Antithrombotic drugs

الكلية المصرية ألطباء الرعاية الحرجة

Training Course in Critical Care Medicine

Asst. Professor of Critical Care MedicineCritical Care Department

Pathophysiology of Haemostasis

Anti-thrombotic Drugs

Treatment of Thromboembolic Disease

Schematic drawing of the platelet (top

figure), showing its alpha and dense

granules and canalicular system. The

bottom figure illustrates the platelet's major

functions, including secretion of stored

products, as well as its attachment, via

specific surface glycoproteins (GP), to

denuded epithelium (bottom) and other

platelets (left). VWF: von Willebrand factor;

TSP: thrombospondin; PF4: platelet factor

4; PDGF: platelet derived growth factor; β-

TG: beta thromboglobulin; ADP: adenosine

diphosphate; ATP: adenosine triphosphate.

Courtesy of Steven Coutre, MD.

AT III

Protein C & S system

Tissue factor pathway inhibitor

(TFPI)

Source: Synthesized by the liver

LysylResidue

ArginineResidueSerine

activecenter

ATIII

Thrombin

Heparin

Action: It inhibits FIXa, Xa, XIa, XIIIa &

thrombin

Source Vit K dependent protein synthesized by liver.

Function Protein C is activated by thrombin thrombomodulin Cx.

Activated Protein C Inactivates coagulationStimulates

fibrinolysisAnti inflammatory

Protein CThrombinThrombomodulinComplex

Stimulates fibrinolysis

Anti inflammatory action

Inactivates coagulation

Activated Protein C

PAI - Factor V (Va) - Factor VIII (VIIIa)

Free protein s

++




Fibrinolytics

Fibrinolytics

Fibrinolytics

Fibrinolytics

Antiplatelet drugs

Acetylsalicylicacid (aspirin)

P2Y12 antagonists

Dipyridamole GPIIb/IIIaantagonists

Used widely in patients at risk of

thromboembolic disease

Beneficial in the treatment and

prevention of ACS and the prevention of thromboembolic

events

Secondary prevention in

patients following stroke, often in

combination with aspirin

Administered intravenously, are

effective during percutaneous

coronary intervention (PCI)

1. Aspirin2. Phosphdiestrase inhibitor: dipyridamole3. Thienopyridines:

Ticlopidine Clopidogrel Prasugrel Ticagrelor

4. GP IIa/IIIb receptor antagonists Abiciximab Tirofeban Eptifibatide

Schematic representation of the mechanism of action of antiplatelet agents. When vascular cells are damaged, platelets bind to exposed collagen via glycoprotein (GP) Ib/IX receptors complexed to von Willebrand factor. These bound platelets undergo degranulation, releasing

Sharis, PJ, Cannon, CP, Loscalzo, J. Ann Intern Med 1998; 129:394.

adenosine diphosphate (ADP) & numerous other substances, including thromboxane A2, serotonin, & epinephrine, that play a role in the recruitment & aggregation process. The released ADP binds to two types of receptors, a low-affinity type 2 purinergic receptor (P2Y12) & a high-affinity purinergic receptor (P2Y1). Ticlopidine & clopidogrel block the binding of ADP to the type 2 purinergic receptor & prevent activation of the GP IIb/IIIa receptor complex & the subsequent aggregation of platelets. The GP IIb/IIIa receptor antagonists prevent platelet aggregation by blocking the binding of the GP IIb/IIIa receptor to fibrinogen, thereby inhibiting fibrinogen-platelet bridging.

Schematic representation of prostanoid synthetic pathways and the enzymes that catalyze the specific reactions. PG:

prostaglandin; Tx: thromboxane.

Rapid absorption of aspirin occurs in the stomach and upper intestine, with the peak plasma concentration being achieved 15-20 minutes after administration

The peak inhibitory effect on platelet aggregation is apparent approximately one hour post-administration

Aspirin produces the irreversible inhibition of the enzyme cyclo-oxygenase and therefore causes irreversible inhibition of platelets for the rest of their lifespan (7 days)

Secondary prevention of transient ischaemic attack (TIA), ischaemic stroke and myocardial infarction.

Prevention of ischaemic events in patients with angina pectoris.

Prevention of coronary artery bypass graft (CABG) occlusion.

Risk of gastrointestinal adverse events (ulceration and bleeding).

Allergic reactions.

Is not a very effective antithrombotic drug but is widely used because of its ease of use.

Lack of response in some patients (aspirin resistance).

The irreversible platelet inhibition.

Both currently available ADP-receptor antagonists are thienopyridines that can be administered orally, and absorption is approximately 80-90%

Thienopyridines are pro-drugs that must be activated in the liver

1. Secondary prevention of ischemic complications in ACS

2. Secondary prevention after MI, ischemic stroke & peripheral vascular disease.

3. After PCI

4. Aspirin resitence

1. Bleeding

2. Resistance: clopidogral

3. Neutroponia: Ticlopcdin

4. Irreversible platelets inhibition

5. Thrombothytopenic purpura

Incompletely absorbed from the gastrointestinal tract with peak plasma concentration occurring about 75 minutes after oral administration.

More than 90% bound to plasma proteins.

A terminal half-life of 10 to 12 hours.

Metabolised in the liver.

Mainly excreted as glucuronides in the bile; a small amount is excreted in the urine.

Secondary prevention of ischaemic

complications after transient ischaemic

attack (TIA) or ischaemic stroke (in

combination with aspirin).

Is not a very effective antithrombotic drug.

Dipyridamole also has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease; chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole.

Available only for intravenous administration.

Intravenous administration of a bolus dose followed by continuous infusion produces constant free plasma concentration throughout the infusion. At the temination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate. Platelet function generally recovers over the course of 48 hours, although the GP IIb/IIIa antagonist remains in the circulation for 15 days or more in a platelet-bound state.

Prevention of ischaemic cardiac complications in patients with acute coronary syndrome (ACS) without ST-elevation and during percutaneous coronary interventions (PCI), in combination with aspirin and heparin.

Abcixiamb: - 0.25 mg/kg (Bolus)

- Maintence: 0.125 mckg/kg/min

Tirofiban: - bolus: 0.4 mcg/kg/over 30 min

- Maintence: 0.1 mcg/kg/min

Eptifibatide: - bolus: 180 mcg/kg

- Maintence: 2 mcg/kg/min

Renal insufficiency

Elderly patients

Women

Vitamin Kantagonists

Warfarin

Coumarin

Unfractionated heparin (UFH)

Low molecular weight heparin (LMWH)

Synthetic pentasaccharides (fondaparinux, idraparinux)

Heparins Direct thrombininhibitors

Hirudin

Recombinant- Hirudin- Bivalirudin

Synthetic- Argatroban- Melagatran- Dabigatran- AZD0837

HeparinPentasaccharide

Thrombin

AT

Prothrombin Thrombin

Antithrombin

Tenase complexTenase complex

FIXaFVIIIa

FXa

FX

Prothrombinase complexFXaFVa

The antithrombin/heparin complexis a poor inhibitor of fibrin-bound thrombin

FXa

Pentasaccharide LMWH

AT

The antithrombin/LMWH complexis a poor inhibitor of fibrin-bound thrombin


Antithrombin

Tenase complexFIXaFVIIIa

FXa

FX


FXa

AT


Antithrombin

Tenase complex

FIXaFVIIIa

FXa

FX


The antithrombin/LMWH complexis a poor inhibitor of fibrin-bound thrombin

Administered by continous intravenous infusion or subcutaneous injection

The clearance involves a rapid, saturable mechanism and a slower, unsaturable mechanism.

A renal pathway is primarily responsible for the slow, unsaturable component

Once in the blood stream, UFH binds to plasma proteins, endothelial cells and macrophages (accounts for the rapid, saturable phase of heparin clearance)

The complex kinetics explains the non-linear relationship between dose and plasma half-life and the variable anticoagulant effect

The apparent biological half-life of heparin increases with increasing doses

Treatment of thromboembolic diseases, mainly as induction of vitamin K antagonists.

Prevention of postoperative VTE.

Prevention of thrombosis after MI.

Prevention of coagulation during extracorporal circulation e.g. during renal dialysis or cardiac surgery.

Treatment of disseminated intravascular coagulation (DIC).

Inconvenience of administration by injection and the need for regular monitoring, which delays hospital discharge and therefore increases the demand on hospital resources.

Risk of heparin-induced thrombocytopenia (HIT).

A relatively high risk of bleeding compared to more recently developed alternatives.

Sometimes associated with osteoporosis in chronic use.

The drawbacks above are reduced with LMWH and UFH has now largely been replaced by LMWH for prevention and treatment of thrombosis.

Initial dose80 units/kg bolus, then 18 units/kg per hour

aPTT <35 sec (<1.2 x control)80 units/kg bolus, then increase infusion rate by 4 units/kg per hour

aPTT 35-45 sec (1.2-1.5 x control)40 units/kg bolus, then increase infusion rate by 2 units/kg per hour

aPTT 46-70 sec (1.5-2.3 x control(No change

aPTT 71-90 sec (2.3-3.0 x control)Decrease infusion rate by 2 units/kg per hour

aPTT >90 sec (>3.0 x control)Hold infusion 1 hour, then decrease infusion rate by 3 units/kg per hour

Subcutaneous UFH: 250 U/Kg/12hrs

Heparin Resistance:

1. Antithrombin III deficiency

2. Increase heparin clearance

3. Increase levels of heparin binding protein

4. Increase fibrinogen, VIII

Treatment: Increase heparin (35.000 U/day)

Bleeding: IV infusion protamine sulphate(20 mg/min or 1 mg/100 heparin)

Typically administered by subcutaneous injection

More predictable dose-response relationship, a 2-4 times longer plasma half-life, and improved bioavailability after subcutaneous administration compared to UFH, due to reduced binding to plasma proteins, macrophages and endothelial cells

Clearance is mostly via a renal pathway, thus the half-life can be prolonged in patients with renal failure

Regular coagulation monitoring is not required. However, in certain situations (if needed) anti-factor Xa activity is measured, as LMWH has less effect on the activated partial thromboplastin time (aPTT).

Treatment of VTE.

Prevention of postoperative VTE and prolonged prophylaxis of VTE after elective hip surgery.

Prevention of VTE in patients with acute medical diseases.

Acute coronary syndrome (ACS).

Prevention of coagulation during extracorporal circulation during renal dialysis.

Effective subcutaneous administration.

No need for regular coagulation monitoring due to more predictable dose-response relationship.

Improved bioavailability.

Longer plasma half life – allows for once-daily dosing.

Reduced risk of toxic effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis.

LMWH has largely replaced UFH as a front-line therapy

Enoxaprin (clexan) → 1 mg/kg twice daily

Nadroparin (Fraxiparin) → 5700 IU/day

Tinzparin(Innohep) → 175 g/kg/day

Fondaprinax (Arixtra) 2.5 mg/day

Dalteparin (Fragmin)→ (100 /kg/12 hrs)

1. Elderly patient < 45 kg

2. Obese patients

3. Renal failure

After subcutaneous injection, peak plasma concentrations are achieved after approximately two hours.

Long plasma half-life, which allows a once-daily regimen.

Exclusively eliminated by the kidneys.

Regular coagulation monitoring is not required. However, in certain situations if needed, anti-factor Xa activity is measured, as fondaparinux has less effect on the activated partial thromobplastin time (aPTT).

Prevention of venous thromboembolism

(VTE) after major orthopaedic surgery

such as hip and knee replacement or hip

fracture repair.

Fondaparinux, like all heparins also carries the disadvantage of only being available in an injectable formulation.

Lack of sufficient information in clinical practice on efficacy and safety.

Fondaparinux has a long plasma half-life and this, taken together with the increased risk of bleeding seen in some studies, raises concerns.

UFH LMWH Penta-saccharide

Mass 5000-30000 1500-6000 1400

Half-life 1-5 h 3-7 h 15 h

Monitoring test aPTT Anti-FXa Anti-FXa

Dosing Fixed Fixed Fixedalternatives

Adjusted by Weight- Adjusted in severemonitoring adjusted renal impairment

Dicoumarol first isolated from sweet clover silage - Caused haemorrhagic disease in cattle. Subsequent synthesis of chemically related coumarin, WARFARIN

- Patent holder = Wisconsin Alumni Research Foundation coumARIN.

The site of action of WARFARIN

Vitamin-K oxidation is coupled to -carboxylation of Glu residues on clotting factor proteins, which is necessary for full biological activity (as Ca++ chelators). Warfarin blocks the vit K epoxide reductase step in this cycle. The delayed onset of Warfarins effect actually reflects the half-lives of these modified clotting factors (shortest, Factor VII 6h; longest, Factor II 40-60h).

Rapidly and completely absorbed after oral administration

Highly protein bound (>99% to serum albumin)

Crosses the placenta (teratogenic)

Breast feeding OK (active W not detected in breast milk)

Variable but usually slow systemic clearance – t1/2 ~24-60hrs

Clearance dependent on hepatic P450s (especially 2C9*)

* Slow metabolism through some alleles explains why ~10% of patients have therapeutic INRs on low doses of Warfarin <1mg/d.

Reduced absorption – cholestyramine or similar resins.

Reduced protein binding – hypoproteinaemic states e.g. nephrotic syndrome

Altered clearance – P450 induction by rifampicin, barbiturate or phenytoin; P450 inhibition by amiodarone, metronidazole and cimetidine.

Altered vit K intake – vitamin K rich foods/supplements or antibiotic induced reduction in gut-derived vitamin K.

Altered levels of clotting factors – reduced in hypermetabolic states e.g. hyperthyroidism; increased in pregnancy.

Augmented bleeding tendency – in combination with antiplatelet agents e.g. NSAIDs. Substitute non-NSAID analgesics with care: dextropropoxyphene and high dose paracetamol (1.5-2g/d) can block W metabolism.

The activity of various clotting proteins (logarithmic scale) is shown here as a function of time after ingestion of warfarin (10 mg/day PO for four consecutive days) by a normal subject. Factor VII activity, to which the prothrombin time is most sensitive, is the first to decrease. Full anticoagulation, however, does not occur until factors IX, X, and prothrombin are sufficiently reduced. Protein C activity falls quickly, and, in some patients, a transient hypercoagulable state may ensue (eg, coumarin necrosis). Redrawn from Furie, B. Oral anticoagulant therapy. In: Hematology: Basic Principles and Practice, 3rd edition, Hoffman, R, Benz, EJ, Shattil, SJ, Furie, B, et al [Eds], Churchill Livingstone, New York, 2000, p. 2040

Schematic representation of the intrinsic (in red), extrinsic (in blue), and common (in green) coagulation pathways. In the clinical laboratory, the intrinsic (and common) pathway is assessed by the activated partial thromboplastin time (aPTT) and the extrinsic (and common) pathway by the prothrombin time (PT). The thrombin time (TT) assesses the final step in the common pathway, the conversion of fibrinogen to fibrin, following the addition of exogenous thrombin. Fibrin is crosslinked through the action of factor XIII, making the final fibrin clot insoluble in 5 Molar urea or monochloroacetic acid. This latter function is not tested by the PT, aPTT, or TT.

Initial Dose:2-5 mg/day: Hepatic impairments

debilitation, CHF, elderly, CRF, high risk of

bleeding5-10 mg/day,

Maintence Dose: (2-10 mg/day)INR: 2-3.

Old age> 70 yearsFemale SexMalignancyCRFPrior strokeDrugs: Aspirin, NSAID,

Antibiotics, Amiodarone, Statin, Fibrate

DMSevere HTNLiver diseaseAnaemiaGFT bleeding

Bleeding

Cholesterol embolization (blue toes syndrome)

Skin Necrosis

Teratogenic

Vascular calcification

Allergy

This figure shows the relative risks and their 95 percent confidence intervals for the occurrence of thromboembolism (closed circles, confidence intervals in yellow) and hemorrhage (open circles, confidence intervals in blue) as a function of the INR range. The comparator for both end-points is the INR range of 2.0 to 3.0 (ie, relative risk of 1.0). Note that hemorrhagic risk becomes dominant at an INR >3, while thromboembolic risk is dominant at an INR <2. Data from: Oake, N, et al. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ 2008; 179:235.

1. Not deactivated by PF4 like heparin

2. No need for AT III

3. Good bioavailability

4. No HIT

5. No platelet activation

• Hirudin (Salivary gland of a leach)

• Lepiruolin (Recominant Hirudin)

• Argatroban• Bivalirudin

• Ximelagatran

• Dabigatran (110, 150 mg)

IV Oral

STREPOKINASE Product of -haemolytic strep – hence anti-strep antibodies will

neutralise it Forms a 1:1 complex with plasminogen – this exposes its

cleavage site promoting conversion to plasmin Has similar affinity for free or bound plasminogen - no clot

selectivitytPA

Binds to fibrin hence clot selectivity Activates plasminogen bound to fibrin - >100-fold faster than

circulating plasminogen enhancing clot selective fibrinolyis Levels of tPA during thrombolytic therapy are 30-300x >

physiological levels – hence some loss of clot selectivity

GUSTO trial supported tPA (accelerated alteplase over SK or alteplase + SK).But . . .

Effect small (10 and 14% difference in 30-day mortality).

Cost - recombinant tPAs 5-10 fold more expensive vs SK

Increased risk of intracerebral bleed with tPAs ( ~ 1% patients)

Choice of rtPA over SK may be prompted by: Age (<75yr) Low risk of intracerebral bleed Size of infarct (especially large anterior MI) Early presentation (<4hr) Previous SK (especially previous 6/12 or ever?)

Risk of serious bleeding is low particularly in the absence of heparin (<1% risk in major trials).It arises from:

1. Lysis of ‘physiological’ clots2. A ‘systemic lysis state’ (depleting fibrinogen, FV and FVIII)

The following are generally contraindications: Active bleeding or haemorrhagic disorder Aortic dissection Significant GI bleed in the previous 3 month Recent cardiovascular surgery or bowel resection Pericarditis Poorly controlled hypertension (DBP >110 mmHg) Proliferative retinopathy CVA in past 3 months or SOL such as abscess/tumour Pregnancy

1. Reteplase (rPA)

• Less fibrin selective

• Longer half life

2. Tenecteplase (TNK-tPA)

• 14 times more fibrin specific

• Single bolus

• Long half life

• Less bleeding

1.Anaphylaxis (0.5%) & allergic

reaction due to anti-SK antibodies

2.Hypotension

3.Bleeding (Minor)




Acute Non ST-MI

Acute ST-MI

DVT & PE

Secondary prevention of stroke

Pregnancy

Early therapy: Low risk pts: Asp + colpidogrel High risk pts (+ve troponin): → GP IIb/III

receptors antagonist infusion. 18 hrs → after PCI, 48 hrs → ACS.

Before PCI: Asp (150 mg) + colpidogral (600 mg) or prasugrel (60 mg)

Long term therapy: Asp (75 to 162 mg/day) + colopidogrel (75

mg) or prosugrel (10 mg) → one year.

Preferred thrombolytic regimens for acute ST elevation myocardial infarctionDrugRecommended IV regimen *Advantages and limitations

Streptokinase 1.5 million units over 30 to 60 minutes

Generally much less costly but outcomes inferior. Used extensively in many countries due to lower cost

Alteplase

(accelerated) 15 mg bolus then 0.75 mg/kg (maximum 50 mg) over 30 minutes then 0.5 mg/kg (maximum 35 mg) over the next 60 minutes

Better outcomes than streptokinase (SK) in GUSTO-1 (30 day mortality 6.3 versus 7.3 percent); more expensive than SK; more difficult to administer because of short half-life

Tenecteplase Single bolus over five to ten seconds based upon body weight: <60 kg = 30 mg60 to 69 kg = 35 mg70 to 79 kg = 40 mg80 to 89 kg = 45 mg≥90 kg = 50 mg

As effective as alteplase in ASSENT-2 with less noncerebral bleeding and need for transfusion; easier to administer (single bolus due to longer half-life) both in and out of hospital; these advantages make tenecteplase the drug of choice in many hospitals in the United States

Reteplase 10 U over two minutes then repeat

10 U bolus at 30 minutes Similar outcomes as alteplase but

easier to administer * All patients are also given aspirin and, with alteplase, reteplase, and tenecteplase, unfractionated heparin as a 60 U/kg bolus (maximum 4000 U) followed by an intravenous infusion of 12 U/kg per hour (maximum 1000 U/hour). Heparin has not been definitively shown to improve outcomes with non-fibrin-specific agents such as streptokinase. However, heparin is recommended with streptokinase in patients who are at high risk for systemic thromboembolism (large or anterior myocardial infarction, atrial fibrillation, previous embolus, or known left ventricular thrombus).

Prophylaxis: LMWH (40 mg/12 hrs) Direct thrombin inhibitors

Treatment of DVT & pulmonary embolism UFH infusion → a PTT 2 times Enoxaprin → 1 mg/kg/12 hrs Thrombolytic therapy:

Massive ilia-femoral DVT with gangrene Haemodynamic unstability Severe hypoxia Large perfusion defects RV failure Patent formamen ovale RA or RV thrombus

T-PA:

100 mg IV over 2 hrs

SK:

250.000 IV over 30 min

100.000/hour → 24-72 hrs

Urokinase:

4400 U/kg IV over 10 min

2200 U/kg → 12 hrs

Non embolic

Aspirin (50-100 mg) + clopidogrel 75 mg

Or aspirin + dipyridamole

AF or embolic stroke:

Low risk → Aspirin

Intermediate or high risk → anticoagulants

(Marivan, Dabigatran)

ASP < ASP + colopidogrel < anticoagulants

AF

Antiphospholipid

Prosethetic valve

Severe CHF

DVT & PE

Eisenmengar syndrome

1. UFH → through the pregnancy (aPTT twice control)

2. LMWH → through the pregnancy (according to the

weight)

3. First trimester → UFH

Second trimester → Marivan

Third trimester → UFH

1. 4. Resume anticoagulant: Vaginal delivery → immediately CS → 12 hrs

Health & Medicine

Antithrombotic drugs