Anticoagulants & Thrombolytics Flashcards
What type of substances promote coagulation?
Procoagulants
What type of substances inhibit coagulation?
Anticoagulants
What term is used to describe the prevention of blood loss?
Hemostasis
What are the four phases of hemostasis?
Vascular constriction
Formation of platelet plug
Formation of blood clot
Clot dissolution
What two process of hemostasis are immediate?
Vascular constriction and Formation of platelet plug
How long does it take the body to form a blood clot when injury occurs?
15-20 seconds to 1-2 minutes
What components are required for clot formation?
Vascular endothelium
Platelets
Plasma mediated hemostasis
What roles do the platelets play in clot formation?
Anchoring sites for coagulation factor activation complexes
Delivery vehicles releasing hemostatically active proteins
Major structural components of the clot
What factors induce prothrombotic endothelial changes?
Thrombin
Hypoxia
High fluid sheer stress
What products in the extracellular matrix promote clot formation?
Collagen Von Willebrand factor Hormones Cytokines Procoagulants
Where do platelets form and what is their normal lifetime?
Formed in the bone marrow and the life of a platelet is 8-12 days
What is the normal concentration of platelets?
150,000-300,000 per microliter
At what platelet count would a person more than likely being to spontaneously bleed?
Less than 50,000 (below 10,000 is considered lethal)
What occurs when platelets are exposed to the extracellular matrix in damaged endothelium?
Adhesion
Activation
Aggregation
What component of the extracellular matrix plays an important role in platelet adhesion to the vascular wall?
Von Willebrand factor
What is the primary role of vWF?
It is a bridging molecule between the sub endothelial matrix and platelets
What occurs during the activation phase of the hemostasis?
Platelets release granular contents (ADP, Ca, serotonin, histamine, TXA2 etc.) resulting in recruitment and activation of additional platelets
What receptors on the surface of platelets bind fibrinogen to provide for cross-linking with adjacent platelets?
Glycoprotein IIb/IIIa
What is the inactivated precursor to thrombin?
Prothrombin
What is the goal of clot formation?
To convert a soluble to insoluble clot
What stimulates activation of new platelets as well as increases platelet aggregation?
Thromboxane A2 (TXA2)
What type of receptor is the TXA2 receptor?
It is a G protein coupled receptor
Why is TXA2 important during tissue injury and inflammation?
It is a known vasoconstrictor
How does TXA2 contribute to activation of new platelets?
It mediates expression of the glycoprotein complex IIb/IIIa in the cell membrane of platelets
Where are most coagulation factors synthesized?
In the liver
How are coagulation factors present in the body when no injury is present?
Inactive proteins
How are coagulation factors labeled?
With Roman Numerals in the others in which they were discovered
What coagulation factor is not a true factor and comes from a person’s diet?
Calcium
Where is Von Willebrand synthesized?
In endothelial cells
What factors are vitamin K dependent for utilization?
II, VII, IX, and X
What is factor I?
Fibrinogen –> fibrin
What is factor II?
Prothrombin –> thrombin
How does the intrinsic pathway begin?
With damage to the blood vessels themselves
What is the common pathway?
It is common to both the intrinsic and extrinsic pathway, it depicts thrombin generation and subsequent fibrin formation
What is factor III?
Tissue thromboplastin
What is the initial step in the extrinsic pathway?
Plasma-mediated hemostasis, begins with exposure of blood plasma to tissue factor
What is the significance of fibrin activation?
Activates platelets and factor XIII
Converts inactive cofactors V and VIII to active forms
Activates factor XI
Up-regulates tissue factor
Stimulates vascular endothelium to express down regulation of fibrinolytic activity
What is factor IV?
Calcium
How does prothrombin contribute to the clotting cascade?
Attaches to receptors on the surface of a platelet
What is factor V?
Proaccelerin, labile factor
What two things would cause a deficiency of prothrombin in the blood?
Lack of vitamin K or liver disease
What causes the formation of fibrin?
Thrombin acts on fibrinogen to form fibrin
What is factor VII?
Serum prothrombin conversion accelerator, proconvertin
How is a meshwork in all directions of blood cells created?
Covalent bonds between fibrin molecules and cross-linking of fibers
What is a clot composed of?
Plasminogen
Plasmin
Fibrin and
Fibrin degradation products
How is plasminogen activated to plasmin?
By tissue plasminogen activator (t-PA) released from the tissue and vascular endothelium
What is factor VIII?
Antihemophilic A Factor
Antihemophilic globulin
What does plasmin do?
It digests fibrin fibers, fibrinogen, Factor V, Factor VIII, prothrombin and Factor XII
What is the function of anticoagulants?
Prevent clot formation or extension of existing clot
What is factor IX?
Plasmin thromboplastin Component (PTC)
Christmas factor
Antihemophilic B Factor
What is the function of anti platelet drugs?
Reduces platelet aggregation and prevents Stroke, MI and TIA
What three drugs do we commonly use that are anticoagulants?
Heparin
Lovenox LMWH
Warfarin
What is Factor X?
Stuart-Prower Factor
Autoprothrombin III
What herbal products have an effect on coagulation?
Garlic, giner, ginko, fish oil, flax seed, cranberry, black cohosh
How does citrate prevent blood clotting in donor blood?
Deionizes the Calcium (negatively charges citrate combines with calcium in the blood to cause an un-ionized calcium compound)
How is citrate metabolized when done blood is given?
Metabolized in the liver and is polymerized into glucose or metabolized
What is Factor XI?
Plasma Thromboplastin antecedent (PTA)
How does Heparin work?
Binds to antithrombin (antithrombin III) and accelerates the normally occurring antithrombin induced neutralization of activated clotting factors (Xa, XII, XI & IX)
What is the purpose of neutralizing thrombin?
It prevents the conversion of fibrinogen to fibrin
Where is heparin produced endogenously?
Basophils, mast cells and the liver
What are the three forms of heparin?
Bovine
Porcine
Endogenous
How does heparin effect the clotting cascade?
It blocks the classic intrinsic and final common pathways
What is the definition of a unit?
One unit of activity as the amount of heparin that maintains the fluidity of 1mL of citrated sheep plasma for 1h after re-calcification
How many units must heparin contain?
At least 120 USP units/mL
Why do we prescribe heparin in units instead of mg?
Commercial preparations varying in the number of USP units per mL
How does temperature affect heparin?
Decrease in body temperature prolongs its elimination half time
How is heparin monitored?
Biologic Activity:
PTT: 1.5-2.5 times pre drug value
ACT:
What is unique about heparin’s dose response?
It is not linear
What is the typical dose of heparin and how much does it increase clotting time?
100u/kg (o.5-1mg/kg) causes blood clotting time to increase from 6 to 30 or more minutes
What enzyme breaks down injected heparin?
Heparinase
How often should ACTs be drawn on a patient receiving heparin therapy?
Baseline
3-5m post administration
30m-1h interval post administration
What lab value is the most widely used and reliable for high heparin concentrations?
Activated Coagulation Time (ACT)
What physiological processes can influence ACT results?
Hypothermia
Thrombocytopenia
Aprotinin
Coagulation deficiencies
How long is a typical control ACT?
80-120s
If a patient is on CPB what is a desirable ACT?
> 400-450s
What is a desirable ACT in patients that are not on CPB but had a vascular procedure done?
> 200-300s
How is an ACT preformed?
Mixing whole blood with an activated substance to initiate activation of the clotting cascade
What is significant about the size of lovenox?
1/3 size of heparin and can cross placenta
Why is it that low molecular weight heparin only has to be given once a day?
There is less binding to the endothelial cells and therefore a longer half life
What are some advantage of using lovenox over heparin?
Lack in need of monitoring
More predictable
Fewer effects on platelet function
Reduced risk of HIT
What is the mechanism of action of lovenox?
It binds to and accelerates antithrombin III, inhibits factor Xa and IIa
What is factor XII?
Hageman factor, glass factor, contact factor
How much lovenox should be administered for DVT prophylaxis?
30mg SQ Q12H
What is one of the most important risk factors of an epidural hematoma?
Anticoagulant therapy/length of use
How does heparin induce thrombocytopenia occur (HIT)?
Heparin-dependent antibodies that agglutinate platelets and produce thrombocytopenia
What is considered mild HIT syndrome?
Platelet count of less than 100,000 cells/mm
30-40% of heparin treated patients
What is considered severe HIT syndrome?
Platelet count of less than 50,000 cells/mm
0.5% -6% of patients treated with heaprin
When would it be okay to administer Heparin to a patient with a history of HIT?
If remote history and no loner can demonstrate antibodies
What medication is not effective if a patient has an antithrombin deficiency?
Heparin, no antithrombin nothing for heparin to bind to
What is the treatment for antithrombin deficiency?
2-4 units FFP in adults OR
Antithrombin concentrate 1,000 units in adults
What drug can be given for heparin reversal?
Protamine
can also give FFP & prothrombin complex concentrate
What is the mechanism of action of protamine?
The positively charged alkaline protamine combines with the negatively charged acidic heparin to form a stable complex void of anticoagulant activity
How is the Heparin-Protamine complex removed from the body?
Removed by Reticuloendothelial system (phagocytosis)
What is the dose of protamine?
1mg for every 100 units of Heparin
It can be guided by last ACT and estimated amount of heparin within the last two hours
If protamine is given too rapidly what can occur?
Histamine release causing HoTN, facial flushing and tachycardia
What effect can the Heparin-protamine complex have on the pulmonary vasculature?
Can cause vasoconstriction –> Pulmonary HTN
What population is at risk for protamine allergy?
Diabetics, insulin contains protamine and chronic exposure to low dose protamine may produce antibodies against protamine
What is another indication for having a protamine allergy?
Fish allergy (protamine derived from salmon sperm)
What is population has the highest actual risk of having a protamine allergy?
Patients that have previously had a reaction to protamine (could be from bypass surgery)
What is the mechanism of action of Coumadin?
Competitively inhibits vitamin K dependent coagulation proteins (Factors II, VII, IX, X)
Inhibits protein C and S which prevent extensive clot formation
How are Coumadin levels measured?
PT/INR
What is the goal of the INR in patients on Coumadin therapy?
2-3
What is the typical dose of Coumadin?
5-10mg orally
Why is Coumadin contraindicated in pregnancy?
It crosses the BBB and is severely teratogenic
How long does it take to see an effect in the patients INR with Coumadin use?
8-12h due to depletion of factor VII, however full clinical effects are not appreciated for several days
What is factor XIII?
Fibrin stabilizing factor, fibrinase
How is the INR calculated?
INR = Platelets PT
Control PT
What is the normal INR range?
0.9-1.2
How often is the INR repeated while on Coumadin therapy?
4-6 weeks
What are INR goals with Coumadin therapy?
2-3 (may be higher with mechanical valve and recurrent MI)
When should Coumadin be discontinued for minor surgery?
D/c 1-5 days prep for PT 20% within baseline
What can be given to offset the effects of Coumadin if emergency surgery is required?
IV Vitamin K
FFP or PCC
What is the mechanism of action of antiplatelet drugs?
Suppress platelet function (inhibit platelet aggregation)
What are three well known antiplatelet drugs given?
ASA
Plavix
NSAIDs
What is the mechanism of action of Aspirin?
Inhibits platelet aggregation by irreversibly inhibiting COX-1, via acetylation, the effects last the life of the platelet (8-12days)
What is the typical dose of Aspirin?
81-325mg
What is the importance of COX-1 in the conversion of arachidonic acid to thromboxane A-2?
COX-1 is the rate limiting enzyme for the conversion
What is ASA utilized for in primary prophylaxis?
Used for prevention in the absence of an established diagnosis of CV disease
What is ASA utilized for in secondary prophylaxis?
Treatment with ASA in the presence of overt CV disease or conditions conferring particular risk.
What are the general guidelines for taking ASA prior to surgery?
It should be continues in both primary and secondary prophylaxis prior to and day of surgery unless surgical procedure has a high EBV
What is the mechanism of action of Plavix?
Inhibits platelet activation and aggregation through the irreversible binding of its active metabolite P2Y12 class od ADP receptors on platelets
What is significant about patients with liver disease taking plavix?
Plavix must be metabolize by CYP enzymes to produce the active metabolite that inhibits platelet aggregation (prodrug)
Liver failure may not get full effects
What laboratory value should be drawn when a patient is taking plavix?
P2Y12 point of care assay, can measure actual level of drug
Which type of stent requires longer use of plavix?
Medicine releasing, delayed healing
How do ASA and plavix act when used in combination?
Synergistically
What is the mechanism of action of NSAIDs in relation to antiplatelet therapy?
Reversibly depress thromboxane A2 production by platelets –> more temporary (24-48h)
What are the two mechanisms in which thrombolytics work?
Process inherent fibrinolytic effects OR
Enhance the body’s fibrinolytic system
What is the main use of thrombolytics?
To restore circulation through a previously occluded vessel
What are contraindication to thrombolytic therapy?
Trauma
Severe HTN
Active bleeding
Pregnancy
What is the most common risk of thrombolytic use?
Hemorrhage or bleeding
What is the mechanism of action of tPa?
It converts plasminogen to the active form, plasmin and plasmin breaks down fibrin
What reaction allows plasminogen to become plasmin?
t-Pa cleaves the plasminogen peptide bond into the serine protease plasmin
Why do we typically seen t-PA given as a bolus and followed by a gtt?
It has a short half life of only about 5 minutes
What agent could you coadminister with t-PA to prevent re-thrombosis?
Heparin
What is significant about the age of the clot?
Older clots have more cross linking and are more compacted = more difficult to dissolve
What are direct thrombin inhibitors?
Class of medications that act as anticoagulants by directly inhibiting the enzyme thrombin (factor II)
What is a benefit to using DTI?
Does not require a cofactor and may be used if patient has a positive history for HIT
What is a major disadvantage to using DTIs?
There is no reversal
What is a major disadvantage to using DTIs?
There is no reversal
What is the mechanism of action of bivalent DTIs?
Block simultaneously the active site and secondary binding site (exosist 1) and act as competitive inhibitors of fibrin
What is the mechanism of action of univalent DTIs?
Block only the active site and can therefore both inhibit unbound and fibrin-bound thrombin
What is the normal bleeding time?
3-10m
What is the normal prothrombin time?
12-14s
What is the normal INR?
0.9-1.2
What is the normal aPTT?
25-35s
What is the normal thrombin time?
less than 30 seconds
What is the normal ACT?
80-150s
What is the normal amount of fibrinogen?
greater than 150mg/dL
Why is TXA2 important during tissue injury and inflammation?
It causes vessel wall vasoconstriction initially after injury
