consequences of thrombus consequencesangina myocardial infaction stroke deep venous thrombosis
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Consequences of thrombus
Anticoagulant Therapy
Coagulation CascadeCoagulation Cascade
Anticoagulant therapy is aimed to: Anticoagulant therapy is aimed to: Prevent clot in patients at risk Prevent clot extension/ embolism Deep venous thrombosis (DVT) & pulmonary embolism (PE)
Activated factor X (FXa) + FVa + Ca++ + phospholipids
Prothrombin (FII) thrombin (FIIa)
Fibrinogen fibrin blood clot
Present on platelets’ surfaces. Act by
accelerating thrombus formation.
This complex and Ca2+ comprise the
prothrombinase complex
Thrombin stimulates platelet aggregation
Phospholipids on platelets stimulate clot formation
Clotting factors are serine protease enzymes
The Key Clotting Factor is:
THROMBIN
Because it acts on many aspects of the coagulation
cascade
Scheme of anticoagulant drugs
THROMBIN INHIBITORS
Thrombin inhibitors can either inactivate thrombin directly or block thrombin formation
Thrombin can be inhibited irreversibly by glycosaminoglycans like heparin through an antithrombin III-dependent mechanism
The enzyme can be inhibited reversibly by hirudin and hirudin derivatives in an antithrombin III-independent manner (direct acting)
In addition to inhibiting thrombin, glycosaminoglycans also block thrombin generation
Antithrombin-III Dependent Antithrombin-III Dependent Thrombin InhibitorsThrombin Inhibitors
Standard Unfractionated Heparin (UFH) Heparin is a mixture of glycosaminoglycan molecules,
which are heterogenous in molecular size The mean molecular weight of heparin is 15,000 D Antithrombin III (ATIII) binding is necessary for its
anticoagulant activity Antithrombin III (ATIII) is a slow endogenous a slow endogenous
progressive inhibitorprogressive inhibitor of thrombin and other clotting enzymes (FXa)
Mode of Action of Heparin
It binds to ATIII through a unique pentasaccharide conformational change in ATIII ↑ activity of ATIII
It binds to ATIII through a unique pentasaccharide conformational change in ATIII ↑ activity of ATIII
N.B. ATIII alone can inhibit thrombin but in a very slow reaction
N.B. ATIII alone can inhibit thrombin but in a very slow reaction
Heparin acts as a template to create (thrombin-ATIII complex)Heparin acts as a template to
create (thrombin-ATIII complex)
N.B. only 1 ATIII bind to 1 thrombin (1:1)
N.B. only 1 ATIII bind to 1 thrombin (1:1)
Then heparin dissociates and is reused againThen heparin dissociates and is reused again
Heparin inactivates thrombin by binding both ATIII and thrombin
To inactivate thrombin
1. Heparin binds to ATIII by the unique penta-saccharidepenta-saccharide
2. Also binds to thrombin through the heparin-binding domainheparin-binding domain
3. Conversely, to inactivate factor Xa, heparin only needs to bind with ATIII through its pentasaccharide sequence
Anti-IIAnti-IIaa activity activity = Anti-X = Anti-Xaa activity activity
Every heparin molecule contains :
Pentasaccharide + heparin binding domain
Targets for Heparin-ATIII Complex
Heparin inhibits several coagulation enzymes including thrombin (factor IIa) and factors IXa, Xa, XIa & XIIa
The enzyme most sensitive to inhibition is factor IIa
The next most sensitive enzyme is factor Xa
By inhibiting these two enzymes heparin inhibits both thrombin activity & thrombin formation
Limitations to Heparin’s useLimitations to Heparin’s use
LIMITATION CAUSE CONSEQUENCE
Pharmacokinetic
- Binding to plasma proteins
- Binding to endothelium and macrophages
- Poor bioavailability at low doses, Marked variability in dose response, Dose-dependent clearance
Biophysical
- Heparin is unable to inactivate thrombin bound to fibrin or fibrin degradation products and factor Xa bound within the prothrombinase complex
- Limited efficacy in preventing arterial thrombosis & reocclusion after successful thrombolysis
Antihemostatic - Heparin binds to platelets and inhibits their function
Heparin-induced bleeding
Need to be given in hospital and monitoring
the patient
Low molecular weight heparin have a mean molecular weight of 5000 D.
Prepared by controlled chemical or enzymatic depolymerization of standard unfractioned heparin are about ⅓ the size of starting material
20% of LMWH molecules contain the pentasaccharide domain
Enoxaparin is the most used LMWHEnoxaparin is the most used LMWH
Low Molecular Weight Heparins (LMWHs)
They contain pentasaccharide inactivation of Factor Xa In contrast, only 25% to 50% of LMWH molecules that have
the pentasaccharide sequence are long enough to interact with both ATIII & thrombin
Mechanism of Action of Low Molecular Weight Heparin (LMWH)
Anti-IIAnti-IIa a < Anti-X < Anti-Xaa activity activity
25% of LMWH can interact with both ATIII and thrombin
The rest only inactivate factor X
Pharmacokinetic Profile of Pharmacokinetic Profile of LMWHLMWH
LMWH exhibit less binding to plasma proteins & cell surfaces (better than heparin)
The reduced binding to plasma proteins results in Better bioavailability (90% vs. 20% of heparin) more predictable anticoagulant response Laboratory monitoring of LMWH activity is not required LMWH has low resistance in comparison to heparin T1/2 = 4 hours (more than heparin) Given at fixed doses once to twice daily by S.C. route, and
is given for both inpatients as well as for outpatients.
Comparison of UFH & LMWH
CharacterCharacter UFHUFH LMWHLMWH
Average Mol wtAverage Mol wt 15,000 5,000
Anti-XAnti-Xaa/anti-II/anti-IIaa activity activity 1/1 2-4/1
aPTT monitoring requiredaPTT monitoring required Yes No
Inactivation of platelet-bound XInactivation of platelet-bound Xaa No Yes
Protein bindingProtein binding Powerful) 4+) Weak (+)
Endothelial cell bindingEndothelial cell binding Powerful) 4+) No
Dose-dependent clearanceDose-dependent clearance Yes No
Elimination half-lifeElimination half-life 30-150 min 2-5 times longer
Biophysical Limitations of Heparin and LMWH
Both heparin and LMWH can’t degrade fibrin-bound thrombin (only free thrombin is degraded) nor Factor Xa
within the prothrombinase complex.
Other Injectable Antithrombotic AgentsOther Injectable Antithrombotic Agents
FondaparinuxFondaparinux, a pentasaccharide, is an AT-III-dependent selective for factor Xselective for factor Xaa
Prevents venous thrombosis associated with orthopedic surgery
Administered > 6 hours postoperatively and the dose is adjusted for patients with renal impairment.
To be revised.……
Therapeutic Uses
o Heparin should be given either IV or S.C. injection.o onset of action: few minutes (IV) 1-2 hours (S.C.)o LMWHs are given by S.C. routeo I.M. injection hematoma formation (thus is avoided)
Treatment of deep vein thrombosis Treatment of pulmonary embolism Prevention of postoperative venous thrombosis in patients
with acute MI phase or one undergoing elective surgery(not emergency surgery)
Reduction of coronary artery thrombosis after thrombolytic treatment
Heparin is the anticoagulant of choice in pregnant women
Adverse Effects
Bleeding: they both lead to bleeding but the bleeding is less in LMWH To treat bleeding: inject antidote protamine sulphateprotamine sulphate (1mg IV for each
100 units of UFH) (reversal effect)
Thrombosis: heparin ↓ ATIII ↑ risk of thrombosis
Cont’d
Thrombocytopenia:: Heparin-induced thrombocytopenia (HIT) is a lifethreatening immune reactionOccurs in 3% of patientsUsually occurs a week from starting heparin therapy HIT ↑ platelet activation platelet aggregation thrombosis.HIT endothelial damageHIT may occur in the early stages of treatmen (within 5 days) but it’s non-immune reaction (not life threatening)LMWHs, though of lower risk, are contraindicated with HIT.
How does HIT occur? Heparin injection immune reaction with
body produce antibody against heparin& also bind to platelet receptor activation of platelet thrombosis
Cont’d
OsteoporosisOsteoporosis occurs with large doses of UFH >20,000 U/day for 6 months or longer (chronic use)
HyperkalemiaHyperkalemia rarely occurs with UFH It is attributed to inhibition of aldosterone secretion It occurs with both low- & high-dose UFH therapy Onset is quick within a week after therapy initiation It is reversible by therapy discontinuation Diabetic & renal failure patients are at higher risk Hypersensitivity: (Antigenicity due to animal source) rarely occurring reactions include urticaria, rash, rhinitis,
angioedema & reversible alopecia(hair loss)
Clinically Approved Direct Clinically Approved Direct Thrombin InhibitorsThrombin Inhibitors
Lepirudin, recombinant hirudin*-like peptide. Direct acting thrombin inhibitor Used in HIT patients (IV injection) Has renal clearance It acts on free thrombin and thrombin bound to fibrin It has potential use in unstable angina patients and after
thrombolysis
* hirudin: is a leech derived anticoagulant
It binds to active site and substrate site of thrombin
DIRECT FACTOR Xa INHIBITORS
They are available by recombinant technology
They are available by recombinant technology
Oral Anticoagulants Vitamin K Antagonists (The Coumarins)Vitamin K Antagonists (The Coumarins)
Vitamin K is co-factor for the hepatic synthesis of clotting factors II, VII, IX & X
Vit. K Vit. K epoxide (active form)By Vit.k reductase
warfarin
Warfarin inhibits Vit. K reductase no active form of Vit. K no synthesis of clotting factorsWarfarin inhibits Vit. K reductase no active
form of Vit. K no synthesis of clotting factors
Vitamin K AntagonistsWarfarin
Onset:Onset: starts after 12-16 hours lasts for 4-5 days Clinical anticoagulant activity needs several days to
develop (due to the already circulating clotting factors)
o So the action of warfarin will appear after the elimination of prior clotting factors.
o Elimination time (factor II needs: 60 hours factor X: 40 hours)
Overlap heparin & warfarin therapyOverlap heparin & warfarin therapy taken together until the effect of warfarin appears (after 5 days) then stop taking heparin.
Vitamin K AntagonistsWarfarin
Warfarin has 100% oral bioavailability, high plasma protein binding & long plasma t1/2 of 36 hours
A high loading dose followed by an adjusted maintenance dose
Warfarin is contraindicated with pregnancy as it crosses the placental barrier and is teratogenic in the first trimester & and induce intracranial hemorrhage in the baby during delivery
Warfarin is metabolized by hepatic Cytochrome P450 enzymes with half-life of 40 hrs
Warfarin Drug Pharmacokinetic & Pharmacodynamic Interactions
Potentiating warfarin Inhibitors of hepatic P450
enzymes (cimetidine, cotrimoxazole, imipramine, amiodarone)
Platelet aggregation inhibitors (NSAIDs e.g. aspirin)
3rd generation cephalosporins* Drugs displacing warfarin from
binding sites (NSAIDs) Drugs reducing the availability of
vitamin K Hepatic disease(↓ clotting factors)&
hyperthyroidism (↑ basal metabolic rate)
Inhibiting Warfarin Vitamin K in some
parenteral feed Inducers of hepatic P450
enzymes (rifampicin, barbiturates, … etc)
Reduction of GIT absorption (cholestyramine)
Diuretics Hypothyroidism
*Cephalosporins potentiate warfarin’s effect by killing vit.k producing normal flora
Warfarin Side-EffectsWarfarin Side-Effects
Drug-drug interactions Bleeding disorder (thus should be monitored)
Treatment for bleeding• Minor bleeding: stop therapy + oral Vitamin K• Severe Bleeding: stop therapy + I.V. Vitamin K
fresh frozen plasma, recombinant factor VIIa or prothrombin complex may be used
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