergic rx in blood transfusion
urticarial reaction, potentially fatal reactions can occur in pts with IgA deficiency
Acute hemolytic reaction - blood transfusions
IgM abs against donor red cells that fix complement; fevers, shaking, chills, flank pain rapidly appear; may progress to DIC, shock, acute renal failure, potentially death
Delayed hemolytic reaction - blood transfusions
typically caused by IgG abs, induce complement activation and cause severe reactions identical to those reacting to ABO mismatches
Transfusion-Related Acute Lung Injury
severe, frequently fatal complication in which factors trigger the activation of neutrophils in lung microvasculature; dramatic onset resp failure during or soon after transfusion, bilateral pulmonary infiltrates, fever, hypotension, hypoxemia
