Anticoagulants, Antiplatelets and Thrombolytics - LeBlanc Flashcards
Name some prototypic anticoagulants.
- unfractionated or high molecular weight Heparin
- low molecular weight heparins
- Factor IIa and Xa inhibitors
- Warfarin (also called Coumadin)
Name some prototypic procoagulants.
- Desmopressin Acetate
Name some prototypic thrombolytic agents.
- tissue plasminogen activator (t-PA)
2. Streptokinase
Name some prototypic Antiplatelet drugs.
- Acetylsalicylic acid - Aspirin
- Clopidogrel bisulfate - Plavix
- Abciximab - ReoPro
Name some prototypic antagonists.
- Protomine sulfate
2. Aminocaproic acid
Under normal physiologic conditions, little or no intravascular coagulation occurs - why?
- coagulation factors are fairly dilute physiologically
- presence of plasma inhibitors
- activated clotting factors are rapidly removed by the liver - (the half life of activated factors may increase with liver disease)
When vascular damage occurs, what physiologic reactions participate to control blood loss?
- platelet adhesion reaction
- platelet activation
- platelet aggregation
- formation of a clot or coagulation
- fibrinolysis
What are 3 broad categories of risk factors for thromboembolism?
- abnormalities in blood flow
- abnormalities in clotting components
- abnormalities in surfaces in contact with blood
Name some abnormalities of blood flow that increase risk of thromboembolism.
- A-fib
- left ventricular dysfunction due to cardiomyopathy, CHF, MI, or ischemic/idiopathic factors
- bed rest/immobilization/paralysis
- venous obstruction due to tumors, obesity and pregnancy
Name some abnormalities of clotting components that increase risk of thromboemoblism.
- protein C/s deficiency
- antithrombin III deficiency
- Activated protein C resistance (Factor V Leiden)
- Antiphospholipid antibody syndrome
- estrogen therapy
- pregnancy
- malignancy
- homocysteinemia
- dysfibrinogenemia
- polycythemia
- myloproliferative disorder
- thrombocytosis
Name some abnormalities of surfaces in contact with blood that increase the risk of thromboembolism.
- vascular injury/trauma
- heart valve disease
- heart valve replacement
- atherosclerosis
- acute MI
- indwelling catheters
- previous DVT, PE
- fractures
- tumor invasion
- chemical irritation - potassium, hypertonic solutions, chemotherapy
Describe the process of platelet aggregation.
- trauma in blood vessel and endothelium
- extravascular space exposed - exposure of collagen fibers and vWF
- collagen binds to GPIa on platelets and vWF binds to GPIb on platelets
- platelets adhere
- adherence triggers increase in intraplatelet calcium which causes platelet to change shape and degranulate
- degranulation leads to release of thromboxane A2, 5-HT and ADP. These factors bind to adjacent platelets - recruiting and activating them
- fibrinogen binds to GPIIb/IIIa on platelets and cross links them
- coagulation cascades are triggered
What is a platelet plug?
In small vessels the process of platelet adherence alone can block bleeding - this is a platelet plug. In larger vessels the clotting processes are activated.
Name 3 hemostatic mechanisms.
- Platelet aggregation and formation of the platelet plug
- vasconstriction or vasospasm
- blood coagulation
What causes vasoconstriction or vasospasm?
- thromboxaneA2 and 5-HT are released by activated platelets. These substances trigger powerful constrictions or vasospasms by stimulating the contraction of smooth muscle cells within the walls of blood vessels.
What are some general characteristics of the coagulation pathways?
- Extrinsic pathway - coagulation occurs due to trauma originating from the extra-vascular space - formation of a macromolecular complex involving thromboplastin or tissue factor and factor VII
- Intrinsic pathway - coagulation is triggered by trauma to the blood itself - from large glycoprotein complexes released by platelets
- Common pathway - the extrinsic and intrinsic pathways converge in the common pathway
What is the purpose of the fibrinolytic system?
It serves to prevent extensive clotting.
What is the main process in fibrinolysis?
This system involves the cleavage of plasminogen to its active form - plasmin. Plasminogen is incorporated into a clot as it forms. Tissue plasmin activator, streptokinase and urokinase cleave Plasminogen into plasmin. Plasmin degrades fibrinogen into fibrinogen degradation products and fibrin clots into fibrin degradation products such as D-dimer.
What is the rate limiting step of coagulation?
The production of thrombin.
What is a summary of the process of clot formation?
- damage to a vessel wall leads to platelet adhesion and the initiation of the coagulation cascade.
- platelet adhesion leads to activation and the release of factors that cause more platelet adhesion and activation.
- the initiation of coagulation leads to the production of thrombin- once this process begins it is reinforced by factor V and more thrombin is made - positive feedback
- platelets aggregate and thrombin leads to active fibrin which causes cross-linking of platelets to form a clot or thrombus
- the production of a clot leads to eventual activation of fibrinolysis and the clot is broken down to its degradation products
What are anticoagulant drugs?
Pharmacological agents used to treat blood coagulation disorders.
What are the 3 main categories of anticoagulant drugs?
- Direct acting anticoagulants such as - Heparin, Factor IIa and Xa inhibitors and calcium chelators
- Indirect acting anticoagulants such as Warfarin (coumadin)
- Antiplatelet agents such as aspirin
What is an important cofactor in the coagulation cascade?
Calcium.
Name some clinical tests used to assess drug therapies used against blood clotting.
- Bleeding time
- platelet count
- PT time - reflects alterations in the extrinsic pathway, normally about 12 seconds
- aPTT - reflects the intrinsic pathway, normally about 24-34 seconds
- Fibrinogen - by immunological tests
- Fibrinogen/Fibrin degradation products and D-dimer
- vWF function
- mixing studies - detection of a simple deficiency of a factor or the presence of clotting inhibitor
What is the name of a reagent that is used to trigger the intrinsic pathway in a aTPP test?
Kaolin.
What is INR?
This is the international normalized ratio. It is an index used to normalize PT.
How is INR calculated and what is the desired value?
- calculated by taking the PT of the patient and dividing by the reference or mean normal PT
- INR is around 1 for a ‘normal’ person
- the therapeutic value that is desired is usually somewhere between 2 and 3.
Describe Heparin.
- an anionic mixture of linear mucopolysaccharide molecules with molecular weights in the range of 3,000 - 30,000
- this is called unfractionated or high molecular weight Heparin
- Heparin is active both in vivo and in vitro
- commercial Heparin is prepared from bovine lung and pig intestinal mucosa so allergy is a possible issue
How does HMWH work?
- inhibits blood coagulation by forming complexes with an alpha globulin (antithrombin III)
- Antithrombin III normally inactivates factors of the coagulation cascade - Kallikerein, XIIa, XIa, IXa, Xa and Thrombin
- when heparin binds to antithrombin III it increases it’s affinity to bind to the clotting factors by 100 fold
- once the factors are bound to the heparin/ATIII complex, heparin dissociates and is able to bind to another fee ATIII
- heparin blocks conversion of prothrombin to thrombin and thus inhibits the synthesis of fibrin to fibrinogen
- At low doses, heparin primarily neutralizes factor Xa
- at high doses it prevents thrombin induced activation of platelets and factors V and VIII
- very effective at suppressing the activity of factors Xa, IXa, XIa and thrombin
- basically inhibits platelet function and increases vascular permeability
What is another name for coagulation factors?
Plasma serine proteases.
Why does heparin bind so well to Antithrombin III?
Antithrombin III has lots of positive charges via its lysine and arganine residues. Heparin is negatively charged.
Why is aTPP used to monitor heparin use?
aTPP or activated partial thromboplastin time evaluates the intrinsic pathway and common pathway factors. Heparin increases the inactivation of factors in the intrinsic and common pathways so if these are decreasing then the aTPP time will increase- it takes longer to clot without the factors.
What condition may Heparin induce?
Moderate to severe thrombocytopenia in 1-4% of patients treated for at least on week. This condition favors hypercoaguability (paradoxically) - this is called HIT or Heparin induced thrombocytopenia. The thrombocytopenia occurs because heparin complexes with platelets.
How is Heparin administered?
- oral administration is NOT effective
- primary ROA is IV
- deep subQ injections can be given but it may take 2-4 hours to reach therapeutic plasma levels due to poor bioavailability
- IM injections avoided due to formation of hematomas
Does Heparin cross the placenta?
No, so it can be used in pregnant women. It does not cross into breast milk either so it can be used in lactating women.
How is Heparin prescribed?
On a unit basis - 100, 400 and 800 units/kg.
Does the half-life of Heparin change due to the dose administered?
Yes.
- 100 units/kg = half life is one hour
- 400 units/kg = half life is 2.5 hours
- 800 units/kg = half life is 5 hours
What are the contraindications for Heparin use?
- pt’s with thrombocytopenia or prior history of HIT
- pt’s with severe HTN
- pt’s susceptible to severe allergies since it is extracted from animal sources
- older patients, especially women
- any situation where active bleeding must be avoided - ulcerative lesions, intracranial hemorrhage, brain or spinal cord surgery
What is the treatment for too much Heparin?
- withdraw infusion
- give Protamine Sulfate or PS - highly basic peptide that binds to heparin and neutralizes its affects
- 1 mg of PS for every 100 units of Heparin given - not to exceed 50mg for any 10 min period
aTTP is used to monitor Heparin therapy - what is the optimum range?
aPTT = 1.5 to 2.5 normal
normal is 24-34 seconds
What is another way to monitor Heparin therapy?
Do an antifactor Xa Heparin activity assay. Want the assay to show 0.3-0.7 units/ml. This is measured at 6 hour intervals after initiation of heparin infusion until there is stabilization then do once daily.
What other things are monitored in Heparin therapy?
- hematocrit
- platelet count
- other signs of hemorrhage
What is low molecular weight Heparin?
These are fractionated forms of Heparin so they have lower molecular weights and are more bioavailable. They selectively accelerate the binding of factor Xa to antithrombin III and since they have shorter chains they do not bind to the factor itself.
What are some clinically used LMWH’s?
- Fragmin
- Innohep
- Lovenox
- Arixtra
What are the advantages of used LMWH over HMWH?
- equal efficacy but more predictable outcome
- LMWH has a half-life of twice that of HMWH
- less frequent dosing regimens are sufficient
- increased bioavailability with subQ injections over HMWH
- less frequent bleeding
What are the clinical indication for heparin therapy?
- blood transfusions
- A-fib
- DIC
- open heart surgery
- PE
- venous thromboembolism
- venous catheter occlusion
How do Thrombin inhibitors work?
- block thrombin by binding to its catalytic site
- given via IV infusion
- given to patients susceptible to developing HIT
- given in coronary angioplasty or coronary by-pass surgery
- examples are Refludan, Angiomax and Argatroban, Pradaxa (given orally)
What are the clinical indications for use of Pradaxa?
- thromboembolitic disorders
2. prophylactic anticoagulant used to minimize the risk of stroke in patients with non-valvular A-fib
How do Factor Xa inhibitors work?
- They inhibit the factor Xa
- they are oral anticoagulants
- Xarelto - given for DVT for both treatment and secondary prophylaxis, given prophylatically in knee and hip surgery, given for non-valvular A-fib, cerebrovascular accidents and PE
- Eliquis - given for nonvalvular A-fib and cerebrovascular accidents
How does Warfarin or Coumadin work?
- Vitamin K is needed for factors II, VII, IX and X - it carboxylates them on specific glutamic acid residues that chelate calcium so they are activated
- Warfarin keeps vitamin K from being regenerated
- It also down-regulates Protein C
- is given orally and is only active in vivo after a latent period of 12-24 hours
What is Protein C?
Protein C binds to thrombomodulin on endothelial cells and this complex alters the specificity of Thrombin and favors the degradation of factors Va and VIIIa into in active proteases. Protein C along with its cofactor protein S are naturally occurring anticoagulants - the down-regulation is why we see procoagulant activity in the early stage of warfarin therapy.
What are the approximate half lives of the factors that warfarin effects?
- factor VII - 6 hours
- factor IX - 24 hours
- factor X - 40 hours
- factor II or prothrombin - 60 hours
Warfarin binds to what in plasma?
Albumin
Where is Warfarin metabolized?
In the liver by cytochrome P450. The inactive metabolites are excreted in the urine.
How is Warfarin therapy monitored?
- PT
2. INR
How do you treat an overdose of Warfarin?
- withdrawal of the drug
- vitamin K supplementation (24 hours til works)
- transfusion of whole blood or plasma if major bleeding involved
What are the contraindications for Warfarin use?
- conditions where active bleeding must be avoided
- vitamin K deficiency
- severe hepatic or renal disease where intensive salicylate therapy is required
- pregnant women
Can Warfarin cross the placenta?
Yes, as well as other Coumarin drugs. Can lead to abortion and birth defects. Newborns are more sensitive to oral anticoagulants than are adults because of lower vitamin K levels and lower rates of metabolism.
Drugs that diminish the response to Warfarin do so how?
- inhibition of drug absorption - Cholestyramine
- induction of hepatic microsomal enzymes
- stimulation of the synthesis of clotting factors
Drugs that increase the response to Warfarin do so how?
- displacement of anticoagulant from plasma proteins
- inhibition of hepatic microsomal enzymes
- reduction in availability of vitamin K
- inhibition of synthesis of clotting factors
- decreased platelet aggregation - Aspirin
What is Desmopressin Acetate?
A procoagulant drug that is a synthetic analogue of ADH. It stimulates the activity of factor VIII.
What is Desmopressin Acetate used for?
- treatment of Hemophilia A with factor VIII levels equal to or greater than 5%
- pt’s with factor VIII antibodies
- treatment of severe von Willebrand’s disease Type I
- pt’s with abnormal molecular forms of factor VIII antigen
How does Acetylsalicylic acid or Aspirin work?
- an anti platelet drug
- inhibits release of ADP by platelets and thus inhibits their aggregation
- aspirin acetylates the COX enzyme of the platelet that synthesizes the precursors for thromboxane A2
- Thromboxane A2 normally is a labile inducer of platelet aggregation and a potent vasoconstrictor
- aspirin is mostly used prophylactically - 81 mg per day
Are the effects of aspirin reversible?
No. Aspirin covalently binds to the COX enzyme so synthesis of new enzyme would be required to stop the effects of aspirin.
What is Ticlopidine?
- an anti platelet drug
- also called Ticlid
- impairs the GPIIb/IIIa receptor on platelets - this receptor binds ADP
- without the ADP response platelet aggregation is prevented
- represents an alternative anti platelet drug for treatment of recurrent stroke in patients intolerant to aspirin
What is Clopidogrel bisulfate?
- an anti platelet drug
- also called Plavix
- impairs the GPIIb/IIIa receptor on platelets so that ADP cannot bind and platelet aggregation is prevented
- less side effects than Ticlopidine
What is Abciximab?
- an anti platelet drug
- also called ReoPro
- a chimeric monoclonal Ab inhibitor of platelet glycoprotein IIb/IIIa - prevents binding of fibrinogen and vWF and thus prevents platelet aggregation
- primarily used in acute coronary syndromes and percutaneous coronary intervention
What does the Fibrinolytic system do?
- plasminogen is converted to active plasmin by cleavage of a single peptide bond
- Plasmin digests fibrin clots and other plasma proteins including clotting factors
- t-PA, urokinase and streptokinase (indirectly) activate the cleaving of plasminogen to plasmin
Thrombolytic agents do what?
- They dissolve fibrin clots
- They tend to dissolve both pathological thrombi and also fibrin deposits at the site of vascular injury so these drugs can produce hemorrhage as a major side effect.
When is thrombolytic therapy indicated?
- pt’s with extensive PE
- acute coronary occlusion
- severe iliofemoral thrombophlebitis
What is t-PA?
- a naturally occurring tissue plasminogen activator that is released from endothelial cells in response to various signals - such as stasis produced by vascular occlusion
- t-PA binds to fibrin and converts plasminogen that is bound to fibrin into plasmin - does not activate free plasminogen very well only that which is bound to fibrin
- free plasmin is rapidly inhibited in the plasma by a2-antiplasmin while fibrin bound plasmin is protected from inhibition
What does Streptokinase do?
- a protein produced by B-hemolyltic streptococci
- has no enzymatic activity but it forms a stable non-covalent complex with plasminogen which causes a conformational change in plasminogen that cleaves a peptide bond on free plasminogen converting it to free plasmin
What are the contraindications to thrombolytic therapy?
- surgery within 10 days including organ biopsy, puncture of non compressible vessels, serious trauma and cardiopulmonary resuscitation
- serious GI bleeding within 3 months
- history of HTN - diastolic pressure greater than 110 mmHg
- active bleeding or hemorrhagic disorder
- previous cerebrovascular accident or active in tracranial bleeding
What is Aminocaproic acid?
- prevents binding of plasminogen and plasmin to fibrin
2. potent inhibitor for fibrinolysis and can reverse states that are associated with excessive fibrinolysis
