Venous

Thromboembolism

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 Definition
• Venous thromboembolism (VTE) results from
clot formation in the venous circulation and is
manifested as deep vein thrombosis (DVT)
and/or pulmonary embolism (PE).

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 Definition
• A DVT is a thrombus composed of cellular
material (red and white blood cells, platelets)
bound together with fibrin strands.
• A PE is a thrombus that arises from the
systemic circulation and lodges in the
pulmonary artery or one of its branches,
causing complete or partial obstruction of
pulmonary blood flow.

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Epidemiology
 VTE is associated with significant global disease burden.
Etiology:
 A number of identifiable factors increase VTE risk.
 Many risk factors fall into categories constituting what is
known as Virchow’s triad:
―Blood stasis(Surgery with general anesthesia, paralysis,
immobility, acute medical illness require hospitalization and
obesity)
―Vascular injury(major orthopedic surgery, trauma, indwelling
catheter)
― Hypercoagulability(malignancy, anthithrombin deficiency,
protein c and s deficiency, factor VIII and XI excess, nephrotic
syndrome, pregnancy, drug therapy includes estrogen derivative
contraceptive , cancer therapy,……)

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 Pathophysiology
• Hemostasis is the process responsible for maintaining
circulatory system integrity following blood vessel damage.
• Hemostatic clots remain localized to the vessel wall and do not
greatly impair blood flow.
• In contrast, pathologic clots like those causing VTE result in
blood flow impairment and often cause complete vessel
occlusion.

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Overview of hemostasis.

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 Pathophysiology

• The intrinsic pathway is activated when

negatively charged surfaces in contact with
the blood activate factor XII, and activated
platelets convert factor XI.
• The extrinsic pathway is activated when
damaged vascular tissue releases tissue
thromboplastin. Vascular injury also exposes
the subendothelium, causing adherence,
activation, and aggregation of platelets.

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coagulation cascade

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 Pathophysiology

• Three primary components “venous stasis,

vascular injury, and hypercoagulability
(Virchow's triad)” play a role in the
development of a pathogenic thrombus.
• Venous stasis is slowed blood flow in the deep
veins of the legs resulting from damage to
venous valves, vessel obstruction, prolonged
periods of immobility, or increased blood
viscosity.

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 Pathophysiology

• Conditions associated with venous stasis include

major medical illness (e.g., heart failure,
myocardial infarction), major surgery, paralysis
(e.g., stroke, spinal cord injury), polycythemia
vera, obesity, or varicose veins.
• Vascular injury may result from major orthopedic
surgery (e.g., knee and hip replacement), trauma
(especially fractures of the pelvis, hip, or leg), or
indwelling venous catheters.

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 Pathophysiology

• Hypercoagulable states include malignancy;

activated protein C resistance; deficiency of
protein C, protein S, or antithrombin; factor VIII
or XI excess; antiphospholipid antibodies; and
other situations.
• Estrogens and selective estrogen receptor
modulators (SERMs) have been linked to venous
thrombosis, perhaps due in part to increased
serum clotting factor concentrations.

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 Pathophysiology

• Once formed, a venous thrombus may:

(1) Remain asymptomatic;
(2) lyse spontaneously;
(3) Obstruct the venous circulation;
(4) Propagate into more proximal veins;
(5) Embolize; or act in any combination of these
ways.
• Even asymptomatic patients may experience
long-term consequences, such as the
postthrombotic syndrome and recurrent VTE.

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 Clinical Presentation

• Most patients with VTE never develop symptoms

from the acute event.
• Symptoms of DVT include unilateral leg swelling,
pain, tenderness, erythema, and warmth.
• Postthrombotic syndrome (a long-term
complication of DVT caused by damage to venous
valves) may produce chronic lower extremity
swelling, pain, tenderness, skin discoloration, and
ulceration.
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 Clinical Presentation Conti…
• Symptoms of PE include dyspnea, tachypnea,
pleuritic chest pain, tachycardia, palpitations,
cough, diaphoresis, and hemoptysis.
• Cardiovascular collapse, characterized by
cyanosis, shock, and oliguria, is an ominous sign.
• Physical signs may include a palpable cord and a
positive Homan's sign(the patient may experience
pain in back of the knee when the examiner
dorsiflexes the foot of the affected leg).
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 Diagnosis

• Assessment of the patient's status should

focus on the search for risk factors (e.g.,
increased age, major surgery, previous VTE,
trauma, malignancy, hypercoagulable states,
and drug therapy).
• Signs and symptoms of DVT are nonspecific,
and objective tests are required to confirm or
exclude the diagnosis.

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 Diagnosis Conti…
• Radiographic contrast studies are the most accurate and
reliable method for diagnosis of VTE.
• Venography is the gold standard for the diagnosis of DVT.
• Contrast venography allows visualization of the entire
venous system in the lower extremity and abdomen.
• Pulmonary angiography allows visualization of the
pulmonary arteries.
• Pulmonary angiography is the gold standard for the
diagnosis of PE.
• The diagnosis of VTE can be made if there is a persistent
intraluminal filling defect on multiple x-ray films.

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 Diagnosis Conti…
• Noninvasive tests (e.g., ultrasonography and the
ventilation-perfusion [V/Q] scan) are used for the initial
evaluation of patients with suspected VTE.
• Doppler ultrasonography can sensitively detect large
thrombi occluding proximal veins but is relatively
insensitive to smaller nonocclusive thrombi and calf
vein thrombi.
• Laboratory Test:
 D-dimer is a fibrin clot degradation product and levels
are significantly elevated in patients with acute
thrombosis. it is not sufficiently specific for the dx of
VTE .

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• A variety of conditions are associated with D-
dimer elevations, including recent surgery or
trauma, pregnancy, advanced age, and cancer;
therefore, a positive D-dimer test is not
conclusive evidence of VTE diagnosis.
• However, a negative D-dimer, for most assays
defined as <500 ng/mL (mcg/L), can be useful
in ruling out the diagnosis of VTE

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 Treatment of VTE
Desired Outcome
The objectives of treating VTE are
To prevent the development of PE and the
postthrombotic syndrome,
To reduce morbidity and mortality from the
acute event, and
To minimize adverse effects and cost of
treatment.
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 Nonpharmacologic Therapy
• Strict bed rest was traditionally recommended following acute DVT
based on the assumption that leg movement would dislodge the clot,
resulting in PE.
• Compression stockings and intermittent pneumatic compression (IPC)
devices prevent VTE by increasing the velocity of venous blood flow
through graded pressure application.
• IPC devices utilize a series of cuffs wrapped around the patient’s legs that
inflate in continuous 1- to 2-minute cycles from the ankles to the knees or
thighs.
• IPC devices should be worn at least 18 hr/day for optimal effectiveness.
• Graduated compression stockings do not reliably reduce VTE in
medically ill patients.
• Mechanical methods do not increase bleeding risk, which makes them
attractive for postoperative VTE prophylaxis, especially in patients with
contraindications to pharmacologic therapies.
• Inferior vena cava (IVC) filters can provide short-term protection against
PE in very high-risk patients by blocking embolization of thrombus
formed below the filter.
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 Tretment: Classification of
antithrombotic drugs

Anticoagulation therapies remain the mainstay of VTE treatment.

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Direct Oral Anticoagulants(DOACs)
• Direct factor Xa inhibitors inactivate circulating and
clot-bound factor Xa.
• Factor Xa inhibators include Rivaroxaban, Apixaban,
Edoxaban and Betrixaban.
• There are no parenteral direct factor Xa inhibitors
available for clinical use.
• DOACs are preferred over traditional anticoagulation
therapy approaches for the treatment of VTE in the
American College of Chest Physician 10th edition
guidelines and edoxaban and rivaroxaban may be
reasonable alternatives to LMWH monotherapy for
patients with cancer-associated VTE.

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 Unfractionated Heparin(UFH)
• The anticoagulant effect of UFH is mediated
through a specific pentasaccharide sequence
on the heparin molecule that binds to
antithrombin, provoking a conformational
change.
• The UFH-antithrombin complex is 100 to 1000
times more potent as an anticoagulant than
antithrombin alone.

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 Unfractionated Heparin Conti…
• Antithrombin inhibits the activity of factors
IXa, Xa, XIIa, and thrombin (IIa). It also inhibits
thrombin-induced activation of factors V and
VIII.
• UFH prevents the growth and propagation of a
formed thrombus and allows the patient's
own thrombolytic system to degrade the clot.

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 Unfractionated Heparin Conti…
• UFH must be given parenterally, preferably by
the intravenous (IV) or subcutaneous (SC)
route.
• IV administration is needed when rapid
anticoagulation is required.
• A loading dose of 80 to 100 units/kg
(maximum 10,000 units) is followed by a
continuous IV infusion at an initial rate of 17
to 20 units/kg/h (maximum 2300 units/h).

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 Unfractionated Heparin: ADR
• Bleeding is the primary adverse effect
associated with UFH.
• The most common bleeding sites are the
gastrointestinal tract, urinary tract, and soft
tissues.
• Critical areas include intracranial, pericardial,
and intraocular sites as well as the adrenal
gland.

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Unfractionated Heparin: ADR Conti…
• Symptoms of bleeding may include severe
headache, joint pain, chest pain, abdominal pain,
swelling, tarry stools, hematuria, or the passing
of bright red blood through the rectum.
• If major bleeding occurs, UFH should be
discontinued immediately and IV protamine
sulfate should be given by slow IV infusion over
10 minutes (1mg/100 units of UFH infused during
the previous 4 hours; maximum 50 mg).

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Unfractionated Heparin: ADR Conti…
• Thrombocytopenia (platelet count less than
150,000/mm3) is common.
• Bruising, local irritation, mild pain, erythema,
histamine-like reactions, and hematoma can
occur at the site of injection.

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Unfractionated Heparin: ADR Conti…
• Hypersensitivity reactions involving chills,
fever, urticaria, and rarely bronchospasm,
nausea, vomiting, and shock have been
reported in patients with heparin-induced
thrombocytopenia (HIT).
• Long-term UFH has been reported to cause
alopecia, priapism, hyperkalemia, and
osteoporosis.

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Features of Heparin-Induced Thrombocytopenia
Features Details
Thrombocytopenia Platelet count of ≤100,000/L or a decrease in
platelet count of ≥50%
Timing Platelet count falls 5–10 days after starting
heparin
Type of heparin More common with unfractionated heparin
than with low-molecular-weight heparin
Type of patient More common in surgical patients than medical
patients; more common in women than in men.
Thrombosis Venous thrombosis more common than arterial
thrombosis

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 Low-Molecular-Weight Heparins

• Low-molecular-weight heparins (LMWHs) are

fragments of UFH that are heterogeneous mixtures of
sulfated glycosaminoglycans with approximately one-
third the molecular weight of UFH.
• Advantages of LMWHs over UFH include:
(1) more predictable anticoagulation dose response;
(2) improved subcutaneous bioavailability;
(3) dose-independent clearance;
(4) longer biologic half-life;
(5) lower incidence of thrombocytopenia; and
(6) less need for routine laboratory monitoring.

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 Low-Molecular-Weight Heparins
Enoxaparin 1 mg/kg every 12 hours or 1.5 mg/kg every 24 hours
Dalteparin 100 units/kg every 12 hours or 200 units/kg every 24hours
Tinzaparin 175 units/kg every 24 hours
Danaparoid
• Danaparoid sodium is structurally distinct from but mechanistically
related to heparin. It is a mixture of three sulfated
glycosaminoglycans: heparan, dermatan, and chondroitin.
• Like heparin, its anticoagulant activity is mediated in part through
its interaction with antithrombin.
Fondaparinux
• Fondaparinux sodium is a selective inhibitor of factor Xa. Similar to
UFH and the LMWHs, it binds to antithrombin, greatly accelerating
its activity. However, it has no direct effect on thrombin activity at
therapeutic plasma concentrations.

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 Direct Thrombin Inhibitors

• These agents interact directly with thrombin

and do not require antithrombin to have
antithrombotic activity.
• They are capable of inhibiting both circulating
and clot-bound thrombin, which is a potential
advantage over UFH and the LMWHs.
• They also do not induce immune-mediated
thrombocytopenia and have been used for the
treatment of HIT.

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 Direct Thrombin Inhibitors

Lepirudin is indicated for anticoagulation in patients with HIT and

associated thromboembolic disease in order to prevent further
thromboembolic complications.
Argatroban is indicated as an anticoagulant for patients with HIT and
for patients at risk for HIT undergoing percutaneous coronary
intervention (PCI).
Bivalirudin is indicated for use as an anticoagulant in patients with
unstable angina undergoing intervention.
Desirudin is indicated for prophylaxis of DVT in patients undergoing
hip replacement surgery.
Ximelagatran is a prodrug converted in the liver to the active moiety
melagatran.
• There are no known agents that reverse the activity of direct
thrombin inhibitors.

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 Warfarin

• Warfarin inhibits the enzymes responsible for

the cyclic interconversion of vitamin K in the
liver.
• By suppressing the production of clotting
factors, warfarin prevents the initial formation
and propagation of thrombi.

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 Warfarin Conti…
• Warfarin has no direct effect on previously
circulating clotting factors or previously
formed thrombi.
• The time required to achieve its anticoagulant
effect depends on the elimination half-lives of
the coagulation proteins.

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 Warfarin Conti…

• Warfarin should begin concurrently with UFH

or LMWH therapy.
• The usual initial dose is 5 to 10 mg.
• In older patients (age greater than 65 years)
and those taking potentially interacting
medications, a starting dose of 2.5 mg should
be considered.

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 Warfarin Conti…

• Warfarin therapy is monitored by the INR

(target: 2 to 3 for DVT or PE).
• Six to 12 weeks of warfarin therapy is
sufficient for symptomatic isolated calf vein
DVT.
• Treatment should be continued for at least 3
months for patients with a proximal vein DVT.

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 Warfarin: ADR

• Hemorrhagic complications ranging from mild

to severe and life-threatening can occur at any
body site.
• The gastrointestinal tract is the most frequent
site of bleeding.
• Bruising on the arms and legs is common, but
a painful hematoma may necessitate
temporary discontinuation of therapy.

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 Warfarin: ADR

• Intracranial hemorrhage is the most serious

complication and often results in permanent
disability and death.
• Patients with a mildly elevated INR (3.5 to 5)
and no signs or symptoms of bleeding can
usually be managed by either reducing the
dose or holding 1 or 2 warfarin doses.

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 Warfarin: ADR
• If rapid reduction of an elevated INR is
required, oral or IV administration of vitamin
K1 (phytonadione) can be given.
• Oral administration is preferable in the
absence of major bleeding.
• The IV route produces the most rapid reversal
of anticoagulation, but it has been associated
with anaphylactoid reactions.

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 Warfarin: ADR

• If the INR is 5 to 9, warfarin doses may be withheld or

may be combined with phytonadione 1 to 5 mg.
• If the INR is greater than 9, a 5-mg oral dose is
recommended.
• Low vitamin K doses reduce the INR consistently within
24 hours without making the patient refractory to
warfarin.
• In the event of serious or life-threatening bleeding, IV
vitamin K should be administered together with fresh
frozen plasma or clotting factor concentrates.

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 Warfarin: ADR

• Nonhemorrhagic adverse effects include the rare

“purple toe syndrome” and skin necrosis.
• Absolute contraindications to warfarin include
active bleeding, hemorrhagic tendencies,
pregnancy, and a history of warfarin-induced skin
necrosis.
• Use with great caution in patients with a history
of gastrointestinal bleeding, recent neurosurgery,
alcoholic liver disease, severe renal impairment,
or inability to keep follow-up appointments for
monitoring.

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Acute skin necrosis in a patient with protein C deficiency who was treated with heparin and
warfarin for deep vein thrombosis that occurred after elective hip surgery.

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 Antiplatelet Agents: Role of Platelets in
Arterial Thrombosis

• In healthy vasculature, circulating platelets are

maintained in an inactive state by nitric oxide
(NO) and prostacyclin released by endothelial
cells lining the blood vessels.
• Endothelial cells also express adenosine
diphosphatase (ADPase) on their surface, which
degrades ADP released from activated platelets.
• When the vessel wall is damaged, release of
these substances is impaired and subendothelial
matrix is exposed.
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Antiplatelet Agents: Role of Platelets in Arterial
Thrombosis

• Platelets adhere to exposed collagen, von

Willebrand factor (vWF), and fibronectin via α2β1,
glycoprotein (GP) Ib-IX, and α5β1 receptors,
respectively, which are constitutively expressed
on the platelet surface.
• Adherent platelets undergo a change in shape,
secrete ADP from their dense granules, and
synthesize and release thromboxane A2.
• Released ADP and thromboxane A2, which are
platelet agonists, activate ambient platelets and
recruit them to the site of vascular injury

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Coordinated role of platelets and the coagulation
system in thrombogenesis.

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 Antiplatelet Agents:
• Aspirin: produces its antithrombotic effect by
irreversibly acetylating and inhibiting platelet
cyclooxygenase (COX)-1, a critical enzyme in the
biosynthesis of thromboxane A2.
• Thienopyridines: include ticlopidine and clopidogrel,
drugs that target P2Y12, a key ADP receptor on
platelets.
• Dipyridamole: By inhibiting phosphodiesterase, blocks
the breakdown of cAMP. Increased levels of cAMP
reduce intracellular calcium and inhibit platelet
activation. Dipyridamole also blocks the uptake of
adenosine by platelets and other cells.

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 Antiplatelet Agents: GPIIb/IIIa
Receptor Antagonists
• Abciximab, eptifibatide, and tirofiban.
• Given as an IV bolus followed by an infusion.
• Because they are cleared by the kidneys, the
doses of eptifibatide and tirofiban must be
reduced in patients with renal insufficiency

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Site of action of antiplatelet drugs

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 Thrombolysis and Thrombectomy

• Thrombolytic agents are proteolytic enzymes that

enhance the conversion of plasminogen to
plasmin, which subsequently degrades the fibrin
matrix.
• Alteplase: For PE, 100 mg by IV infusion over 2 h.
For DVT, 0.05-mg/kg/h continuous infusion over
24 hours (maximum, 150 mg) or 80- to 100-mg
infusion over 2 hours.
• Reteplase: For PE, 10 units IV bolus followed 30
minutes later by a second 10 units IV bolus.
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 Thrombolysis and Thrombectomy

• Streptokinase: 250,000 units bolus infusion over 30

minutes followed by a continuous IV infusion of
100,000 units/h for 24 hours (PE) or 24 to 72 hours
(DVT).
• During the thrombolytic infusion, UFH or LMWH
therapy should be temporarily withheld.
• Venous thrombectomy may be performed to remove a
massive obstructive thrombus in a patient with
significant iliofemoral venous thrombosis, particularly
if the patient is either not a candidate for or has not
responded to thrombolysis.

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The fibrinolytic system and its regulation

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 Pregnancy

• Anticoagulation therapy is commonly used

for the prevention and treatment of VTE
during pregnancy.
• UFH and LMWH do not cross the placenta
and are preferred during pregnancy.

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 Evaluation of Therapeutic Outcomes

• Patients should be monitored for resolution of

symptoms, the development of recurrent thrombosis,
and symptoms of the post-thrombotic syndrome, as
well as for adverse effects from the treatments.
• Hemoglobin, hematocrit, and blood pressure should be
monitored carefully to detect bleeding from
anticoagulant therapy.
• Coagulation tests (aPTT, PT, INR) should be performed
prior to initiating therapy to establish the patient's
baseline values and guide later anticoagulation.

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 Evaluation of Therapeutic Outcomes

• Outpatients taking warfarin should be

questioned about medication adherence and
symptoms related to bleeding and
thromboembolic complications.
• Any changes in concurrent medications
should be carefully explored.
• Diet Counseling required when the patient
take warfarine.

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End

60
 Group Assignment(5%)
Group 1: Pharmacotherapy of Cardiopulmonary
Resuscitation
Group 2: Pharmacotherapy of Rheumatoid
Valvular Heart Disease
Group 3: Pharmacotherapy of Congenital Heart
Diseases in Paediatrics

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 Quiz 1
1. Mention the three Etiology of VTE or identifiable factors that
increase VTE risk?
2. Which anticoagulant is safe and effective for prevention and
treatment of VTE during pregnancy?
3. Why Strict bed rest was recommended following acute DVT
occurrence?
4. Vitamin k (phytonadionen) for warfarin likely Protamine
sulfate for heparin.(True/False)
5. What is the major limitation of pharmacological treatment of
thrombosis?

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