Ch 14 Flashcards
1
Q
_ is defined as a reduction of total circulating red cell mass and reduces the oxygen-carrying capacity leading to hypoxia
A
Anemia
2
Q
Anemia is usually diagnosed based on reduction in _ and _
A
hematocrit and hemoglobin
3
Q
Acute blood loss are mainly due to loss of 1 volume and clinical feature depend on _ of hemorrhage and whether it’s external or internal.
A
intravascular
rate
4
Q
In Anemia due to acute blood loss, the reduction in oxygenation triggers increased secretion of _ 1_which stimulates the proliferation of 2 in the marrow.
A
- Erythropoietin
2. committed erythroid progenitos (CFU-E)
5
Q
In anemia due to acute blood loss, the CFU-E that’s released takes about _ days for the progeny to mature and appears as newly released _ in peripheral blood
A
5
reticulocytes –> peaks to 10-15% of peripheral RBC by day 8
6
Q
In chronic blood loss, anemia will occur only if
A
rate of loss exceeds the marrow regenerative capacity or when iron reserves are depleted
7
Q
most hemolytic anemias have what features in common?
A
- shortened red cell life span below 120 days
- elevated EPO levels and increased erythropoiesis
- accumulation of Hb degradation products (e.g. bilirubin)
8
Q
Hemolysis can be extra or intravascular. What are clinical features of extravascular hemolysis?
A
Extravascular hemolysis usually occurs in macrphages of spleen and clinical features include anemia, splenomegaly, and jaundice; modest reductions in haptoglobin
9
Q
Clinical features of intravascular hemolysis
A
- anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, and jaundice
- reduced serum haptoglobin
10
Q
Morphology of hemolytic anemia
A
- increased numbers of erythroid precursors (normoblasts) in marrow
- prominent reticulocytosis in peripheral blood due to increased EPO
- accumulation of hemosiderin in spleen, liver, bone marrow
11
Q
List major inherited forms of hemolytic anemia
A
- Hereditary spherocytosis
- G6PD def
- glutathione synthetase def
- Pyruvate kinase def
- hexokinase def
- Sickle Cell disease
- Thalassemia
- Paroxysmal nocturnal hemoglobinuria
- immunohemolytic anemia
12
Q
_ is an AD (commonly) 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
A
Hereditary spherocytosis (HS)
13
Q
Pathophysiology of hereditary spherocytosis
A
Mutation leading to deficiency of ankyrin, band 3, spectrin or band 4.2, proteins that are involved in tethering interaction and stabilizing the lipid bilayer –> reduce the assembly of skeleton, destabilizing he overlying plasma membrane. Leads to increased fragility with loss of membrane blebs and cells have a spheroid shape due to lack of spectrin
14
Q
Morphology of Hereditary spherocytosis
A
Spherocytic RBC are small and lack central pallor; reticulocytosis and marrow erythroid hyperplasia.
- Cords of Billroth shows prominent erythrophagocytosis
15
Q
Diagnosis of hereditary spherocytosis is based on what factors?
A
- family history
- hematologic findings
- increased RBC osmotic fragility
- increased RBC Hg concentration
- anemia (normocytic)
- moderate splenomegaly
- jaundice
16
Q
Pts with hereditary spherocytosis generaly h ave a stable clinical course due to compensatory increased EPO, but sometimes the course is punctuated by _ and usually triggered by an acute parvovirus
A
aplastic crises
17
Q
What is the normal function of glucose-6-phosphate dehydrogenase (G6PD) ?
A
An enzyme in the hexose monophosphate shunt that reduces micotinamide adenine dinucleotide phosphate (NADP) to NADPH; in turn; NADPH reduces RBC glutathione, providing protection against RBC oxidative injury
18
Q
Pathophysiology of hemolytic anemia due to G6PD
A
- oxidant stress (inflammation, drugs, foods such as fava beans) causes hemoglobin sulfhydryl cross-linking and protein denaturation. The altered Hb precipitates as Heinz bodies that can cause direct hemolysis; and precipitated Hb can attach to inner cell membrane, reduce deformability and increase susceptibility to splenic macrophage destruction
19
Q
Inheritance pattern of G6PD
A
X-linked recessive
- heterozygosity provides protection against malaria
20
Q
Which form of G6PD is responsible for most clinical significant heolytic anemias?
A
G6PD(-) and G6PD Mediterranean
21
Q
Clinical features of G6PD deficiency induced hemolytic anemia
A
- usually asymptomatic (w/o inducing stimuli)
- With oxidative stress pt experience fatigue, jaundice, back pain, dark urine
- in Serology: low Hb; high reticulocyte and unconjugated bili and low serum heptoglobin
- Blood smear: Heinz bodies and Bite cells (looks like something bit a piece of the RBC off)
22
Q
_ is a hereditary heoglobinopathy caused by a point mutation in beta-globin that promotes polymerization of deoxygenzated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage
A
Sickle Cell disease
23
Q
Normal adult RBC contains mainly HbA (a2b2), along with some HbA2 (a2d2) and fetal RBC has HbF; a2y2) In sickle disease, where is the point mutation and what’s replaced for what?
A
Point mutation is on the sixth codon of b-globin that leads to replacement of glutamate residue with a valine residue. Result in mutant Hb substitutes for normal B-globin to generate HbS
24
Q
Inheritance pattern of Sickle Cell
A
autosomal recessive. heterozygous people are asymptomatic
25
Pathophysiology of sickle cell
When deoxygenated, HbS polymerizes into long, stiff chains that deform (sickle) RBCs. This in turn causes chronic hemolysis, microvascular occlusion, and tissue damage.
26
What variable affect the rate and degree of sickling?
1. Interaction of HbS with other types of Hb within RBCs as seen in people who are heterozygous, or fetal hb
2. Mean cell heoglobin concentration (MCHC)
3. Intracellular pH
4. Transit time of Red cells through microvascular bed
27
Explain how HbS interacts with normal and fetal hemoglobin. What is HbSC disease?
- Heterozygotes with sickle cell trait, about 40% is HbS and rest are normal HbA and so these people do not sickle except under profound hypoxia.
- HbF inhibits polymerization of HbS and so infants don't experience sickle until about 5-6 months when HbF starts to fall.
- HbC is a variant form of hemoglobin and commonly found where HbS is found. HbC is due to lysine substituted for glutamate. People with HbCS tend to lose salt and water and become dehydrated and IC concentration of HbS increase and sickles termed HbSC disease which is milder than sickle cell disease
28
How does MCHC affect HbS? How does thalassemia affect this?
Increased MCHC (due to dehydration) facilities sickling cuz HbS concentrated increased. Pt with coexistant a-thalassemia (which reduce Hb synthesis) has a milder disease
29
How does intracellular pH affect sickling?
decreased pH reduce O2 affinity of Hb and so increases fraction of deoxygenated HbS at any given O2 tension and augment tendency for sicking
30
How does microvascular transit time affect sicking?
slower transit time increases sickling
31
Explain how sickling cause damage to RBC
- as HbS polymers grow they herniate through membrane skeleton and causes influx of Ca2+, and induce cross linking of membrane proteins and activate ion channels that permits efflux of K and H2O.
- repeated sickling --> RBC become dehydrated, dense and rigid even when fully oxygenated -> hemolysis and removed by mononuclear phagocytes
32
what is the most clinically important aspect of sickle cell?
Microvascular occlusion --> tissue hypoxia and infarction.
| - dependant on RBC stickiness rather than on the sickle shape
33
Morphology of Sickle cell disease
- peripheral blood: variable numbers of sickled cells, reticulocytosis and target cells due to RBC dehydration
- bone marrow is hyperplastic
- Crewcut skull on x ray
- Howell-Jolly bodies seen in some red cells due to asplenia
- in childhood slight slenomegaly
- Autosplenectomy in adulthood (fibrosis, progressive shrinkage)
34
Clinical features of sickle cell disease
- moderately severe hemolytic anemia and associated with reticulocytosis, hyperbili, and presence of irreversible sickled cells
- vaso-occlusive cises aka pain crises (due to episodes of hypoxic injury and infarction
- In kids commonly present as painful bone crises and manifests as hand-foot syndrome
- acute chest syndrome involving lung (fever, cough, chest pain, and pul infiltrates
- Priapism: hypoxic damage and ED
- vascular obstruction can cause stroke and retinopathy leading to loss of vision acuity/blindness
- chronic tissue hypoxia --> impairment of growth and development, hypertonicity in renal medulla leading to hyposthenuria
- susceptibility to infection with encapsulated organisms (pneumococus, h.flu)
35
Modes of diagnosis of sickle cell disease
- Labs (normocytic or microcytic anemia): increased reticulocyte and low haptoglobin
- Histo: sickling, howell-holly bodies, bone marrow hypercellularity
- Xray: chest syndrome, hair-on-end/crew cut skull
- Eletrophoresis: HbS, increased HbF, no HbA
- Metabisulfite screen: induce sickling at any HbS concentration; positive in sickle cell trait and sickle cell anemia
36
Hydorxyurea is the mainstay tx of sickle cell. How does it work?
- DNA synthesis inhibitor
- increase red cell HbF levels and decrease WBC production
- Has antiinflammatory effects
37
_ are a heterogenous group of disorders caused by inherited mutations that decrease the synthesis of either the a-globin or b-globin chains that compose adult hemoglobin, HbA (a2b2), leading to anemia, tissue hypoxia, and red cell hemolysis related to imbalance in globin chain synthesis
Thalassemia syndromes
38
Alpha chains inHbA are encoded by a-globin genes on what chromosome?
Beta-globin?
Alpha globin in 16; beta in 11
39
Thalassemia syndromes are common in what part of the world?
-Mediterranean countries, parts of africa and southeast asia
40
Beta-thalassemia are caused by mutations that diminish synthesis of beta-globin chains. Common mutations leading to this include _
- splicing mutations: most common cause of beta+-thalassemia
- Promoter region mutations, associated with beta+ thalassemia
- Chain termination mutations: common cause of Beta(0) thalassemia
41
Imapired beta globin synthesis results in anemia in what two mechanisms?
1. Deficit in HbA synthesis produces underhemogloinized hypochromatic microcytic red cells with subnormall oxygen transport capacity
2. imbalance in alpah and beta globin synthesis --> diminish survival of Red cells and precursors --> ineffective erythropoiesis --> extravascular hemolysis
42
In severe beta-thalaseemia, ineffective erythropoiesis leads to what two important consequences?
1. severe uncompensated anemia leads to massive erythroid hyperplasia in marrow and extensive extramedullary hematopiesis. The expanding mass of red cell precursor erodes bony cortex and impairs bone growth and produce skeletal abnormalities; and extramedullary hematopoiesis in liver, spleen, lymph nodes steals nutrients from those sites and leads to severe cachexia
2. excessive absorption of dietary iron cuz hepcidin is suppressed -- >excess iron accumulation in parenchymal organs esp liver --> secondary hemochromatosis
43
Classify the types of beta thalassemia and their salient feature
1 gene involvement: called B-thalassemia minor (chain be be truncated, B+, or deleted, B0); B/B+ is the most benign form; may be caused by mutation in Kozak consensus sequence
2 gene involvement: called B-thalassemia major; B0/B0 is the most severe form; a,a,a,a hemoglobin present
44
B-Thalassemia Major:
A. most common in what part of the world?
B. Manifests by what age?
C. salient clinical findings
A. Mediterranean countries, part of Africa and southeast Asia
B. by 3-6 months when HbF starts to go down
C. severe microcytic anemia requiring transfusion; in untransfused Hb is 3-6; red cells lack HbA in B0/B0; marked elevated HbF; chipmunk facies due to secondary extramedullary hematopoiesis; HSM; cardiac disease resulting from progressive iron overload and hemochormatosis; survival to third decade possible with iron chelator and transfusion; bone marrow transplant is the possible cure
45
Morphology of B-thalassemia major
- anisoscytosis and poikilocytosis, microcytosis and hypochromia
- marked expansion of marrow with erosio nof cortical bone and new bone formation.
- exramedullary hematopoiesis common with splenomegaly
- bones of face and skull --> crewcut appearance on skull
- hemosiderois and secondary hemochormatosis
46
Peripheral blood finding of B-thalassemia minor
minor abnormalities, including hypochromia, microcytosis, basophilic stippling, and target cells
47
Electrophoresis finding of B-thalassemia minor
increased HbA2 (a2d2 hemoglobin)
48
B-thalassemia minor is usually asymptomatic, but it's important to recognize the b-thalassemia trait becuase _
1. superficially resembles hypochromic microcytic anemia of iron def
2. genetic counseling
49
a-thalassemia are caused by inherited deletion that result in reduced or absent synthesis of a-globin chains. A. normally how many a-globin genes are there and what is severity dependent on?
four alpha chains. severity of disease depends on how many a-globin genes are affected
50
what is hemoglobin Barts?
Seen in newborns with a-thalassemia where excess unpaired y-globin chains form y4 tetramers
51
HbH is seen in which form of thalassemia?
A-thalassemia. due to excess b-globin chains that forms B4 tetramers
52
what is a-thalassemia trait?
- either one chromosome has both a-globin genes or each chromosome has a deletion of one gene (2 gene deletion)
- clinical picture similar to b-thalaseemia minor (mild anemia with RBC hyperplasia)
53
What is hemoglobin H (HbH) disease
deletion of three a-globin genes -> suppression of a chain synthesis and formation of unstable HbH tetramers;
- similar to b-thalaseemia intermedia
- severe anemia
54
What form of a-thalassemia causes hydrops fetalis
when all four genes are deleted (A0/A0)
- when fetus starts to make y-globin tetramers (HbBarts), high o2 affinity prevents O2 release to tissues and is not compatible with life.
55
_ is a disease that results from acquired mutations in phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for synthesis of certain membrane-associated complement regulatory proteins
Paroxysmal nocturnal hemoglobinuria (PNH)
56
In PNH, PIGA mutations leads to deficient expression of a family of proteins normally anchored into cell membrane via _1_. Among the GPI-linked proteins affected includes: 2_. Their deficiency leads to _3_
1. glycosylphosphatidylinositol (GPI)
2. Decay-accelerating factor (CD55), membrane inhibitor of reactive lysis (CD59) and C8-binding protein.
3. RBC hypersensitivity to complement and thus activated and manifests as intravascular hemolysis by C5b-C9 MAC. Granulocyte and platelet GPI-linked protiens are also affected and thus predispose to thrombosis esp in portal, cerebral, and hepatic veins. Thrombosis is the leading close of death
57
Diagnosis and treatment of PNH
- Diagnosis: flow cytometry to detect red cells that are deficiency in GPI-linked proteins such as CD59
- Treatment: Eculizumab to prevent conversion of C5 to C5a. reduce hemolysis and also reduce risk of thrombosis
58
_ are hemolytic anemias caused by antibodies that bind to red cells, leading to their premature destruction
Immunohemolytic anemias
59
Diagnosis of immunohemolytic anemia requires detection of antibodies and/or complements on RBC using what test?
direct Coombs test: pts RBCs are mixed with ab directed against humanimmunoglobulin or complement, with RBC agglutination constituting a positive test
60
Difference between direct and indirect Coombs test
Direct: tests pt's RBC to sera containing ab
Indirect: pt's serum tested for it's ability to agglutinate in commercially available red cells with defined antigens
61
Most common type of immunohemolytic anemia
warm antibody type, half of which are idiopathic (primary) and rest associated with predisposing condition or drugs
62
In warm antibody type immunohemolytic anemia:
A. Is RBC hemolysis intra or extravascular?
B. Which Ig on RBC binds to F receptors on phagocytes leading to hemolysis?
A. extravascular
| B. IgG
63
In drug induced warm antibody type immunohemolytic anemia, what are the two mechanism by which hemolysis is caused?
1. Antigenic drugs: usually presents 1-2 weeks after drug is given (penicillin and cephalosporins) bind to RBC membrane and recognized by antidrug antibodies
2. Tolerance-breaking drugs: a-methyldopa is the prototype, induce produce of antibodies against RBC antigens paritcularly Rh blood group
64
In cold agglutinin type immunohemolytic anemia:
A. caused by which Ig?
B. has association with what microorganisms?
C. Chronic cold agglutinin is associated with what
D. Pathohhysiology of hemolysis
E. Common signs
A. IgM antibody
B. Mycoplasma pneumoniae, EBV, CMV, flu, HIV
C. B cell neoplasms
D. Bindingof IgM to RBC in areas where temp may fall below 30 degree C, such as exposed fingers, toes or ears. IgM binding agglutinates the RBC and fixes complement and as the blood circulates and warms IgM is released usually before complement mediated hemolysis. But the transient interaction of IgM is enough to deposit sublytic quantities of C3b which then leads to removal of RBC by phagocytes in spleen, liver and bone marrow
E. vascular obstruction caused by the agglutinated RBC results in pallor, cyanosis, and Raynauds
65
Cold hemolysin occurs in _1_ where it's capable of cuasing substantial (sometimes fatal) intravascular hemolysis. The autoantibodies are _ 2_that bind to the P blood group antigen at low temp and fix complement and when temp is elevated hemolysis occurs. Most cases occur in kids after viral infection and are transient
1. Paroxysmal cold hemolgobinuria
| 2. IgG
66
Hemolytic anemia resulting from trauma to red cells, the most significant hemolysis caused by trauma to RBC is seen in people with _ 1_ and _2_. Characteristic findings in blood smear includes _
1. cardiac valve prostheses: due to shear forces that create turbulent flow
2. microangiopathic disorders: associated with disseminated intravascular coagulation, but can occur in thrombotic thrombocytopneic purpura (TTP), hemolytic uremic syndrome (HUS), malignant HTN, SLE, and cancer.
3. red cell fragments (schistocytes): burr cells, helmet cells and triangle cells
67
Most common and important anemias associated with red cell underproduction are those caused by _
nutritional deficiencies, followed by secondary to renal failure and chronic inflammation
68
Common to various causes of magablastic anemia is impairment of _
DNA synthesis that leads to ineffective hematopoiesis and distinctive morphologic changes, including abnormally large erythroid precursors and red cells. RNA/protein synthesis are usually normal
69
common causes of megablastic anemia
1. Vit B12 dif (decreased uptake or impaired absorption
2. Folic acid deficiency
3. Unresponsive to Vit B12 or folic acid therapy
1 and 2 are MOST common
70
Morphology of megablastic anemia
- prominent peripheral blood anisocytosis with abnormally large and oval RBC (macro-ovalcytes)
- In the marrow, erythroid precursor nuclear maturation lags behind cytoplasmic maturation; compensatory megablastic hyperplasia
- abnormal granulopoiesis with gaint metamyelocytes and band forms in marrow and hypersegmented neutrophils in peripheral blood
71
_ is a form of megaloblastic anemia caused by an autoimmune gastritis that impairs the production of intrinsic factor, which is required for vitamin B12, uptake from the gut
Percinious anemia
72
Most deficiencies of B12 results from impaired absorption as seen in _
1. achlorhydria - impairs B12 release from R binders
2. Gastrectomy causing loss of IF
3. Pernicious anemia
absorption
4. Malabsorption syndrome
5. Increased requirements (e.g. pregnancy)
6. Resection of distal ileum preventing IF-B12
73
THe fundamental cause of impaired DNA synthesis in vitamin B12 deiciency is _
reduced availability of FH4, most of which is trapped as N5-methyl FH4.
74
In the pathogenesis of percinicous anemia, which antibody is responsible for 75% of cases and blcoks the bending of vitamin B12 to IF
Type I antibody
75
What is type II and Type III antibodies in pernicious anemia directed against?
Type II antibodies block IF or IF-B12 binding to ileal receptor
Type III antibodies directed against parietal protein pump proteins that affect acid secretion
76
Morphology of Pernicious anemia
- Bone marrow shows megaloblastic erythroid hyperplasia, giant myelocytes and metamyelocytes and hypersegmented neutrophils, and large, multilobed nuclei in megakaryocytes
- Atrophic glossitis; the tongue is shiny, glazed and red
- gastric fundal atrophy (intestinalization)
- CNS lesion occur in 75% characterized by demyelination of dorsal and lateral spinal cord tracts
77
Clinical Features of Pernicious anemia:
A. Onset is insidious with symptoms mainly due to _
B. Diagnosis
A. anemia and posterolateral spinal tract involvement (spastic paresis and sensory ataxia
B. presence of megaloblastic anemia, leukopenia and hypersegmented neutrophils, low serum B12 lvels, elevated hmocysteine and methylmalonic acid; confirmed by profound reticulocytosis after parenteral B12 admin; serum anti-IF antibodies
78
Folate def and B12 def causing megablastic anemia have similar pathologic features, except with two key difference such as
1. Gastric atrophy
| 2. Neurologic sequelase of B12 def do not occur
79
Diagnosis of folate def requires demonstration of reduced _
serum or RBC folate
80
Pathogenesis of folic acid deficiency causing megablastic anemia
- Folic acid is absorbed in jejunum and ileum and is used in tetrahydrofolate as coenzyme and is important for DNA and RNA synthesis.
81
Epidemiology of folic acid def
- MOST common vit deficiency in US
- MOST common cause of megablastic anemia
- can manifest after 4 months (depleted storage from liver)
82
Folic acid def is associated with what conditions?
- chronic hemolytic anemias
- Malnutrition: alcoholism, elderly, psychiatric comorbidity
- Pregnancy: increased folate requirement
- Malabsorption: celiac disease, tropical sprue
- Drugs: phenytoin, methotrexate, sulfonamides
83
S/S of folic acid def
- anemia: fatigue, weakness, SOB
| - glossitis, pallor
84
How is folic acid def associated megablastic anemia diagnosed?
- Peripheral blood smear: hypersegmented lobes in neutrophils, macrocytosis
- Serum: decreased folic acid, increased homocysteine; normal methylmalonic acid (MMA) unlike vit 12 def which has increased MMA
- decreased reticulocyte count
- may see pancytopenia
85
The most common nutritional disorder in the world
Iron def anemia
86
Iron balance is maintained by regulating the absorption of dietary iron across
duodenal epithelium
87
Iron def anemia occurs when iron reserves are depleted and it is accompanied by low _, _, and _
serum iron, ferritin, and transferrin saturation levels
88
Morphology of Iron def anemia
hypochromic, microcytic anemia with increased RBC central pallor and poikilocytosis
- marrow: mild to moderate erythroid hyperplasia, with loss of stainable iron in marrow macrophages
89
Clinical Features of iron def anemia
- fatigue and pallor
- depletion of essential iron-contianing enzymes causes alopecia,, koilonychia, and atrophy of tongue and gastric mucosa
- Plummer-Vinson triad of hypochromic microcytic anemia, and atrophic glossitis, and esophgeal webs
90
Alteration in Hepcidin (main regulator of iron) have a central role in diseases involving disturbances of iron metabolism. Give some examples of how
1. anemia of chronic disease caused by inflammatory mediators that increase hepatic hepcidin production
2. mutation in TMPRSS6, which normally suppresses hepcidin production when iron is low. affected pts have high hepcidin leading to reduced iron absorption and failure to respond to iron therapy
3. hemochromatosis where hepcidin activity is low
4. secondary hemochromotosis due to ineffective erythropoiesis such as beta-thalassemia and myelodysplastic syndromes
91
Salient features and characteristics of anemia of chronic disease
- associated with chronic inflammation, infection, neoplasm, elevated IL 6 which increase hepatic hepcidin production and reduce Iron export from duodenual epithelium and macrophages
- low EPO
- low Iron, high ferritin
- normocytic /normochronmic or microcytic/hypochronmic anemia
92
_ is a type of anemia that refers to a syndrome of chronic primary hematopoietic failure and attendant pancytopenia
Aplastic anemia
93
Most known cases of aplastic anemia are due to
- exposure to chemical and drugs including chemo and organic solvent benzene;
- other causes includes viral infection; whole body irradiation and some specific genetic or acquired abnormalities such as Fanconi anemia, telomerase defect
94
Major etiologies of aplastic anemia (2)
1. immune-mediated suppression of marrow progenitors: activated TH1 produce IFNy which suppress and kill hematopoietic progenitors
2. intrinsic abnormality of stem cells
95
Morphology of aplastic anemia
- hypocellular marrow (hematopoietic cells are replaced by fat cells), with secondary effects due to granulocytopenia (infection) and thrombocytopenia (bleeding)
96
Clinical features of aplastic anemia
- insidious with symptoms related to pancytopenia; anemia (weakness, pallor, dyspnea; thrombocytopenia (petechiae, ecchymoses); neutropenia manifest as minor infections
- no splenomgealy
97
Pure red cell aplasia is a form of marrow failure due to
erythroid precursor suppression either associated ith B19 parvovirus infection or autoimmune destruction either due to drugs or disease
98
what is myelophthisc anemia
space occupying lesions (metastic cancer or granulomatous disease) destroy/distort the marrow architecture and depress hematopoiesis; pancytopenia results, often with immature precursors in peripheral blood
99
Prothrombin time (PT) tests what factors? Prolonged PT means what?
- extrinsic and common coagulation pathways.
| - prolonged PT can result from deficiency or dysfunction of factor V, VII, X, prothrombin, and fibrinogen
100
PTT tests for what factors? Prolonged PT means what
- Intrinsic and common clotting pathways
| - prolongation of PTT means def or dysfunction of V, VIII, IX, X, XI, or XII, prothrombin, or fibrinogen
101
Bleeding disorders caused by vessel wall abnormalities are relatively common but usually cause only _
petechia and purpura without serious bleeding. Platelet counts and coagulation and bleeding time are typically normal
102
Common causes of bleeding disorder caused by vessel wall abnormalities
1. Infection (meningococcus and richettsia) - microvascular damage (vasculitits) or IDC
2. Drug reaction: immune deposition and hypersensitivity vasculitis
3. Poor vascular support: abnormal collagen synthesis (scurvy, ehlers-danlos), loss of perivascular supporting tissue (Cushing), or vascular wall amyloid deposition
4. Henoch- Schonlein purpura: systemic hypersensitivity due to immune complex deposition
5. Hereditary hemorrhgic telangiectasia (osler-weber-Rendu syndrome): AD disorder characterized by dilated, thin-walled vessels
103
Common causes of thrombocytopenia
1. Decreased production due to ineffective megakaryopoiesis (HIV, myelodysplastic syndrome) or generalized marrow disease (aplastic anemia, cancer)
2. Decreased survival: DIC, immune mediated destruction,
3. Sequestration in red pulp of enlarged spleens
4. Dilution due to masive tansufsion
104
Chronic immune thrombocytopenia purpura (ITP) is caused by _
autoantibodies to platelets; primary or in setting of exposure or pre existing conditions
105
Pathogenesis of ITP
platelet autoantibodies are usually directed toward one of two platelet antigens -- the platelet membrane glycoprotiens complexs IIb/IIIa or Ib/IX. Destruction of antibody-coated platelets occurs in spleen, and splenectomy is beneficial
106
Clinical features of ITP
- usually seen in women younger than 40
- long history of easy bruising or
- cutaneous bleeding --> petechiae
- initially: melena, hematuria, or heavy mense
- bleeding time is prolonged; prothrombin and partial thromboplastin time are normal;
- most pts respond to glucocorticoids, some require splenectomy or immunomodulation
107
acute immune thrombocytopenic purpura (Acute ITP) is self-limited disorder usually seen in kids and usually due to _
after viral infection; platelet destruction is due to transient production of anti-platelet autoantibodies
108
Drug induced thrombocytopenia occurs when drugs act as _
haptens on platelet proteins or participate in formation of immune complexes that deposit on platelet surfaces; antibodies to drugs or modified platelet molecules then cause platelet removal via macrophages ingestion
109
Heparin induced thrombocytopenia (HIT) comes in two flavors: type I and type II thrombocytopenia. State cause of each
type I: occurs rapidly after onset of therapy most likely from direct platelet-aggregating effect on heparin. Of little clinical significance and resolves
Type II: less common but serious. occurs 5-14 days after therapy and leads to venous and arterial thrombosis
110
HIV associated thrombocytopenia is due to both diminished platelet production and increased destruction. Explain
Megakaryocytes express both CXCR4 and CD4 and thus can be directly infected by HIV and infected cells are prone to apoptosis and defective platelet production.
- HIV also dysregulates B cells and leads to anti-platelet autoantibodies production and thus premature destruction
111
Thrombotic microangiopathies which includes thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are characterized by what common findings?
B. Caused by?
C. Clinical manifestation are due to _
D. TTP is associated with inherited def in _ which limits size of vWF. in Acquired form of TTPpts often have antibodies directed against _
E. HUS most commonly follows _ which injures endothelial cells and promotes dysregulated platelet activation and aggregation
F. TTP is common in
G. HUS is common in
H. effective treatment for both
A. thrombocytopenia,
- microangiopathic hemolytic anemia
- fever
- transient neurologic deficits (in TTP) or renal failure in HUS
B. Caused by excessive platelet activation
C. clinical manifestation are due to widespread hyaline microthrombi in arterioles and capillaries composed of dense aggregates of platelets and fibrin
D. ADAMTS13
E. infection with verotoxin-producing E Coli
F. women
G. kids and elderly during outbreaks of food poisoning
H. plasma exchange or plasmapheresis
112
List and describe common congenital defects that leads to bleeding disorders related to defective platelet functions.
1. Defective platelet adhesion: AR disorder Bernard-Soulier syndrome caused by deficient platelet membrane glycoprotein complex GpIb-Ix
2. Defective platelet aggregation: Glanzmann thrombasthenia, AR disorder caused by deficiency of platelet membrane glycoprotein GpIIb-IIIa
3. Disorders of platelet secretion of prosglandins and/or granulebound ADP that promote further aggregation
113
List and describe common acquired defects that leads to bleeding disorders related to defective platelet functions.
1. Aspirin: inhibits cyclooxygenase and can suppress the synthesis of thromboxane A2.
2. Uremia: causes defects in platelet adhesion, granule secretion, and aggregation
114
Hemorrhagic diatheses related to abnormalities in clotting factors differs from that seen with platelet deficiencies. Name two differences
1. Spontaneous petechiae or purpura is uncommon, more often, bleeding manifests as large ecchymoses or hematomas after injury or as prolonged bleeding after laceration or surgery
2. Bleeding into GI and urinary tracts, and particularly into weight bearing joints (hemarthrosis) is common
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Causes of acquired deficiencies in clotting factors _
1. Vit K def --> depressed synthesis of factors II, VII, IX, and X and protein C
2. Liver failure --> def synthesis of multiple coagulation factors
3. DIC --> def in multiple coagulation factors
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Hereditary deficiencies of clotting factors typically affect a single clotting factor. Examples include:
The most common inherited disorders are heophilia (A and B) and von Willebrand disease
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Link between Factor VIII-vWF complex and disease
The factor VIII-vonWillebrand factor complex need each other to stabilize each other. Deficient levels of vWF leads to commensurate reductions in factor VIII. VIII is needed for factor IXa activation of factor X; factor VIII def causes classic hemophilia A.
- vWF mediates platelet adhesion to subendothelial matrix by bridging platelet glycoproteins Ib-IX and collagen.
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Most common heritable bleeding disorder
Von Willebrand disease, autosomal dominant
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S/S of von willebrand disease
- mucocutaneous bleeding: epistaxis, gingival bleeding, petechiae, easy bruising, menorrhagia
- increased bleeding after aspirin use
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There are three types of Von willebrand disease. Differentiate each type
- Type I and 3 are associated with reduced levels of vWF.
- Type 1 is autosomal dominant and most common and clinically mild.
- Type 3 is uncommon and autosomal recessive variant associated with marked vWF def and a severe phenotype
- Type 2 is autosomal dominant caused by qualitative defects in vWF. Type 2A is most common; vWF levels are normal, but ability to form most active high-molecular-weight multimer is defective, leading to functional deficit. Pts have mild to moder bleeding
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How is von willebrand disease diagnosed?
- Normal or increased PTT ( like hemophilia)
- normal PT
- increased bleeding time (like hemophilia)
- decreased vWF antigen
- Ristocetin cofactor assay shows decreased platelet agglutination
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_ is the most common hereditary disease associated with life-threatening bleeding.
Hemophilia A, X-linked
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Hemophilia A is characterized by reduced amount and/or activity of which factor?
VIII
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Symptomatic patients with hemophilia presents as _. B. how is diagnosis made?
C. treatment
- massive hemorrhage after trauma or operative procedures
- easy bruising, hemoarthroses, soft tissue bleeding
- spontaneous hemorrhages in regions of body normally subject to trauma; this can lead to progressive, crippling deformities
- increased partial thromboplastin time (intrinsic pathway defect)
B. assay for factor VIII
C. replacement therapy with recombinant factor VIII or VIII concentrates
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Hemophilia B is also X linked recessive but is caused by factor _ deficiency
IX
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Both Hemophilia A and B lead to inadequate generation of what factor?
thrombin
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_ is thrombohemorrhagic disorder characterized by excessive activation of coagulation leading to formation of thrombi in the microvasculature and symptoms are related to tissue ischemia and/or bleeding caused by consumption of clotting factors or activation of fibrinolytic pathways
Disseminated Intravascular Coagulation
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Two major mechanism of DIC
1. release of tissue factor or thromboplastic substances into circulation
2. Widespread endothelial cell injury
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Examples of thromboplastic substances causing DIC
- placenta or amniotic fluid
- granules of leukemic cells in acute promyelocytic leukemia
- mucus released from certain adenocarcinoma
- bacterial endotoxins that activate monocytes to release TNFa
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Examples of things that can cause widespread endothelial cell injury leading to DIC
- antigen-antibody complex deposition (SLE)
- hypoxia
- acidosis
- temperature extremes
- infection (meningoocci, rickettsiae)
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Morphology of DIC
- microthrombi, with infarction, and in some cases, hemorrhages,
- in lungs, oalveolar capillary microthrombi can lead to ARDS.
- in adrenals, DIC leads to Waterhouse-Friderichsen syndrome seen in meningooccemia
- SHeehan postpartum pituitary necrosis is a form of DIC compicating labor and delivery
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how is DIC diagnosed?
- Labs: elevated PT, PTT, bleeding time, fibrin split products, D dimers; decreased platelets and plasma fibrinogen
- blood smear will show shistocytes
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Clinical features of DIC
- 50% occurs in obstetric pts with pregnancy complications --> bleeding commonly;
- Others: carcinomatosis (thrombosis commonly), sepsis, and trauma
- Microangiopathic hemolytic anemia
- Respiratory symptoms
- neurologic signs and symptoms
- oliguria and ARF
- circulatory failure and shock
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Treatment for DIC
- treat underlying disorder
- Administer: FFP to replace all of coagulation fracture
- consider heparin for thrombotic complications
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Most common complications of transfusion
febrile nonhemolytic reaction: fever, chills, mild dyspnea within 6hrs
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In allergic reaction of blood transfusion, severe potentially fatal allergic reactions most likely occurs in pts with what deficiency?
IgA deficiency, triggered by IgG that recognizes IgA in the infused blood product
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In blood transfusion, what is meant by Urticartial allergic reaction
a reaction thats triggered by presence of an allergen in the donated blood product that is recognized by IgE
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Transfusion related acute hemolytic reactions usually are caused by preformed _ against donor red cells that fix comlement
IgM, usually due to patient ID error. Presents as fever, shaking chills, flank pain, positive direct Coombs test. can progress to DIC, shock, ARF and death
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transfusion related delayed hemolytic reaction are caused by ab that recognize RBC antigens that the recipeint was sensitized previously and typically caused by _ antibodies to foreign protein antigens.
IgG
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_ is a severe, frequently fatal complication of blood transfusion in which factors in a transfused blood product trigger the activation of neutrophils in the lung microvasculature
Transfusion-related acute lung injury (TRALI)
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TRALI has been implicated as "second hits" with transfused blood product that recognize antigens bound to which MHC?
MHC class I
