Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), with significant morbidity and mortality in the U.S. An estimated 2 million people develop VTE each year, driven by risk factors like venous stasis, endothelial injury, and hypercoagulable states. Treatment aims to restore circulation and prevent complications using anticoagulants and monitoring for adverse effects.

1. VENOUS
THROMBOEMBOLISM
(VTE)
T.SOUJANYA
PHARM.D

2. CONTENTS:
• Definition of venous thromboembolism (DVT & PE)
• Epidemiology
• Etiology & risk factors
• Pathophysiology
• Clinical presentation of deep vein thrombosis (DVT)
• Clinical presentation of pulmonary embolism (PE)
• Treatment of VTE
• Patient care
• Reference/bibliography

3. DEFINITION:
Venous thromboembolism (VTE) is a condition in which a blood
clot (thrombus) forms in the vein, which in some cases then breaks free
and enters the circulation as an embolus, finally lodging in and
completely obstructing a blood vessel.
e.g. in lungs causing pulmonary embolism (PE).
Venous thromboembolism (VTE) includes:
1. Deep vein thrombosis (DVT)
2. Pulmonary embolism (PE)

4. CONTD…
1. DEEP VEIN THROMBOSIS (DVT):
The most common type of venous thromboembolism is deep vein
thrombosis, which occurs in veins deep within the muscle. It is the
formation of a blood clot in one of the deep veins in the body, usually in
the leg.
2. PULMONARY EMBOLISM (PE):
It is a serious & potentially life-threatening condition. It usually
happens due to an underlying blood clot in the leg (DVT). The embolus
may cause blockage in a blood vessel in the lungs. A massive pulmonary
embolism can cause collapse and death.

5. EPIDEMIOLOGY:
The true incidence of VTE in the general population is unknown
because a substantial portion of patients, perhaps greater than 50%, have
clinically silent disease. An estimated 2 million people in the United
States develop VTE each year; 600,000 are hospitalized, and 60,000 die.

6. ETIOLOGY & RISK FACTORS:
More than 100 years ago, Rudolf Virchow described a triad of
factors that are thought to contribute to thrombosis.
a) Venous stasis
b) Endothelial injury
c) Hypercoagulable state

7. CONTD..
a) VENOUS STASIS:
It may be due to:
Prolonged bed rest (4 days or more)
A cast on the leg
Limb paralysis from stroke or spinal cord injury
Extended travel in a vehicle

8. CONTD…
b) ENDOTHELIAL INJURY:
It may be due to:
Trauma, surgery
Invasive procedure may disrupt venous integrity
Iatrogenic causes of venous thrombosis are increasing due to the
widespread use of central venous catheters, particularly subclavian and
internal jugular lines. These lines are an important cause of upper
extremity, particularly in children.

9. CONTD…
c) HYPERCOAGULABLE STATE:
Surgery and trauma (40% of all thromboembolic disease)
Malignancy
Increased oestrogen
Inherited disorders of coagulation: deficiency of protein-S, protein-C,
anti-thrombin III.
Acquired disorders of coagulation: nephrotic syndrome, anti-
phospholipid antibodies.
Age, obesity and drug therapy are the other factors that cause venous
thromboembolism.

10. PATHOPHYSIOLOGY:
Vascular injury can expose the sub endothelium. Platelets readily
adhere to the sub endothelium, using glycoprotein Ib receptors found on
their surfaces and facilitated by von Willebrand factor. This causes
platelets to become activated, releasing a number of procoagulant
substances into the local circulation that stimulate platelets to expose
glycoprotein IIb-IIIa receptors.

11. These receptors allow the
platelets to adhere to one another,
resulting in platelet aggregation. In
addition, the damaged vascular
tissue releases tissue factor, also
known as tissue thromboplastin,
which activates the extrinsic
pathway of the coagulation cascade.
Fibroblasts eventually invade
the thrombus, scarring vein wall and
destroying valves. Patency may be
restored, valve damage is
permanent, affecting directional
flow.

12. Venous trauma
Stimulates the clotting cascade
Activate platelets
Stimulates platelets to expose glycoprotein IIb-IIIa receptors
Platelets aggregate at the site when venous stasis present
Platelets and fibrin from the initial clot
RBCs are trapped in the fibrin meshwork
Thrombus propagates in the direction of blood flow
Inflammation triggers
(causes tenderness, swelling & erythema)
Thrombus break and travel through circulation
(emboli)

13. CLINICAL PRESENTATION OF DVT:
General:
Venous thromboembolism most commonly develops in patients
with identifiable risk factors during or following a hospitalization. Many
patients, perhaps the majority, have asymptomatic disease. Patients may
die suddenly of pulmonary embolism.
Symptoms:
The patient may complain of leg swelling, pain, or warmth.
Symptoms are nonspecific, and objective testing must be performed to
establish the diagnosis.

14. CONTD…
Signs:
i) The patient’s superficial veins may be dilated, and a “palpable cord”
may be felt in the affected leg.
ii) The patient may experience pain in back of the knee when the
examiner dorsiflexes the foot of the affected leg.
Laboratory Tests:
i) Serum concentrations of D-dimer, a by-product of thrombin
generation, usually are elevated.
ii) The patient may have an elevated erythrocyte sedimentation rate
(ESR) and white blood cell (WBC) count.

15. CONTD…
Diagnostic Tests:
i) Duplex ultrasonography is the most commonly used test to
diagnosis DVT. It is a non-invasive test that can measure the rate
and direction of blood flow and visualize clot formation in proximal
veins of the legs. It cannot reliably detect small blood clots in distal
veins. Coupled with a careful clinical assessment, it can rule in or
out the diagnosis in the majority of cases.
ii) Venography (also known as phlebography) is the “gold standard”
for the diagnosis of DVT. However, it is an invasive test that
involves injection of radiopaque contrast dye into a foot vein. It is
expensive and can cause anaphylaxis and nephrotoxicity.

16. CLINICAL PRESENTATION OF PE:
General:
Pulmonary embolism most commonly develops in patients with risk
factors for VTE during or following a hospitalization. While many patients
develop a symptomatic DVT prior to developing a PE, many do not. Patients
may die suddenly before effective treatment can be initiated.
Symptoms:
i) The patient may complain of cough, chest pain, chest tightness, shortness
of breath, or palpitation.
ii) The patient may spit or cough up blood (haemoptysis).
iii) When PE is massive, the patient may complain of dizziness or light-
headedness.
iv) Symptoms may be confused with a myocardial infarction or pneumonia,
and objective testing must be performed to establish the diagnosis.

17. CONTD…
Signs:
i) The patient may have tachypnoea (increased respiratory rate) and
tachycardia (increased heart rate).
ii) The patient may appear diaphoretic (sweaty).
iii) The patient’s neck veins may be distended.
iv) In massive PE, the patient may appear cyanotic and may become
hypotensive. In such cases, oxygen saturation by pulse oximetry or
arterial blood gas likely will indicate that the patient is hypoxic. In the
worst case, the patient may go into circulatory shock and die within
minutes.
Laboratory Tests:
i) Serum concentrations of D-dimer, a by-product of thrombin generation,
usually are elevated.
ii) The patient may have an elevated erythrocyte sedimentation rate (ESR)
and white blood cell (WBC) count.

18. CONTD…
Diagnostic Tests:
i) Ventilation-perfusion (V/Q) and computed tomographic (CT) scans
are the most commonly used tests to diagnosis PE. A V/Q scan
measures the distribution of blood and airflow in the lungs. When
there is a large mismatch between blood and airflow in one area of
the lung, there is a high probability that the patient has a PE. Spiral
CT scans can detect emboli in the pulmonary arteries.
ii) Pulmonary angiography is the “gold standard” for the diagnosis of
PE. However, it is an invasive test that involves injection of
radiopaque contrast dye into the pulmonary artery. The test is
expensive and associated with a significant risk of mortality.

19. TREATMENT OF VTE:
GOALS OF TREATMENT:
1. To allow normal circulation in limbs.
2. To prevent damage to the valves of veins thus reducing the risk of
swollen post-phlebitic limb.
3. To prevent associated PE & Recurrence of either PE or venous
thrombosis.
4. To provide medication without adverse effects.
5. To improve the quality of life.

20. CLASSIFICATION OF DRUGS:
a) Parenteral anticoagulants:
i. Indirect thrombin inhibitors:
• Heparin (UFH-unfractionated heparin)
• Low molecular weight heparins (LMWHs): enoxaparin, dalteparin,
tinzaparin, ardeparin, reviparin.
• Synthetic: fondaparinux
ii. Direct thrombin inhibitors: lepirudin, bivalirudin, argatroban.
b) Oral anticoagulants: Warfarin.
c) Thrombolytics: streptokinase, urokinase, alteplase, reteplase,
tenecteplase.

21. 1. UNFRACTIONATED HEPARINS:
MOA:
Heparin binds and accelerates the activity of plasma antithrombin III.
Heparin-antithrombin III complex then inhibits activated clotting factors by
forming stable complexes with them. At low concentration, heparin
selectively inhibits the conversion of prothrombin to thrombin and thus
prevents further thrombus formation.
ADRs:
They mainly include bleeding, heparin induced thrombocytopenia
(HIT), hypersensitivity reactions can occur rarely, osteoporosis, reversible
alopecia has been reported.
Dose:
Unfractionated heparin: 5000-10,000 U (children 50-100 U/kg) i.v.
bolus followed by 750-1000 U/hr i.v. infusion.

22. 2. LOW MOLECULAR WEIGHT HEPARINS:
MOA:
They are isolated from standard heparin by various techniques. They
produce anticoagulant effect mainly by inhibition of Xa through antithrombin. They
are given subcutaneously.
ADRs:
They mainly include bleeding (but less than with unfractionated heparin),
heparin induced thrombocytopenia (HIT), severe neurologic injury for patients
undergoing spinal puncture.
Dose:
• Enoxaparin: 20mg (0.2ml) and 40mg (0.4ml) prefilled syringes, 20-40mg OD,
S.C. (start 2 hours before surgery)
• Dalteparin: 2500 IU s.c. OD for prophylaxis; 100 U/Kg 12 hourly or 200 U/Kg 24
hourly s.c. for treatment of deep vein thrombosis.
• Reviparin: 13.8 mg (eq. to 1432 anti Xa IU) in 0.25 ml prefilled syringe; 0.25 ml
s.c. once daily for 5–10 days.

23. 3. FONDAPARINUX:
MOA:
It is a synthetic parenteral anticoagulant. It binds to antithrombin
and selectively inhibits factor Xa. It does not require routine laboratory
monitoring. It is administered subcutaneously.
ADRs:
They mainly include bleeding, no heparin induced
thrombocytopenia (HIT), local irritation i.e., injection site bleeding, rash
and pruritus, anaemia, nausea etc.
Dose:
• Fondaparinux: 5–10 mg s.c. once daily

24. 4. DIRECT THROMBIN INHIBITORS:
MOA:
They directly inhibit thrombin an is used as an anticoagulant in
patients with heparin induced thrombocytopenia (HIT) and prevents the
conversion of fibrinogen to fibrin. It is administered intravenously and
requires aPTT monitoring.
ADRs:
The common adverse reactions are bleeding, antibody production,
back pain, nausea, headache.
Dose:
• Lepirudin: 0.4mg/kg slow i.v. bolus followed by 0.15mg/kg/hr as a
continuous infusion for 2-10 days if clinically needed.
• Bivalirudin: 250mg i.v.
• Argatroban: 2µg/kg per minute (not to exceed 10 µg/kg per minute)

25. 5. ORALANTICOAGULANTS:
MOA:
They interfere with the synthesis of vitamin K dependent clotting
factors in liver. Clotting factors II, VII, IX and X are synthesized in liver
as inactive proteins. These factors are rich in glutamic acid residues and
are carboxylated in liver where vitamin K acts as a cofactor.
Vitamin K is converted to inactive epoxide from by oxidation and
is regenerated to its active form by epoxide reductase enzyme. Warfarin
is structurally similar to vitamin K, hence it competitively inhibits the
synthesis of vitamin K-dependent factors by inhibiting epoxide
reductase enzyme and thus produces anticoagulant effect.

26. Descarboxy factors
II, VII, IX and X
Factors II, VII, IX and X
(with carboxylated γ-glutamate residues)
Active vitamin K Vitamin K epoxide
hydroquinone (inactive)
vitamin K epoxide reductase
NAD warfarin NADH
ADRs:
Bleeding, skin necrosis, purple toe syndrome, teratogenicity, osteoporosis,
other effects include agranulocytosis, leukopenia, diarrhoea, nausea, anorexia etc.
Dose:
 Warfarin - 5mg daily, maintenance dose: 2-10mg for 2 days.

27. 6. THROMBOLYTICS:
MOA:
They promote the conversion of plasminogen to plasmin. Plasmin
degrades fibrin into fibrin degradation products and thus rapidly
dissolve the blood clot.
Plasminogen
t-PA Thrombolytics
Plasmin
Fibrin fibrin degradation products
+

28. CONTD…
ADRs:
Bleeding due to activation of circulating plasminogen, other
effects include nausea, vomiting, hypotension, anaphylactic reactions,
cardiac dysrhythmias can be dangerous.
Dose:
• Streptokinase: 7.5-15 lac IU infused over 1 hour
• Alteplase (rt-PA): 15mg IV bolus inj, followed by 50mg over 30 min,
then 35mg over the next 1 hour
• t-PA (tissue plasminogen activator):0.9mg/kg IV (maximum 90kg)
over 1 hour in selected patients within 3 hours of onset.

29. PATIENT CARE:
1. Patient should be monitored for resolution of symptoms, the
development of recurrent thrombosis & symptoms of post
thrombotic syndrome.
2. Hgb, haematocrit & BP should be monitored carefully to detect
bleeding from anticoagulant therapy.
3. Coagulation tests (aPTT, PT, INR) should be performed prior to
initiating therapy to establish the patients baseline values & guide
late anti coagulation.
4. Patients taking warfarin should be questioned about medication
adherence & symptoms related to bleeding and thromboembolic
complications.

30. REFERENCE/BIBLIOGRAPHY:
Textbook of Pharmacotherapy: A
Pathophysiologic approach by
Joseph T. Dipiro.