14 Flashcards
Anemia
nemia
Reduction of the total circulating red cell mass below normal limits
Decreased O2 carrying capacity = tissue hypoxia
patients are pale, weak, and easily fatigued with malaise
Mild dyspnea on exertion
Fatty change in the liver, myocardium, kidney
Diagnosed via hematocrit or hemoglobin
Etiology may be determined by RBC morphology (size, shape, hemoglobinization
Microcytic, normochromic
Di sorder of hemoglobin synthesis, mostly due to iron deficiency
Microcytic anemia
generally impaired maturation of RBC precursors in the bone marrow
Normocytic, normochromic
Lots o divers things
Hematocrit Ratio of packed RBCs to total blood volume (the concentration)
Not good for acute blood loss
Volume percentage of red blood cells in blood
Approximately 3x the [hemoglobin
Hematocrit Ratio of packed RBCs to total blood volume (the concentration)
Not good for acute blood loss
Volume percentage of red blood cells in blood
Approximately 3x the [hemoglobin
Mean cell volume
Mean cell volume (MCV): the average volume of a red cell expressed in femtoliters (fL)
Normal: 80-100
Mean cell hemoglobin
Mean cell hemoglobin: the average content (mass) of hemoglobin per red cell expressed in picograms
Changes the color of RBCs
Mean cell {hemoglobin}
Mean cell [hemoglobin]: the average concentration of hemoglobin in a given volume of packed red cells expressed in grams per deciliter
Changes the color of RBCs
Red cell distribution width (RDW)
Red Cell Distribution Width (RDW): the coefficient of variation of red cell volume
an elevated RDW implies that the marrow is pumping out reticulocytes (larger cells)
elevated RDW is a reactive phenomenon observed in states of anemia with a functioning marrow
Acute blood loss
Effects are due to loss of intravascular volume
If massive → cardiovascular collapse, shock, and death
Normocytic-normochromic – because it is a loss of normal blood
Clinical acute blood loss
Clinically depends on rate of hemorrhage, and whether bleeding is internal or external
Survival acute blood loss
Survival: rapid shift of water from interstitial fluid compartment to restore blood volume
Hemodilution
Decreased hematocrit
Low oxygenation
EPO release from kidneys
Epo
EPO (erythropoietin)
Stimulates proliferation of committed erythroid progenitors (CFUE) in the marrow
Released from the kidney
CFUE progeny mature and are seen as reticulocytes in five days in peripheral blood
Reticulocytosis within 7 days (10-15% reticulocytes) if severe enough
Reticulocytes appear larger and with a blue-red polychromatophilic cytoplasm
Thrombocytosis and leukocytosis may also occur
Chronic blood loss
Chronic Blood Loss
Anemia only occurs if the rate of loss exceeds the marrow regenerative capacity or when iron reserves are depleted
Male and postmenopausal women: assume colon cancer until proven otherwise
Hemolytic anemia
Definition
Red cell life span < 120 days
Elevated EPO levels
Accumulation of hemoglobin degradation products (i.e. unconjugated bilirubin that’s related to amount of liver function
Morphology hemolytic anemia
Increased erythroid precursors (normoblasts) in the marrow due to increased EPO production
Prominent reticulocytosis in peripheral blood
Hemosiderosis: accumulation of hemosiderin (iron containing pigment) from RBC phagocytosis
Extramedullary hematopoiesis if severe
Chronically may lead to elevated bilirubin in the bile → pigment gallstones (cholelithiasis
Extravascular hemolysis
Definition
Occurs mostly in the macrophages of the spleen
Predisposed by RBC membrane injury, reduced deformability or opsonization
CLINCIALLY extravascular hemolysis
Anemia, splenomegaly (mostly extravascular) and jaundice
Variable decreased in haptoglobin (the protein that binds to hemoglobin in plasma)
Splenectomy is often beneficial for these patients – a lot of the RBC destruction happens in the spleen
Intravascular hemolysis
RBC rupture due to mechanical injury (mechanical cardiac valves), complement fixation (mismatched blood transfusion), intracellular parasites (malaria) or extracellular toxins (clostridial enzymes
Clincial intravascular hemolysis
Clinically
Anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, jaundice
No splenomegaly
Markedly reduced serum haptoglobin
haptoglobin: α2-globulin that binds free hemoglobin and prevents its excretion in the urine
is “consumed” when there is any form of hemolysis occurring
Renal hemosiderosis (iron accumulation in the tubular cells)
Excess unconjugated bilirubin
Free hemoglobin may be oxidized to methemoglobin (brown color that can go into the urine) when haptoglobin is depleted
Hereditary spherocytosis
Inherited disorder due to intrinsic defects of the red cell membrane skeleton
RBCs become spheroid, less deformable, and more vulnerable to splenic sequestration and destruction
Predominantly extravascular hemolysis
Most prevalent in Northern Europe
Inheritance pattern hereditary spherocytosis
Inheritance pattern
75% are autosomal dominant
More severe in patients who are compound heterozygotes that have two separate mutations
Pathogenesis hereditary spherocytosis
Pathogenesis
Decreased density (insufficiency) of membrane skeletal components due to mutation in ankyrin, band 3, spectrin, or band 4.2
ankyrin and band 4.2 binds spectrin to the transmembrane ion transporter band 3
protein 4.1 binds the “tail” of spectrin to another transmembrane protein, glycophorin A
Reduced stability of the lipid bilayer and loss of membrane fragments occurs as RBCs age
RBC assumes spheroidal shape, is trapped in the cords of Billroth and destroyed by splenic macrophages after about 10-20 days instead of the normal 120 days
RBC loss of K+ and H2O also occurs and may be due to low RBC glucose or altered pH
Morphology hereditary spherocytosis
orphology
Spherocytosis is distinctive but not pathognomonic
small, dark-staining (hyperchromic) red cells lacking the central zone of pallor
Reticulocytosis, marrow erythroid hyperplasia, hemosiderosis
Moderate splenomegaly (very characteristic and consistent) due to congestion of cords of Billroth and increased number of macrophages
Cholelithiasis in 40-50% of patients due to pigment stones
Diagnose hereditary spherocytosis
Family history, hematology findings & lab evidence
Osmotic fragility/lysis test in hypotonic solution
Lab hereditary spherocytosis
Increased RDW and MCHC
Clincial hereditary spherocytosis
patients present with variable anemia, splenomegaly and jaundice
If severe, like in compound heterozygotes, can present at birth and require exchange transfusion
Increased risk of aplastic crisis due to parvovirus B19 infection since it stops hematopoiesis for a couple of weeks
RBC counts drop to dangerous levels
Hemolytic crises due to infectious mononucleosis (#1 cause is EBV; #2 is CMV) may also occur
No splenomegaly
Many patients will develop gall stones (pigment
Treatment hereditary spherocytosis
Splenectomy
after splenectomy, the spherocytes persist but the anemia is corrected
Increased risk of sepsis
Anemia resolves but Howell-jolly bodies (residual RNA) remain (in all asplenic patients
G6PD
Enzyme in the hexose monophosphate shunt
Normally reduces NADP → NADPH
NADPH normally reduces RBC glutathione and protects against oxidative stress
Oxidative stress may be due to:
Fava beans, antimalarial drugs (Quinidine, primaquine, and chloroquine), sulfonamides, nitrofurantoins, infection, inflammation
Resistance to Plasmodium falciparum (malaria
G6PD defiency
G6PD- Deficiency
X-linked recessive deficiency
*G6PD- (African variant) prominent in African Americans, and is less severe
Episodic (not chronic) hemolysis due to oxidative stress
In deficient cells, oxidative stress causes hemoglobin sulfhydryl crosslinking and protein denaturation
cross-linking of reactive sulfhydryl groups on globin chains become denatured and from membrane bound precipitates called Heinz bodies (appear as dark inclusions visible with crystal violet)
Heinz bodies (denatured hemoglobin) can damage the membrane enough to cause intravascular hemolysis
As macrophage remove the Heinz bodies, they create “bite cells” or become spherocytic
G6pd Mediterranean variant
G6PD Mediterranean Variant
Markedly decreased t1/2 of this enzyme causes significant intravascular hemolysis with oxidative stress
Protein misfolding = increased susceptibility to proteolytic degradation
Prevalent in the Middle East
Enzyme activity makes older RBCs prone to hemolysis with oxidative stress
Self-limited because young RBC’s not affected
HBA
A2b2
HbA2
Azdelta2
High HbA2 is a b thalassemia (minor trait)
HbC
Ok
HcF
A2 gamma2
HbH
B4
HbS
A2b^s2
Hemoglobin Bart’s
Gamma 4
Sickle cell trait (SA a2b^s2
Hereditary hemoglobinopathy due to a point mutation provides protection v. falciparum malaria
Intracellular parasites consume O2 and decrease intracellular pH, which both promote sickling and distorted cells are cleared more rapidly by phagocytes keeping parasite loads down
Sickling impairs PfEMP-1 membrane knob formation which normally allows the parasite to adhere to endothelial cells (cerebral malaria
Sickle cell anemia/disease (ss,b^s2B^s2)
Hereditary hemoglobinopathy due to a point mutation (6th position) (glutamate → valine) in β-globin that promotes polymerization of deoxygenated hemoglobin, leading to:
Red cell distortion
(extravascular) hemolytic anemia
Microvascular obstruction –> most serious clinical features
Ischemic tissue damage
Heterozygotes only affected in settings of profound hypoxia
Pathogenesis sickle cell disease
Deoxygenated hemoglobin forms RBC polymers when deoxygenated converting the free flowing cytosol into viscous gel
They then form long, needlelike fibers within RBCs causing a sickle shape; rate and degree depend on:
Interactions with other types of hemoglobin in the cell
HbA interferes with the polymerization of the HbS
Mean cell [Hb] (MCHC)
decreased MCHC levels cause a milder disease, like in homo HbS patients with α-thalassemia
intracellular dehydration increases the MCHC and facilitates sickling
Intracellular pH: decrease in pH increases the likelihood for sickling
Transit time of RBCs through microvascular beds: slower time increases the amount of deoxygenation and sickling
Found most commonly in the spleen, bone marrow, and inflamed tissues
HbSC disease ==1 of each mutant gene
Compound heterozygotes with RBCs that tend to lose salt and water (dehydration)
[Hb] is then increased and there is a tendency for polymerization
Glutamic acid → lysine (“lyCine”)
Crystals are seen on blood smear
More mild than sickle cell disease
Fetal sickle cell anemia
HbF is protective, and patients often present at 6 months when these levels decline
treatment of sickle cell disease with hydroxyurea enhances expression of HbF
End stage sickle rbc
Repeated damage leads to influx of Ca++ and efflux of K+ and H2O
Chronically this causes RBCs to become dehydrated, dense and rigid
These cells become end stage, non-deformable, irreversibly sickled cells that retain the sickle shape even when fully oxygenated
Hemolysis severity is proportional to the number of irreversibly sickled cells that are sequestered and extravascularly hemolyzed
Sickle cell stasis
Higher than normal levels of adhesion molecules are expressed, which are upregulated during inflammatory reactions
increased tendency for the cells to arrest while moving through microvasculature causing sickling and obstruction
Vicious cycle of sickling, obstruction, hypoxia ensues
Free hemoglobin binds to and inactivates NO leading to increased vascular tone and enhanced platelet aggregation
Stasis, sickling and thrombosis
Morphology sickle cell stasis
Peripheral blood: irreversibly sickled cells, reticulocytosis and target cells due to RBC dehydration
Howell-jolly bodies (residual RNA) due to asplenia
Massive erythroid hyperplasia and extramedullary erythropoiesis
Complications sickle cell stasis : autosplenectomy
splenomegaly caused by trapping of sickled red cells in the cords and sinuses during childhood
chronic erythrostasis –> splenic infarction, fibrosis, and progressive shrinkage
only a fibrous nubbin of fibrous splenic tissue remains by adolescence
Complications: expansion of the marrow leads to bone remodeling
Skull: prominent cheekbones and changes in the skull that resemble a “crewcut”
facial bones: chipmunk facies
Other complications
Pigment gallstones and hyperbilirubinemia
Microvascular occlusions of tissue (stroke, retinal problems, growth retardation)
Vascular stagnation of subcutaneous tissue → leg ulcers in adults
chronic hypoxia is responsible for a generalized impairment of growth and development
pain crises/vasoocclusive crises—most important complication
mplication
Episodes of hypoxic injury and infarction causing severe pain in the area
Often no predisposing cause is identified
infection, dehydration, and acidosis all favor sickling
Bones, lungs, liver, brain, spleen, penis
Bone crises are common in children (difficult to distinguish from acute osteomyelitis)
Can manifest as dactylitis or acute chest syndrome
Dactylitis/hand foot syndrome
Vasoocclusive infarcts in the bones leading to swollen hands and feet
extremely common and often difficult to distinguish from acute osteomyelitis
Common presenting sign in African American infants ∼ 6 months old with sickle cell disease
Acute chest syndrome
Vasoocclusive crisis of the lungs in sickle cell patients
Fever, cough, chest pain, pulmonary infiltrates
Most common cause of death in adult patients with sickle cell anemia
Often precipitated by pneumonia
Causes vasodilation, slowing blood flow which increases dehydration, acidemia and deoxygenation creating a vicious cycle
May require transfusion or prove fatal
Priapism
Occurs in 45% of males after puberty and may lead to hypoxic damage and erectile dysfunction
Sickle cell anemia: sequesteration crises
Children with intact spleens have massive entrapment of sickle RBCs → rapid splenic enlargement, hypovolemia and possible shock
May require transfusion or prove fatal
Sickle cell anemia: sequesteration crises
Sickle Cell Anemia: Sequestration Crises
Children with intact spleens have massive entrapment of sickle RBCs → rapid splenic enlargement, hypovolemia and possible shock
May require transfusion or prove fatal
Aplastic crises
Parvovirus B19 infection of red cell progenitors causes a transient cessation of erythropoiesis and sudden worsening of anemia
Can occur in patients with sickle cell anemia
Hyposthenuria
Hypertonicity of the renal medulla can cause damage leading to the inability to concentrate urine
This increases the risk of dehydration and its attendant risk
Infections
Increased risk of infection due to encapsulated pathogens: Strep pneumo, haemophilus influenzae
Increased risk of S. Typhi osteomyelitis, S. Pneumoniae and H. Influenzae
Haemophilus influenza
Most common cause of death in children with sickle cell anemia
Can cause septicemia and meningitis
Vaccinate children to reduce this risk
Prophylactic antibiotics may be necessary
Diagnosis
Based on clinical signs and symptoms and laboratory testing of hemoglobin
Metabisulfite screen is (+) in both disease and trait
Electrophoresis
Prenatal amniocentesis or chorionic biopsy
Prognosis
90% survive to age 20, 50% survive to 50+
Treatment
Hydroxyurea (DNA synthesis inhibitor) increased HbF and has an anti-inflammatory effect
HSC transplant is possible
Thalassemia
Heterogenous group of disorders due to inherited mutations that decrease synthesis of either the α-globin or β-globin chains that compose adult HbA (α2β2)
2 α-globin genes (4 alleles) on chromosome 16
1 β-globin gene (2 alleles) on chromosome 11
Causes anemia, tissue hypoxia and RBC hemolysis due to the imbalance of globin chain synthesis
Anemia due to decreased RBC production and decreased RBC lifespan
Heterozygotes are protected from falciparum malaria
B thalassemia
dysregulation of the synthesis of β-globin chains
Under hemoglobinized microcytic, hypochromic RBCs with subnormal O2 transport capacity
RBC life span is diminished due to imbalance of α and β globin synthesis
Reduced beta-globin chain synthesis from beta-thalassemia leads to RBC microcytosis, hypochromia, ineffective erythropoiesis, and excessive iron absorption. There is chronic anemia, because the major hemoglobin A1 [α2β2] is produced insufficiently. The nature of the mutation, typically affecting RNA transcript production, determines the severity of the disease.
Anemia b thalassemia
Ineffective erythropoiesis
Extravascular hemolysis due to sequestration
B^0 thalassemia
Absent synthesis of the β-globin chain
Most common mutation: chain terminator creating premature stop codons
B^+ thalassemia
Absent synthesis of the β-globin chain
Most common mutation: chain terminator creating premature stop codons
Pathogenesis b thalassemia
unpaired α chains precipitate within RBC precursors → insoluble inclusions
Inclusions cause membrane damage → precursor apoptosis
In severe disease this causes ineffective erythropoiesis
Those not destroyed are released with inclusions and membrane damage and are susceptible to splenic sequestration and extravascular hemolysis
Severe cases b thalassemia
Massive erythroid hyperplasia due to ineffective erythropoiesis
Expansion causes erosion of the bony cortex impairing bone growth and creating skeletal abnormalities
crew cut and chipmunk facies?
Extensive extramedullary hematopoiesis: liver, spleen, lymph nodes
Severe cachexia as nutrients is stolen from tissues that are O2 starved for erythroid progenitors
Excessive absorption of dietary iron due to suppressed hepcidin and in combination with repeat transfusions leads to iron overload (secondary hemochromatosis)
ineffective erythropoiesis suppresses hepcidin, a critical negative regulator of iron absorption
increased absorption of iron from the gut with low hepcidin levels
decreased absorption of iron from the gut with high hepcidin levels
Hereditary hemochromatosis results from increased iron absorption with markedly increased iron stores. The iron accumulation in tissues results in manifestations such as hepatomegaly, skin pigmentation, diabetes mellitus, heart disease, arthritis, and hypogonadism.
A 46-year-old man has had worsening arthritis and swelling of his feet for the past year. On physical examination he has rales audible in all lung fields. A chest radiograph shows cardiomegaly and pulmonary edema. Laboratory studies show Hgb 13.0 g/dL, Hct 39.1%, MCV 86 fL, platelet count 255,500/uL, and WBC count 5920/uL. His serum iron is 406 microgram/mL with iron binding capacity 440 microgram/mL and ferritin 830 ng/mL (storage form of iron is markedly elevated). Which of the following is the most likely diagnosis?
Hereditary Hemochromatosis
Morphology b thalassemia
Anisocytosis (variable RBC size)
Poikilocytosis (variable shape)
Hypochromic
Target cells: hemoglobin collects in the center of the cell
Basophilic stippling == indicator of toxic injury to RBCs
Fragmented RBCs
Massive erythroid hyperplasia (crewcut + chipmunk facies)
Iron overload: hemosiderosis and 2° hemochromatosis, affecting the heart, liver and pancreas mostly
B thalassemia major-high HbF
Individuals with alleles
Β+ / β+
Β+ / β°
Β° / β°
have a severe, transfusion dependent anemia beginning at 6-9 months of age
Hemosiderosis may occur secondary to transfusions
Epidemiology b thalassemia major
Common in Mediterranean countries, Africa, Southeast Asia
Clincial b thalassemia major
major red cell hemoglobin is HbF (markedly elevated)
HbA2 levels are sometimes high but more often are normal or low
high HbA2 is a β-thalassemia minor/trait
high HbF is a β-thalassemia major
Extravascular hemolysis
*Hepatosplenomegaly (extramedullary hematopoiesis)
Massive erythroid hyperplasia of skull (crewcut) and face (chipmunk facies)
Risk of aplastic crisis due to parvovirus B19
Treat and prognosis b thalassemia
Requires chronic transfusions: survival to 3rd decade
Predisposed to secondary hemochromatosis (cardiac problems)
May require iron chelators (EDTA)
May cure with HSC transplant
Untreated = early death due to anemia
B thalassemia minor trait
Individuals with alleles (heterozygous)
Β+ / βwild-type
Β° / βwild-type
Much more common
Mild, asymptomatic, microcytic, hypochromic anemia
Usually asymptomatic heterozygous carriers
B thalassemia minor trait clincial
Clinical
Mild anemia with hypochromic, microcytic, basophilic stippling and target cells in peripheral blood
Mild erythroid hyperplasia
Can be mistaken for iron deficiency anemia in pregnancy as they were asymptomatic before
B thalassemia minor trait diagnosis
Increased HbA2
Normal HbF
high HbA2 is a β-thalassemia (minor/trait)
high HbF is a β-thalassemia (major)
Must confirm diagnosis to rule out iron deficient anemia
B thalassemia intermedia
Heterozygous variant of moderate severity
May have
Two defective β-globin genes and an α-globin gene defect which improves erythropoiesis effectiveness and red cell survival by lessening the imbalance in α- and β-chain synthesis
One defective β-globin gene and extra copies of α-globin genes, worsening the imbalance
Not transfusion dependent
A thalassemia
Inherited gene deletion → absent or reduced synthesis of α-globin chains
Infants: unpaired γ-globin chains form tetramers call “Hemoglobin Barts”
Adults: unpaired β-globin chains form tetramers called “HbH”
β and γ chains are more soluble than free α-globin chains, and form more stable homotetramers –> hemolysis and ineffective erythropoiesis are less severe than in β-thalassemia
A thalassemia 4 alleles on chromosome 16
4 alleles on chromosome 16
1 allele deleted = asymptomatic
2 allele deleted = mild anemia with increased RBC count
Cis deletion *Asian
children of affected individuals are at increased risk of clinically significant α-thalassemia
symptomatic α-thalassemia is fairly common
Trans deletion *African American
symptomatic α-thalassemia is uncommon
A thalassemia 3 alleles deleted
Severe anemia HbH tetramers
A thalassemia 4 alleles deleted
4 alleles deleted = lethal in utero (hydrops fetalis) – “Hemoglobin Barts”
Silent carrier state
Deletion of a single gene causing a barely detectable reduction in globin chain synthesis
patients are asymptomatic with slight microcytosis
A thalassemia trait
Cis deletion: Asians
Α/α : -/-
*offspring are at significant risk of disease
Trans deletion: African Americans
Α/- : α/-
Microcytosis with minimal anemia and no abnormal physical signs and symptoms (asymptomatic)
α-thalassemia trait is clinically similar to β-thalassemia minor
Hemoglobin H disease HBH
Deletion of three genes
Most common in Asian populations
Tetramers of β-globin chains form == called HbH
HbH has extremely increased affinity for O2 (not useful for O2 delivery to tissues)
tissue hypoxia disproportionate to the level of Hb
HbH is prone to oxidation –> precipitation and intracellular inclusions promoting RBC sequestration and phagocytosis in the spleen
Resembles β-thalassemia intermedia
Does not require transfusions
Hydrops fetalis
Deletion of all 4 genes
tetramers of γ-globin chains form called Hemoglobin Barts in the fetus
Greatly increased affinity for O2 = tissue hypoxia
Fetal distress beginning 3rd trimester
Intrauterine fetal transfusion can save infants that used to die in utero
Severe pallor, generalized edema and massive hepatosplenomegaly – similar to hemolytic disease of newborn
Lifelong dependence on transfusions (risk of iron overload)
HSC transplant is curative
Paroxysmal nocturnal hemoglobinuria
Acquired mutation of phosphatidylinositol glycan complementation Group A gene (PIGA)
Only hemolytic anemia caused by an acquired genetic defect
Enzyme is essential for synthesis of certain membrane associated complement regulatory proteins
Absent glycosylphosphatidylinositol (GPI) = cells susceptible to destruction by complement
Mutations paroxysmal nocturnal hemoglobinuria
PIGA gene is X-linked and subject to lionization
A single acquired mutation –> deficiency in production of GPI which attaches important proteins to the cell membrane allowing complement dysregulation
PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity
CD55 (DAF) decay accelerated factor
CD59: membrane inhibitor or reactive lysis (MIRL; most important)
Membrane inhibitor of reactive lysis
Potent inhibitor of C3 convertase
Prevents spontaneous activation of the alternative complement pathway
C8 binding protein
Clincial PNH
inical
RBCs are abnormally susceptible to lysis or injury by complement
Intravascular hemolysis caused by the C5b-C9 membrane attack complex
25% of cases = paroxysmal and nocturnal
Shallow nighttime breathing = respiratory acidosis which activates complement
Chronic hemolysis is typical = mild to moderate anemia
Heme iron is lost in urine (hemosiderinuria) eventually leads to iron deficiency (can exacerbate the anemia
Complications
RBCs are abnormally susceptible to lysis or injury by complement
Intravascular hemolysis caused by the C5b-C9 membrane attack complex
25% of cases = paroxysmal and nocturnal
Shallow nighttime breathing = respiratory acidosis which activates complement
Chronic hemolysis is typical = mild to moderate anemia
Heme iron is lost in urine (hemosiderinuria) eventually leads to iron deficiency (can exacerbate the anemia)
Complications
Leading cause of disease-related death: Venous thrombosis (40%) of the hepatic, portal or cerebral veins
5-10% develop acute myeloid leukemia (AML) or myelodysplastic syndrome
hematopoietic stem cells have suffered some type of genetic damage
Diagnosis PNH
Flow cytometry detection of RBCs deficient in GPI linked proteins (CD59
Treatment PNH
Eculizumab (prevents C5 conversion to c5a)
Decreases hemolysis, risk of thrombosis, and required transfusions
Increases risk of meningococcal infection
Immunosuppression may benefit some patients with marrow aplasia
Definitive treatment: HSC transplant
A 42-year-old man has had multiple episodes of painful red nodules on his skin from dermal venous thrombosis, as well as abdominal pain from mesenteric vein thrombosis over the past year. He notes passing darker urine. Laboratory studies show Hgb 9.4 g/dL, Hct 29.2%, MCV 100 fL, platelet count 215,000/microliter, and WBC count of 8800/microliter. His RBCs show increased sensitivity to complement lysis. Flow cytometry is most likely to show reduction in which of the following markers on his RBCs
(D) CORRECT. He has paroxysmal nocturnal hemoglobinuria (PNH) an acquired stem cell disorder from mutation in the PIGA gene that renders RBCs very sensitive to complement lysis, as well as thrombosis in unusual veins. There is also risk for leukemia. The RBC markers CD55 and CD59 are reduced with PNH
Immunohemolytic anemias
Immunohemolytic Anemias (IHAs) – most physicians call these “autoimmune hemolytic anemias”
Definition
antibodies bind to RBCs causing their premature destruction
Diagnosis immunohemolytic anemia
Diagnosed via the presence of antibodies and/or complement on RBCs from the patient
Direct Coombs antiglobulin test: patient’s RBCs are mixed with donor serum – this is a screen
agglutination means patient has RBCs coated with antibodies
Indirect Coombs antiglobulin test: patients serum is mixed with donor RBCs
agglutination means patient has antibodies to patient’s RBCs
Direct coombs antiglobulin test
Direct Coombs Antiglobulin Test
patient’s RBCs are mixed with antibodies specific for human immunoglobulin or complement
(+) if the patient’s RBC’s have immunoglobulins already attached to them, which are then attacked by the antihuman antibodies added
If immunoglobulin or complement is present on the RBC surface agglutination occurs (clumping)
Indirect Coombs Antiglobulin Test
Commercial RBCs with defined Antigens are mixed with the patient’s serum
(+) if patient’s serum has immunoglobulins against the Antigens on the commercial/donor RBCs
Characterizes the antigen target and temperature dependence of the responsible antibody
Treatment:
Remove initiating factors, immunosuppression or splenectomy
Warm antibody type of immunohemolytic anemia
Most common type of immunohemolytic anemia
50% are idiopathic (and poorly understood).
Also caused by drugs, autoimmune disorders (especially SLE), lymphoid neoplasms
Pathogenesis warm antibody type of immunohemolytic anemia
Usually due to IgG (or less frequently IgA) antibodies – “warm weather is Great”
Extravascular hemolysis
IgG coated RBCs bind Fc receptors on phagocytes
Partial phagocytosis occurs as RBC membrane is removed
RBC’s become spherocytes that are sequestered in the spleen = splenomegaly
Antigenic drugs
Offending agent binds to RBCs after an IV infusion
1-2 weeks after initiation of therapy, hemolysis occurs due to antibody binding to the drug or a complex of the drug and RBC membrane
Extravascular hemolysis within phagocytes (most common as the antibodies act as opsonins)
Commonly due to penicillins and cephalosporins
Tolerance breaking drugs
olerance Breaking Drugs
Offending agents induce production of antibodies against RBC Antigens
Particularly the Rh Antigens
10% of patients taking α-methyldopa develop auto-antibodies (direct Coombs test) and 1% have clinically significant hemolysis
Cold agglutination type of immunohemolytic anemia
IgM antibodies bind RBCs avidly at low temperatures (0˚C to 4˚C) – “cold weather is MMMiserable”
Acute: self-limited, rarely induce clinically important hemolysis
appear transiently following infection (e.g. mycoplasma pneumonia, EBV, CMV, influenza virus, HIV
Chronic cold agglutination type of immunohemolytic anemia
Chronic: symptomatic
Idiopathic or associated with B cell neoplasms (eg CLL)
chronic cold agglutinin immunohemolytic anemia caused by IgM antibodies is more difficult to treat
Clincial cold agglutination type of immunohemolytic anemia
happens in extremity vascular beds where the temperature may fall below 30°C
can lead to obstruction → pallor, cyanosis and Raynaud’s
Minimal complement-mediated hemolysis, but opsonized cells are phagocytosed in spleen, liver and bone marrow
