This document provides information about anti-thrombotic drugs and their use in treating thromboembolic disease. It discusses the pathophysiology of hemostasis and covers various classes of anti-thrombotic drugs including antiplatelet drugs like aspirin, anticoagulants like unfractionated heparin and warfarin, and direct thrombin inhibitors. It provides details on the mechanisms of action, pharmacokinetics, indications for use, and side effects of these commonly used anti-thrombotic medications. Diagrams are included to illustrate platelet function and the mechanisms of different antiplatelet and anticoagulant drugs.

1. ‫الحرجة‬ ‫الرعاية‬ ‫لبطباء‬ ‫المصرية‬ ‫الكلية‬
Training Course in Critical Care Medicine

2. Asst. Professor of Critical Care Medicine
Critical Care Department

3.  Pathophysiology of Haemostasis
 Anti-thrombotic Drugs
 Treatment of Thromboembolic Disease

6. 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.

8.  AT III
 Protein C & S system
 Tissue factor pathway inhibitor
(TFPI)

9.  Source: Synthesized by the liver
Lysyl
Residue
Arginine
ResidueSerine
active
center
ATIII
Thrombin
Heparin
 Action: It inhibits FIXa, Xa, XIa, XIIIa &
thrombin

10. Source Vit K dependent protein synthesized by liver.
Function Protein C is activated by thrombin
thrombomodulin Cx.
Activated Protein C Inactivates coagulation
Stimulates fibrinolysis
Anti inflammatory

11. Protein C
Thrombin
Thrombomodulin
Complex
Stimulates
fibrinolysis
Anti inflammatory action
Inactivates
coagulation
Activated Protein C
PAI- Factor V (Va)
- Factor VIII (VIIIa)
Free protein s
++

13.  Pathophysiology of Haemostasis
 Anti-thrombotic Drugs
 Treatment of Thromboembolic Disease

14. Fibrinolytics

15. Fibrinolytics

16. Fibrinolytics

17. Fibrinolytics

22. Antiplatelet drugs
Acetylsalicylic
acid (aspirin)
P2Y12
antagonists
Dipyridamole GPIIb/IIIa
antagonists
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)

23. 1. Aspirin
2. Phosphdiestrase inhibitor: dipyridamole
3. Thienopyridines:
 Ticlopidine
 Clopidogrel
 Prasugrel
 Ticagrelor
4. GP IIa/IIIb receptor antagonists
 Abiciximab
 Tirofeban
 Eptifibatide

24. 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.

25. Schematic representation of prostanoid synthetic pathways
and the enzymes that catalyze the specific reactions. PG:
prostaglandin; Tx: thromboxane.

27.  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)

28.  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.

29.  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.

31.  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

32. 1. Secondary prevention of ischemic
complications in ACS
2. Secondary prevention after MI, ischemic
stroke & peripheral vascular disease.
3. After PCI
4. Aspirin resitence

33. 1. Bleeding
2. Resistance: clopidogral
3. Neutroponia: Ticlopcdin
4. Irreversible platelets inhibition
5. Thrombothytopenic purpura

35.  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.

36.  Secondary prevention of ischaemic
complications after transient ischaemic
attack (TIA) or ischaemic stroke (in
combination with aspirin).

37.  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.

39.  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.

40.  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.

41.  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

42.  Renal insufficiency
 Elderly patients
 Women

43. Vitamin K
antagonists
 Warfarin
 Coumarin
 Unfractionated
heparin (UFH)
 Low molecular
weight heparin
(LMWH)
 Synthetic
pentasaccharides
(fondaparinux,
idraparinux)
Heparins
Direct thrombin
inhibitors
 Hirudin
 Recombinant
- Hirudin
- Bivalirudin
 Synthetic
- Argatroban
- Melagatran
- Dabigatran
- AZD0837

58. HeparinPentasaccharide
Thrombin
AT
Prothrombin Thrombin
Antithrombin
Tenase complexTenase complex
FIXa
FVIIIa
FXa
FX
Prothrombinase complex
FXa
FVa
The antithrombin/heparin complex
is a poor inhibitor of fibrin-bound
thrombin

59. FXa
Pentasaccharide
LMWH
AT
The antithrombin/LMWH complex
is a poor inhibitor of fibrin-bound
thrombin
Prothrombin Thrombin
Antithrombin
Tenase complex
FIXa
FVIIIa
FXa
FX
Prothrombinase complex
FXa
FVa

60. FXa
AT
Prothrombin Thrombin
Antithrombin
Tenase complex
FIXa
FVIIIa
FXa
FX
Prothrombinase complex
FXa
FVa
FXa
FVa
The antithrombin/LMWH complex
is a poor inhibitor of fibrin-bound
thrombin

61.  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

62. 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).

63.  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.

64. Initial dose 80 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

65.  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 µ heparin)

66.  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).

67.  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.

68.  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

69.  Enoxaprin (clexan) → 1 mg/kg twice daily
 Nadroparin (Fraxiparin) → 5700 IU/day
 Tinzparin(Innohep) → 175 µg/kg/day
 Fondaprinax (Arixtra) 2.5 mg/day
 Dalteparin (Fragmin)→ (100 µ/kg/12 hrs)

70. 1. Elderly patient < 45 kg
2. Obese patients
3. Renal failure

71. 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).

72. Prevention of venous thromboembolism
(VTE) after major orthopaedic surgery
such as hip and knee replacement or hip
fracture repair.

73. 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.

74. 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 Fixed
alternatives
Adjusted by Weight- Adjusted in severe
monitoring adjusted renal impairment

75.  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 γ-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).

76.  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.

77. 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.

78. 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

79. 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.

80. Initial Dose:
2-5 mg/day: Hepatic impairments
debilitation, CHF, elderly, CRF, high risk of
bleeding
5-10 mg/day,
Maintence Dose:
(2-10 mg/day)
INR: 2-3.

81. Old age> 70 years
Female Sex
Malignancy
CRF
Prior stroke
Drugs: Aspirin, NSAID,
Antibiotics, Amiodarone,
Statin, Fibrate
DM
Severe HTN
Liver disease
Anaemia
GFT bleeding

82.  Bleeding
 Cholesterol embolization (blue toes syndrome)
 Skin Necrosis
 Teratogenic
 Vascular calcification
 Allergy

83. 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.

84. 1. Not deactivated by PF4 like heparin
2. No need for AT III
3. Good bioavailability
4. No HIT
5. No platelet activation

85. • Hirudin (Salivary gland
of a leach)
• Lepiruolin (Recominant
Hirudin)
• Argatroban
• Bivalirudin
• Ximelagatran
• Dabigatran
(110, 150 mg)
IV Oral

86. STREPOKINASE
 Product of β-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
selectivity
tPA
 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 >

87. 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)

88. Risk of serious bleeding is low particularly in the absence of
heparin (<1% risk in major trials).
It arises from:
1. Lysis of ‘physiological’ clots
2. 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

89. 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

90. 1.Anaphylaxis (0.5%) & allergic
reaction due to anti-SK antibodies
2.Hypotension
3.Bleeding (Minor)

91.  Pathophysiology of Haemostasis
 Anti-thrombotic Drugs
 Treatment of Thromboembolic Disease

92.  Acute Non ST-MI
 Acute ST-MI
 DVT & PE
 Secondary prevention of stroke
 Pregnancy

93. 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.

94. Preferred thrombolytic regimens for acute ST elevation myocardial infarction
Drug Recommended 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).

95.  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

96.  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

97.  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

98.  AF
 Antiphospholipid
 Prosethetic valve
 Severe CHF
 DVT & PE
 Eisenmengar syndrome

99. 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