Al-Esraa University College

Pharmacy Department

Therapeutics I
Lec 2
Thrombosis
Dr.Mohammed Ali Alobaidy
F.I.C.M.S – Clinical Pharmacy

Venous Thromboembolism
• Venous thromboembolism (VTE) is the development of a ‘thrombus’, principally containing fibrin
and red blood cells, in the venous circulation. Which is most often called a deep vein thrombosis
(DVT).
• If part of a thrombus in the venous circulation breaks off, it may become lodged in the pulmonary
arterial circulation, causing pulmonary embolism (PE).

• In VTE, the structure of the thrombus is different from that in arterial thromboembolism (
ATE ).
- In the VTE a mesh of fibrin and red blood cell is the main structure with few platelets (RED
THROMBUS)
- Whereas in ATE platelets are the main components of this thrombi (WHITE THROMBUS)
• VTE occurs primarily due to a combination of stagnation of blood flow and
hypercoagulability.
• Vascular injury is also a recognized causative factor but is not necessary for the
development of venous thrombosis.
• Sluggishness of blood flow may be related to:
1. bed rest,
2. surgery or
3. reduced cardiac output, for example, in heart failure.

• Factors increasing the risk of hypercoagulability include:

1. Surgery,
2. Pregnancy,
3. Estrogen administration,
4. Malignancy,
5. Myocardial infarction and
6. Several acquired or inherited disorders of coagulation, as follow:
1- Inherted disorders
• Protein C deficiency: Protein C deficiency is inherited through
autosomal dominant transmission.

• Such patients are at increased risk not only for VTE but also for
warfarin induced skin necrosis, which occurs because protein C is a
vitamin K dependent antithrombotic factor that can be further
suppressed by the administration of warfarin.

• Thrombosis in the small vessels of the skin may occur if large loading
(induction) doses of warfarin are given to such patients when the
suppression of the antithrombotic effects of these factors occurs before
the antithrombotic effects warfarin (3-5 days after starting therapy)

• Protein S deficiency: Protein S deficiency is probably even rarer than

protein C deficiency

• Factor V Leiden: The presence of factor V Leiden, which means that a

point mutation occurred in factor V gene that causes the activated factor V
molecule to be resistant to deactivation by activated protein C
• it may in itself be of little consequence until there is another risk factor,
such as immobility or use of the contraceptive pill.

• Antithrombin III deficiency: Antithrombin III deficiency is a rare

autosomal dominant inherited abnormality associated with a reduced plasma
concentration of this protein.
• The defect may not result in clinical problems until pregnancy or until
patients enter their fourth decade, when venous and, to a lesser extent,
arterial thrombosis becomes more common.
 • Lupus anticoagulant: Lupus anticoagulant, an antibody against
phospholipid in cell membrane which is a prothrombotic immunoglobulin.
Patients affected are more prone to thromboembolism. It is also found in the
Primary antiphospholipid syndrome (PAPS), where it may signify an
increased risk of venous and arterial thrombosis and for recurrent
miscarriage.
• Rx of PAPS?

• 2- Estrogens:
• increase the circulating concentrations of clotting factors I, II, VII, VIII, IX
and X and reduce fibrinolytic activity. They also depress the concentrations
of antithrombin III, which is protective against thrombosis.
• This effect is dose related, and venous thrombosis was more often seen with
contraceptive pills containing high (50 micrograms) estrogen than with the
present lower dose preparations.
• Hormone replacement therapy, pregnancy and the puerperium (up to 6
weeks after delivery) are also recognized risk factors for VTE.

3- Malignancy:
• VTE is more common in malignancy, and the risk may be up to five folds greater than in those without
malignancy. All solid tumors are associated with VTE. The absolute risk seems to be related to the type
of tumor and its stage and treatment with chemotherapy. The exact mechanisms responsible for the
increased risk of VTE in malignancy are not known

4- Surgery
• it is related, in part,
1- to stagnation of venous blood in the calves during the operation and recovery.
2- Tissue trauma may also play a role because VTE appears to be more common in operations that
involve marked tissue damage, such as orthopedic surgery.

• The most important risk factors associated with VTE after surgery are:
1. duration of anesthesia and procedure of more than 90 minutes (or 60 minutes if surgery involves lower
limbs or pelvis),
2. acute surgical admission with an inflammatory or intra abdominal condition and expected significant
reduction in mobility.
3. Other patient related risk factors for VTE include age older than 60 years, dehydration, known
thrombophilias, obesity (body mass index >30 kg/m2), one or more significant comorbidities, personal
history or first degree relative with previous VTE, use of hormone replacement therapy or estrogen
containing contraceptives and varicose veins with associated phlebitis. These will add to the risk, if
present, but are also independent risk factors.
Clinical Manifestations
• Deep Venous Thrombosis (DVT) occurs in the veins of the lower
limbs and pelvis.
• In some patients, there may not be any local symptoms or signs, and
the onset of pulmonary embolism (PE) may be the first evidence of
the presence of VTE.
• In other cases, patients classically present with pain involving the calf
or thigh, associated with swelling, redness of the overlying skin and
increased warmth.
• In a large DVT that prevents venous return, the leg may become
discolored and edematous.
• Massive venous thrombus can occasionally result in gangrene,
although this occurs very rarely now that effective drug therapies are
available.
 Pulmonary Embolism
• Obstruction of a major pulmonary artery presenting with shortness of
breath and chest pain, together with marked hemodynamic
disturbance: severe hypotension and right ventricular failure. It may
also result in , hemoptysis (coughing up blood).

Investigations
Deep vein thrombosis
1- Ultrasound
• It is now the initial investigation of choice in clinically suspected DVT.
2- Venography
3- Magnetic resonance imaging (MRI)
• Magnetic resonance imaging (MRI) is also non invasive and avoids radiation
exposure.

• Pulmonary Embolism
1- CT Pulmonary angiography: is a minimally invasive and most specific test in the
diagnosis of PE. It involves the intravenous administration of iodine containing
contrast media to allow radiographic imaging to detect whether blood is flowing to all
parts of the lungs or whether a PE is causing blockage in the pulmonary arterial
vasculature.

2- Ventilation perfusion scanning

Treatment
Heparin (UFH):
• prevents the conversion of prothrombin to thrombin.
• Heparin also inhibits the production of activated clotting factors IX, X, XI
and XII.
LMWH: (Enoxaparin, Tinzaparin, Daltiparin)
• inactivate only factor Xa.

• They are not absorbed via the gastrointestinal tract and must be given by
intravenous infusion or deep subcutaneous (never intramuscular) injection.
• It does not cross the placenta and does not appear in breast milk.
• It is metabolized by the liver, and excreted renally.

• LMWHs vs Heparin: LMWH have advantages over UFH:

1- Have longer duration of action and.
2- They can be given once or, twice daily in a fixed dose.
3- More predictable dose response than UFH so it doesn’t need laboratory
monitoring, except for patients with high risk of bleeding.
4- LMWHs may produce fewer hemorrhagic complications

• The major adverse effect of all heparins is hemorrhage, which is more common in
patients with severe heart or liver disease, renal disease, and in older than 60
years.

• The risk of hemorrhage is increased in those given UFH by intermittent

intravenous bolus rather than by continuous intravenous administration.
• UFH is monitored by the activated partial thromboplastin time (APTT) The
therapeutic range for the APTT during UFH therapy must be between 1.5 and 2.5
times the normal values.
• Rapid reversal of the effect of UFH can be achieved using protamine
sulphate (ANTIDOT)
• Protamine sulfate can inhibit the prolongation in clotting time
induced by LWMHs, but does not fully inhibit their anti factor Xa
activity.

• Heparins, particularly UFH, may also cause thrombocytopenia (low

platelet count) For this reasons, patients should have a platelet count
on the day of starting UFH, and alternate day platelet counts should be
performed till day14..
• This may occur in two forms:

Heparin induced thrombocytopenia& Heparin associated thrombocytopenia

thrombosis (HITT) (HAT)

occurs after about 6 days of treatment occurs 3 5 days after treatment

sever mild

Platelets count fall 50% or more Less than 50% fall in platelets count

Heparin should be stopped immediately Heparin can be continued

Not associated with thrombosis

Associated with thrombosis

Immune response to heparin Non immune response

• if HIT is strongly suspected or confirmed, heparin should be stopped
and an alternative agent such as a heparinoid or hirudin commenced.

• Heparin induced osteoporosis is rare but may occur when the drug is
used during pregnancy and may be dose related. Other adverse effects
of heparin are alopecia, urticaria and anaphylaxis, but these are also
rare.

• LMWH, UFH or fondaparinux should be administered with warfarin

for at least 5 days or until the international normalized ratio (INR) has
been in the therapeutic range for 2 successive days, whichever is the
longer.

• Heparinoids: Danaparoid is a heparinoid that acts by inhibiting factor Xa and, like LMWHs, is
given by subcutaneous injection or IV.
that is licensed for:
• prophylaxis of DVT in patients undergoing general or orthopedic surgery.
• treatment of individuals who develop HIT but still need ongoing anticoagulation.
• It should be avoided in severe renal insufficiency and severe hepatic insufficiency.

• Hirudins: Direct thrombin inhibitors

• Lepirudin
• is licensed for anticoagulation in patients with HIT who require parenteral anti thrombotic
treatment.
• The dose of lepirudin is adjusted according to the APTT, and it is given intravenously by infusion.
• Avoided in those with poor renal function.

• Bivalirudin
• It is licensed for anticoagulation in patients undergoing percutaneous coronary intervention (PCI).
• It has to be administered parenterally.
• Hemorrhage is also an important adverse effect of this agent.
• Fondaparinux: Factor Xa Inhibitor
• Fondaparinux inhibits factor Xa but without effect on factor IIa.
Therefore, At doses normally used for treatment, it does not
significantly affect coagulation tests, and routine monitoring of these
is not necessary.
• It has to be given parenterally (subcutaneous).
It is used for :
- prophylaxis of VTE in high risk situations
- treatment of acute DVT acute PE
- treatment of unstable angina or non ST segment elevation myocardial
infarction (NSTEMI) and for the treatment of ST segment elevation
myocardial infarction (STEMI).
- Hemorrhage is the most important adverse effect

Oral anticoagulants
Warfarin (Vitamin K antagonist)
• Although it is not the only coumarin anticoagulant available, warfarin
is by far the most widely used drug in this group because of its
potency, duration of action and more reliable bioavailability.
• Warfarin prevents the reduction of vitamin K epoxide to vitamin K by
epoxide reductase.
• Warfarin is metabolized by the liver via the cytochrome P450 system.
• The effect of warfarin is monitored using the prothrombin time, and
INR.
The optimum therapeutic range for the INR differs
depending on the clinical indication.

Warfarin
interactions
• The major adverse effect of warfarin is hemorrhage, which often occurs at the
site of a predisposing abnormality, such as an ulcer or a tumor.
• The risk of bleeding is increased by excessive anticoagulation, although this may
not need to be present for severe hemorrhage to occur.

• To reduce the risk of hemorrhage

- Close monitoring of the degree of anticoagulation of warfarin is important.
- It is also important to reduce the duration of therapy of the drug to the minimum
effective period to reduce the period of risk.

• warfarin induced skin necrosis, which may occur over areas of adipose tissue
such as the breasts, buttocks or thighs, especially in women, and is related to
relative deficiency of protein C or S. this mainly occure if warfarin was started
with loading dose (10 mg)

• Warfarin is teratogenic
Duration of treatment
• On the basis of the available evidence, therapy may be required for
approximately 6 months after the first DVT or PE.

• It may be possible to reduce the duration of therapy in patients who have

had a postoperative episode because it is likely that the risk factor has been
reversed (unless immobility continues).

• In patients with a second episode, therapy may be required for even longer
How long?

• In patients with more than two episodes, lifelong treatment may be

necessary to reduce the risk of recurrence.

• Direct acting oral anticoagulants DOACs:

• (e.g. apixaban, dabigatran, edoxaban and rivaroxaban) are highly effective
agents, but like all anticoagulants, they can cause potentially life threatening
bleeding in some patients. They are contraindicated in valvular diseases

• The DOACs have been shown in clinical trials to be generally safe for use
without routine anticoagulant monitoring.
• The absence of such monitoring may be a disadvantage in some cases, as it
is not possible to identify signs of sub therapeutic or supra therapeutic
plasma levels until a thromboembolism or hemorrhage occurs.
• When considering the use of a DOAC, it is advised that the Cockcroft Gault
formula is used to calculate an accurate creatinine clearance before
initiation.
• Dose reductions are advised with DOACs at different levels of renal
impairment, and they are also contraindicated at different levels of
impairment.
• Hemorrhage is the major adverse effect of the DOACs.
• Idarucizumab, a monoclonal antibody fragment, is licensed for
reversal of the anticoagulant effect of dabigatran. It binds to both free
and thrombin bound dabigatran, reversing the anticoagulant effect
within minutes.
• Andexanet alfa, which is a recombinant modified human factor Xa,
has been shown to reverse the anticoagulant effects of apixaban and
rivaroxaban.

• Dabigatran: is an oral direct thrombin

inhibitor that has a rapid onset of action.
• It is a prodrug which is hydrolyzed to
active dabigatran in the liver.
• Because 80% of activated dabigatran is
excreted unchanged through the
kidneys:
1- it should be avoided in patients with
severe renal impairment (creatinine
clearance <30 mL/min),
2- dose should be reduced in moderate
renal impairment (creatinine clearance 30
50 mL/min).
• Rivaroxaban: is an oral factor Xa inhibitor. Two thirds of the dose is
metabolized, principally by CYP450 enzymes, and the remaining third is
excreted unchanged in the urine.
• It should also be used with caution in patients with creatinine clearance less
than 30 mL/min (severe renal impairment)
• And is contraindicated in those with creatinine clearance less than 15
mL/min.

• Some CYP3A4 inhibitors significantly increase rivaroxaban serum

concentration, particularly ketoconazole and other azoles also HIV protease
inhibitors such as ritonavir. Therefore, The use of rivaroxaban is not
recommended in patients receiving concomitant systemic treatment with
these agents.
• The CYP3A4 inducer rifampicin (and possibly other inducers of this
cytochrome) reduces rivaroxaban concentration.
• Apixaban: is an oral factor Xa inhibitor , Around 30% of the dose is
excreted unchanged in urine.
✓ It is not recommended if the creatinine clearance is less than 15
mL/min.
✓ The dose should be reduced if the eGFR is between 15 and 30, or if
serum creatinine ≥133 mmol/L and the patient’s age is ≥80 years or the
patient’s body weight is ≤60 kg.

• Edoxaban: is an oral factor Xa inhibitor.

• The manufacturer advises a reduction in edoxaban dose in moderate to
severe renal impairment and to avoid using the medicine in end stage
renal disease or in dialysis.

• All DOAC are substrates of p GP, and co administration of potent

inhibitors like ciclosporin, erythromycin, ketoconazole, quinidine
or verapamil increases thier exposure, necessitating a
recommended reduction in dose.
• p-GP: a transporter protein that if inhibited, will increase the level of
free drug
WHAT IS CHADS2VASc score???
When would you use it?

Fibrinolytic drugs:

• Thrombolytic therapy is used in life threatening acute massive PE.

• It has been used in DVT, particularly in those patients where a large
amount of clot exists and venous valvular damage is likely.
• However, fibrinolytic drugs are potentially more dangerous than
anticoagulant drugs.

• Thrombolytic therapy absolute and relative contraindications?

Arterial thromboembolism

• Acute myocardial infarction is the commonest clinical presentation of

acute arterial thrombosis. Stroke is commonly caused by athero-
thromboembolism from the great vessels or embolism arising from the
heart (approximately 80% of strokes).
• Peripheral arterial thrombosis or thromboembolism may also occur,
most often in the lower limb.
• Antiplatelet drugs are often used for prophylaxis, but surgical
embolectomy and/or fibrinolytic therapy may be needed for treatment
of acute thrombotic events to avoid consequent ischemic damage.

Etiology
• Arterial thromboembolism is normally associated with vascular injury and
hypercoagulability.
1- Vascular injury is most often due to atheroma which is aggravated by
smoking, hypertension, hyperlipidemia or diabetes mellitus.

2- Hypercoagulability may be associated with increased plasma fibrinogen

levels and an increase in circulating cellular components, for example,
polycythemia or thrombocythemia.

• Thrombus formed in the artery contains larger proportion of platelets.

• Estrogens are likely to increase the risk of arterial and venous thrombosis.
• Hyperlipidemia may also increase the risk of hypercoagulability, as well as
enhance thrombotic risk through its role in the progression of atheroma and
vascular injury.
Treatment and prevention
• Aspirin cyclo-oxygenase inhibitor ---› inhibit TXA2 ---› inhibit platelet
aggregation
• The major adverse effect of aspirin is gastro intestinal irritation and bleeding.

• This problem is much more common with higher doses of aspirin (300 mg or
more) that were once used in the prevention of arterial thromboembolism but
are less common with the doses (e.g. 75 mg) now used.
• Concomitant use of ulcer healing drugs, particularly proton pump inhibitors,
can reduce the risk of peptic ulceration.

• There is also little evidence that buffered or enteric coated preparations of aspirin
are safer in this respect. However, the vast majority of patients tolerate low dose
aspirin well, and it is normally given as a single oral dose of aspirin.
• Aspirin may also, rarely, induce asthma, particularly in patients with co
existing reversible airway obstruction.
• Other patients have a form of aspirin hypersensitivity that may result in
urticaria and/or angioedema. In this situation, there may be cross reactivity
with other NSAIDs.
• Hemorrhagic stroke is a rare but very serious complication of therapy with
aspirin (and with other antiplatelet agents).

• Aspirin must not be given to children or people younger than 16 years

because of the risk of the rare but life threatening possibility of Reye’s
syndrome, which may cause liver and renal failure.

• Aspirin is an established treatment for the secondary prevention of

cardiovascular events.

Clopidogrel ADP (P2Y12) antagonist

• is a prodrug
• It is given once daily for the reduction of atherosclerotic events in those with pre existing
atherosclerotic disease.
• In this respect, it may be a useful alternative to aspirin in aspirin allergic subjects, but
hemorrhage occurs with the same frequency as aspirin, and thrombocytopenia
(sometimes severe) may be more with clopidogrel than with aspirin therapy.

• Activation to its active metabolite may be subject to a genetic polymorphism of CYP450

2C19 and may also be reduced by the proton pump inhibitor omeprazole or esomeprazole,
so the use of alternative gastroprotective agents may need to be considered if required.

Clopidogrel is licensed for

- the prevention of atherothrombotic events (myocardial infarction, ischemic stroke,
established peripheral arterial disease, and acute coronary syndrome in combination with
aspirin) and
- the prevention of atherothrombotic and thromboembolic events in atrial fibrillation.
Prasugrel: ADP (P2Y12) antagonist
• inhibits platelet activation and aggregation. It is a prodrug whose active
metabolite irreversibly binds to P2Y12 class of ADP receptors on platelets.
• In combination with aspirin, it is recommended by NICE as an option for
preventing atherothrombotic events in adults with acute coronary syndrome
(unstable angina [UA], NSTEMI or STEMI) undergoing primary or delayed
PCI.

• Ticagrelor:
• like prasugrel and clopidogrel, ticagrelor blocks ADP receptors of subtype
P2Y12. However, unlike the other antiplatelet drugs, it has a binding site
different from ADP (it is an allosteric antagonist), and the blockade is
therefore reversible.
• It is an active drug and does not require activation by metabolism.

• Ticagrelor in combination with low dose aspirin is recommended for up to

12 months as a treatment option in adults with acute coronary syndromes.

• Dipyridamole: Phosphodiesterase inhibitor ---› ↑ CAMP ---› inhibit

platelet aggregation.
• is prescribed as an adjunct to oral anticoagulation for prophylaxis of
thromboembolism associated with prosthetic heart valves.
• Dipyridamole modified release preparations 200 mg twice a day may
be used in combination with aspirin 75 mg daily for long term vascular
prevention in people with ischemic stroke or TIA, if clopidogrel 75 mg
daily cannot be used.
• If clopidogrel and aspirin cannot be tolerated or are contraindicated,
then modified release dipyridamole 200 mg twice a day would be used
by itself.
• Adverse effects include headache (to which tolerance may gradually
develop) gastro intestinal problems, flushing and hypotension
• Glycoprotein IIb/IIIa inhibitors:
• prevent platelet aggregation by blocking the binding of fibrinogen to
receptors on platelets.
Abciximab (Repro vial)
is a monoclonal antibody which binds to coronary glycoprotein IIb/IIIa
receptors and to other related sites.
• It is recommended as an adjunct to heparin and aspirin for the prevention of
ischemia complications in patients undergoing PCI.
• Abciximab should be used once only to avoid further risk of
thrombocytopenia.
Eptifibatide and tirofiban
• they also inhibit glycoprotein IIb/IIIa receptors;
• they are licensed for use with heparin and aspirin to prevent acute MI in
patients with unstable angina or NSTEMI.
• Abciximab, eptifibatide and tirofiban all have to be administered
parenterally and should be used by specialist clinicians only

Q&A