Hematologic agents 1 and 2 Flashcards
Define thrombosis
pathological state that occurs when there is a shift in the hemostasis balance that causes pro-coagulation processes to dominate over the anticoagulation and fibrinolytic processes. This leads to complications when blood clots (thrombi) become big enough to significantly limit blood flow locally, or at distant sites after the thrombi embolize. Thrombosis is the leading cause of death worldwide.
Describe common causes of thrombosis.
o Vessel injury such the rupturing of an atherosclerotic plaque
o Stasis of blood (slow or sluggish movement of blood)
o Dysfunction in endothelia cells, platelet, and/or leukocytes
o Over-activation of components of the coagulation system or platelets system or reduced activation of components of the anticoagulant or fibrinolytic system
Describe the general uses of each of anticoagulants
It is important to prevent the coagulation cascade in undamaged normal vascular systems. Endothelial cells of the vasculature also express factors that reduce the clotting cascade-induced fibrin generation by both reducing thrombin production and removing thrombin from the circulation.
Treatment and prevention of venous thrombosis/venous thromboembolism
Atrial fibrillation
Major surgeries
Cancer
Deep vein thrombosis (DVT) and pulmonary thromboembolism
Also used in conjunction with antiplatelet drugs to treat myocardial infarction
Describe the general uses of each of antiplatelets
Used in the primary prevention in patients at high risk for myocardial infarction or stroke
Acute myocardial infarction, coronary angioplasty, coronary bypass surgery, or stroke
Secondary prevention to prevent recurrence
Describe the general uses of each of fibrinolytics
These drugs are used to lyse clots that are leading to certain types of acute myocardial infarction, strokes, and pulmonary embolism.
These drugs increase the conversion of plasminogen into plasmin.
Remember that plasmin is the enzyme that cleaves fibrin, thereby dissolving blood clots.
Alteplase (recombinant tissue plasminogen activator [rt-PA] is most commonly used.
metabolism of P2Y12 antagonists clopidogrel and prasugrel
Clopidogrel and prasugrel are irreversible P2Y12 inhibitors that are prodrugs that have to be activated by metabolism in the liver
Comparison P2Y12 antagoists
Both prasugrel and ticagrelor appear to have superior results when compared to clopidogrel in some clinical outcomes.
However, both prasugrel and ticagrelor have greater rates of fatal and life-threatening bleeding than clopidogrel.
Therefore, prasugrel and ticagrelor are not recommended for use in patients with previous history intracranial bleeding.
metabolism of P2Y12 antagonists cangrelor and ticagrelor
Ticagrelor, and the newest P2Y12 antagonist cangrelor, do not need to be metabolized to become activated.
Unlike clopidogrel and prasugrel, ticagrelor and cangrelor are reversible. More rapid coagulation recovery upon discontinuation
pharmakokinetics warfarrin
Close to 100 % oral bioavailability
Highly bound to serum albumin (only unbound drug is active)
Small volume of distribution
Full antithrombotic effect takes about 3-5 days
Warfarin does not reduce activity of previously synthesized coagulation factors (½ life of prothrombin is approx. 48 hours).
Thus, at onset of warfarin treatment some patients are supplemented with fast acting anticoagulants (heparin, LMWH, or fondaparinux).
Long therapeutic ½ life (time to normal coagulation after cessation approx. 5-7 days)
adverse effecfts warfarin
o Warfarin is a teratogen, and should not be given to pregnant females. Placental transfer
Birth defects
o Hemorrhage (most common)
o Necrosis (rare disorder)
Warfarin-induced necrosis is believed to be caused by a precipitous fall in protein C.
Leads to a hypercoagulable state
Large amounts of fibrin found in microcirculation
Patients with low protein C levels for genetic reasons might be more susceptible.
Route of admin warfarrin
Oral
MOA warfarrin
Activity of Factors II, VII, IX, and X are vitamin K dependent
Activity of protein C and protein S are also vitamin K dependent
A reduced form of vitamin K is used as a cofactor in the carboxylation of key glutamate residues in these factors.
Allows Ca2+ to bind, which facilitates activation of these factors
Warfarin (Coumadin) is an anticoagulant that works by inhibiting vitamin K reduction leading to a decrease in activation of Factors II, VII , IX and X.
Identify the drugs and other factors that potentiate anticoagulant effect of warfarin.
Many drugs, disease states, or nutrient deficiencies can either potentiate or reduce the effectiveness of warfarin.
In general, any drug that reduces the levels of vitamin K in the body potentiates the anticoagulant effect of warfarin.
We get much of our vitamin K from our gut flora.
Thus, broad spectrum antibiotics that kill gut flora cause a reduction in vitamin K levels.
We get some of our vitamin K through our diet. A diet low in vitamin K rich food can reduce vitamin K levels.
Intestinal and liver disorders that lower bile acid production can prevent the absorption of vitamin K from our intestines.
Drugs that potentiate the anticoagulant effect of warfarin (increase INR).
o Non-steroidal anti-inflammatory drugs
o Certain serotonin reuptake inhibitors
o Anti-platelet drugs
o Drugs that decrease hepatic metabolism (hepatic metabolism is the main elimination route of heparin).
o Certain statins (cholesterol lowering drugs) are metabolized
Decreased hepatic function with liver disease can decrease the clearance of warfarin, which increase INR.
o Diseases of the intestine (such as Crohn’s disease) that reduce vitamin K absorption also increase INR.
o Renal insufficiency can cause hypoalbuminemia (increase INR).
Remember that warfarin binds highly to plasma albumin, and that warfarin bound to albumin is inactive.
Less albumin means more free (active) warfarin.
Drugs like aspirin that bind highly to albumin can compete with warfarin
Describe the mechanisms by which drugs reduce warfarin’s effects.
Drugs that reduce the anticoagulant effect of warfarin (lower INR). o Rifampin (antibiotic), carbamazepine (mood stabilizer) and barbiturates increase hepatic elimination of heparin by inducing CYP2C9.
heperin
Heparin sulfate is a proteoglycan found on the surface of vascular endothelial cells.
Binds to antithrombin to increase inhibition of factor Xa and thrombin
Heparin is a family of sulfated-polysaccharides of varying molecular weights found in mast cells and thought to be required for histamine storage.
Not normally found in the plasma
Heparin can be isolated from tissues rich in mast cells (usually animal intestines or lungs)
Unfractionated heparin contains polysaccharide chains of 5-30 kDa.
Administered parenterally to inhibit coagulation
adverse effects heparin
Most common complication is bleeding
Bleeding can occur in patients within normal therapeutic range.
Because heparin has short ½ life, discontinuation of administration often used to stop mild bleeding.
If bleeding is severe, protamine sulfate can be administered to inhibit heparin.
Protamine is a basic polypeptides that binds to and inactivate longer heparin molecules.
Osteoporosis
Long term heparin usage (> 1-6 months)
MOA heparin
A specific pentasaccharide sequence in heparin binds to antithrombin (AT)
Changes conformation of AT causing it to have a higher affinity for factor Xa
This accelerates the rate of factor Xa inhibition without affecting thrombin inhibition.
Heparin can also increase AT-induced inhibition of thrombin.
It does this by acting as a molecular bridge that brings thrombin into close contact with AT.
Only longer heparin molecules can facilitate this .
Route admin Heparin
Heparin has to be administered parenterally. (usually IM, IV, or subcuntaneous means any route other than oral
Describe the mechanism of heparin-induced thrombocytopenia (type II).
Uncommon
o Significant mortality
o Immune thrombocytopenia
o Heparin can bind platelet-secreted platelet factor 4
o Antibodies are generated towards PF4/heparin complex
o Antibodies can bind to platelets and activate them and cause them to be cleared by macrophages
o Causes venous and arterial thrombosis
Compare and contrast the pharmacokinetics, adverse effects, mechanisms of action, contraindications, and antidotes, between enoxaparin (low molecular weight heparin), heparin (unfractionated), fondaparinux, direct thrombin inhibitors, and Factor Xa inhibitors.
Fondaparinux has all of the pharmacokinetic benefits that LMWH has over unfractionated heparin.
Use factor Xa assay to measure coagulation.
Protamine does not reverse the anticoagulant effect of fondaparinux.
The main drawback of DTIs is that specific antidotes do not exist, or are not as well established
Hemodialysis and administration of active factor VII or prothrombin complex concentrate can be used to reverse bleeding
.
Identify the route of administration of the direct thrombin inhibitors (DTIs)
Parenteral: Bivalirudin, lepirudin, and argatroban
Oral: Dabigatran
Identify the route of administration of Factor Xa inhibitors(rivaroxaban apixaban and babigatran)?
Orally administered
Describe the mechanism that explains why the DTIs can inhibit thrombin bound to fibrin, while heparin/antithrombin complex cannot.
Both heparin/antithrombin complex and DTIs can inhibit soluble thrombin.
However, only the DTIs can inhibit thrombin bound to fibrin.
Heparin binds both fibrin and thrombin independently of heparin/AT complex.
This prevents heparin/AT complex from binding to thrombin
Describe the appropriate blood coagulation assays used for the monitoring of warfarin
The Prothrombin time (PT) assay is generally used.
A patient’s blood is collected in Ca2+ free conditions.
o Thromboplastin (tissue factor and phospholipids) then is added to the blood sample.
o Finally, Ca2+ is added and the time for clot formation is measured.
o Results are given as the International normalized ratio (INR).
o INR is calculated by first normalizing patient’s PT to mean normal PT.
o This ratio is then raised to a power designated international sensitivity index (ISI), which is a function of the specific thromboplastin reagent being used.
Describe the appropriate blood coagulation assays used for the monitoring of heparin
The assay used most frequently is the activated partial thromboplastin time (aPTT) assay (this is also called the partial thromboplastin (PTT) assay).
Place patient’s plasma (which contains citrate to chelate Ca2+ and prevent coagulation) into a tube and mixed with phospholipids, Ca2+, and a negatively charged surface like glass beads, which initiates the intrinsic pathway and common pathway
Measurement of the time it takes for the intrinsic and common pathways to cause blood clotting
Describe the appropriate blood coagulation assays used for the monitoring of low molecular weight heparin (enoxaparin) therapy.
Monitoring is not as intensive as with heparin, and typically not as important in determining dosage changes.
However, monitoring is still done, especially when there are bleeding problems.
LMWH and fondaparinux often do not increase activated partial thromboplastin times (aPTTs) even though they are providing therapeutic effects.
The anti-factor Xa assay (which a direct measure of the activity of factor Xa) is used to monitor both LMWH and fondaparinux.
Identify drugs that can reverse the actions of warfarin,
No real antagonists
If reversal of warfarin anticoagulant effect is necessary, vitamin K can be administered.
Reversal requires time because new factors have to be synthesized
Emergent reversal can be accomplished by administering fresh plasma.
Identify drugs that can reverse the actions of heparin
short half life so just end treatment
Protamine sulfate is a basic polypeptide that bind to and inactivate longer heparin molecules.
Identify drugs that can reverse the actions of fibrinolytics
Aminocaproic acid (Amicar) and Tranexamic acid (Cyklokapron)
Blocks interaction of plasmin with fibrin (thus preventing fibrin degradation)
Used in treatments of hemophilia
Used to reverse bleeding caused by fibrinolytic therapy
Identify the therapeutic uses of alteplase. Tissue plasminogen activators (t-PAs)
Patients presenting to hospital with myocardial infarction with ST elevation or new left bundle branch block (both indicators of acute ischemic myocardial infarction)
Within 12 hours of the onset of chest discomfort (or other signs of acute myocardial infarction)
Not used for non- ST elevated myocardial infarction because risks of (intracranial bleeding) outweigh the benefits
Therapy in patients older than 75 is controversial
Other uses include:
Acute thrombotic stroke within 3h of onset (tPA), in selected patients
Clearing thrombosed shunts and cannulae
Acute arterial thromboembolism
Life-threatening deep vein thrombosis and pulmonary embolism (streptokinase, given promptly)
Identify the abolute contraindications for the use of the fibrinolytics (alteplase).
>24 hours since onset of symptoms Prior intracranial hemorrhage Stroke within past year Intracranial neoplasm Active bleeding/bleeding diathesis Suspected aortic dissection Significant closed-head or facial trauma within 3 months
MOA Apixaban (Eliquis)
o Directly inhibits factor Xa
