Term
| Does cAMP activate or inhibit platelet function? |
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Definition
| cAMP inhibits platelet activation. This cAMP pathway is the pathway stimulated by PGI2 (prostacyclin). Activating factors, such as thromboxane (TXA2), work through the IP3/DAG pathway and activation of phospholipase A2. |
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Term
| Describe the activation of platelets at the site of endothelial injury. |
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Definition
Endothelial cells lining the inner surface of blood vessels synthesize prostaglandins (ex: prostacyclin PGI2), which prevent platelet adhesion. An Injury to blood vessels damages these endothelial cells. This will remove the local prostaglandin synthesis and expose the subendothelial tissue (basal lamina) underneath. As we know by now, basal lamina contains collagen. When collagen is exposed on the inner surface of vessels, von Willebrand Factor creates a bridge between the collagen of damaged vessels and a GPIb/IX receptor on the platelet membrane. Platelets will now adhere to the damaged site. Once a platelet is bound, it becomes ‘activated’ by inverting negatively charged membrane phospholipids (pt-serine and pt-inositol) so that they now face outside. In addition, they release chemicals such as thromboxane, ADP, and serotonin(also called 5-HT). These substances cause further aggregation and activation of platelets at the site and are also vasoconstrictors. Activated platelets are important for 2 reasons. One, they expose receptors (gp-IIb and gp-IIIa) on their membrane that can bind fibrinogen (which now cross-links adjacent platelets) and two, they serve as a substrate for the coagulation cascade that is initiated by binding Ca++ to their modified negative phospholipid membrane. Aggregation of fibrinogen at this site is important because it is the precursor to fibrin, which will form a mesh network over the wound once activated by the coagulation cascade. Prothrombin is also concentrated on activated platelets. It is important that these components be localized to the surface of only the activated platelets because we do not want clotting occurring throughout the circulatory system.
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Term
| By what mechanism does aspirin inhibit platelet activation and coagulation? |
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Definition
| Aspirin (acetylsalicylic acid) is an irreversible inhibitor of Cox-I and Cox-II. When given at low doses, this inhibits platelet production of TXA2 and endothelial production of PGI2. However, the endothelial cells are able to upregulate PGI2 by producing more cyclooxygenase enzymes. Platelets have no nucleus and no machinery to create new enzymes, so they cannot recover TXA2 production. Therefore, aspirin affects platelets much more heavily. This means relatively large prevention of activating factors, without a drop in the inhibition of platelet function! |
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Term
| What is the MoA of Clopidogrel? |
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Definition
Clopidogrel is an antiplatelet drug that irreversibly blocks the ADP receptors (P2Y12R) on the surface of platelets. This prevents platelet activation by ADP, a strong stimulus!
Clopidogrel is often added to aspirin to increase the overall antiplatelet effect. (recall that increasing the dose of aspirin decreases the antiplatelet effect, and is why the higher doses of aspirin used for analgesic action do not strongly affect hemostasis) |
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Term
| What antiplatelet drugs target the Gp IIb/IIIa receptor complex? |
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Definition
Abciximab, the monoclonal antibody, binds noncompetetively to the receptor complex. It is the more effective inhibitor of this complex.
Eptifibatide and Tirofiban competetively inhibit the Gp IIb/IIIa receptor complex.
Gp IIb/IIIa receptor complexes are exposed on the surface of activated platelets. They are involved in binding fibrinogen and cross-linking platelets to form a platelet plug. Inhibitors of this complex therefore inhibit platelet aggregation.
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Term
| Can you list 3 differences between the HMWH and LMWH forms of Heparin? |
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Definition
Low molecular weight fractions (LMWH)...
1) are more selective inhibitors of factor Xa
2) cause fewer bleeding complications
3) carry less risk of thrombocytopenia
...than HMWH.
According to Babinni, this makes LMWH the superior treatment choice. |
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Term
| What is the MoA for Heparin? |
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Definition
Heparin binds antithrombin III (AT III) and accelerates its antiprotease function. Heparin's high negative charge makes it interact most strongly with thrombin, therefore thrombin is the most sensitive factor to inhibition by AT-III.
By inhibiting the coagulation cascade, Heparin is a strong anticoagulant. It is also a quick anticoagulant because it targets the factors that are in the serum. (compare this with warfarin, which acts slowly through synthesis inhibition)
It is important to note that heparin's efficacy is entirely dependent on the patients AT-III concentration. If the patient is deficient in AT-III, heparin will not be very useful. |
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Term
| How do heparin and warfarin differ in their inhibition of clotting factors? |
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Definition
| Heparin neuralizes activated factors in the patient's plasma but has no effect on the synthesis of the coagulation factors. On the other hand, warfarin inhibits the synthesis of clotting factors, but does not affect the already synthesized factors in the patient's plasma! This explains why the onset of warfarin's effects is delayed, whereas heparin's effects are rapid. |
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Term
| What drug blocks the conversion of plasminogen to plasmin? |
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Definition
| Aminocaproic Acid blocks the conversion of plasminogen to plasmin. It also blocks the binding of plasmin to fibrin. |
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Term
| What do you know about the pharmacokinetics of heparin? |
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Definition
Heparin has an oral bioavailability of 0! It is administered by IV (or SC). It does not leave the plasma compartment, having a Vd of roughly 4L.
Metabolism follows a zero-order process
(like phenytoin, alcohol, and salicylate) |
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Term
| What test is used to monitor heparin treatment? |
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Definition
The aPTT test is used to monitor heparin's effects. (recall: the aPTT measures the intrinsic pathway)
Heparin treatment is accompanied by a prolonged aPTT. Too much heparin will greatly prolong the aPTT and induce bleeding. |
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Term
| A woman was administered much too much heparin by a careless resident, and she began to show epistaxis, hematomas, and hematemesis. What drug should be given? |
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Definition
| Protamine sulfate can be given to reverse heparin induced bleeding. It is given by IV infusion. Recall that heparin has a strong negative charge that helps keeps it in the vascular compartment. Protamine sulfate has a strong positive charge, and it complexes with and neutralizes heparin in the plasma compartment. |
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Term
| What drugs directly inhibit thrombin? |
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Definition
Lepirudin (also desirudin, bivalirudin and other 'rudins") bind the active site of thrombin, preventing its coaulant activity.
These are modified forms of hirudin, the anticoagulant in leech saliva.
It is "rude" (lepirudin) to stick a leech on someone. |
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Term
| What is drotrecogin alpha? |
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Definition
Drotrecogin alpha is a recombinant form of protein C. It is administered to patients with severe sepsis.
Recall: protein C inactivates factors Va and VIIIa. |
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Term
| What is the MoA of warfarin? |
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Definition
Warfarin is a member of the coumarin antigoagulants. It is a vitamin K analogue that blocks vitamin K reductase. This inhibits the pathway needed for vitamin K recycling. Without vitamine K, an essential cofactor, the synthesis of coagulation factors by the liver is inhibited!
The factors which require gamma-carboxylation (vit. K cofactor) are II, VII, IX, X and protein C.
The (-) membranes of activated platelets bind Ca++, which bind gamma-carboxyglutamate residues on prothrombin). Factors II, VII, IX, X all undergo this gamma-carboxylation (thereby all bind to the Ca++ and platelet membrane). This process of carboxylation requires Vitamin K. Warfarin inhibits the ability to produce gamma-carboxyglutamate residues. |
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Term
| Why is the onset of warfarin's effects delayed by a few days after therapy is started? |
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Definition
Warfarin only inhibits the synthesis of new coagulation factors (II, VII, IX, X). The clotting factors in the blood are still active until they are metabolized. Ex: thrombin (factor II) has a half-life of 60 hrs!
This is why warfarin therapy is often given in association with heparin over the first few days. Heparin provides a quick block of the currently circulating factors. A few days later, heparin is withdrawn, and warfarin can be effective on its own because the circulating factors have been metabolized and warfarin is now preventing the synthesis of new ones. |
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Term
| How can warfarin promote a transient protein C deficiency? |
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Definition
Protein C has a short half-life compared to other gamma-carboxylated coagulation factors. This means that it is metabolized faster, so with warfarin therapy, the plasma levels of protain C will disappear sooner than (ex:) thrombin.
Protein C is metabolized fastest, so it will be the first to feel the effects of decreased synthesis. |
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Term
| What are some important facts about warfarin pharmacokinetics? |
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Definition
Warfarin has a great bioavailability (> 95%).
Most importantly, warfarin is almost entirely bound to plasma albumin (98%). This means that other compounds binding plasma albumin (ex: sulfa drugs, aspirin, bilirubin) can displace warfarin and increase toxicity. For example, even if it increases the free plasma warfarin by only 2%, this still doubles the free drug concentration and can lead to toxicity and excessive bleeding!
monitor warfarin effects with the PT test. |
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Term
| Which lab test is used to monitor the effect of warfarin? |
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Definition
| The PT test, which measures the extrinsic pathway, is most useful to measure the effects of warfarin. |
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Term
| A person has an MI and needs an anticoagulant. Which drug do you choose? |
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Definition
| Choose heparin for fast anticoagulant situations. It would be inappropriate to choose warfarin here because it takes a few days for its effects to take hold. |
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Term
| A young woman recently became pregnant. She is on long-term anticoagulant therapy. What should you do? |
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Definition
| Long term anticoagulant therapy is most often with warfarin. If long term therapy is needed, heparin is only used to start the therapy for the first few days while warfarin's effects take hold. (recall that heparin must be given by IV while warfarin has great oral bioavailability). However, warfarin is a category X drug and therefore absolutely contraindicated in pregnancy because of proven teratogenic effects. This young woman must be switched to heparin during her pregnancy! |
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Term
A patient suffers from warfarin-induced bleeding. What can be administered to reverse this effect?
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Definition
Vitamin K is the warfarin antidote!
However, if the bleeding is severe, vitamin K takes too long to cause an appreciable effect (6-24 hours). In these cases, administer fresh frozen plasma and/or clotting factors. |
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Term
| Can you name some drugs that increase warfarin toxicity because they inhibit the CYP450 system? |
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Definition
Cimetidine
Metronidazole
Amiodarone
Erythromycin
Phenytoin
SSRIs
Omeprazole
(Acute Alcohol Binging also inhibits warfarin metabolism, whereas chronic alcoholism promotes its metabolism) |
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Term
| Can you list some drugs that may lead to therapeutic failure of warfarin because of their induction of the CYP450 system? |
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Definition
Barbiturates
Carbamazepine
Ripampin
Chronic Alcoholism |
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Term
| What is the pathway by which clots are broken down (fibrinolysis)? |
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Definition
Once the tissue is healed, it is important to remove the clot to open up the blood vessel and to prevent a thrombus, which could lead to myocardial infarction or stroke. Inactive plasminogen is constantly circulating in the blood stream. It will bind to Tissue Plasminogen Activator(tPA), which is activated by fibrin in the clot, and become converted to plasmin (other activators are urokinase and streptokinase). The specificity and activation requirement of these factors limits plasmin’s activity to the site of injury.
Endothelial cells also secrete Plasminogen Activator Inhibitor (PAI), which inhibits tPA at sites where it is not bound to fibrin. An additional safeguard against activated plasmin roaming free in the bloodstream is a2-antiplasmin, which circulates the blood and destroys any free and unbound plasmin not associated with clots.
In locations of still-active clotting, high levels of thrombin produced by the cascade are able to bind Thrombin-activated Fibrinolysis Inhibitor (TAFI), which prevents activation of plasmin at the clot site and allows the clotting process to continue. |
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Term
| What is the MoA of streptokinase? |
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Definition
Streptokinase promotes the conversion of plasminogen to its active form, plasmin. Plasmin then cleaves fibrin, destroying the fibrin clots!
However, because streptokinase activates plasminogen to plasmin everywhere, this leads to a systemic lytic state, in which clotting is inhibited on a massive scale.
(it is for this reason why alteplase, which is more specific for plasminogen bound to fibrin clots, is preferred nowadays) |
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Term
| What is the MoA of alteplase? |
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Definition
| Alteplase is a recombinant form of Tissue Plasminogen Activator. Recall: tPA is effective only around the area of the fibrin clot. This allows activation of plasminogen to plasmin only where it is needed. This is a reason why alteplase (also: reteplase, tenecteplase) are preferred fibrinolytic drugs to streptokinase. |
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Term
| What are common uses for alteplase? |
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Definition
| Alteplase is a fibrinolytic drug. It is used in the case of myocardial infarction, arterial thromboembolism, and percutaneous coronary interventions. These drugs are used only acutely because they are "dangerous", according to Babbini. |
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Term
| What are common reasons for vitamin K deficiency induced bleeding? |
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Definition
Newborns do not have the normal gut flora responsible for a portion of our Vitamin K uptake.
Vitamin K deficiency can also be seen in the elderly
vitamin K deficiency is associated with abnormal bleeding. |
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Term
| What diseases is desmopressin used in? |
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Definition
Desmopressin is used in Hemophilia A because it increases factor VIII activity. It also increases vWF release from platelets and is therefore used in von Willebrand Disease.
(recombinant factor VIII is the main treatment for Hemophilia)
Desmopressin is used most often to treat central diabetes insipidus, replacing the activity of ADH that is lacking in these patients. |
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Term
| A patient is bleeding because of therapy with alteplase. What drug do you give? |
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Definition
Alteplase is a fibrinolytic drug. It activates plasmin, causing the breakdown of clots.
Aminocaproic Acid is an inhibitor of plasmin, and therefore an inhibitor of fibrinolysis that can be used to treat bleeding caused by fibrinolytic therapy, and even in hemophiliacs. |
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Term
| What drugs would be used in a patient that presents to the ER with a painful, unstable angina? |
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Definition
| IV nitroglycerin is used to relieve the ischemic episode, and hopefully relieve the pain. To reduce intracoronary clotting, administer aspirin (oral) and heparin (IV) |
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Term
| What drugs are given IV to patients undergoing percutaneous transluminal angioplasty? |
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Definition
Heparin and abciximab are give to patients undergoing angioplasty.
Heparin activates AT-III
Abciximab binds Gp IIb/IIIa |
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Term
| What is the standard treatment for an uncomplicated DVT? |
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Definition
| Short-term Heparin followed by long-term warfarin is the standard treatment for uncomplicated DVTs. |
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Term
| Why are thrombolytic drugs (alteplase, streptokinase) contraindicated in pericarditis? |
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Definition
| Pericarditis is an inflammatory state. Recall that in these states, the vascular system becomes more permeable and becomes damaged. Thrombolytic drugs in a patient with pericarditis may cause pericardial hemorrhages leading to cardiac tamponade! Use techniques like auscultating for a friction rub to differentiate pericarditis from acute ischemia or MI. |
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Term
| What drugs can block platelet aggregation? |
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Definition
To block platelet aggregation you should seek to block COX-1, GpIIb/IIIa, or the ADP receptor.
Aspirin irreversibly inhibits the Cox enzymes
Abciximab blocks GpIIa/IIIb
Clopidogrel blocks the ADP receptor |
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Term
| When are alteplase or streptokinase typically employed? |
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Definition
Alteplase and Streptokinase are fibrinolytic drugs. They are reserved for cases of
1) dissolving clots in stroke
2) massive pulmonary embolism
3) myocardial infarction |
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