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
MOA Argatroban
Argatroban inhibits thrombin by binding directly to active site in thrombin that cleaves fibrinogen into fibrin.
Like the other DTIs, lepirudin can inhibit thrombin that is free and thrombin that is already bound to fibrin.
MOA Bivalirudin
Bivalirudin inhibits thrombin by binding directly to active site in thrombin that cleaves fibrinogen into fibrin.
It also binds to fibrin binding site of thrombin (considered bivalent because it binds to 2 sites).
Like the other DTIs, lepirudin can inhibit thrombin that is free and thrombin that is already bound to fibrin.
MOA Dabigatran
Inhibits thrombin by binding directly to active site in thrombin that cleaves fibrinogen into fibrin.
Like the other DTIs, dabigatran can inhibit thrombin that is free and thrombin that is already bound to fibrin.
**directly inhiits thrombin
MOA Fondaparinux (Arixtra)
Similar to heparin and LMWH
Binds to antithrombin and increases the rate of factor Xa inhibition.
No effect on antithrombin-induced inhibition of thrombin.
MOA Heparin
Mechanism of action
By itself, heparin has no anticoagulant effects.
It produces its anticoagulant effect by binding to antithrombin (AT).
AT is a serine protease that is produced in the liver and is present in blood
plasma.
AT normally slowly inactivates coagulation factors (most notably factors IIa
(thrombin) and Xa.
An unique pentasaccharide sequence in heparin binds to antithrombin
The binding of heparin to antithrombin causes a conformational change in
antithrombin, which significantly increases the rate at which it binds to and
inhibits factor Xa.
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 heparin molecules of 18 saccharide units or larger can facilitate this.
MOA Lepirudin
Lepirudin inhibits thrombin by binding directly to the active site in thrombin that cleaves fibrinogen into fibrin.
Also binds to fibrin binding site of thrombin (considered bivalent because it binds to 2 sites).
Like the other DTIs, lepirudin can inhibit thrombin that is free and thrombin that is already bound to fibrin
This is an advantage over the heparin/antithrombin complex, which cannot inhibit fibrin-bound thrombin.
Lepirudin is a recombinant from of hirudin that is approved to replace heparin in patients with heparin-induced thrombocytopenia.
MOA Vorapaxar *(antiplatelet)
Thrombin molecules produced by the coagulation cascade bind to PARs on platelet surface causing an increase in platelet activation.
Vorapaxar Inhibits effects of thrombin on platelets by inhibiting the platelet protease-activated receptor (PAR-1)
Pharmkinetics:
Administered orally
Side effects include intracranial hemorrhage
Vorapaxar should not be given to patients with active pathological bleeding, history of intracranial bleeding, or in patients that have had previous transient ischemic attack or stroke.
Reduction in thrombotic cardiovascular events in patients with established peripheral artery disease or history of myocardial infarction
MOA Rivaroxaban
Rivaroxaban directly inhibits factor Xa.
MOA Warfarin
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.
MOA Low molecular weight heparin
Enoxaparin
Indirect inhibitor of factor Xa
Binds to antithrombin and increases its rate of inhibition of factor Xa
MOA Aspirin
Platelet COX-1 is necessary for the production of thromboxane A2 by platelets (Figure 2).
Aspirin Irreversibly inhibits cyclooxygenase I (COX-1), and to a lesser extent COX-2.
Because platelets do not have the nuclei or other organelles, they cannot produce more COX-1 enzyme to replace the inhibited enzyme.
The decrease in COX-1 activity by aspirin reduces thromboxane A2 synthesis by platelets.
Reduced thromboxane A2 production decreases platelet activation and aggregation.
MOA Clopidogrel
The activation of P2Y12 by ADP leads to a decrease in intracellular levels of cAMP and a rise in intracellular Ca2+ levels.
Elevated intracellular Ca2+ levels leads to platelet activation.
Clopidogrel is an irreversible P2Y12 receptor inhibitor.
By inhibiting ADP activation of P2Y12, clopidogrel (and the other P2Y12 antagonists) reduce platelet activation.
**irreversible
MOA Ticagrelor
Reversibly inhibitor of P2Y12 receptor
MOA Cangrelor
Reversible inhibitor of P2Y12 receptor
MOA Prasugrel
Irreversibly inhibitor of P2Y12 receptor
MOA Diphyridamole
Dipyridamole is a phosphodiesterase inhibitor that prevents phosphodiesterases from converting cAMP into AMP (causes increase in cAMP levels).
Increased platelet cAMP levels lower intracellular Ca2+ levels, which reduces platelet activation and aggregation.
o By itself, dipyridamole has little anti-thrombotic effects.
o Aggrenox is a formulation of extended release dipyridamole mixed with aspirin.
o Some studies suggest that this combination is beneficial in reducing the reoccurrence of strokes in patients who have had previous strokes. However, this is somewhat controversial because other studies suggest that there is no increase in effectiveness with the combination than with aspirin alone.
o Dipyridamole is a vasodilator that can be used in combination with warfarin to inhibit embolization form mechanical heart valves.
o Cilostazol is another platelet phosphodiesterase inhibitor used in the clinic.
MOA Abciximab
As described above, GPIIb/IIIa (also called αIIbβ3) is a platelet surface receptor that undergoes a conformational change upon platelet activation.
This conformation change allows GPIIb/IIIa to serve as a receptor for fibrinogen.
Fibrinogen cross-bridges form between activated GPIIb/IIIa on nearby platelets causing increased aggregation (facilitates platelet plug formation).
Abciximab is the fragment antigen-binding (Fab) fragment of a monoclonal antibody directed against GPIIb/IIIa.
Binding of abciximab to GPIIb/IIa prevents platelet aggregation by preventing the fibrinogen cross-bridges from forming between platelets.
Abciximab also binds to receptors related to GPIIb/IIIa on leukocytes, which might account for the added antiinflammatory and antiproliferative effects of abcixiamab.
Abciximab is commonly used in patients undergoing coronary interventions (angioplasty) and to treat acute coronary syndromes (e.g., unstable angina, myocardial infarction).
Often used in combination with both aspirin and heparin to prevent restenosis after angioplasty
MOA Eptifibatide
A peptide that prevents fibrinogen from binding to GPIIb/IIIa
Indications (see abciximab indications)
Like abciximab, also given as intravenous bolus followed by infusion
Unlike abciximab, it binds more specifically to GPIIb/IIIa.
Eptifibatide has a longer plasma ½ life than abciximab.
Shorter receptor bound ½ life than abciximab
12
Lower risk of thrombocytopenia than abciximab
MOA Tirofiban
A nonpeptide small molecular inhibitor of GPIIb/IIIa
Similar indications as abciximab and eptifibatide
Lower risk of thrombocytopenia that abciximab
Similar ½ life as eptifibatide
MOA Alteplase
Tissue plasminogen activators (t-PAs) . increases converision of plasminogen to plasmin which cleaves fibrin
Anticoagulants (11)
Apixaban (Eliquis) Argatroban Bivalirudin Dabigatran Fondaparinux (Arixtra) Heparin Lepirudin Dipyridamole (Persantine) Vorapaxar (Zontivity) Rivaroxaban (Xarelto) Warfarin (Coumadin) Low molecular weight heparin (Enoxaparin)
Fibrinolytics (1)
Alteplase
Antiplatelet drugs (9)
Aspirin Clopidogrel Ticagrelor Cangrelor Prasugrel Dipyridamole Abciximab Eptifibatide Tirofiban
Arterial thrombosis
Thrombi in arteries or arterioles
Arterial thrombosis is the most common cause of acute coronary syndrome (e.g., myocardial infarction and unstable angina).
Most common cause of ischemic stroke
Arterial thrombosis is associated with vascular damage caused by diabetes mellitus and hyperlipidemias.
Atherosclerosis is a major cause of arterial thrombosis.
Arterial thrombi are usually rich in platelets giving them a white appearance.
Platelet activation important component of arterial thrombosis.
Venous thrombosis
Common acquired risk factors are cancer, atrial fibrillation, placement of mechanical heart valves, major surgery (with major lower limb orthopedic surgery carrying a particularly high risk), prolonged bed rest, oral contraceptives (especially in women who have another risk factor such as factor V Leiden).
Common inherited disorders including loss of function mutations in antithrombin, protein S, and protein C, and the factor V Leiden mutation.
Venous thrombi do not contain a lot of platelets, but instead are composed of primarily fibrin and trapped red blood cells, giving them a red appearance.
Less involvement of platelet activation and aggregation than in arterial thrombosis
Often occur at valve cusps where there is stasis (slow moving/sluggish blood flow)
Can lead to venous thromboembolism (VTE) which can cause pulmonary embolism (PE)
Pulmonary embolism etiology
Pulmonary embolism occurs when the thrombus lodges in the pulmonary arterial circulation (this is usually caused by venous thromboembolism from the legs).
What do platelets secrete in response to vascular insult?
secrete serotonin and thromboxane A2, both of which also induce vasoconstriction. Additionally, the activation of the coagulation system produces thrombin. Thrombin induces blood vessel endothelial cells to secrete
endothelin-1, which is a potent vasoconstrictor. Overall, vasoconstriction functions to slow blood flow
by the injury to reduce blood loss. Additionally, the decreased velocity of blood allows platelets to have
a better chance of adhering to the injury site.
Adverse effects aspirin
Bleeding risk (from erosive gastritis and/or peptic ulcers)
Patients with H. pylori infection are at greater bleeding risk.
Can induce bronchospasms (more common in patients with asthma).
P2Y12 inhibitors
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Glycoprotein IIB IIIA inhibitors
Abciximab
Eptifibatide
Tirofiban
Pharmakokinetics of Abciximab
Abciximab is administered as intravenous bolus followed by infusion.
Free plasma abciximab is cleared rapidly from circulation (t1/2 approximately 30 min).
However, the t1/2 of platelet bound abciximab is approximately 24 hours.
Major adverse effects of abciximab are bleeding and rare thrombocytopenia.
Vorapaxar (antiplatelet)
Protease activated receptor (PAR) antagonist
Recently approved by FDA for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease
Can cause life-threatening intracranial bleeding
Contraindicated in patients with previous stroke or
Dual antiplatelet therapy
Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 antagonist
DAPT often administered for some period of time after coronary angioplasty
DAPT shown to reduce myocardial infarction and cardiac death
Triple antiplatelet therapy
Triple therapy with warfarin, aspirin, and clopidogrel is used in some patients with atrial fibrillation and coronary artery disease.
Clinical use warfarin
Prevent progression or recurrence of venous thrombosis and thromboembolism (DVT, atrial fibrillation, mechanical heart valves, major surgeries)
Also given to patients with acute myocardial infarction to prevent recurrent coronary ischemia
Useful in long-term management because it is orally active
Warfarin is a small lipid soluble derivative of vitamin K.
Warfarin competes with vitamin K for vitamin K reductase (VCORC1).
Stuff that increases potentiates warfarins effects (increase INR longer to coag)
broad spectrum antibiotics A diet low in vitamin K rich food Intestinal and liver disorders that lower bile acid production (no absorb k) Non-steroidal anti-inflammatory drugs o Certain serotonin reuptake inhibitors o Anti-platelet drugs o Drugs that decrease hepatic metabolism statins liver disease chrons disease Renal insufficiency can cause hypoalbuminemia aspirin
Stuff that decreases warfarins effects (Dec INR coag faster)
Rifampin (antibiotic)
carbamazepine (mood stabilizer)
barbiturates
Indirect inhibitors of thrombin and/or Factor Xa (anticoagulant effect exerted through binding to antithrombin)
Heparin (parenteral)
Enoxaparin (low molecular weight heparin) (parenteral) *
Fondaparinux (parenteral) *
Direct thrombin inhibitors
Lepirudin (parenteral)
Bivalirudin (parenteral)
Argatroban (parenteral)
Dabigatran (oral)**
Direct factor Xa inhibitors
Rivaroxaban (oral) **
Apixaban (oral) **
Vitamin K antagonists (VKAs)
Warfarin (oral)
Protease activated receptor (PAR) antagonist
Vorapraxar
Heparin and Low molecular weight heparin (LMWH) (generic version called enoxaparin) therapeutic use
Prevention and treatment of venous thrombosis
Prevention of thrombosis during coronary angioplasty
Heparin induced thrombocytopenia type I
Most common
o Platelet (thrombocyte) counts fall within first two days of administration
o Heparin can increase platelet aggregation which causes a decrease in circulating platelet numbers (thrombocytopenia)
o This is not thought to mediated by the immune system.
o Little clinical consequence
Heparin pharmokinetics
Heparin has to be administered parenterally.
To achieve anticoagulant effect rapidly, heparin is usually administered intravenously.
It can be administered by subcutaneous injection, but this can reduce bioavailability by more than 50 %.
Effective ½ life of heparin approx. 90 min (requires frequent dosing)
After heparin enters circulation
Binds not only to antithrombin, but other plasma proteins, and endothelium of vessel walls
Interaction with plasma proteins other than antithrombin reduces anticoagulant activity
Acute-phase proteins (plasma proteins that change in response to inflammation), which can be elevated in ill patients
Platelet factor 4 (PF4) (secreted by platelets)
Levels of heparin binding proteins differ from person to person cause fixed doses to be unpredictable.
Heparin can be cleared by 2 mechanisms
Non-saturable involving the kidneys and liver
A rapid process of binding to and being taken up by endothelial cells
Because binding sites on endothelial cells are limited, this is a saturable process (as the dose of heparin increases there are fewer sites to bind).
Thus, clearance decreases as dose increases (dose-dependent clearance).
Remember, t1/2 = 0.693 x Vd/CL.
Thus, t1/2 increases as dose increase.
Does of 100, 400, 800 units/kg (half lives of anticoagulant activity are approx. 1, 2.5, and 5 hours, respectively).
Low molecular weight heparin (LMWH) (generic version called enoxaparin) pharmokinetics
Enoxaparin is prepared from unfractionated heparin by depolymerization
Most of the molecules in low molecular weight heparin preparations are too short to bridge antithrombin with thrombin. Thus, LMWH has very little effect on the thrombin inhibition by antithrombin
Like unfractionated heparin, a significant side effect of LMWH is bleeding.
LMWH has better bioavailability after subcutaneous injection (patients can give themselves injections outside the clinic or hospital).
LMWH has a longer effective ½ life after subcutaneous injection (less often dosing than heparin).
LMWH binds less to plasma proteins and endothelial cells which causes a more predictable anticoagulant response and easier dosing.
This makes coagulation monitoring less necessary in most patients.
It is cleared mainly by the kidney in a dose-independent manner which makes dosing simpler.
Lower risk for heparin-induced thrombocytopenia and osteoporosis
LMWH is safer for longer term use.
Because LMWH clearance is more dependent of kidneys, it is not usually used in patients with significant renal impairment (unfractionated heparin should instead be used).
Protamine only partially reverses LMWH.
Heparin-induced thrombocytopenia
Use lepirudin or argatraban instead
New oral anticoagulants advantages over warfarin (apixaban dabigatran and rivaroxaban)
Faster onset of action
Larger therapeutic window
Low potential for food and drug interactions
Predictable anticoagulant effect removing need for routine monitoring
While overall bleeding risk is similar to warfarin, there is a lower risk of intracranial/intracerebral bleeding than warfarin.
Identify the relative contraindications for the use of the fibrinolytics (alteplase).
12 to 24 hours since onset of symptoms
Age > 75 years
Systolic blood pressure > 180mmHg or diastolic blood pressure > 110mmHg
Prior allergic reaction to thrombolytics
prego or lactating
bleeding disorder
Prolonged cardiopulmonary resuscitation (>10min) Recent internal bleeding (
