Exam 2 Flashcards
Antihyperlipidemics
agents which decrease the concentration of circulating lipoproteins
Least dense lipoproteins
Chylomicrons
lipoproteins transform form of GI absorbed triglycerides
chylomicrons
rapidly removed from circulation into adipose tissue and skeletal muscle
VLDL are synthesized in ___________.
liver
Which lipoproteins transport lipids to peripheral tissues?
Very low density lipoproteins (VLDL)
Which lipoproteins are the major transporter of cholesterol?
low density of lipoproteins (LDL)
bad lipoprotein
Where are LDL’s synthesized?
liver
Where are HDL synthesized?
liver
Which lipoproteins are reverse cholesterol transporters (tissue to liver)?
High-density lipoproteins
“good” lipoprotein
Atherosclerotic plaques develop with addition of:
Cholesterol
Calcium
Collagen
Fibrin
High concentrations of ___________ lead to an increased risk of atherosclerosis based on the movement of “sticky” cholesterol to vessel walls and the build-up of plaques.
LDL
Increased ratio of ____________ is considered desirable.
HDL: LDL
Is dietary cholesterol the only source of body cholesterol?
no-liver synthesized cholesterol based on body levels.
What levels of plasma concentration should be decreased in order to help lower cholesterol levels?
triglycerides because they are used to synthesize cholesterol
Hyperlipidemia occurs in _____% of the population.
15-20%
Risk factors of hyperlipidemia
PEGSS
Poor diet
Excessive alcohol consumption
Genetics
Smoking
Sedentary lifestyle
Primary goal in treatment of hyperlipidemia
to lower LDL and triglycerides while increasing HDL/LDL ratio
What is the first-line therapy in hyperlipidemia?
diet modification and excercise plans
-however, not likely to be extremely effective at lowering very high cholesterol and triglyceride levels
-diet rich in unsaturated fats decreases LDL and increases HDL
-drug therapy can be very effective and useful in most patients
Which agents are recommended for use in patients with high LDL but near normal Triglyceride levels?
Bile acid binding resins
Drugs that are bile acid binding resins
Cholestyramine (Questran)
Colestipol (Colestid)
Colesvelam (Welchol)
are bile acid-binding resins water soluble?
no, water insoluble cation exchange resins that bind up released bile salts (and their attached cholesterol) in the GI tract and prevent their reabsorption
Bile-Acid binding resins result in a ________% decrease in circulating LDL cholesterol (plasma triglycerides may increase due to increased hepatic LDL receptors and increased LDL catabolism.
30%
Bile-acid binding resins adverse effects
-constipation
-poor compliance (sand-like consistency)
-abdominal cramping
-absorption of fat-soluble vitamins
-may bind to several other drugs (ex. digitalis, beta-blockers etc.) so separate doses
What are considered first-line antihyperlipidemics ?
bile acid binding resins
What is the MOA of HMG-CoA reductase inhibitors (Statins)?
inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase)
-therefore block cholesterol synthesis (not dietary) and decrease LDL cholesterol.
-decreased LDL levels also stimulate the production of hepatic LDL receptors and thus further decreases the plasma LDL level
-all act in primarily in the liver to decrease production of cholesterol
Statins are considered first-line therapeutics, however their side effect profile is _______________ than bile acid binding resins.
greater
HMG CoA reductase inhibitor drugs
-Lovastatin
-Atorvastatin (lipitor)
-Fluvastatin (Lescol)
-Pravastatin (Pravachol)
-Simvastatin (Zocor)
-Rosuvastatin (Crestor)
-Pitavastatin (Livalo)
Which agents are very useful in cases of genetic hypercholesterolemia?
HMG-CoA reductase inhibitors
Which antihyperlipidemics should be avoided in pregnancy?
HMG-CoA reductase inhibitors
Statins decrease plasma cholesterol by up to ____% and decrease triglyceride levels by _______%.
30%
10-20%
Statins have a ________ (high or low) first-pass effect.
high
Adverse effects of Statins
-may increase plasma aminotransferase levels (d/c if levels increase more than 3x normal)
-skeletal muscle weakness/pain
-linked to increased plasma creatinine phosphokinase
-may become severe leading to rhabdomyolysis and renal failure
-more common when taking certain drugs such as macrolide Abx and antifungal agents
- effects may be less with Flubastatin
-Rosuvastatin may be more likely to cause
Which medication should be avoided in patients taking Statins?
Sux unless absolutely necessary
-linked use of Sux in patients taking statins with increased risks of muscle pain and injury up to rhabdomyolysis and related kidney damage
How are Statins metabolized?
partly CYP3A4
Which statin is metabolized by CYP2C9 which is not affected by grapefruit juice?
Pitavastatin
How does grapefruit juice affect statins?
-grapefruit juice contains compounds (furanocoumarins) which inhibit CYP3A4 thus increasing duration of many statins and possibly leading to increased risk of rhabdo or other myopathy and muscle pain
-especially seen with SAL :)
-Simvastatin
-Atorvastatin
-Lovastatin
MOA of Niacin (Nicotinic Acid)
-decreases both VLDL and LDL plasma levels
-mech unclear, believed to act by increasing VLDL clearance and decreasing VLDL synthesis which then leads to decrease in conversion to LDL
-inhibits free fatty acid release from adipose tissue
Niacin can lower LDL by ____ with up to a _______ decrease in triglycerides.
30%
50%
Niacin increased HDL levels ______%
20-30%
Adverse effects of Niacin
-benefits closely linked to dose, higher doses not well tolerated
-large doses can lead to hepatic damage, which is believe to be due to a direct hepatic effect
-hyperglycemia
-increased plasma uric acid levels
-potent vasodilator, which leads to flushing, headaches and potential orthostatic hypotension and syncope
-flushing (and pruritus) is prostaglandin mediated and can be avoided by pretreatment with aspirin
-abdominal pain and diarrhea
-increased risk of skeletal muscle myopathy when given with HMG-CoA reductase inhibitors.
What are the fibrate drugs?
Fenofibrate
Gemfibrozil
Clofibrate
MOA of Gemfibrozil (Lopid)
-stimulation of lipoprotein lipases which break down triglycerides
-used mainly to treat patients with increased triglycerides without increased LDL cholesterol
Gemfibrozil (Lopid) lowers triglycerides up to _____% and increase HDL up to____%.
50%
20%
How is Gemfibrozil eliminated?
renal in unchanged form, care in renal compromised patients
Adverse effects of Gemfibrozil
-small increase in patient development of gallstones
-increased risk of skeletal muscle myopathy, esp administered with Statins
-GI upset
-Arrythmias are possible and so should not be used in patient with a history of heart disease
How do fenofibrates effect levels?
-more effective at lowering triglycerides than cholesterol
-increases HDL cholesterol somewhat but not very effective at lowering LDL cholesterol
Ezetimibe (Zetia) MOA
-different than other agents
-inhibitor of intestinal cholesterol transport
-does not inhibit liver synthesis of cholesterol or increase biliary excretion
-reduces LDL cholesterol while increasing HLD cholesterol in patients with hypercholesterolemia
Metabolism of Ezetimibe (Zetia)
liver glucuronidation then excreted in urine
unchanged form excreted primarily in feces
enterohepatic recycling occurs
t1/2 of Ezetimibe
22 hours
Which med is recommended only when other agents either are not effective or tolerated but to controversy concerning true effectiveness?
Ezetimibe (Zetia)
PCSK9 inhibitor drugs
Alirocubmab (Praluent)
Evolocumab (Repatha)
When were PCSK9 inhibitors approved?
2015
newest class for lowering cholesterol
How do PCSK99 inhibitors work?
-monoclonal antibodies which inhibit human proprotein convertase subtilisin kexin 9 binding to liver LDL receptors allowing more LDL particles to be reabsorbed by the liver and decrease circulating LDL
Which agents are for patients no able to take other antihypercholesterolemics or other agents are not working?
PCSK9 inhibitors
Which med is a prodrug activated by coenzyme A which inhibits adenosine triphosphate citrate lyase in liver?
Bempedoic acid (NExletol)
enzyme is needed for cholesterol synthesis
which drug was approved for use in familial hypercholesterolemia in combination with statin therapy and dietary control?
Bempedoic acid (Nexletol)
-not first line therapy
Side effects of Bempedoic acid
-muscle spasms, back and limb pain , gout, diarrhea
-more serious SE include tendon rupture (0.5%)
-weak transport protein inhibition may account for increased gout attacks and increased blood statin levels (simvastatin and pravastatin mainly)
Withold ______ during perioperative period. Can decrease platelet counts and increase prothrombin time.
Niacin
Which med caused cutaneous and peripheral vasodilation (flushing) which can lead to hypotension with general anesthetics.
Niacin
Which agents have higher risk of rhabdomyolysis than the statins in hospitalized patients and should be d/c’d prior to surgery?
fibrates
Antiplatelet drugs action
to decrease plt aggregation and formation of a plt plug
Anticoagulants inferfere with the____________.
coagulation cascade, thus blocking thrombus formation
How is the platelet plug strengthened?
addition of fibrin to form a cross-linked matrix via the coagulation cascade
Platelets contain mainly ______ and since they do not contain _____ they cannot synthesize additional _______.
cox-1
DNA
COX
How does high intracellular cAMP levels interfere with platelet aggregation?
high CaMP inhibits aggregation
How do low intracellular cAMP levels interfere with platelet aggregation?
low CaMP enhance aggregation
cAMP levels are controlled by ______.
TX-A2 (and other mediators)
Dipyridamole (Persantine) is a _______ inhibitor.
PDE-5 inhibitor, however it is only weakly antiplatelet and usually given with warfarin to decrease thrombus formation in heart valve replacement or with aspirin.
What can dipyridamole (Persantine) induce?
angina in susceptible patients due to a vasodilatory property which can increase cardiac steal.
Which are prodrugs that are activated in the liver and covalently bind to the P2Y12 receptor protein, decreasing platelet aggregation?
Clopidogrel (plavix)
Ticlodipine
Uses of Ticlodipine
decreases embolus risk after coronary stent placement and use in patients who cannot tolerate aspirin
Uses of Clopidogrel
-prevent secondary MI, Stroke, PVD, bypass graft surgery
How is Cangrelor (Kengreal) different than Clopidogrel?
it is an active compound so does not require metabolic activation
-it is an IV agent that has been shown to decrease mortality when used with Clopidogrel in CV stent placement in MI patients
What is an oral P2Y12 irreversible inhibitor used to decrease clotting risks in CV stent patients?
Prasugrel (Effient)
-similar to Clopidogrel
-used with low dose aspirin
What is a oral P2Y12 reversible inhibitor?
Ticagrelor (Brilinta)
acts on a different site and produces an allosteric change blocking ADP binding
-CYP3A4 inhibitors (grapefruit juice, ketoconazole etc) can lead to increased risk of excessive bleeding
What is considered the final pathway in aggregation?
glycoprotein IIb/IIIa receptor
GPIIb/IIIa receptors on platelet surface is the location that binds fibrinogen allowing platelets to bind together during aggregation. Blocking this binding site keeps platelets from aggregating
What are the glycoprotein IIb/IIIa receptor antagonists
-Abciximab (reopro)
-eptifabatide (Integrilin)
-Tirofiban (aggrastat)
Which Glycoprotein IIB/IIIa receptor antagonist is a monoclonal antibody for IV use?
Abciximab (reopro)
What is the t1/2 of Abciximab?
12-24 hours
affinity for receptor very strong (almost irreversible)
-recommend with aspirin or warfarin to decrease SE risk
How do you reverse Abciximab?
with platelet infusions
Which Glycoprotein IIB/IIIa receptor antagonist is a synthetic peptide with a high affinity but shorter t1/2 (2-4 hours) than Abciximab?
Eptifibatide (Integrilin)
Which Glycoprotein IIB/IIIa receptor antagonist is a non-peptide tyrosine analog with t1/2 2-4 hours?
Tirofiban (Aggrastat)
Which anticoags are useful for arterial and venous thrombotic disease?
Thrombin inhibitors
Which are the Thrombin inhibitors?
-Bivalrudin (Angiomax)
-Argatroban (Acova)
-Dabigatran (Pradaxa)
-Lepirudin
-Recombinant Hirudin
What are the ADP inhibitors?
also known as P2y12 inhibitors:
Clopidogrel (Plavix)
Prasugrel (Effient)
Ticagrelor (Brillinta)
Ticlodipiine (Ticlid)
Which thrombin inhibitors can be used as a heparin replacement in patients not responding to heparin or experiencing heparin-induced thrombocytopenia?
Recombinant Hirudin (Desirudin)
Which thromin inhibitor is a peptide that directly inhibits thrombin without the need of antithrombin that heparin requires?
recombinant hirudin
Which is a synthetic peptide similar to Hirudin?
Bivalrudin (Angiomax)
Which is a arginine derivative used in place of heparin that is a thrombin inhibitor?
Argatroban (acova)
in addition to its direct thrombin inhibition, it triggers nitric oxide release which increases perfusion in peripheral vascular disease
Where is heparin found?
in mast cell and nerve terminal vesicles
What is heparin structurally?
strongly acidic glycosaminoglycan of high molecular weight chains with 10-100 monosaccharide residues
Heparin is _______ at physiologic pH , which explains most SE.
polyanionic
What does heparin require for action?
a cofactor–>antithrombin III
What factors does Heparin inhibit?
Coag factors:
IXa
Xa
XIa
XIIa
thrombin activity
Heparin metabolism
50% metabolized
50% eliminated unchanged in the urine
t1/2 heparin
1-2 hours
increases dramatically in liver or renal disease
Can heparin be given in pregnancy?
yes, fairly safe since it does not cross placenta
Heparin activity is due to a specific _________________ sequence.
pentasaccharide
Heparin effects can be immediately reversed with _________ which is a _____________.
Protamine
ionic binder
Low-molecular weight heparins
Enoxaparin (Lovenox)
Dalteparin (Fragmin)
How is low-molecular weight heparin produced?
by cleavage of heparin into smaller polysaccharide chains
-all have the specific pentasaccharide required for activity like heparin
-more bioavailable than Heparin when given SQ
Why do LMWH decrease side effects?
less binding to cells and other proteins due to lower overall charge
Which anticoagulant acts with antithrombin to inhibit factor Xa but not thrombin?
Fondaparinux (Arixtra)
Warfarin administration should be d/c’d how many days prior to surgery?
2-5 days
What can be given to reverse effects of warfarin if needed for emergency surgery?
Vitamin K or FFP to provide prothrombin
Warfarin clearance rate is decreased with:
Amiodarone
Cimetadine
Omeprazole
Should Warfarin be avoided in pregnancy?
Yes! crosses placenta into fetus and produces exaggerated actions in fetus
How do oral anticoagulants such as warfarin work?
-act as competitive inhibitors of Vitamin K, which is needed for synthesis of prothrombin
-therefore they decrease the amount of prothrombin available to be converted to thrombin by factor Xa
-due to this mechanism, these agents have fairly slow onsets (24-48 hours) and long durations (2-5 days_
Thrombin converts _______ to ________ which are crosslinked by factor _____ to form thrombotic web.
fibrinogen to fibrin
crosslinked by factor XIIIa
Is Dabigatran considered safer than warfarin?
yes
Which oral anticoagulant is an esterase prodrug form activated by plasma and liver esterases?
dabigatran (Pradaxa)
-binds to bound free and clot-found thrombin
How is Dabigatran metabolized and excreted?
80% renally excreted
remainer metabolized by liver
D/C Rivaroxaban (Xarelto) _______ hours prior to surgery?
24-48 hours
D/C Apixaban (Eliquis) _______ hours prior to surgery?
24-48 hours
D/C Edoxaban (savaysa) _______ hours prior to surgery?
24-48 hours
What newer oral anticoagulants is a new variant of factor Xa inhibitors specifically approved for hospitalized and transitioning patients to prevent DVT And VTE formation?
Betrixaban (Bevyxxa)
-d/cd by manufacturer in 2020 prior to corporate buy-out
Which drug is a recombinant product to reverse factor Xa inhibotrs?
Adexanet alfa (Andexxa)
effective but very expensive :25k
Thrombolytic agents MOA
-used to dissolve formed clot
-primary indication is emergency tx of a coronary occlusion
-convert plasminogen to plasmin which is an enzyme responsible for cleaving fibrin molecules, thus breaking apart the ‘web’ matrix of a thrombus
recommended in patients within 12 hours of onset of MI symptoms with ST segment elevation
Thrombolytic agents (drugs)
Streptokinase (Streptase)
Alteplase (Activase)
Which thrombolytic agent is isolated from beta-hemolytic streptococci?
Streptokinase (Streptase)
-acts by binding to plasminogen causing other molecules to be converted to plasmin which then breaks down fibrin
-allergic reactions possible in patients who have been exposed to beta-hemolytic streptococcal infections
Which is a recombinant form of tissue plasminogen activator?
Alteplase (Activase)
more expensive than streptokinase
Blood composition
92% water
8% solutes
Plasma is _______ % of blood volume
50-55%
What is serum?
plasma that has been allowed to clot to remove fibrinogen (may interfere with diagnostic tests)
polycythemia
too many cells
anemia
too few cells
-reduction in the total number of erythrocytes in circulating blood or in the quality or quantity of hemoglobin
Causes of anemia:
-impaired erythrocyte production
-acute or chronic blood loss
-increased erythrocyte destruction
-combination of above
Classification of anemia
-etiologic factor(cause)
-size
identified by terms that end in ‘cytic”
macrocytic (large)
microcytic (Small)
normocytic (normal)
-hemoglobin content
-identified in terms that end in “chromic”
-hypochromic (decreased amount)
Anisocytosis
-RBC are present in various sizes
Poikilocytosis
RBCs present in various shapes
Clniical manifestations of anemia
-reduced O2 carrying capacity: hypoxia
-snycope, angina, compensatory tachycardia, and Jordan dysfunctions
Classic anemia symptoms:
-fatigue
-weakness
-dyspnea
-elevated HR
-pallor
Treatment of anemia
-transfusions
-dietary correction
-administration of supplemental vitamins or iron
-correction of underlying condition
What are macrocytic-normochromic anemias also termed?
Megaloblastic anemias
What is the patho of macrocytic-normochromic anemia?
RBCs are unusually large.
Deoxyribonucleic acid (DNA) synthesis is defective.
Due to deficiencies in vitamin B12 or folate.
Co-enzymes for nuclear maturation and the DNA synthesis pathway
Ribonucleic acid (RNA) processes occur at a normal rate.
Results in unequal growth of the nucleus and cytoplasm.
What is the most common macrocytic anemia?
Pernicious anemia
What is pernicious anemia caused by?
vitamin B12 deficiency
-lacks intrinsic factor from gastric parietal cells required for vitamin B12 absorption
-may be a congenital or autoimmune disorder
-autoantibodies against intrinsic factor
Conditions that increase risk of pernicious anemia
-past infection with Helicobacter pylori
-gastrectomy
-proton-pump inhibitors
Clinical manifestations of pernicious anemia
-weakness, fatigue
-paresthesias of feet, fingers, difficulty walking
-loss of appetite, abdominal pain, weight loss
-sore tongue that is smooth and beefy red, secondary to atrophic glossitis
-“lemon yellow” (sallow) skin as a result of a combo of pallor and icterus
-neuro symptoms from nerve demyelination-not reversible even with tx
-often unrecognizable in older adults because of its subtle slow onset and presentation
Evaluation of pernicious anemia
-methylmalonic acid and homocysteine levels elevated early in disease
-gastric bx
Treatment of pernicious anemia
-parenteral or high oral doses of vitamin B12
-if left untreated,death
-life-long tx required
What is folate deficiency anemia?
Folate is an essential vitamin for RNA and DNA synthesis.
Absorption of folate occurs in the upper small intestine; is not dependent on any other facilitating factors.
folate deficiency anemia is common in:
Is common in alcoholics and individuals with chronic malnourishment.
Folate deficiency anemia is associated with what in fetus?
neural tube defects
Clinical manifestations of folate deficiency anemia
Severe cheilosis: Scales and fissures of the lips and corners of the mouth
Stomatitis: Mouth inflammation
Painful ulcerations of the buccal mucosa and tongue: Characteristic of burning mouth syndrome
Dysphagia (difficulty swallowing), flatulence, and watery diarrhea
Neurologic symptoms: Usually not seen
Treatment of folate deficiency
Oral dose of folate is administered daily until normal blood levels are obtained.
Life-long treatment is not necessary.
causes of microcytic-hypochromic anemias
Disorders of iron metabolism
Disorders of porphyrin and heme synthesis
Disorders of globin synthesis
Microcytic-hypochromic anemia characterized by:
Are characterized by RBCs that are abnormally small and contain reduced amounts of hemoglobin
Most common type of anemia worldwide
iron-deficiency anemia
Highest risk of iron deficiency anemia
Older adults, women, infants, and those living in poverty
Which anemia is associated with cognitive impairment in children
iron deficiency anemia
Causes of iron deficiency anemia
Inadequate dietary intake
Excessive blood loss
Chronic parasite infestations
Metabolic or functional iron deficiency
Menorrhagia (excessive bleeding during menstruation)
Use of medications that cause gastrointestinal bleeding (aspirin, nonsteroidal antiinflammatory drugs [NSAIDs])
Surgical procedures that decrease stomach acidity, intestinal transit time, and absorption (e.g., gastric bypass)
Insufficient dietary intake of iron
Eating disorders, such as pica (craving and eating nonnutritional substances such as dirt, chalk, and paper)
Clinical manifestations of iron-deficiency anemia
Fatigue, weakness, shortness of breath
Pale earlobes, palms and conjunctivae
Brittle, thin, coarsely ridged, and spoon-shaped (concave or koilonychia) nails
Red, sore, painful tongue
Angular stomatitis: Dryness and soreness in the corners of the mouth
Become symptomatic: When hemoglobin (Hgb) 7 to 8 g/dl
Tx of iron-deficiency anemia
Iron replacement therapy: Iron dextran
Sodium ferric gluconate complex in sucrose (Ferrlecit) and iron sucrose injection (Venofer)
Duration of therapy: Usually 6 to 12 months after the bleeding has stopped but may continue for as long as 24 months
Evaluation of iron-deficiency anemia
serum ferritin
What is sideroblastric anemia?
Makes up a group of disorders characterized by anemia.
Is caused by a defect in mitochondrial heme synthesis.
Altered mitochondrial metabolism causes ineffective iron uptake and results in dysfunctional hemoglobin synthesis.
Ringed sideroblasts in the bone marrow are diagnostic.
Sideroblasts: Erythroblasts contain iron granules that have not been synthesized into hemoglobin.
What are the clinical manifestations of sideroblastic anemia?
Iron overload (hemochromatosis)
Enlarged spleen (splenomegaly) and liver (hepatomegaly)
Evaluation of sideroblastic anemia
Bone marrow examination: Diagnostic
Dimorphism: Normocytic and normochromic cells concomitantly observed with microcytic-hypochromic cells
Reversible sideroblastic anemia associated with
alcoholism
Treatment of sideroblastic anemia
Identify causative agents (drugs or toxins)
Transfusion
Iron-depletion therapy
Phlebotomy
Prolonged administration of erythropoietin
Hereditary: Pyridoxine (B6) therapy; life-long maintenance therapy at a lowered dose
Congenital: Stem cell transplantation
Myelodysplastic syndrome: Recombinant human erythropoietin
Normocytic-normochromic anemia
Are characterized by RBCs that are relatively normal in size and hemoglobin content but insufficient in number.
No common cause, pathologic mechanisms, or morphologic characteristics exist.
Are less frequent than macrocytic-normochromic and microcytic-hypochromic anemias.
Pancytopenia
reduction or absence of all three types of blood cells
Pure RBC aplasia
only RBCs affected
Faconi anemia
rare genetic anemia from defects in DNA repair
Clinical manifestations of aplastic anemia
Hypoxemia, pallor (occasionally with a brownish pigmentation of the skin)
Weakness along with fever and dyspnea with rapidly developing signs of hemorrhaging if platelets are affected
Patho of aplastic anemia
Hypocellular bone marrow that has been replaced with fat
Evaluation of aplastic anemia
bone marrow bx
Tx of aplastic anemia
Bone marrow transplantation
Peripheral blood stem cell transplantation
May receive radiation or chemotherapy before procedure
Immunosuppression
Antithymocyte globulin with cyclosporin
Corticosteroidal medications
Identification of high-risk individuals
If not treated or identified, death occurs
Post-hemorrhagic anemia
Acute blood loss from the vascular space
Clinical manifestations
Depends on the severity of the blood loss
Treatment
Intravenous administration of saline, dextran, albumin, or plasma
Large volume losses: Fresh whole blood
Clinical manifestations of hemolytic anemia
May be asymptomatic
Jaundice (icterus)
Splenomegaly
Evaluation of hemolytic anemia
Bone marrow: Abnormally increased numbers of erythrocyte stem cells (erythroid hyperplasia)
Tx of hemolytic anemia
Acquired: Removal of the cause or treatment of the underlying disorder
First line: Corticosteroids
Second line: Splenectomy and Rituximab (Rituxan) (monoclonal antibody)
Paroxysmal nocturnal hemoglobinuria: Eculizumab (Solaris)
Pathologic mechanisms of anemia
Decreased erythrocyte lifespan
Suppressed production of erythropoietin
Ineffective bone marrow response to erythropoietin
Altered iron metabolism
Relative polycythemia
Is a result of dehydration.
Fluid loss results in relative increases of RBC counts and hemoglobin and hematocrit values.
Resolves with fluid intake.
Polycythemia
overproduction of RBCs
Paroxysmal nocturnal hemoglobinuria
Deficiency in CD55 and CD59: Cause complement-mediated intravascular lysis and release of hemoglobin
Anemia, hemoglobinuria, severe fatigue, abdominal pain, and thrombosis
Autoimmune hemolytic anemia
Autoantibodies against antigens normally on the surface of erythrocytes
Drug induced hemolytic anemia
Form of immune hemolytic anemia that is usually the result of an allergic reaction against foreign antigens
Called the hapten model
Penicillin, cephalosporins (more than 90%), hydrocortisone
Disease leading to anemia of chronic disease
-AIDS
-Malaria
-RA
-Lupus
-Hepatitis
-Renal Failure
-Malignancies
Polycythemia Vera
Chronic neoplastic, nonmalignant condition
Overproduction of RBCs (frequently with increased levels of WBCs [leukocytosis] and platelets [thrombocytosis])
Splenomegaly
Patho of Polycythemia vera
Is an acquired mutation in Janus kinase 2 (JAK2).
Negates the self-regulatory activity of JAK2 that allows the erythropoietin receptor to be constitutively active, regardless of the level of erythropoietin.
Disease can convert into acute myeloid leukemia.
Polycythemia vera s/s
Spleen becomes enlarged, frequently with abdominal pain and discomfort.
As the disease progresses, blood cellularity and viscosity increases.
Intense, painful itching is intensified by heat or exposure to water (aquagenic pruritus
Treatment of polycythemia vera
Phlebotomy: Withdrawal of 300 to 500 ml of blood at a time to reduce erythrocytosis and blood volume
Low-dose aspirin
Interferon-α
Hydroxyurea
Radioactive phosphorus
Hereditary Hemochromatosis
Common inherited, autosomal recessive disorder of iron metabolism
Characterized by increased gastrointestinal iron absorption with subsequent tissue iron deposition
Excess iron deposited in the liver, pancreas, heart, joints, and endocrine gland, causing tissue damage
s/s of hereditary hemochromatosis
Fatigue, malaise
Abdominal pain, arthralgias, and impotence
Hepatomegaly, abnormal liver enzymes, bronzed skin, diabetes, and cardiomegaly
Treatment of Hereditary hemochromatosis
Phlebotomy; refrain from taking iron and vitamin C supplements and consuming raw shellfish; alcohol use in moderation
What are the myeloproliferative RBC disorders?
- Polycythemia vera
- Relative Polycythemia
- Hereditary Hemochromatosis (iron overload)
Quantitative disorders of leukocyte function
-Increases or decreases in cell numbers
-Bone marrow dysfunction or premature destructionof cells
-Response to infectious microorganism invasion
Qualitative disorders of leukocytes
Disruption of leukocyte function
Phagocytic cells (granulocytes, monocytes, macrophages) may lose their phagocytic capacity to function.
Lymphocytes may lose their capacity to respond to antigens.
Leukocytosis
-Counts are higher than normal.
-Is a normal protective physiologic response to stressors or to the invasion of microorganisms.
-Can be pathological
Leukopenia
Counts are lower than normal.
Is always abnormal.
Low white blood cell (WBC) count predisposes a person to infections.
What is evident in the first stages of infection or inflammation?
Granulocytosis (Neutrophilia)
-If the need for neutrophils increases beyond the supply, then immature neutrophils (banded neutrophils) are released into the blood.
-Premature release of immature leukocytes is termed a shift-to-the-left-producing more of precursor cells (bands or stabs)
Leukemoid reaction
Causes of Neutropenia
-Prolonged severe infection
-Decreased production
-Reduced survival
-Abnormal neutrophil distribution and sequestration
Congenital Neutropenia
Cyclic neutropenia and neutropenia with congenital immunodeficiency diseases
Multiple syndromes
Acquired neutropenia
Multiple conditions (hypoplastic anemia, aplastic anemia, leukemias, lymphomas [Hodgkin, non-Hodgkin]; myelodysplastic syndrome)
Secondary Neutropenia
Lower count from other disorders (e.g., immune disorders and drugs); toxin, drug or environmental
Causes of Granulocytopenia (Agranulocytosis)
-Interference with hematopoiesis
-Immune mechanisms
-Chemotherapy destruction
-Ionizing radiation
Eosinophilia
-eosinophil count increased
-hypersensitivty reactions trigger release of eosinophilic chemotactic factor or anaphylaxis from mast cells
Causes of Eosinophilia
-allergic disorders
-parasitic invasions
Eosinopenia
eosinophil count decreased
Primary cause of eosinopenia
-migration of cells to inflammatory sites
Other causes of eosinopenia
-Surgery
-Shock
-Trauma
-Burns
-Mental distress
Basophilia
-Circulating numbers of basophils increase.
-Occurs in inflammation and hypersensitivity reactions.
-Contain histamine that is released in allergic reactions
BAsopenia
-Circulating numbers of basophils decrease.
-Occurs in acute infections, hyperthyroidism, and long-term steroid therapy
Monocytosis
-Numbers of circulating monocytes increase.
-Usually occurs with neutropenia in later stages of bacterial infections.
-Found in chronic infection and correlates with extent of myocardial damage.
Monocytopenia
-Numbers of circulating monocytes decrease.
-Very little is known about this condition.
causes:
Prednisone treatments
Hairy cell leukemia
Lymphocytosis
-Circulating lymphocytes increase.
-Occurs from acute viral infections
Epstein-Barr virus (EBV)
-Other causes
Leukemia, lymphomas, some chronic infections
Lymphocytopenia
Circulating lymphocyte counts decrease.
Occurs from immune deficiencies, drug destruction, viral destruction, radiation, or acquired immunodeficiency syndrome (AIDS)
Infectious Mononucleousis
Acute, self-limiting viral infection of B lymphocytes
Commonly caused by the EBV—85%
Transmission: Usually by saliva through personal contact (e.g., kissing, hence the term kissing disease)
Clinical manifestations of Infectious Mononucleosis
Malaise, arthralgia
Classic triad of symptoms:
Fever
Pharyngitis
lymphadenopathy of the cervical lymph nodes
Diagnostic test for infectious mononucleosis
Monospot qualitative test for heterophilic antibodies
Treatment of infectious mononucleosis
Rest and alleviation of symptoms with analgesics and antipyretics and penicillin or erythromycin-takes about 6 weeks to clear
Ibuprofen, not aspirin, for children and adolescents because of reported incidence of Reye syndrome
Leukemias
Are malignant disorders of the blood and blood-forming organs.
Exhibit uncontrolled proliferation of malignant leukocytes.
Overcrowding of bone marrow
Decreased production and function of normal hematopoietic cells
Classification
Predominant cell of origin: Myeloid or lymphoid
Rate of progression: Acute or chronic
Acute leukemia
Presence of undifferentiated or immature cells, usually blast cells
Rapid onset with short survival
Chronic Leukemia
Predominant cell is mature but does not function normally
Slow progression
Risk Factors of Leukemia
-Cigarette smoking, exposure to benzene, and ionizing radiation
Human immunodeficiency virus (HIV), hepatitis C, human -T-lymphotropic virus type 1 (HTLV-1)
-Drugs that cause bone marrow depression-chemotherapeutic drugs
Pancytopenia
reduction in all cellular components of the blood
What is the most common childhood leukemia?
acute lymphocytic leukemia (ALL)
greater than 30% lymphoblasts in bone marrow or blood
What is the cause of ALL?
Genetic anomaly: Philadelphia chromosome
Reciprocal translocation (portion of one chromosome gets transferred to another chromosome and they swap) results in abnormal chromosome.
Occurs between chromosomes 9 and 22.
Risk factors of ALL
Prenatal x-ray exposure
Postnatal exposure to high-dose radiation
Viral infections with HTLV-1: Can cause a rare form of ALL and EBV
Down syndrome
What is the most common adult leukemia?
acute Myelogenous leukemia (AML)
mean age, 67 years
Down syndrome increases risk
AML results from
-Abnormal proliferation of myeloid precursor cells
-Decreased rate of apoptosis-
-Arrest in cellular differentiation
-Mutation in the receptor tyrosine kinase FLT3
Risk factors of AML
Exposure to radiation, benzene, and chemotherapy
Hereditary conditions
Clinical manifestations o Leukemia
-Fatigue caused by anemia
-Bleeding resulting from thrombocytopenia (reduced -numbers of circulating platelets)
-Fever caused by infection
-Anorexia, weight loss, diminished sensitivity to sour and sweet tastes, wasting away of muscle, and difficulty swallowing
-Central nervous system (CNS) involvement
Treatment of Leukemia
Chemotherapy
Supportive measures
Blood transfusions, antibiotics, antifungals, antivirals
Allopurinol: Prevents the production of uric acid (which is elevated from cellular death because of treatment)-killing of cells can lead to build up of purines leading to increased uric acid
Stem cell transplantation
Bone marrow transplant
Complications of Leukemia
Anemia
Treatment: Blood products
Neutropenia
Treatment: Granulocyte colony-stimulated factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF)
Low WBC count
Treatment: Colony-stimulating factors to prevent infections
Chronic myelogenous Leukemia (CML)
Is usually diagnosed in adults.
Is a myeloproliferative disorder that also includes polycythemia vera, primary thrombocytosis, and idiopathic myelofibrosis.
Philadelphia chromosome is often present and BCR-ABL1 causes initiation of CML
Chronic Lymphocytic Leukemia (CLL)
Affects monoclonal B lymphocytes.
Has a familial tendency.-genetic component
Is common in adults older than 50 years.
Clinical manifestations of CLL
Is asymptomatic at the time of diagnosis.
Lymphadenopathy is the most common finding.
Suppresses humoral immunity, and increases infection with encapsulated bacteria.
CML phases
Infections, fever, and weight loss
Chronic phase
Lasts 2 to 5 years
Symptoms: May not be apparent
Accelerated phase
Lasts 6 to 18 months
Primary symptoms develop: Splenomegaly-cells get trapped in spleen
Terminal blast phase
“Blast crisis”
Survival: Only 3 to 6 months
Tx of CML
Chlorambucil (chemotherapeutic), administered with or without corticosteroids, on a daily or intermittent schedule
Chemotherapy
No cure for CML
Tyrosine Kinase Inhibitors (e.g. Imatinib (Gleevec))
Combined chemotherapy
Biologic response modifiers
Allogeneic stem cell transplantation-from different genetic lines, not from direct close relative
Lympadenophathy
enlarged lymph nodes that become palpable and tender
Local lymphadenopathy
Drainage of an inflammatory lesion located near the enlarged node
General Lymphadenopathy
Occurs in the presence of malignant or nonmalignant disease
Causes of Lympadenopathy
Neoplastic disease
Immunologic or inflammatory conditions
Endocrine disorders
Lipid storage diseases
Unknown causes
Primary lymphoid tissue
Thymus
Bone marrow
Secondary Lymphoid Tissue
SLIT
Spleen
Lymph nodes
Intestinal Lymphoid tissue
Tonsils
2 categories of malignant lymphomas
-Hodgkin Lymphoma–linked to EBV
-non-hodgkin lymphoma
What is necessary for the diagnosis of Hodgkin lymphoma but not specific to Hodgkin Lymphoma?
Reed-Sternberg cells in lymph nodes
What are Reed Sternberg cells derived from?
Are derived from malignant B cells that usually become binucleate.
Release cytokines-signaling substances that signal other immune system cells to proliferate
Clinical manifestations of Hodgkins lymphoma
Enlarged painless neck lymph nodes
Lymphadenopathy, causing pressure or obstruction
Mediastinal mass
Fever, weight loss, night sweats, pruritus, fatigue
Tests for Hodgkin’s Lymphoma
Chest x-rays, lymphangiography, and biopsy (biopsy most indicative of Hodgkin lymphoma)
Tx of Hodgkin’s lymphoma
Approximate cure rate: 75%
Combined treatment with radiation therapy and chemotherapy
High-dose chemotherapy with bone marrow or stem cell transplantation
Monoclonal antibodies
Nonmyeloablative allogeneic stem cell transplantation
