Term
| What two, somewhat unrelated but interconnected, processes are required for clot formation? |
|
Definition
1. Platelet activation and adhesion: formation of “white” clots
2. Coagulation cascade (fibrin production): formation of “red” clots |
|
|
Term
| What type of vessels are white clots found? Why? |
|
Definition
| The arterial side of the circulation because rapid blood flow at these sites does not allow fibrin to accumulate |
|
|
Term
| What type of pathologies are white clots associated with? |
|
Definition
| Transient ischemic attacks, strokes, unstable angina and myocardial infarction |
|
|
Term
|
Definition
| Activated platelets through the action of thrombin, ADP, thromboxane A2 and, interaction of the platelet with tissue collagen |
|
|
Term
| What type of vessels are red clots found? Why? |
|
Definition
The venous side of the circulation because the slow rate of blood flow allows fibrin accumulation and the enmeshment of red cells in the clot.
(a small white clot initiates the formation of the red clot) |
|
|
Term
| What is fibrin production a classic pathway example of? |
|
Definition
Signal amplification by an enzymatic activation cascade
(ie, serine proteases beget serine proteases; some of the clotting factors before fibrinogen are proteases; many activators and inhibitors of the cascade are found in plasma and damaged tissues) |
|
|
Term
| Why is vitamin K needed for clotting? |
|
Definition
Liver-synthesized factors VII, IX, X, and II require vit-K dependent carboxylation of 9-12 glutamate residues
Carboxylation is necessary for binding of calcium, which facilitates binding of clotting factors |
|
|
Term
| Why would chelating agents inhibit coagulation? |
|
Definition
| Chelating interfere with calcium binding, which normally facilitates binding of clotting factors to anionic phospholipids on activated cell surfaces |
|
|
Term
|
Definition
An endogenous inactivator of XIa, VIIIa and Va (which are non-protease protein cofactors)
Synthesis of protein C is also dependent on vitamin K |
|
|
Term
| What activates Protein C? |
|
Definition
| Thrombin. Since protein C is factor inactivator, thrombin acts as a negative feedback regulator. |
|
|
Term
| What type of pathologies are red clots associated with? |
|
Definition
| Deep vein thrombosis, particularly in legs, and, if pieces of the clot break off, pulmonary embolism |
|
|
Term
|
Definition
| A protease which breaks down cross-linked fibrin in existing clots (fibronolysis and thrombolysis) |
|
|
Term
| Why doesn't plasmin indiscriminately break down all clots, "good" and bad? |
|
Definition
Its wide-spread effect is limited by circulating inhibitors such as α2-antiplasmin
Local endogenous activators of plasminogen conversion also exist (tissue plasminogen activator and thrombin) |
|
|
Term
| Define the intrinsic pathway. What factors are involved? |
|
Definition
| Coagulation pathway so-called because all of the factors involved are intrinsic to the plasma (factor XII and kininogens) |
|
|
Term
| How is the intrinsic pathway measured in vitro? |
|
Definition
| By the addition of phospholipids and kaolin |
|
|
Term
| Define the extrinsic pathway. What factors are involved? |
|
Definition
| Coagulation pathway so-called because some factors used to initiate clotting are transmembrane cellular proteins extrinsic to plasma (tissue factor and factor VIIa) |
|
|
Term
| How is the extrinsic pathway measured in vitro? |
|
Definition
| By addition of thromboplastin (saline extract of brain containing tissue factor and phospholipids); prothrombin time. |
|
|
Term
| List three categories of indirect acting anticoagulants |
|
Definition
1. Unfractionated heparin
2. Low molecular weight heparins
3. Orally effective direct acting anticoagulants |
|
|
Term
| Where is heparin derived? |
|
Definition
Heparin occurs naturally in mast cells bound with histamine and serotonin
Made from pig intestine or beef lung from slaughter material, which contain a lot of mast cells
Standardized by bioassay in units |
|
|
Term
| Describe the chemical structure of heparin |
|
Definition
| Heparin is a sulfated glycosaminoglycan (sulfated mucopolysaccharide) which starts out as a proteoglycan of MW around 1,000,000 and is degraded to fragments of 2,000 to 30,000 daltons |
|
|
Term
| Describe the mechanism of action of heparin |
|
Definition
| Heparin binds with antithrombin III increasing the rate at which this inhibitor binds to thrombin (factor IIa) and factor Xa one thousand-fold |
|
|
Term
| Define antithrombin III (AT-III) |
|
Definition
An anticoagulate suicide substrate which works by binding irreversibly to thrombin and factor Xa
It will not work on fibrin already bound to a fibrin clot |
|
|
Term
| What does the inhibition of factor Xa by antithrombin III require? |
|
Definition
| A specific pentasaccharide in heparin |
|
|
Term
| What does the inhibition of factor IIa by antithrombin III require? |
|
Definition
| The pentasaccharide structure plus 13 additional monosaccharide units to be present in heparin |
|
|
Term
| List 2 reasons why a patient may have resistance to heparin |
|
Definition
1. Plasma proteins (ex. platelet factor 4) inhibiting binding of heparin to AT-III
2. Acquired deficiency of AT-III (cirrhosis, nephrotic syndrome, septic shock) (this can be treated with AT-III powder) |
|
|
Term
| List three actions of heparin which are of no known clinical significance |
|
Definition
1. Activation of lipoprotein lipase in plasma increasing the hydrolysis of triglycerides, a “clearing effect” as the plasma becomes less cloudy.
2. Inhibits the proliferation of vascular smooth muscle cells.
3. High doses will inhibit platelet aggregation. |
|
|
Term
How is heparin administered?
Which routes are not used, and why? |
|
Definition
Either by intravenous (immediate effect) or subcutaneous (large response variation)
Not given intramuscularly (i.m.) because of the probable occurrence of hematomas
Not given orally because of the high degree of ionization at sulfate groups |
|
|
Term
| Can heparin be administered during pregnancy? Why or why not? |
|
Definition
| It can be used in pregnant or breastfeeding woman because it is highly ionized and won't cross into the fetus/milk |
|
|
Term
| Describe the pharmacokinetics of heparin |
|
Definition
Highly bound to plasma protein;
Metabolized by the reticuloendothelial system
Small amounts eliminated by the kidney
Follows Michaelis-Menten kinetics |
|
|
Term
| List four therapeutic uses of heparin |
|
Definition
1. To prevent thrombus formation or emboli in susceptible people while waiting for oral anticoagulant drugs to become effective
2. Prevention of clot formation in recurrent thromboembolic states
3. For anticoagulation, in patient or in vitro
4. Adjunct in patients with unstable angina or acute myocardial infarction (during angioplasty, stent, bypass, etc) |
|
|
Term
| List the four major adverse effects of heparin |
|
Definition
1. Hemorrhage
2. Thrombocytopenia
3. Osteoperosis, vertebral fractures
4. Allergic reactions (biogenic) |
|
|
Term
| Describe risk factors that lead to hemorrhage from heparin |
|
Definition
1. High dose or iv bolus used
2. Patient history: elderly women, patients with platelet dysfunction, renal failure or alcoholism, previous bleeding problems, recent surgery or trauma |
|
|
Term
| Define type 1 heparin-induced thrombocytopenia (HIT) |
|
Definition
Transient; generally mild in symptoms
Caused by heparin-induced platelet aggregation; 25% incidence of treated patients
Sometimes referred to as HAT (heparin-associated thrombocytopenia). |
|
|
Term
| Define type II heparin-induced thrombocytopenia (HIT) |
|
Definition
| Severe and delayed (5 -10 days after start of therapy); caused by binding of heparin to platelet factor 4 with the subsequent generation of IgG antiplatelet antibodies and a marked fall in platelet count |
|
|
Term
| List four contraindications to the use of heparin |
|
Definition
(1) Active bleeding and/or severe thrombocytopenia
(2) Surgery to closed areas (brain, eye, spinal cord, etc.)
(3) Use in alcoholics: probably related to liver disease and decreased production of coagulant factors.
(4) Person known to be allergic to heparin |
|
|
Term
| What is the antidote to heparin? How does it work? |
|
Definition
protamine sulfate
It is basic and binds 1:1 to the acidic sulfates in heparin |
|
|
Term
| List the four low-molecular weight heparins he wants us to know |
|
Definition
Dalteparin (Fragmin)
Enoxaparin (Lovenox)
Fondaparinux [synthetic pentasaccharide] (Arixtra)
Tinzaparin (Innohep) |
|
|
Term
| Can the low-molecular weight heparins be substituted for one another? |
|
Definition
| No, not by weight or by their ability to inactivate factor Xa |
|
|
Term
| Describe the MOA of low-molecular weight heparins |
|
Definition
Inhibit factor Xa much more than IIa
Do not to prevent clotting related
only to thrombin production
Require less monitoring for effect |
|
|
Term
| How are low-molecular weight heparins administered? |
|
Definition
| s.c., but not i.m. or i.v. |
|
|
Term
| Describe the pharmacokinetics of low-molecular weight heparins |
|
Definition
| They have more predictable rates of absorption than unfractionated heparin and slower rates of degradation |
|
|
Term
| List adverse reactions of low-molecular weight heparins |
|
Definition
Bleeding and thrombocytopenia (less frequently than unfractionated heparin)
Less osteopenia |
|
|
Term
| What is the antidote of low-molecular weight heparins? |
|
Definition
| The anticoagulant activity of LMWH’s is partially reversed by administration of protamine, except for the synthetic fondaparinux |
|
|
Term
| What are the only orally-effective direct-acting factor Xa inhibitors? |
|
Definition
|
|
Term
| What is rivaroxanban approved for? |
|
Definition
| As a replacement for warfarin and LMWH’s for the prevention or treatment of venothrombosis during knee and hip surgery and for the prevention of stroke in patients with atrial fibrillation |
|
|
Term
| What is apixaban approved for? |
|
Definition
|
|
Term
| What is the largest barrier to using orally-effective direct-acting factor Xa inhibitors? |
|
Definition
| They are substrates for CYP3A4 and for P-glycoprotein which means that drug-drug interactions could be a factor in their effectiveness as anticoagulants |
|
|
Term
| Why aren't orally-effective direct-acting factor Xa inhibitors used instead of warfarin? |
|
Definition
| Even though both classes have a lot of drug interactions and bleeding problems, orally-effective direct-acting factor Xa inhibitors are much more expensive than warfarin |
|
|
Term
| List the direct thrombin inhibitors |
|
Definition
Agratroban
Bivalirudin (Angiomax)
Desirudin (Iprivask)
Dabigatran (Pradata)
Lepirudin (Refludan) |
|
|
Term
Define Lepirudin
When is it used? When should it be avoided? |
|
Definition
A direct irreversible thrombin inhibitor, a derivative of hirudin (derived from leeches)
Used in patients at high risk for heparin-induced type II thrombocytopenia (HIT-II)
Should be avoided in severe renal disease |
|
|
Term
Define bivalirudin
When is it used? |
|
Definition
A direct-acting, but reversible, inhibitor of the activity of both free and clot-bound thrombin (contains hirudin)
Used in the treatment of people with unstable angina subjected to angioplasty concurrent with aspirin |
|
|
Term
| Why is bivalrudin better than lepirudin? |
|
Definition
| Bivalrudin has a better dose-response and activates protein C whereas lepriduin inhibits the activity of this endogenous anticoagulant factor |
|
|
Term
Define agratroban
When is it used? |
|
Definition
A competitive inhibitor of thrombin not related structurally to hirudin but is based on the structure of arginine
It is metabolized by CYP450, so should be avoided in liver disease but fine for people with renal insufficiency |
|
|
Term
| Define dabigatran and briefly describe its pharmacokinetcs |
|
Definition
A polar, orally effective direct thrombin inhibitor that is a prodrug and requires an acidic environment
Not metabolized by CYP, instead substrate for P-glycoprotein (interaction with amiodarone or verapamil)
Excreted by the kidneys, an active metabolite (avoid in renal impairment) |
|
|
Term
| What is the therapeutic use of dabigatran? |
|
Definition
Found to be more effective than warfarin for prevention of clots in patients with atrial fibrillation (but is much more expensive and has bleeding issues)
Can also be used to prevent VTE (but is not as effective as enoxaparin) |
|
|
Term
| List two orally effective indirectly acting anticoagulants |
|
Definition
Warfarin (Coumadin)
Phytonandione [K1] (Mephyton) |
|
|
Term
| Briefly describe the history of warfarin |
|
Definition
Outbreak of hemorrhage in dairy cows traced to chemical in spoiled clover silage, dicumoral, a structural analog of vit K
Used since the 1940s as a rodenticide, patented by the University of Wisconsin
1950s someone tried to kill themselves with it but lived, scientists realized it could be used to prevent clots without killing humans |
|
|
Term
| Describe the chemical properties of warfarin |
|
Definition
| Chemically synthesized and occurs as a mixture of isomers which differ in anticoagulant activity (S-form is 5-fold more potent than R-form), metabolism and interaction with other drugs |
|
|
Term
| Describe the MOA of warfarin |
|
Definition
Warfarin competitively inhibits the reduction of oxidized vitamin K
Vitamin K is involved in the carboxylation and calcium binding of glutamate residues in coagulation factors (factors II, VII, IX, X and proteins C and S) |
|
|
Term
| Why does warfarin take days to onset? |
|
Definition
Warfarin has no effect on the carboxylated proteins already in the plasma so proteins must degrade first
Factor II, for example, has a degradation half-life of 60 hours |
|
|
Term
| What can change vitamin K available to the liver? |
|
Definition
|
|
Term
| Describe the pharmacokinetics of warfarin |
|
Definition
Oral absorption, bound to plasma protein
Time of onset is slow (3-6 days)
Time of offset is slow (2-5 days)
Metabolized and inactivated by CYP-P450 (S via 2C9 and R 1A2) |
|
|
Term
| Compare and contrast the ROA for warfarin vs. other anticoagulants |
|
Definition
| warfarin is given orally and unfractionated heparin and others are administered by the i.v. or s.c. route. |
|
|
Term
| Compare and contrast the duration of action for warfarin vs. other anticoagulants |
|
Definition
| Is days for warfarin versus hours for heparin and other parenteral anticoagulants; warfarin is given for longer periods of time than is heparin |
|
|
Term
| Compare and contrast the monitoring for warfarin vs. other anticoagulants |
|
Definition
| (3) Close monitoring is more important for warfarin therapy than for heparin therapy mainly because of its long duration of action and the inability to quickly terminate the anticoagulant effect of warfarin |
|
|
Term
| List adverse effects of warfarin |
|
Definition
1. Hemorrhage
2. Hemorrhagic skin necrosis
3. Teratogeneis related to lower carboxylation of bone proteins (pregnancy category X) |
|
|
Term
| Define hemorrhagic skin necrosis |
|
Definition
A rare warfarin complication which affects the microvasculature in extremities, subcutaneous fat, penis and breast tissue starting 3-10 days after the initiation of therapy
Considered to involve decreased amounts of the endogenous anticoagulant protein C |
|
|
Term
| What is the antidote for warfarin? |
|
Definition
vitamin K (phytonadione) or either i.v. plasma or clotting factor preparations
Use vitamin K if INR is greater than 5.0. If <5 and patient not bleeding, just stop warfarin until INR normal |
|
|
Term
| List interactions which enhance the anticoagulant effects of warfarin |
|
Definition
1. Displacement from albumin due to loop diuretics, valproate and others (however, unbound warfarin quickly eliminated)
2. Inhibition of warfarin metabolism due to competitive substrates for CYP450s |
|
|
Term
| List major CYP450 inhibitors |
|
Definition
| Macrolides, azole antifungals, cimetadine |
|
|
Term
| List four drug-type interactions that would increase the bleeding tendency of warfarin |
|
Definition
1. Induction of bleeding sites (ulcers, NSAIDs)
2. Inhibition of platelet aggregation (aspirin, antithrombolytics)
3. Inhibition of hepatic synthesis of clotting factors; antineoplastic drugs
4. Low vitamin K (diet, antibiotics) |
|
|
Term
| List three drug-type interactions that would decrease the bleeding tendency of warfarin |
|
Definition
1. CYP450 induction (barbiturates, rifampin, carbamazepine and others)
2. Increased liver synthesis of coagulation factors, estrogens
3. Inhibition of absorption of warfarin (cholestyramine) |
|
|
Term
| List three patient factors that would enhance warfarin |
|
Definition
1. Hepatic disease (less coagulation factor synthesis)
2. Genetic differences in metabolic degradation
3. Factor IX mutation |
|
|
Term
| List two patient factors that would decrease the effects of warfarin |
|
Definition
1. Consumption of vitamin K
2. Hereditary resistance because of decreased vitamin K epoxide reductase affinity or quantity |
|
|
Term
| Are the thrombolytic drugs enzymes? |
|
Definition
| No, they bind to plasminogen and increase its conversion to an active protease, plasmin: this conversion occurs naturally under the influence of factor XIIa and kallikrein |
|
|
Term
|
Definition
| A factor that terminates clots when they are no longer needed; will degrade both fibrinogen and fibrin. |
|
|
Term
| Give an example of a "good" clot |
|
Definition
One which is on a cerebral artery or vein thus keeping an individual from bleeding into the cranial space
“Good” clots may occur at other sites in the body |
|
|
Term
| Define alpha2-antiplasmin |
|
Definition
| An endogenous inhibitor of plasmin that makes normal-dose infusions of plasmin impractical as the primary therapeutic agent for thrombolysis |
|
|
Term
| What is the principle use of a thrombolytic drug? |
|
Definition
| Acute myocardial infarction |
|
|
Term
| List five thrombolytic drugs |
|
Definition
Alteplase Recombinant (Activase)
Reteplase (Retavase)
Streptokinase (Streptase)
Tenecteplase (TNKase)
Urokinase (Abbokinase) |
|
|
Term
|
Definition
A thrombolytic drug rarely used but cheap.
Derived from streptococci and may be allergenic; aspirin given concurrently with streptokinase improves outcome |
|
|
Term
|
Definition
A thrombolytic made from fetal monkey cells, once taken off the market due to viral infection concerns
Indicated for acute massive pulmonary thrombosis |
|
|
Term
| Define alteplase (tissue plasminogen activator) |
|
Definition
| tPA is synthesized normally by vascular endothelium; these plasmin activators work better on plasminogen bound to fibrin which avoids systemic activation |
|
|
Term
| What are the three brand names of alteplase (tissue plasminogen activator)? |
|
Definition
Reteplase, Recombinant and Tenecteplase
Slight differences in fibrin specificity and half-life between the three drugs |
|
|
Term
| What are the contraindications of thrombolytic drugs? |
|
Definition
| Active or recent serious bleeding episodes, hypertension and a history of strokes |
|
|
Term
| Define antithrombic drugs |
|
Definition
| Agents which decrease platelet activation and aggregation |
|
|
Term
| List two factors that initiate platelet aggregation and come from outside the platelet |
|
Definition
|
|
Term
| List two factors that inhibit platelet aggregation and come from outside the platelet |
|
Definition
| Catecholamines and prostacyclin |
|
|
Term
| List three factors generated by the platelet which are released and interact with membrane receptors to enhance aggregation |
|
Definition
| ADP, thromboxane A2, and serotonin |
|
|
Term
| List two factors generated inside the platelet and which act inside the platelet to influence aggregation |
|
Definition
cyclic AMP (decreases aggregation)
calcium (increases aggregation) |
|
|
Term
| Describe the mechanism of action of aspirin |
|
Definition
Acetylates irreversibly and inhibits the activity of cyclooxygenase, the enzyme essential for the production of prostaglandins
Both the synthesis of thromboxane A2 and PGI2 are inhibited; but, as platelets have no nuclei, they have no means of synthesizing new thromboxane and their ability to aggregate is inhibited permanently |
|
|
Term
| What is the role of thromboxane A2 in clot stabilization |
|
Definition
| Thromboxane A2 acts through a Gqα-coupled receptor to increase the intracellular concentration of IP3 and DAG, these two second messengers increase the content of GPIIb/IIIa receptors in the membrane, enhancing fibrinogen binding |
|
|
Term
| List four inhibitors of platelet puriergic receptors |
|
Definition
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor
All are concomitant with aspirin |
|
|
Term
| What is the mechanism of action of inhibitors of platelet purinergic receptors? |
|
Definition
ADP acts at two purinergic receptors on the platelet membrane to enhance activation and aggregation, P2Y1 and P2Y12
All four drugs inhibit P2Y12, preventing platelet activation and aggregation |
|
|
Term
| Describe the actions of the two purinergic receptors on the platelet membrane: P2Y1 and P2Y12 |
|
Definition
P2Y1 is coupled to Gqα and causes phospholipase activation, formation of IP3 and subsequent Ca release
P2Y12 receptor is coupled to Giα which inhibits the activity of adenylyl cyclase and decreases the cellular content of cyclic-AMP |
|
|
Term
| Describe the pharmacokinetics of the platelet purinergic receptor inhibitors |
|
Definition
They are prodrugs, CYP450 activates the sulfhydryl group that forms an irreversible disulfide bridge with P2Y12
Clopidigrel in particular is activated by CYP2C19 |
|
|
Term
| How is Ticagrelor different from the other platelet purinergic receptor inhibitors? |
|
Definition
Ticagrelor does not require CYP activation and is the only reversible inhibitor among them
It is considered to be superior to clopidogrel is preventing cardiovascular death and myocardial infarction in patients with acute coronary syndrome |
|
|
Term
| How is Ticlopidine different from the other platelet purinergic receptor inhibitors? |
|
Definition
| Ticlopidine has been associated with an incidence of severe neutropenia and agranulocytosis, so its overall usefulness is considered limited and its only FDA approved indication is for reduction of the risk of thrombotic stroke in patients who have stroke precursors |
|
|
Term
| How is Clopidogrel different from the other platelet purinergic receptor inhibitors? |
|
Definition
Lower risk of neutropenia/agranulocytosis
Wider list of approved indications including reduction of stroke, myocardial infarction and problems associated with the acute coronary syndrome
Combination therapy of aspirin and clopidrogrel is synergistic |
|
|
Term
| How is Parasugrel different from the other platelet purinergic receptor inhibitors? |
|
Definition
Faster and more uniform absorption than clopidigrel, with fewer incidences of ischemic cardiovascular events
However, associated with more serious bleeding effects |
|
|
Term
|
Definition
A vasodilator drug which increases the platelet concentration of cyclic-AMP because it is an inhibitor of phosphodiesterase
Has no use as a general antithrombotic drug
Its only approved use is in conjunction with warfarin for the prevention of thormboemboli in patients receiving prosthetic heart valves. |
|
|
Term
|
Definition
is the Fab fragment of a humanized, chimeric monoclonal antibody which binds at or near the GPIIb/IIIa receptor to inhibit aggregation
Also binds at the vitronectin site on platelets which enhances the inhibition of aggregation
Used in conjunction with aspirin and heparin during angioplasty and the combination is effective in preventing restenosis, recurrent MI and death |
|
|
Term
| Define Eptifibatide/Tirofiban |
|
Definition
Both agents bind at the fibrinogen binding site of the GPIIb/IIIa receptor of platelets to inhibit aggregation
Effectiveness is considered to be less than that found with abciximab probably because they do not interact with the vitronectin receptor |
|
|
Term
|
Definition
This agent is not an inhibitor of platelet aggregation but of platelet formation
Acts by decreasing the maturation of megakaryocytes; high incidence of palpitations and heart failure; contraindicated during pregnancy. |
|
|
Term
| List six hemostatic agents |
|
Definition
Aminocaproic Acid (Amicar)
Toliet paper :) (collagen, gelatin, cellulose)
Tranexamic Acid (Cyklokapron)
Topical thrombin
Fibrinogen Fibrin Sealant
Astringints (Al salts, styptic pencils) |
|
|
Term
| Define the mechanism of action of the hemostatic agents, Aminocaproic acid/Tranexamic acid |
|
Definition
| Chemically similar to the amino acid, lysine, and are competitive inhibitors of the activation of plasminogen. |
|
|
Term
| When are the hemostatic thrombolytic agents, Aminocaproic acid/Tranexamic acid used? |
|
Definition
| They are used as adjunctive therapy in hemophilia, to quickly reverse bleeding during fibrinolytic therapy if required and for control of minor bleeding in hemophiliacs who must have minor surgery, particularly dental surgery |
|
|
