Ch. 15 - RBC Disorders

Question 1

hypersplenism

Answer 1

syndrome assoc. with splenomegaly - anemia, leukopenia, thrombocytopenia – due to sequestration of formed elements and enhanced phagocytosis

Question 2

infections due to splenectomy?

Answer 2

pneumococci, meningococci, H. influenza

Question 3

Nonspecific acute Splenitis:

Answer 3

• enlargement of spleen due to blood-borne infection
• mild splenomegaly – soft and fluctuant
• acute congestion of red pulp
• Infiltrates of neutrophils, plasma cells, +/- eosinophils

Question 4

Congestive Splenomegaly:

Answer 4

• chronic venous outflow obstruction resulting in enlarged spleen
• red pulp is congested in early congestion – becomes more fibrous and cellular with long-standing congestion

Causes:

1. Cardiac decompensation: left side heart failure → resulting in right sided heart failure → venous congestion
2. Cirrhosis of liver: *main cause of congestive splenomegaly
   a. due to alcohol or schistosomiasis
   b. massive enlargement
3. Obstruction of extrahepatic portal vein/splenic vein:
   a. pylephlebitis = inflammation of portal vein
   b. compression of blood vessels
   c. mild/moderate enlargement

Question 5

Splenic Infarcts:

Answer 5

• spleen lacks extensive collateral blood supply, along with brain/kidneys is most common site of emboli to lodge
• emboli often originate from heart: aka infectious endocarditis
• may occur with splenomegaly
• can lead to decreased splenic function and increased risk of infections w/ encapsulated bacteria bacteria (pneumococcus, H. influenza, meningococcus)

Question 6

sections of the spleen

Answer 6

Blood takes two routes to reach the splenic vv:

1. Open circulation: flow through capillaries into the cords, from which blood cells squeeze through gaps (this is where examination occurs by macrophages)
2. Closed circulation: blood passes directly and rapidly through capillaries to the splenic vv

Red Pulp = where macrophages reside within the cords of billroth allowing for open circulation and trapping of old senescent RBC’s

White pulp = where T cells and B cells are located – B cells found in the germinal center

Function of the Spleen:

1. Phagocytosis of blood cells and particulate matter
2. Antibody production: T and B cells interact at the edges of white pulp follicles to make plasma cells
3. Hematopoeisis: can become major site of EMH in severe chronic anemia, CML and primary myelofiboris
4. sequestration of formed blood elements: harbors 30-40% of platelet mass in the body (with splenomegaly up to 80-90% of platelets can be sequestered → thrombocytopenia)

Question 7

Cells of thymus:

Answer 7

Thymic epithelial cells (form “Hassall’s Corupscles” in the medulla) and immature lymphocytes of T cell lineage called “thymocytes”
• Have antigen independent T-cell receptor maturation with gene rearrangement, negative selection of self-reactive clones and positive selection of MHC-recognizing clones (self vs. non-self); so, may play a significant role in autoimmune disorders
• progenitor cells migrate from marrow to tbymus and mature into T cells
- Macrophages, dendritic cells, few B cells, rare neutrophils and eosinophils with scattered myoid (muscle-like) cells also found within the thymus; latter cells may be related to myasthenia gravis (musculoskeletal autoimmune disorder – antibodies directed against acetylcholine receptors - causing loss of function)

Question 8

DiGeorge Syndrome

Answer 8

= thymic hypoplasia/aplasia accompanied by parathyroid developmental failure

a. see severe deficits in cell-mediated immunity and variable hypoparathyroidism
b. assoc. w/ other defects - 22q11 deletion syndrome

Question 9

Thymic Cysts:

Answer 9

a. lesions that are <4 cm cysts are benign, however neoplastic thymic masses may have cystic features – thus a symptomatic pt with cystic lesions should be evaluated for a true neoplasia – lymphoma or thymoma

Question 10

Thymic Hyperplasia:

Answer 10

“Thymic Follicular Hyperplasia”
• appearance of thymic lymphoid follicles containing predominantly B lymphocytes
• most freq. encountered in myasthenia gravis (65-75% of cases) - and other AI diseases

Question 11

Thymoma

Answer 11

= tumors of thymic epithelial cells – usually contain benign immature T cells “thymocytes”
• arise in anterior superior mediastinum, but sometimes in neck, thyroid, pulmonary hilus
• 40% present with symptoms from impingement on mediastinal structures
• 30% to 45% present in patients with myasthenia gravis. – typically benign thymomas
• other assoc. AI diseases: hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositis-polymyositis, and Cushing syndrome
o thymocytes that arise in thymomas produce long lived CD4+ and CD8+ T cells that may have something to do with the AI diseases and abnormal “education” of T cells

Question 12

Non-invasive thymomas:

Answer 12

cytologically benign and non-invasive

a. medullary-type epithelial cells or a mixture of medullary and cortical type cells

Question 13

Invasive thymoma:

Answer 13

cytologically benign, but invasive (metastatic) – penetrate through the capsule into surrounding tissues, but do not have
a. most commonly of cortical-type

Question 14

Thymic Carcinoma

Answer 14

cytologically malignant

a. squamous cell carcinoma type
b. lymphoepithelioma type (50% assoc. w/ EBV)

Question 15

normal Hgb?

Answer 15

Men:13.6-17.2

Women: 12.0-15.0

Question 16

Normal Hematocrit?

Answer 16

men: 39-49%
women: 33-43%

Question 17

normal RBC count?

Answer 17

men: 4.3-5.9
women: 3.5-5.0

Question 18

retic count?

Answer 18

0.5-1.5%

Question 19

MCV

Answer 19

82-96

mean cell volume = : the average volume of a red cell expressed in femtoliters (fL)

MCV >100 = macrocytosis
MCV <80 = microcytosis

Question 20

MCH

Answer 20

mean cell hemoglobin: 27-33

= : the average content (mass) of hemoglobin per red cell, expressed in picograms

Question 21

MCHC

Answer 21

mean cell hgb concentration: 33-37

= the average concentration of hemoglobin in a given volume of packed red cells, expressed in grams per deciliter

Question 22

RCDW

Answer 22

11.5-14.5

= the coefficient of variation of red cell volume (RDW) – increased with more retics

increased RDW = means lots of retics

Question 23

Poikilocytic =

Answer 23

Poikilocytic = abnormal shape

Question 24

Clinical Presentation of Anemia:

Answer 24

pale, weakness, malaise, easy fatigability, dyspnea on mild exertion
• hypoxia can cause fatty changes to liver, myocardium and kidney → angina pectoris, oliguria/anuria
• CNS hypoxia → dizziness, dimness of vision, faintness, h/a

Question 25

Anemia of Acute Blood Loss:

Answer 25

• effects are mainly due to loss of intravascular volume which if massive can lead to CV collapse, shock and death
• results in hemodilution due to blood volume restoration from intravascular shift, lowering hematocrit
• reduction in O2 results in increased erythropoietin → stimulating CFU-E
• takes 5 days for retics to appear in peripheral blood
• if bleeding is significant results in massive decrease in BP → increased adrenergic hormones → mobilization of granulocytes and leuocytosis
• initially RBCs appear normocytic normochromic however after production increases see macrocytes due to reticulocytosis along with thrombocytosis

Question 26

Hemolytic Anemias:

Answer 26

• shortened RBC life span below the normal 120 days
• elevated EPO levels – and compensatory increase in erythropoiesis
• accumulation of hemoglobin degradation products
- destruction of senescent RBCs takes place in macrophages abundant in spleen, liver and bone marrow
• in both types see increase in unconjugated bilirubin
Morphology: increased number of erythroid precursors (normoblasts) in marrow, retics in blood, hemosiderin, EMH if severe in liver, spleen and LN’s, elevated biliary excretion resulting in pigment gallstones

Question 27

Extravascular Hemolysis:

Answer 27

destruction of RBCs w/in phagocytes
• caused by alterations that render RBCs less deformable → red cell sequestration and phagocytosis by macrophages located w/in splenic cords
• see anemia, splenomegaly*** and jaundice, decrease in plasma haptoglobin (an alpha1 globulin that binds free Hgb and prevents its excretion in the urine)

Question 28

Intravascular hemolysis

Answer 28

less common
• caused by mechanical injury, complement fixation, intracellular parasites, exogenous toxic factors
• mechanical injury due to prosthetic valves, thrombotic narrowing or repeated physical trauma such as marathon running
• see anemia, hemoglinemia, hemoglobinuria, hemosiderinuria, and jaundice, depleted serum haptoglobin
• as serum haptoglobin is depleted free Hgb oxidizes to methemoglobin (brown color seen in urine)
• renal hemosiderosis- accumulation of iron released from Hgb accumulating in renal tubular cells
• NOTE: splenomegaly is NOT seen here!

Question 29

Caues of Hereditary spherocytosis:

Answer 29

• HS is an inherited disorder caused by intrinsic defects in RBC membrane skeleton → renders cells spheroid, less deformable and vulnerable to splenic sequestration and destruction.
• autosomal dominant – more common in northern Europe
• caused by diverse mutations that lead to insuffic. of membrane skeletal components – and decreased RBC life to 10-20 days: mutations in ankyrin, band 3, spectrin, band 4.2
Morphology:
• spherocytosis: small, hyperchromic RBCs lacking central zone of pallor
• retics, marrow hyperplasia, hemosiderosis, mild jaundice
• cholelithiasis – pigment stones
• moderate splenomegaly

Question 30

Clinical features of Hereditary spherocytosis:

Answer 30

• RBCs have increased MCH concentration due to dehydration and loss of K+
• chronic hemolytic anemia → splenomegaly, jaundice (30% present asymptomatic)
• Aplastic crises: usually triggered by an acute parvovirus infection, which infects and kills red cell progenitors, causing red cell production to cease until an immune response commences, generally in 1 to 2 weeks. Because of the reduced life span of HS red cells, cessation of erythropoiesis for even short time periods leads to sudden worsening of the anemia. Transfusions may be necessary to support the patient until the immune response clears the infection.
• Hemolytic Crises: intercurrent events leading to increased splenic destruction of red cells (e.g., infectious mononucleosis); these are clinically less significant than aplastic crises.

tx: Splenectomy – due to spleen causing premature death of RBC’s – after splenectomy the spherocytes persist but the anemia is corrected (but more prone to sepsis)

Question 31

Glucose-6-Phosphate Dehydrogenase Deficiency:

Answer 31

• Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries and lead to hemolysis.
• most common triggers are infections , in which oxygen-derived free radicals are produced by activated leukocytes - viral hepatitis, pneumonia, and typhoid fever are most likely
• can also be caused by drugs (primaquine, chloquine, sulfonamides) and food (fava beans)
• X-linked recessive: more common in Mediterranea and middle east

Morphology:
• Heinz bodies: reactive sulfahydryl groups on globin chains – shows up as little spots
• “Bite cells” – splenic cord macrophages pluck out Heinz bodies, resulting in deformed RBCs
• spherocytes

Clinical Presentation:
• oxidants cause intravascular and extravascular hemolysis
• hemolysis is greater in people with highly unstable G6PD Mediterranean variant
• only older cells are at risk for lysis – thus it is self-limiting and hemolysis stops when only younger G6PD-replete red cells remain
• see reticulocytes in recovery phase
• occurs intermittently: thus splenomegaly and cholelithiasis are absent

Question 32

Sickle Cell Disease Pathogenesis

Answer 32

• caused by a point mutation in β-globin that promotes the polymerization of deoxygenated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage.
• Sickle cell disease is caused by a point mutation in the sixth codon of β-globin that leads to the replacement of a glutamate residue with a valine residue.

Sickle Cell Trait: 8-10% of African Americans are heterozygous for HbS
o HbS has protection against falciparum malaria: due to stiffened cells being cleared more rapidly and impairing the formation of knobs created by the parasite
o red cells don’t sickle except under conditions of profound hypoxia
o milder sickling

Sickle cell disease: almost all of the Hgb in red cell is HbS
o less severe if HbF remains

Pathogenesis:
• Increased MCHC: intracellular dehydration increases the MCHC, facilitating sickling
• Decrease in pH: reduces the O2 affinity of Hgb and increases fraction of deoxygenated HbS
• Sickling occurs in microvascular beds when they remain for longer periods of time – blood flow is sluggish in spleen and BM and vascular beds that are inflamed
• with repeated bouts of sickling, RBCs become more dehydrated, dense, rigid → irreversibly sickled
• Microvascular occlusions: red cell membrane damage, due to sharp sticky sickle red cells → aggregate and obstruct → hypoxia → increased sickling

Question 33

Morph of Sickle Cell Disease

Answer 33

Morphology:
• sickled cells, reticulocytosis, target cells
• Howell-Jolly bodies due to asplenia
• cheekbones are prominent and skull marrow expanded due to EMH
• pigment gallstones, hyperbili due to increased Hgb breakdown
• autosplenectomy: spleen is enlarged in early childhood, but with time result sin splenic infarction and progressive shrinking
• infarctions in bones, brain, kidney, liver, retina,

Question 34

CF of Sickle Cell Disease?

Answer 34

Clinical features:
• hemolytic anemia – w/ retics, hyperbilirubenemia and irreversibly sickled cells

Vaso-occlusive crises, aka pain crises, are episodes of hypoxic injury and infarction that cause severe pain in the affected region
o infection, dehydration and acidosis all favor sickling and can act as a trigger
o involves bones, lungs, liver, brain, spleen and penis
o Priapism: hypoxic damage and erectile dysfunction
o loss of visual acuity
o crippling

Acute chest syndrome: vaso-occlusive crisis involving the lungs → fever, cough, c/p, pulmonary infiltrates – very dangerous

Sequestration crises occur in children with intact spleens. Massive entrapment of sickled red cells leads to rapid splenic enlargement, hypovolemia, and sometimes shock.

Aplastic crises stem from the infection of red cell progenitors by parvovirus B19, which causes a transient cessation of erythropoiesis and a sudden worsening of the anemia.

• Chronic → impairment of growth and development and organ damage affecting the spleen, heart, kidneys, and lungs.
• Increased susceptibility to infection with encapsulated organisms due to altered spleen fn: . Pneumococcus pneumoniae and Haemophilus influenzae septicemia and meningitis
• ddx made clinically and by use of metabisulfite which induces sickling, along with Hgb electrophoresis
• tx: hydroxyurea: increases HbF levels, and has anti-inflammatory effect

Question 35

Thalassemia Syndromes:

Answer 35

• group of disorders caused by inherited mutations that decrease the synthesis of either the α-globin or β-globin chains that compose adult hemoglobin, HbA (α β ), leading to anemia, tissue hypoxia, and red cell hemolysis related to the imbalance in globin chain synthesis → decreased red cell production and life span
• chromosome 16 = alpha chain
• chromosome 11 = beta chain
• β-thalassemia is caused by deficient synthesis of β chains, whereas α-thalassemia is caused by deficient synthesis of α chains.
• Mediterranean basin, Middle East, tropical Africa, the Indian subcontinent, and Asia – protection against malaria

Question 36

β-Thalassemias

Answer 36

• caused by mutations that diminish the synthesis of β globin genes
• β0 mutations = absent β globin gene synthesis
• β+ mutations = reduced, but detectable β synthesis
Pathogenesis:
• splicing mutations are the most common cause – mutations exist w/in introns/exons and destroy the normal RNA splice junctions
• deficit in HbA synth. produces hypochromic, microcytic red cells with subnormal O2 transport capacity, and there is a dimished survival of red cells and their precursors due to imbalance in alph and beta-globin synthesis
• Unpaired α chains precipitate within red cell precursors, forming insoluble inclusions→membrane damage → apoptosis of red cells, and makes them prone to splenic sequestration and extravascular hemolysis
• insoluble inclusions → ineffective erythropoiesis → massive erythroid hyperplasia in marrow and extensive EMH (in liver, spleen, LN’s) → erodes bony cortex and produces skeletal abnormalities
• erythroid progenitors of EMH steal O2 → further oxygen depletion in other tissues → severe cachexia in untreated pts.
• ineffective erythropoiesis → excessive absorption of dietary iron (high EPO suppresses hepcidin) → secondary hemochromatosis

Question 37

β-Thalassemia Major

Answer 37

• Mediterranean countries, parts of Africa, and Southeast Asia
• anemia manifests 6-8 mos after birth, with Hgb levels 3-6 gm/dL

Morphology:
• anisocytosis (variation in size), poikilocytosis (variation in shape), microcytosis and hypochromia
• target cells (Hgb collects at the center of the cell), basophilic stippling (erythrocytes show small dots at periphery), fragmented cells
• elevated retic count
• normoblasts (red cell precurors) are seen in periphery
• striking expansion of hematopoietically active marrow: bones of face and skull show erosion → “crew cut” appearance
• enlargement of spleen due to EMH
• Hemosiderosis (due to extravascular lysis) and secondary hemochromatosis (accumulation of iron in liver, heart and other organs due to suppression of hepcidin) → iron deposition in heart, liver and pancreas

Clinical Features:
• untreated children suffer from growth retardation and die at early age due to anemia
• cheekbones and other bony prominences are enlarged and distorted
• hepatosplenomegally due to EMH
• patients req. heavy transfusion → cardiac disease resulting from iron overload and secondary hemochromatosis (must be treated with iron chelators)
• with transfusions and iron chelation, survival is possible to third decade
• Hematopoietic stem cell transplantation is the only therapy offering a cure and is being used increasingly.

Question 38

β-Thalassemia Minor

Answer 38

• much more common than β-thalassemia major
• patients are heterozygous carriers of a β+ or β0 allele
• patients are usually asymptomatic. Anemia, if present, is mild
• peripheral blood smear typically shows some red cell abnormalities, including hypochromia, microcytosis, basophilic stippling, and target cells. Mild erythroid hyperplasia is seen in the bone marrow.
• . Hemoglobin electrophoresis usually reveals an increase in HbA2 (α2δ2 ) to 4% to 8% of the total hemoglobin (normal, 2.5% ± 0.3%), reflection of an elevated ratio of δ-chain to β-chain synthesis.
• HbF levels are generally normal or occasionally slightly increased. (In major they are very increased!)
• Iron deficiency can usually be excluded through measurement of serum iron, total iron-binding capacity, and serum ferritin.
• The increase in HbA2 is diagnostically useful

Question 39

α-Thalassemias

Answer 39

• caused by inherited deletions that result in reduced or absent synthesis of α-globin chains
• anemia stems both from a lack of adequate hemoglobin and the presence of excess unpaired globin chains (β, γ, and δ)
• Hemoglobin Barts: excess unpaired γ-globin chains form γ4 tetramers in newborns
• HbH: excess β-globin chains form β4 tetramers in older children and adults
• Because free β and γ chains are more soluble than free α chains and form fairly stable homotetramers, hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias.
Clinical Features:
• clinical syndromes are determined by number of alpha-globin genes that are deleted, and severity is proportional to number of alpha globin genes that are deleted

Question 40

four types of alpha thalassemias?

Answer 40

Silent Carrier State:
• deletion of a single alpha-globin gene

Alpha-Thalassemia trait:
• deletion of two alpha globin genes from a single chromosome or deletion of one alpha globin gene from each of two chromosomes
• more common in Asia/Africa
• see small red cells (microcytosis), minimal/no anemia, no abnormal physical signs, HbA2 levels are normal or low (a gene that in humans codes for the alpha globin chain of hemoglobin)

Hemoglobin H Disease:
• HbH disease caused by deletion of three alpha-globin genes
• more common in Asian populations
• HbH = tetramers of Beta globin – has high affinity for O2 → tissue hypoxia disproportionate to level of Hgb
• moderately severe anemia similar to B-thalassemia intermedia

Hydrops Fetalis:
• most severe form of alpha thalassemia, caused by deletion of all four alpha-globin genes
• Hemoglobin Barts formed, that have high affinity for O2 and deliver very little O2 tissues
• fetal distress is seen in third trimester of pregnancy
• fetus shows severe pallor, generalized edema, massive hepatosplenomegally
• lifelong dependence on blood transfusions for survival

Question 41

Paroxysmal Nocturnal Hemoglobinuria:

Answer 41

• a disease that results from acquired mutations in the phospha¬tidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for the synthesis of certain membrane-associated complement regulatory proteins.
• rare, the only hemolytic anemia caused by an acquired genetic defect.
• as a result of PIGA mutations the GPI genes are deficient, causing mutations that occur in a hematopoietic stem cell progeny
• Red cells deficient in these GPI-linked factors are abnormally susceptible to lysis or injury by complement. This manifests as intravascular hemolysis , which is caused by the C5b-C9 membrane attack complex.
• tendency for red cells to lyse at night is explained by a slight decrease in blood pH during sleep, which increases the activity of complement.

CF’s:
• anemia ranges from mild to severe
• hemosiderinuria: loss of heme iron in the urine → iron deficiency anemia
• **thrombosis = leading cause of death, 40% of patients suffer from venous thrombosis, often involving the hepatic, portal, or cerebral veins – 5-10% of patients develop AML or MDS
• Flow Cytometry for DDx, detects red cells lack of CD59 proteins

Question 42

Immunohemolytic Anemias

Answer 42

• Antibodies bind to red cells → premature destruction

- “autoimmune hemolytic anemias”

Question 43

Direct Coomb’s antiglobulin tests:

Answer 43

patients red cells are mixed with sera containing abs that are specific for human IgG or complement, if either of the IgG or complement is present on the surface of the RBCs then it causes agglutination, which appears as clumping

Question 44

Indirect Coombs antiglobulin tests:

Answer 44

patients serum is tested for its ability to agglutinate commercially available red cells bearing particular defined antigens (used to characterize Ag target and temp dependence of responsible Ag)

Question 45

Warm Antibody Type

Answer 45

(IgG Antibodies Active at 37°C)
• most common form (idiopathic, SLE, AI disorders, drugs, lymphoid neoplasms)
• IgG causes extravascular hemolysis
• loss of membrane → red cells to spherocytes → splenic sequestration

Causes:
o Antigenic Drugs: hemolysis follows large IV doses of penicillin or cephalosporins – which bind to RBC membranes and are recognized by antidrug Abs
o Tolerance-breaking drugs: alpha-methyldopa

Question 46

Cold Agglutinin Type

Answer 46

(IgM Antibodies Active Below 37°C)
• sometimes appear after mycoplasma infection, infectious mononucleosis (EBV), CMV, influenza, HIV
• disorder is self-limited and Abs rarely induce imp. hemolysis

clinical sx occur where IgM binds in vascular beds where temp may fall – fingers, toes and ears → vascular obstruction causing pallor, cyanosis and Raynaud phenomenon

Question 47

Cold Hemolysin Type

Answer 47

(IgG Antibodies Active Below 37°C)
• “paroxysmal cold hemoglobinuria” – rare and sometimes fatal intravascular hemolysis and hemoglobinuria
• IgGs bind to RBCs in periphery → lysis via complement when RBCs reach warm central areas
• occurs mainly in children following viral infections

Question 48

Hemolytic Anemia resulting from trauma to RBCs:

Answer 48

• most commonly caused by individuals with cardiac valve prostheses (artificial mechanical valves)- hemolysis stems from shear forces produced by turbulent blood flow and pressure gradients across damaged valves

Microangiopathic hemolytic anemia: is most commonly seen with disseminated intravascular coagulation, but it also occurs in thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, systemic lupus erythematosus, and disseminated cancer.
o ***The common pathogenic feature in these disorders is a microvascular lesion that results in luminal narrowing, often due to the deposition of fibrin and platelets. These vascular changes produce shear stresses that mechanically injure passing red cells.

Regardless of the cause, traumatic damage leads to the appearance of red cell fragments ( schistocytes ), “burr cells,” “helmet cells,” and “triangle cells” in blood smears.

Question 49

Anemias of Diminished Erythropoiesis

Answer 49

• most common and important anemias associated with red cell underproduction are those caused by nutritional deficiencies, followed by those that arise secondary to renal failure and chronic inflammation.
• ex: Megaloblastic anemia, iron deficiency anemia, anemia of CD, aplastic anemia, pure red cell aplasia, polycythemia
• less common disorders that lead to generalized bone marrow failure, such as aplastic anemia, primary hematopoietic neoplasms, and infiltrative disorders that lead to marrow replacement (e.g., metastatic cancer and disseminated granulomatous disease).

Question 50

Megaloblastic Anemias:

Answer 50

Pernicious anemia and folate deficiency
• due to impairment of DNA synth that leads to ineffective hematopoiesis and dinstinctive large erythroid precursors and cells
• VitB12 and Folate are both coenzymes reqd for synth of thymidine – thus results in impaired DNA synth.

Morphology:
• macro-ovalocytes: larger than normal, with lots of hgb
• hyperchromic cells without MCHC increase
• anisocytosis, poikilocytosis
• retic count is low
• neutrophils show nuclear hypersegmentation
• megaloblastic changes in erythroid development
• giant metamyelocytes and band forms
• marrow hyperplasia as a response to increased EPO, howevere the messed up DNA synth causes ineffective hematopoiesis → pancytopenia

Question 51

Normal B12 synthesis:

Answer 51

• VitB12 is called “cobalamin”
• Vit B12 is freed from binding proteins in food through action of pepsin in the stomach and binds to salivary protein called haptocorrin
• in duodenum B12 is released from haptocorrin by action of pancreateic proteases and associated with intrinsic factor (IF)
• IF-B12 complex is transported to ileum where it is endocytosed by ileal enterocytes that express a receptor for IF called cubulin
• Within ileal cells, VitB12 associated with carrier protein trancobalamin II and is secreted into the plasma
• Transcolbalamin II delivers Vit B12 to liver and other cells of the body

Question 52

Biochemical Functions of Vit B12:

Answer 52

1. Vit B12 and folate are reqd for essential cofactor in conversion of homcysteine to methionine for methionine synthase (ultimately yielding thymine for DNA synthesis)
2. Vit B12 is reqd for isomerization of methylmalonyl CoA to Succinyl CoA – thus deficiency results in increased plasma and urine levels of methylmalonic acid → leads to formation of abnormal fatty acids into neuronal lipids
   a. neurological complications assoc. w/ VitB12 defic. are not improved with folate administration

Note: the neurologic complications of B12 deficiency. Tend to exhibit spastic paraparesis, sensory ataxia and severe parathesias of the lower limbs.

Question 53

Pernicious Anemia

Answer 53

• Pernicious anemia = form of megaloblastic anemia caused by autoimmune gastritis that impairs production of IF, required for vitamin B12 uptake from the GI tract
• more prevalent in Scan¬dinavian and other Caucasian populations - median age at diagnosis is 60 years, and it is rare in people younger than 30
• is believed to result from an autoimmune attack on the gastric mucosa resulting in chronic atrophic gastritis.
o Type I Auto-Ab: blocks binding of VitB12 to IF
o Type II Auto-Ab: prevents binding of IF-VitB12 complex to ileal receptor
o Type III Auto-Ab: nonspecific
• autoantibodies are of diagnostic utility, but they are not thought to be the primary cause of the gastric pathology; rather, it seems that an autoreactive T-cell response initiates gastric mucosal injury and triggers the formation of autoantibodies.
o associated with other AI disorders: AI thyroiditis and adrenalitis

Morphology:
• megaloblastic anemia
• stomach shows diffuse chronic gastritis and fundic gland atrophy, affecting both chief cells and parietal cells
• glandular epithelium is replaced by mucus-secreting goblet cells → metaplasia called intestinalization
• tongue becomes shiny and beefy, atrophic glossitis
• parenteral admin of VitB12 correct megaloblastic changes in marrow, but gastric atrophy and achlorydria persist

Clinical Features:
• insidious onset – detect serum Abs to IF often
• increased risk of gastric carcinoma

Question 54

• Achlorhydria:

Answer 54

production of pepsin is low/loss of pepsin secretion occurring in older adults, results in VitB12 not being readily released from proteins in food

Question 55

• Gastrectomy:

Answer 55

IF is not secreted in the stomach, and thus not available for uptake in the stomach

Question 56

• Ileal Resection/Disease:

Answer 56

can remove or damage the site of intrinsic factor-vitamin B12 complex absorption.

Question 57

• Tapeworms:

Answer 57

(particularly those acquired by eating raw fish) compete with the host for B12 and can induce a deficiency state.

Question 58

what causes increased demand for Vit B12?

Answer 58

• Pregnancy, hyperthyroidism, disseminated cancer, and chronic infection: result in an increased demand for vitamin B12 and thus can produce a relative deficiency, even with normal absorption.

Question 59

General Morphology of B12 deficiency:

Answer 59

• megaloblastic anemia
• CNS lesions – demyelination of dorsal and lateral spinal tracts, sometimes followed by loss of axons → spastic paraparesis, sensory ataxia, severe parasthesias in lower limb
• elevated homocysteine levels → risk for atherosclerosis and thrombosis, may increase incidence of vascular disease

Question 60

ddx of VitB12 deficiency?

Answer 60

1. moderate to severe megaloblastic anemia
   
   2. leukopenia with hypersegmented granulocytes
   3. low serum B12, and
   4. elevated serum levels of homocysteine and methymalonic acid.
      Note: In a true case of pernicious anemia, reticulocytosis and a rising HCT begins about 5 days after parenteral administration of B12.
      
      • tx: administration of B12 reverses/halts neuro defects, but gastric changes and risk of carcinoma are not affected

Question 61

Folic Acid Deficiency?

Answer 61

• results in a megaloblastic anemia having the same pathologic features as that caused by vitamin B deficiency.
• Metabolic processes dependent upon Folate: (1) purine synthesis, (2) conversion of homocysteine to methionine, which also reqs. B12, (3) deoxythymidylate monophosphate synthesis (dTMP)
• entirely dependent on dietary sources for their folic acid: vegetables such as lettuce, spinach, asparagus, and broccoli. Certain fruits (e.g., lemons, bananas, melons)

Etiology: decreased intake, increased reqs, impaired utilization
• chronic alcoholics: cirrhosis results in trapping of folate within the liver, excessive urinary loss and disordered metabolism of folate
• Sprue: malabsorption syndrome
• Drugs: anticonvulsant, oral contraceptives
• Increased DNA synthesis: relative deficiency seen in pregnancy, infancy, hyperactive hematopoiesis, disseminated cancer
• Methotrexate: folic acid antagonist → affects rapidly growing cells in bone marrow and GI tract

** Differences from VitB12 deficiency: serum homocysteine levels are increased, but methylmalonate concentrations are normal. Neurological changes do NOT occur

Question 62

Iron Deficiency Anemia:

Answer 62

Microcytic, hypochromic anemia
• The most common nutritional disorder in the world: most common in developing nations, but in the US seen in toddlers, adolescent girls(menstruation) and women of child-bearing age (before menopause).
o chronic blood loss is the most common cause of iron deficiency in the western world!
• dietary iron in the US obtained from animal products and the rest (albeit inorganic) from vegetables

• In IDA, ferritin levels < 12 μg/L, in iron overload, levels approaching 5000 μg/L may be seen.
o iron excretion is through the shedding of mucosa and skin epithelial cells, up to 1 to 2 mg lost each day

Etiology: 1. dietary lack (impoverished, teens), 2. impaired absorption (Celiacs), 3. increased req (pregnant, CD), 4. occult blood loss (menstruation, GI bleed)
o Sprue: “Celiac Disease” – impairs iron absorption and other fats are malabsorbed → chronic diarrhea

Morphology:
• microcytic, hypochromic anemia
• anemia only appears when iron stores are completely depleted and this is accompanied by low serum iron, low ferritin levels, low transferrin saturation levels.
• Prussian blue stain indicates disappearance of stainable iron from macrophages in the bone marrow
• Poikilocytosis in form of small “pencil cells” is also seen

Clinical Presentation:
• depletion of iron cells → koilonychias, alopecia, atrophic changes in tongue and gastric mucosa and intestinal malabosorption
• depletion of iron in CNS → appearance of Pica, affected individuals consume non-foodstuffs
• Plummer- Vinson syndrome (esophageal webs, m/h anemia and atrophic glossitis)

Question 63

• Hepcidin:

Answer 63

regulates iron absoption, released from the liver in response to increases in intrahepatic iron levels – it is resp. for inhibiting iron transfer through binding to ferroportin and causing it to be endocytosed and degraded
o as hepcidin levels rise, iron becomes trapped w/in duodenal cells and is lost as cells are sloughed
o with low iron levels, hepcidin synth falls
o anemia of chronic disease: see increased inflammatory mediators → increased hepcidin → decreased iron absorption
o Ineffective erythropoiesis: i.e. β thal major and myelodysplastic syndromes, suppress hepcidin levels even when iron stores are high

Question 64

ddx of IDA?

Answer 64

1. HCT and Hgb are decreased
2. Serum iron and ferritin are low
3. TIBC is high (low transferrin saturation = high TIBC)
4. serum hepcidin is low
5. hypochromia, microcytosis, modest poikilocytosis

Question 65

Anemia of Chronic Disease:

Answer 65

• Impaired red cell production associated with chronic diseases that produce systemic inflammation is likely the most common type of anemia in hospitalized patients in the US
• Stems from reduction of erythroid progenitors and impaired iron utilization

Three major categories:
o chronic microbial infections: osteomyelitis, bacterial endocarditis, lung absesses
o chronic immune disorders: RA and enteritis
o neoplasms such as carcinomas of lung/breast and HL

inflammation → high hepcidin → low serum iron, reduced TIBC and abundant stored iron in tissue macrophages
o IL-6 stimulates hepcidin → reduced transfer of iron from storage pool
o hepcidin suppresses EPO → EPO levels are very low

high hepcidin levels → enhances the body’s ability to fend off infections that req. iron for pathogenicity (i.e. H. influenza)

Clinical Features:
• anemia is mild, dominant sx are those of underlying disease
• normocytic/normochromic, or hypochromic/microcytic (as anemia of ID)

Question 66

Aplastic Anemia causes:

Answer 66

• syndrome of chronic primary hematopoietic failure and pancytopenia

Causes:
o majority of patients due to AI mechanisms, usually aqd;
o chemical agents (chemo causing bone marrow suppression)
o idiosyncratic fashion following exposure to drugs – chloramphenicol and gold salts
o viral infections: viral hepatitis
o whole body irradiation can destroy HSC’s
o defects in telomerase

Fanconi Anemia: rare autosomal recessive disorder that causes defects in complex reqd for DNA repair

Other causes:

1. defects in telomerase found in 5-10%
2. abnormally short telomeres seen in 50% of patients

**Two major mechanisms thought to be involved in the majority of cases: extrinsic immune-mediated suppression of marrow progenitors, and an intrinsic abnormality of stem cells : see Th1 cells that are activated causing IFNgamma and TNF that suppress and kill HSC’s

Question 67

morphology of Aplastic anemia?

Answer 67

Morphology:
• hypocellular bone marrow that is largely devoid of HSC, often only fat cells, fibrous stroma and scattered lymphocytes and plasma cells
• “dry tap” – due to marrow aspirates not being filled with cells
• granulocytopenia, thrombocytopenia, causing mucocutaneous bacterial infections and abnormal bleeding

Clinical Features:
• insidious onset
• anemia is progressive with weakness, pallor, dyspnea
• thrombocytopenia → petchiae and ecchymoses
• neutropenia → persistent minor infections and s/o of chills, fever, prostration
• splenomegaly is usually absent
• red cells are slightly macrocytic and normochromic
• reticulocytopenia
• marrow is hypocellular (as opposed to ALL or MDS)
• 5 year survival

Question 68

Pure Red Cell Aplasia:

Answer 68

• pure red cell plasia is a primary marrow disorder where only erythroid progenitors are suppressed – most cases stem from autoimmune phenomenon

Etiology:
• thymoma – have to remove thymoma for tx
• large granular lymphocytic leukemia
• drug exposure, AI disorders
• Parvovirus B19 infection: preferentially infects and destroys RBC progenitors – if person already has severe hemolytic anemia then even a brief cessation of erythropoiesis results in rapid worsening of anemia, producing an aplastic crisis

Question 69

Myelophthisic anemia:

Answer 69

form of marrow failure in which space-occupying lesions replace normal marrow elements
o commonest cause is metastatic cancer – carcinomas of breast, lung, prostate
o spent phase of myeloproliferative disorders
o All cause marrow fibrosis and result in release of nucleated erythroid precursors and immature granulocytic forms (leukoerythroblastosis) into peripheral smears
o teardrop-shaped red cells: deformed during release from bone marrow

Question 70

Chronic Renal Failure:

Answer 70

• anemia is proportional to uremia

* due to diminished synth of EPO by damaged kidneys → inadequate RBC production

Question 71

Hepatocellular Liver Disease:

Answer 71

• folate and iron deficiencies are seen in this setting, and anemia is often slightly macrocytic due to lipid abnormalities associated with liver failure, which cause RBC membranes to acquire phospholipid and cholesterol as they circulate in the peripheral blood

Question 72

Polycythemia:

Answer 72

: abnormally high RBC count, usually with corresponding increase in Hgb level

Relative Polycythemia: when there is hemoconcentration due to decreased plasma volume – results from dehydration due to water deprivation or prolonged vomiting or diarrhea, diuretics

Absolute Polycythemia: when there is an increase in total red cell mass
o Primary form: results from an intrinsic abnormality of hematopoietic precurors (Polycythemia Vera)
o Secondary: when red cell progenitors are responding to increased levels of EPO (ex. EPO elaborating tumors)

Question 73

Prothrombin time (PT

Answer 73

This test assesses the extrinsic and common coagulation pathways. The clotting of plasma after addition of an exogenous source of tissue thromboplastin (e.g., brain extract) and Ca2+ ions is measured in seconds. A prolonged PT can result from deficiency or dysfunction of factor V, factor VII, factor X, prothrombin, or fibrinogen

Question 74

Partial thromboplastin time (PTT).

Answer 74

This test assesses the intrinsic and common clotting pathways. The clotting of plasma after addition of kaolin, cephalin, and Ca2+ ions is measured in seconds. Kaolin activates the contact-dependent factor XII, and cephalin substitutes for platelet phospholipids. Prolongation of the PTT can be due to deficiency or dysfunction of factors V, VIII, IX, X, XI, or XII, prothrombin, or fibrinogen, or to interfering antibodies to phospholipid.

Question 75

Bleeding Disorders caused by Vessel Wall Abnormalities

Answer 75

ex. infections, drug rxns, scurvy, ehlers-danlos syndrome, HSP, hereditary hemorrhagic telangiectasia, perivascular amyloidosis

• most often present with small hemorrhages (petechiae and purpura) in the skin or mucous membranes, particularly the gingivae. On occasion, however, more significant hemorrhages occur into joints, muscles, and subperiosteal locations, or take the form of menorrhagia, nosebleeds, gastrointestinal bleeding, or hematuria.
  • The platelet count and tests of coagulation (PT, PTT) are usually normal, pointing by exclusion to the underlying problem.

Question 76

bleeding disorder of infections?

Answer 76

vessel wall abnormality problem

induce petechial and purpuric hemorrhages, particularly meningococcemia, other forms of septicemia, infective endocarditis, and several of the rickettsioses (which have predilection for endothelium –> damage).
• Due to microbial damage to the microvasculature (vasculitis) and disseminated intravascular coagulation.

Question 77

drug rnx bleeding disorder?

Answer 77

problem of vessel wall

sometimes induce cutaneous petechiae and purpura without causing thrombocytopenia.
• vascular injury is mediated by the deposition of drug-induced immune complexes in vessel walls, which leads to hypersensitivity ( leukocytoclastic ) vasculitis = brisk vasculitis due to neutrophil response

Question 78

Scurvy(Vit C defic) and the Ehlers-Danlos syndrome

Answer 78

causes vessel wall abnormality –> bleeding disorder

microvascular bleeding that results from collagen defects that weaken vessel walls.
• same mechanism may account for the spontaneous purpura that are commonly seen in older adults and the skin hemorrhages that are seen with Cushing syndrome, in which the protein-wasting effects of excessive corticosteroid production cause loss of perivascular supporting tissue.

Question 79

HSP

Answer 79

Henoch-Schönlein purpura: systemic immune disorder (systemic IgA deficiecy) of unknown cause that is characterized by a purpuric rash, colicky abdominal pain, polyarthralgia, and acute glomerulonephritis.
• results from the deposition of circulating immune complexes of IgA within vessels throughout the body and within the glomerular mesangial regions.

Question 80

Hereditary hemorrhagic telangiectasia

Answer 80

bleeding disorder caused by vessel wall abnormality

(also known as Weber-Osler-Rendu syndrome ) : autosomal dominant disorder that can be caused by mutations in at least five different genes, most of which modulate TGF-β signaling.
• dilated, tortuous blood vessels with thin walls that bleed readily
• Bleeding can occur anywhere, but it is most common under the mucous membranes of the nose (epistaxis), tongue, mouth, and eyes, and throughout the gastrointestinal tract.

Of all the conditions, serious bleeding is most often associated with hereditary hemorrhagic telangiectasia

Question 81

Perivascular amyloidosis:

Answer 81

bleeding disorder caused by vessel wall abnormality

weakens blood vessel walls and causes bleeding.
• This complication is most common with amyloid light-chain (AL) amyloidosis and often manifests as mucocutaneous petechiae.

Question 82

Thrombocytopenia

Answer 82

= count less than 100,000 platelets/µL
• 20,000 to 50,000 platelets/µL → posttraumatic bleeding,
• 20,000 platelets/µL → spontaneous (nontraumatic) bleeding.
• Normal PT and PTT.
• associated bleeding usually involves small vessels and can more seriously cause intracranial bleeding

Question 83

causes of thrombocytopenia?

Answer 83

1. Decreased Platelet production:
   a. conditions that depress marrow output: i.e. drugs and alcohol
   b. HIV may infect megakaryocytes and inhibit platelet production
   c. MDS
2. Decreased Platelet survival
   a. immune thrombocytopenia: destruction of platelets by deposition of Abs or immune complexes
   b. Alloantibodies: arise when platelets are transfused or cross the placenta
   c. non-immunologic causes: DIC and thrombotic microangiopathies
   d. mechanical injury
3. Sequestration
   a. spleen normally sequesters 30% to 35% of the body’s platelets, but this can rise to 80% to 90% when the spleen is enlarged, producing moderate degrees of thrombocytopenia.
4. Dilution
   a. massive transfusions

Question 84

cuases of chronic ITP?

Answer 84

Chronic Immune Thrombocytopenic Purpura (ITP):
• caused by autoantibody mediated destruction of platelets
o can occur in the setting of a variety of predisposing conditions and exposures (secondary – i.e.: SLE, HIV, CLL) or in the absence of any known risk factors (primary or idiopathic)

Pathogenesis:
• Autoantibodies: directed against platelet membrane glycoproteins IIb-IIIa or Ib-IX, can be demonstrated in the plasma and bound to platelet surfaces in about 80% of patients
o majority of cases, the antiplatelet antibodies are of the IgG class.
o antiplatelet antibodies act as opsonins that are recognized by IgG Fc receptors expressed on phagocytes, leading to increased platelet destruction
o autoantibodies may also bind to and damage megakaryocytes leading to decreases in platelet production that further exacerbate the thrombocytopenia
• thrombocytopenia is usually markedly improved by splenectomy, indicating that the spleen is the major site of removal of opsonized platelets
o splenic pulp is high in plasma cells → thus removal results in source of autoABs

Question 85

morphology/CF of chronic ITP?

Answer 85

Morphology:
• principal changes of thrombocytopenic purpura are found in the spleen, bone marrow, and blood, but are not specific.
• Secondary changes related to the bleeding diathesis may be found in any tissue or structure in the body.
• spleen is of normal size – however see congestion of sinusoids and enlargement of splenic follicles
• marrow reveals a modestly increased number of megakaryocytes
• peripheral blood often reveals abnormally large platelets (megathrombocytes) due to accelerated thrombopoiesis

Clinical Features:
• adults women younger than 40
• insidious onset characterized by bleeding into the skin/mucosal surfaces
• cutaneous bleeding seen in pinpoint hemorrhages
• petechiae → echymoses
• hx of easy bruising, nosebleeds, bleeding from the gums, and hemorrhages into soft tissues from relatively minor trauma.
• disease may manifest first with melena, hematuria, or excessive menstrual flow.
• Subarachnoid hemorrhage and intracerebral hemorrhage are serious and sometimes fatal complications
• Splenomegaly and lymphadenopathy are uncommon in primary disease (if present, think ITP or B-cell neoplasm)
• low platelet count, normal or increased megakaryocytes in the bone marrow, and large platelets in the peripheral blood
• PT and PTT are normal
tx: most patients respond to glucocorticoids and splenectomy

Question 86

Acute ITP?

Answer 86

Acute Immune Thrombocytopenic Purpura:
• Also caused by autoantibodies
• Acute ITP is mainly a disease of childhood occurring with equal frequency in both sexes
• Symptoms appear abruptly often 1 to 2 weeks after a self-limited viral illness, which appears to trigger the development of autoantibodies although the mechanism(s) are not clear.
• Unlike chronic ITP, acute ITP is self-limited usually resolving spontaneously within 6 months
• Glucocorticoids are given only if the thrombocytopenia is severe.
• 20% of children, usually those without a viral prodrome, thrombocytopenia persists. These less fortunate children have a childhood form of chronic ITP that follows a course similar to the adult disease.

Question 87

Drug-Induced Thrombocytopenia:

Answer 87

• can induce thrombocytopenia through direct effects on platelets and secondary to immunologically-mediated platelet destruction

quinine, quinidine, and vancomycin- all bind platelet glycoproteins and in one way or another create antigenic determinants that are recognized by antibodies

Heparin-induced thrombocytopenia (HIT)
o Type I: occurs rapidly after initiation of therapy. Generally resolves and typically is of little importance
o Type II: Less common. more clinically important. Begins 5-14 days after initiation of therapy. Results in severe, sometimes life threatening venous and arterial thromboses (even in the setting of thrombocytopenia)

Question 88

HIV associated Thrombocytopenia:

Answer 88

• Thrombocytopenia is one of the most common hematologic manifestations of HIV infection.
• Both impaired platelet production and increased destruction contribute.
• CD4 and CXCR4, the receptor and coreceptor, respectively, for HIV are found on megakaryocytes, allowing these cells to be infected → megakaryocytes to be apoptosed
• HIV infection also causes B-cell hyperplasia and dysregulation which predisposes to the development of autoantibodies → opsonize platelets, promoting their destruction by mononuclear phagocytes in the spleen

Question 89

Thrombotic Microangiopathies:

Answer 89

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
• They are caused by insults that lead to excessive activation of platelets, which deposit as thrombi in small blood vessels
o intravascular thrombi cause a microangiopathic hemolytic anemia and widespread organ dysfunction, and the attendant consumption of platelets leads to thrombocytopenia.

• While DIC and thrombotic microangiopathies share features such as microvascular occlusion and microangiopathic hemolytic anemia, they are pathogenically distinct.
o In TTP and HUS (unlike in DIC), activation of the coagulation cascade is not of primary importance, and hence laboratory tests of coagulation, such as the PT and PTT, are usually normal.

Question 90

(TTP)

Answer 90

Thrombotic Thrombocytopenic Purpura

= the pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits and renal failure
o deficiency in plasma enzyme ADAMTS13
o ADAMTS13 nomally degrades vWF, in its absence, these multimers accumulate in plasma and promote platelet activation and aggregation + endothelial injury → TTP exacerbation
o inherited or acquired

Question 91

HUS

Answer 91

Hemolytic-Uremic Syndrome (HUS)

• HUS = microangiopathic hemolytic anemia and thrombocytopenia (absence of neurologic symptoms) the prominence of acute renal failure, and its frequent occurrence in children.
o associated with infectious gastroenteritis caused by Escherichia coli strain O157:H7 infection, which elaborates a Shiga-like toxin → alters endothelial cell fn causing platelet activation and aggregation
o children are at higher risk – suspect with bloody diarrhea
o treated supportively

Question 92

Atypical HUS

Answer 92

= associated w/ defects in complement factor H, membrane cofactor protein (CD46) or factor I (all of which normally act to prevent excessive activation of the alternative C’ pathway)

Question 93

bleeding disorders due to defective platelet functions?

Answer 93

• Inherited disorders of platelet function can be classified into three pathogenically distinct groups: (1) defects of adhesion, (2) defects of aggregation, and (3) disorders of platelet secretion (release reaction).
  ex. bernard-soulier syndrome, glanzmann thrombasthenia,

Question 94

Bernard-Soulier syndrome

Answer 94

= defective adhesion of platelets to subendothelial matrix.
• caused by an inherited deficiency of the platelet membrane glyco¬protein complex Ib-IX.
• This glycoprotein is a receptor for vWF and is essential for normal platelet adhesion to the subendothelial extracellular matrix.
• Affected patients have a variable, often severe, bleeding tendency. (defective adhesion)

Question 95

Glanzmann thrombasthenia

Answer 95

Defective platelet aggregation: Glanzmann thrombasthenia
• transmitted as an autosomal recessive trait.
• platelets fail to aggregate in response to adenosine diphosphate (ADP), collagen, epinephrine, or thrombin because of deficiency or dysfunction of glycoprotein IIb-IIIa, an integrin that participates in “bridge formation” between platelets by binding fibrinogen
• bleeding tendency is often severe.

Question 96

aspirin

Answer 96

Acquired Defects of platelet function:

1. aspirin: irreversible inhibitor of COX1, which is reqd for synth of thromboxaneA2 and prostaglandins – these mediators play imp. role in platelet aggregation → antiplatelet effects
2. Uremia

Question 97

storage pool disorders

Answer 97

Disorders of platelet secretion are characterized by the defective release of certain mediators of platelet activation, such as thromboxane and granule-bound ADP.

Question 98

Hemorrhagic Diatheses Related to Abnormalities in Clotting Factors:

Answer 98

• Bleeding due to isolated coagulation factor deficiencies most commonly manifests as large posttraumatic ecchymoses or hematomas, or prolonged bleeding after a laceration or any form of surgical procedure
• Unlike bleeding seen with thrombocytopenia, bleeding due to coagulation factor deficiencies often occurs into the gastrointestinal and urinary tracts and into weight-bearing joints (hemarthrosis).
• most common and important inherited deficiencies of coagulation factors affect factor VIII (hemophilia A), and factor IX (hemophilia B). Deficiencies of vWF (von Willebrand disease) influences both coagulation and platelet function.
• Acquired deficiencies usually involve multiple coagulation factors and can be based on decreased protein synthesis or a shortened half-life. Vitamin K deficiency results in the impaired synthesis of factors II, VII, IX, X and protein C
  • Many of these factors are made in the liver and are therefore deficient in severe parenchymal liver disease.

Question 99

The Factor VIII-vWF Complex:

Answer 99

• Factor VIII is an essential cofactor of factor IX, which converts factor X to factor Xa – mostly made in sinusoidal endothelial cells and Kupffer cells
• Once factor VIII reaches the circulation it binds to vWF, which is produced by endothelial cells
• vWF stabilizes factor VIII which has a half-life of about 2.4 hours when free and 12 hours when bound to vWF in the circulation
• vWF promotes the adhesion of platelets to subendothelial matrix through bridging interactions b/w platelet glycoprotein Ib-IX, vWF and matrix components such as collagen
• Upon vascular injury, the second pool of vWF binds collagen in the subendothelial matrix causing platelet adhesion
• Factor VIII fn = measured by coagulation assays
• vWF fn = measured by ristocetin agglutination test

Question 100

Von Willenbrand Disease:

Answer 100

• most common inherited bleeding disorder of humans
• bleeding tendency is usually mild and often goes unnoticed until some hemostatic stress, such as surgery or a dental procedure, reveals its presence
• symptoms = spontaneous bleeding from mucous membranes (e.g., epistaxis), excessive bleeding from wounds, or menorrhagia
• transmission is usually autosomal dominant
• wide variability in gene expression through families – due in part to modifying genes that influence circulating levels of vWF, which show a wide range in normal populations

Question 101

Type 1 and Type 3 von Willebrand disease :

Answer 101

quantitative defects in vWF.

• Type I = autosomal dominant disorder characterized by a mild to moderate vWF deficiency, accounts for about 70% of all cases – associated with a spectrum of mutations that interfere with maturation of vWF protein and result in rapid clearance from the plasma
• Type 3 (an autosomal recessive disorder) = very low levels of vWF and correspondingly severe clinical manifestations
o Because a severe deficiency of vWF has a marked effect on the stability of factor VIII, some of the bleeding characteristics resemble those seen in hemophilia
o disease is usually caused by deletions or frameshift mutations involving both alleles

Question 102

Type 2 von Willebrand disease

Answer 102

= qualitative defects in vWF

• autosomal dominant disorder
• vWF is expressed in normal amounts, but missense mutations are present that lead to defective multimer assembly.
• Large and intermediate multimers, representing the most active forms of vWF, are missing from plasma.
• accounts for 25% of all cases and is associated with mild to moderate bleeding.

Question 103

Tx: People undergoing dental work/surgery with vWD?

Answer 103

can be treated with desmopressin, which stimulates vWF release, or with infusions of plasma concentrates containing factor VIII and vWF.

Question 104

Hemophilia A

Answer 104

(Factor VIII deficiency):
• most common hereditary disease associated with life-threatening bleeding
o tendency toward easy bruising and massive hemorrhage after trauma or operative procedures
o “spontaneous” hemorrhages frequently occur in regions of the body that are susceptible to trauma, particularly the joints, where they are known as hemarthrose
o Recurrent bleeding into the joints leads to progressive deformities that can be crippling
o Petechiae are characteristically absent.

X-linked recessive trait → affects mainly males

• exhibits a wide range of clinical severity that correlates well with the level of factor VIII activity
• > 1% of normal → severe disease; 2% to 5% of normal → moderately severe disease; 6% to 50% of normal levels →mild disease

variety of mutations: most severe deficiencies result from an inversion involving the X chromosome that completely abolishes the synthesis of factor VIII
o Mutations permitting some active factor VIII to be synthesized are associated with mild to moderate disease

** DDx: Prolonged PTT and a normal PT (due to abnormality in intrinsic pathway)

treated with infusions of recombinant factor VIII

Question 105

Hemophilia B

Answer 105

(“Christmas Disease”, Factor IX Deficiency):
• disorder clinically indistinguishable from factor VIII deficiency
• X-linked recessive trait and shows variable clinical severity
• the PTT is prolonged and the PT is normal
• Ddx: possible only by assay of the factor levels
• treated with infusions of recombinant factor IX.

Question 106

Disseminated Intravascular Coagulation (DIC):

Answer 106

• thrombohemorrhagic disorder characterized by the excessive activation of coagulation and the formation of thrombi in the microvasculature of the body
• occurs as a secondary complication of many different disorders
• consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolysis

• symptoms relating to the tissue hypoxia and infarction caused by the microthrombi; hemorrhage caused by the depletion of factors required for hemostasis and the activation of fibrinolytic mechanisms

Etiology:
• not a primary disease – occurs in the course of a variety of clinical conditions → pathologic activation of coagulation or the impairment of clot-inhibiting mechanisms
• Two major mechanisms trigger DIC: (1) release of tissue factor or other, poorly characterized procoaagulants into the circulation, and (2) widespread injury to endothelial cells.
• endothelial injury → TNF induces endothelial cells to express tissue factor on surface and decrease expression of thrombomodulin, shifting balances towards coagulation
• DIC most often assoc. w/ obstetric complications, malignant neoplasms, sepsis and major trauma

Question 107

Two results of DIC:

Answer 107

1. widespread deposition of fibrin: → ischemia and microangiopathic hemolytic anemia – due to fragmentation of RBCs as they squeeze through narrowed microvasculature
2. consumption of platelets and clotting factors → hemorrhagic diathetsis (plasmin cleaves fibrin and also digests factors V and VIII, reducing their concentration)

Question 108

morphology/CF of DIC?

Answer 108

Morphology:
• thrombi in brain, heart, lungs, kidneys, adrenals, spleen, liver
• bilateral renal cortical necrosis from small thrombi in glomeruli
• hyaline membranes in lungs
• microinfarcts in CNS
• “Waterhouse-Friderichsen syndrome” = massive adrenal hemorrhages

Clinical Features:
• onset can be fulminant, as in endotoxic shock or amniotic fluid embolism, or insidious and chronic, as in cases of diffuse carcinomatosis or retention of a dead fetus
o 50% of the affected are obstetric patients having complications of pregnancy – usually reversible
• microangiopathic hemolytic anemia ; dyspnea, cyanosis, and respiratory failure; convulsions and coma; oliguria and acute renal failure; and sudden or progressive circulatory failure and shock
• acute DIC- obstetric complications or major trauma = bleeding diathesis
• chronic DIC - cancer patients = thrombotic complications

Question 109

febrile nonhemolytic reaction of tranfusion

Answer 109

= fever and chills, sometimes with mild dyspnea, within 6 hours of a transfusion of red cells or platelets
• most common reaction, sx are short lived

Question 110

Allergic Reactions of transfusion:

Answer 110

• Patients with IgA deficiency- the reaction is triggered by IgG antibodies that recognize IgA in the infused blood product – potentially fatal
• Urticarial allergic reactions (wheels and hives that itch)- triggered by the presence an allergen in the donated blood product that is recognized by IgE antibodies in the recipient – usually tx with antihistamines

Question 111

Acute Hemolytic Reactions: of transfusion

Answer 111

• caused by preformed IgM antibodies against donor red cells that fix complement.
o high affinity “natural” IgM antibodies, usually against polysaccharide blood group antigens A or B, bind to red cells and rapidly induce complement-mediated lysis, intravascular hemolysis, and hemoglobinuria.
o Fever, shaking chills, and flank pain appear rapidly
• most commonly stem from an error in patient identification or tube labeling that allows a patient to receive an ABO incompatible unit of blood
• direct Coombs test is typically positive

Question 112

Delayed hemolytic reactions of transfusions:

Answer 112

caused by antibodies that recognize red cell antigens that the recipient was sensitized to previously, for example through a prior blood transfusion. These are typically caused by IgG antibodies to foreign protein antigens and are associated with a positive direct Coombs test and laboratory features of hemolysis (e.g., low haptoglobin and elevated LDH)

Question 113

Transfusion-Related Acute Lung Injury: (TRALI)

Answer 113

• severe, frequently fatal complication in which factors in a transfused blood product trigger the activation of neutrophils in the lung microvasculature
• more frequently in patients with preexisting lung disease.
Clinical presentation:
• dramatic sudden onset respiratory failure, during or soon after a transfusion.
• Diffuse bilateral pulmonary infiltrates that do not respond to diuretics are seen on chest imaging.
• fever, hypotension and hypoxemia.
• treatment is largely supportive and the outcome is guarded; mortality is 5% in uncomplicated cases and up to 67% in those who were severely ill.

Question 114

Complications of Transfusion Infections:

Answer 114

• Most bacterial infections are skin flora, indicating that the contamination occurred at the time that the product is taken from the donor
• bacterial contamination is much more common in platelet preparations (b/c must be stored at room temp)
• sx: fever, chills, hypotension
• HIV rate of transmission = 1 in 2 million
• Hep C = 1 in 1 million
• Hep B = 1 in 500,000

Question 115

what cell type is seen with DIC?

Answer 115

schisocytes

Question 116

Ristocetin-dependent platelet aggregation

Answer 116

if abnormal, think vWF

Question 117

abnormal spectrin?

Answer 117

hereditary spherocytosis

Question 118

fever, thrombocytopenia, microangiopathic hemolytic anemia, neuro problems, renal failure

Answer 118

TTP

confirmed by demonstration of von Willebrand factor monomers in the serum.

These abnormalities are produced by
small platelet-fibrin thrombi in small vessels in multiple organs. The heart, brain, and kidney often are severely affected.

Question 119

inability to correct PTT by mixing with normal plasma

Answer 119

Failure to correct PTT by normal plasma
indicates the presence of an inhibitor in the patient’s serum. About 15% of patients with hemophilia eventually develop an
inhibitor to factor VIII. The antiphospholipid syndrome has similar PT and PTT findings because an inhibitor is present, but
these patients have thromboses and bleeding, typically in adulthood, and without a family history.

Question 120

Vitamin K deficiency

Answer 120

leads to an abnormal PT.

Question 121

Complement lysis is enhanced

Answer 121

PNH

Question 122

random organ effects of different types of anemias?

Answer 122

The hemolysis that accompanies sickle cell anemia results in an increased indirect hyperbilirubinemia, which
favors the development of gallstones containing bilirubin pigment. Cirrhosis can occur because of hemochromatosis in β-
thalassemia major. Chronic atrophic gastritis leads to loss of parietal cells, and the resulting vitamin B12 malabsorption
causes pernicious anemia. Stillbirths suggest thalassemia major. Esophageal webs occur rarely in the setting of chronic
iron deficiency anemia.

Question 123

Myelophthisic anemia

Answer 123

prostatic adenocarcinoma that has metastasized to the bone. High
alkaline phosphatase, hypercalcemia, and a leukoerythroblastic pattern in the peripheral blood (immature WBCs and
RBCs) are a consequence of the tumor acting as a space-occupying lesion. Myelophthisic anemias also may be caused
by infections.

Question 124

inherited or acquired deficiency of the

von Willebrand factor (vWF) metalloproteinase

Answer 124

TTP

The absence of ADAMTS-13 gives rise to large multimers of vWF that promote widespread platelet aggregation,
and the resulting microvascular occlusions in brain, kidney, and elsewhere produce organ dysfunction, thrombocytopenia,
microangiopathic hemolytic anemia (MAHA), and bleeding.

Question 125

Defective aggregation of platelets in the presence of ADP and
thrombin

Answer 125

Glanzmann Thrombasthenia