Venous

thromboembolism
(VTE)
CVS-I
Introduction:
• Term referring to blood clots in the veins
• VTE includes:
• Deep vein thrombosis (DVT)
• occurs when a blood clot develops in a deep vein, most
commonly in the lower leg, thigh, or pelvis, but can also
occur in the arm
• Pulmonary embolism (PE)
• occurs when a part of the clot breaks off and travels to
the lungs, which can be life-threatening.
Arterial vs venous thrombus arterial:
• Most often occurs in medium-sized vessels rendered
thrombogenic by atherosclerosis
• Arterial thrombosis usually consists of a platelet-rich clot
VENOUS
• Venous thrombosis is triggered by blood stasis or
inappropriate activation of the coagulation cascade
• Venous thrombosis typically involves a clot that is rich in
fibrin, with fewer platelets than are observed with arterial
clots
Pathophysiology:
• The arrest of bleeding following vascular injury, or hemostasis, is
essential to life
• Within the vascular system, blood remains in a fluid state,
transporting oxygen, nutrients, plasma proteins, and waste
• With vascular injury, a dynamic series of reactions involving a
complex interplay of thrombogenic and antithrombotic stimuli
results in the local formation of a hemostatic plug that seals the
vessel wall and prevents further blood loss
• A disruption of this delicate system of checks and balances may
lead to inappropriate clot formation within the blood vessel that
subsequently obstructs blood flow or embolizes to a distant
vascular bed
Virchow triads:
Clinical assessment models for DVT
and PE:
• Clinical assessment improves the diagnostic accuracy of a noninvasive test
• Simple assessment checklists can be used to stratify patients into high,
moderate, and low probability of a DVT or PE
• Patients with a high pretest probability of VTE have a greater than 60% chance of
having VTE compared with only 5% in the low pretest probability group.
• Clinical assessment can rule in or rule out the diagnosis of VTE with reasonable
certainty when its results are consistent with those of a noninvasive test
• In patients with a moderate pretest probability of VTE and an abnormal lower
extremity ultrasonogram, the diagnosis of VTE can be reasonably concluded
• If the results of the clinical assessment and the ultrasonogram are inconsistent,
venography or angiography should be performed to make the definitive diagnosis
Classes of drugs used for VTE:
• CLASS OF DRUGS USED FOR VTE
(Anticoagulants/Antithrombotics) Unfractionated Heparin (UFH
• Low-Molecular-Weight Heparins (LMWHs):
• • Dalteparin
• • Enoxaparin
• • Nadroparin
• • Tinzaparin
• Anti-Factor Xa Inhibitors:
• • Fondaparinux
• Indrapraniux
Cont’d
Direct Thrombin Inhibitors (Dtis):
• Argatroban
• Bivalirudin
• Desirudin
• Lepirudin
• Ximelagatran
Vitamin K antagonists:
• • Warfarin (Coumadin)
Treatment/management:
Anticoagulant:
ANTICOAGULANTS
• The anticoagulant drugs inhibit either the action of the coagulation factors (for example,
heparin) or interfere with the synthesis of the coagulation factors (for example, vitamin K
antagonists such as warfarin)
A. Heparin and low molecular weight heparins (LMWH):
• Heparin is an injectable, rapidly acting
• interfere with the formation of thrombi
• occurs naturally as a macromolecule complexed with histamine in mast cells, where its
physiologic role is unknown
• Extracted for commercial use from porcine intestinal mucosa
• Strongly acidic because of the presence of sulfate and carboxylic acid groups
• Isolation of enoxaparin, produced by enzymatic de-polymerization of unfractionated heparin
• Other LMWHs include dalteparin, tinzaparin
• • LMWHs are heterogeneous compounds about one-third the size of unfractionated heparin.
2. Therapeutic use:
• Heparin and the LMWHs limit the expansion of thrombi by preventing
fibrin formation. These agents are used for the treatment of acute
venous thromboembolism (DVT or PE)
• Heparin and LMWHs are also used for prophylaxis of postoperative
venous thrombosis in patients undergoing surgery (for example, hip
replacement) and those with acute MI
• Anticoagulants of choice for treating pregnant women, because they
do not cross the placenta, due to their large size and negative charge
• LMWHs do not require the same intense monitoring as heparin,
thereby saving laboratory costs and nursing time.
• These advantages make LMWHs useful for both inpatient and
outpatient therapy.
3. Pharmacokinetics:
• Heparin must be administered subcutaneously or intravenously, because the drug does not
readily cross membranes
• The LMWHs are administered subcutaneously
• Heparin is often initiated as an IV bolus to achieve immediate anticoagulation, followed by
lower doses or continuous infusion of heparin, titrating the dose so that the activated partial
thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control
• [Note: The aPTT is the standard test used to monitor the extent of anticoagulation with
heparin.)
• Anticoagulant effect with heparin occurs within minutes of IV administration (or 1 to 2 hours
after subcutaneous injection)
• Anti-factor Xa activity of the LMWHs occurs about 4 hours after subcutaneous injection.
• It is usually [Link] to monitor coagulation values with LMWHs because the plasma
levels and pharmacokinetics of these drugs are more predictablé
• However, in renally impaired, pregnant, and obese patients, monitoring of factor Xa levels is
recommended with LMWHs.
Cont'd
• In blood, heparin binds to many proteins that neutralize its
activity
• Heparin is taken up by the monocyte/macrophage system, and it
undergoes depolymerization and desulfation to inactive products.
• Inactive metabolites, as well as some of the parent heparin and
LMWHs, are excreted into the urine.
• Renal insufficiency prolongs the half-life of LMWHs
• Dose of LMWHs should be reduced in patients with renal
impairment
- Half-life of heparin is approximately 1.5 hours, whereas the half-
life of the LMWHs is, ranging from 3 to 12 hours.
4. Adverse effects:
• The chief complication of heparin and LMWH therapy is bleeding
• Careful monitoring of the patient and laboratory parameters is required to
minimize bleeding.
• Excessive bleeding may be managed by discontinuing the drug or by
treating with protamine sulfate
• When infused slowly, the latter combines ionically with heparin to form a
stable, 1:1 inactive complex. It is very important that the dosage ot
protamine sulfate is carefully titrated (1 mg for every 100 units of heparin
administered)
• Heparin preparations are obtained from poreine sources and, therefore,
may be antigenic
• Possible adverse reactions include chills, fever, urticaria, and anaphylactic
shock
Cont'd
• Heparin-induced thrombocytopenia (HIT) is a serious condition, in which
circulating blood contains an abnormally low number of platelets
• Reaction is immune-mediated and carries a risk of venous and arterial
embolism
• Heparin therapy should be discontinued when patients develop HIT or show
severe thrombocytopenia.
• In cases of HIT, heparin can be replaced by another anticoagulant, such as
argatroban. [Note: LMWHs can have cross-sensitivity and are not recommended
in HIT.)
• In addition, osteoporosis has been observed in patients on long-term heparin
therapy
• Heparin and LMWHs are contraindicated in patients who have hypersensitivity
to heparin, bleeding disorders, alcoholism, or who have had recent surgery of
the brain, eye, or spinal cord.
B. Warfarin:
Warfarin (Coumarin anticoagulant) owe their action to the
ability to antagonize the cofactor functions of vitamin K
• • The INR is the standard by which the anticoagulant
activity of warfarin therapy is monitored
• • The goal of warfarin therapy is an INR of 2 to 3 for
most indications, with an INR of 2.5 to 3.5 targeted for
some mechanical valves and other indications
• • Warfarin has a narrow therapeutic index- important to
monitor INR
Mechanism of action:
• Factors II, VII, IX, and X require vitamin K as a cofactor for their
synthesis by the liver
• These factors undergo vitamin K-dependent post-translational
modification, whereby a number of their glutamic acid residues are
carboxylated to form y-carboxyglutamic acid residues
• The V-carboxyglutamy, residues bind calcium ions, which are essential
for interaction between the coagulation tactors and platelet membranes
• In the carboxylation reactions, the vitamin K-dependent carboxylase
fixes
CO2 to form the new COOH group on glutamic acid
• The reduced vitamin K cofactor is convertec to vitamin K epoxide during
the reaction.
Cont’d
• Vitamin K is regenerated from the epoxide by vitamin K epoxide
reductase, the enzyme that is inhibited by warfarin
• Warfarin treatment results in the production of clotting factors with
diminishe activity (10% to 40% of normal), due to the lack of sufficient
y-carboxyglutamy side chains. Unlike
• Peak effects may be delayed for 72 to 96 hours, which is the time
required to deplete the pool of circulating clotting factors
• The anticoagulant effects of warfarin can be overcome by the
administration of Vitamin K
• • Reversal following administration of vitamin K takes approximately
24 hours (the time necessary for degradation of already synthesized
clotting factors).
Therapeutic use:
2. Therapeutic use:
Warfarin is used in the prevention and treatment of DVT
and PE, stroke prevention, stroke prevention in the
setting of atrial fibrillation and/or prosthetic heart valves,
protein C and S deficiency, and antiphospholipid
syndrome
• Also used for prevention of venous thromboembolism
during orthopedic or gynecologic surgery
Pharmacokinetics:
- Warfarin is rapidly absorbed after oral administration (100% bioavailability with
little individual patient variation)
* Highly bound to plasma albumin, which prevents its diffusion into the
cerebrospinal fluid, urine, and breast milk
• Drugs that have a greater affinity for the albumin-binding site, such as
sulfonamides, can displace the anticoagulant and lead to a transient, elevated
activity
- Warfarin readily crosses the placental barrier
• Mean half-life of warfarin is approximately 40 hours.
• Warfarin is metabolized by the CYP450 system (including the 2C9, 2C19, 2C8,
2C18, 1A2, and 3A4 isoenzymes) to inactive components
• Inactive metabolites are excreted in urine and feces
• Warfarin has numerous drug interactions that may potentiate or attenuate its
anticoagulant effect. The list of interacting drugs is extensive.
Adverse effects:
• Hemorrhage, and the agent has a black box warning for bleeding risk
• frequently monitor the INR and adjust the dose of warfarin
• Minor bleeding may be treated by withdrawal of the drug or administration
of oral vitamin K1
• Severe bleeding may require greater doses of vitamin K given IV
• Whole blood, frozen plasma, and plasma concentrates of blood factors may
also be used for rapid reversal of warfarin
• Skin lesions and necrosis are rare complications of warfarin therapy
• Purple toe syndrome, a rare, painful, blue-tinged discoloration of the toe
caused by cholesterol emboli from plaques, has also been observed with
warfarin therapy
• Warfarin is teratogenic and should never be used during pregnancy
• If anticoagulant therapy is needed during pregnancy, heparin or LMWH may
be administered
C. Argatroban:
• Synthetic parenteral anticoagulant that is derived from l-arginine
• It is a direct thrombin inhibitor
• Used for the prophylaxis or treatment of venous thromboembolism
in patients with HIT, and it is also approved for use during PCI in
patients who have or are at risk for developing HIT.
• Metabolized in the liver and has a half-life of about 39 to 51
minutes.
Monitoring includes aPTT, hemoglobin, and hematocrit
• Used in patients with renal dysfunction
• Used cautiously in patients with hepatic impairment
• Major side effect is bleeding.
D. Bivalirudin and desirudin:
• Bivalirudin & desirudin are parenteral anticoagulants that are analogs of
hirudin, a thrombin inhibitor derived from medicinal leech saliva
• Drugs are selective direct thrombin inhibitors that reversibly inhibit the
catalytic site of both free and clot-bound thrombin
• Bivalirudin is an alternative to heparin in patients undergoing PCI who
have or are at risk for developing HIT
• Also in patients with unstable angina undergoing angioplasty
• Patients with normal renal function, the half-life of bivalirudin is 25
minutes.
• Dosage adjustments are required in patients with renal impairment
• Desirudin is indicated for the prevention of DVT in patients undergoing
hip replacement surgery.
• Bleeding is the major side effect of these agents.
E. Fondaparinux:
• Fondaparinux is a pentasaccharide anticoagulant that is synthetically
derived.
• Selectively inhibits only factor Xa
• By selectively binding to antithrombin III, fondaparinux potentiates (300- to
1000-fold the innate neutralization of factor Xa by antithrombin III
• Approved for use in the treatment of DVT and PE and for the prophylaxis of
venous thromboembolism in the setting of orthopedic and abdominal surgery
• Well absorbed from the subcutaneous route with a predictable
pharmacokinetic profile & requires less monitoring than heparin. Fondaparinux
is
• Eliminated in the urine mainly as unchanged drug with an elimination half-life
of 17 to 21 hours.
• C/l in patients with severe renal impairment
• Bleeding is the major side effect of fondaparinux
Thrombolytic agents:
• Agents that activate the conversion of plasminogen to plasmin, a
serine protease that hydrolyzes fibrin and, thus, dissolves clots
• Streptokinase, one of the first such agents to be approved,
causes a systemic fibrinolytic state that can lead to bleeding
problems.
• Alteplase acts more locally on the thrombotic fibrin to produce
fibrinolysis
• Urokinase is produced naturally in human kidneys and directly
converts plasminogen into active plasmin
• Fibrinolytic drugs may lyse both normal and pathologic thrombi.
Mechanism of action:
• All act either directly or indirectly to convert plasminogen to
plasmin, which, in turn, cleaves fibrin, thus lysing thrombi
• Clot dissolution and reperfusion occur with a higher
frequency when therapy is initiated early after clot formation
because clots become more resistant to lysis as they age.
• Unfortunately, increased local thrombi may occur as the
clot dissolves, leading to enhanced platelet aggregation and
thrombosis.
• Strategies to prevent this include administration of
antiplatelet drugs, such as aspirin, or antithrombotics such as
heparin
Therapeutic use:
• Thrombolytic agents are usually administered intravenously.
Thrombolytic agents are helpful in restoring catheter and shunt
function, by lysing clots causing occlusion
• Also used to dissolve clots that result in strokes
3. Adverse effects:
• Hemorrhage is a major side effect- do not distinguish between
the fibrin of an unwanted thrombus and the fibrin of a beneficial
hemostatic plug
• C/= pregnancy, and in patients with healing wounds, a
history. Ot cerebrovascular accident, brain tumor, head trauma,
intracranial bleeding, and metastatic cancer.
A. Alteplase, reteplase,
tenecteplase:
• Alteplase (formerly known as tissue plasminogen activator or PA) is a serine
protease originally derived from cultured human melanoma cells, now obtained
as a product of recombinant DNA technology.
• Reteplase, genetically engineered, smaller derivative of recombinant tPA.
• Tenecteplase is another recombinant tPA with a longer half-life and greater
binding affinity for fibrin than alteplase
• Alteplase has a low affinity for free plasminogen in the plasma, but it rapidly
activates plasminogen that is bound to fibrin in a thrombus or a hemostatic plug
• Alteplase is said to be “fibrin selective” at low doses.
• Alteplase is approved for the treatment of MI, massive PE, and acute ischemic
stroke.
• Reteplase and tenecteplase are approved only for use in acute MI, although
reteplase may be used off-label in DVT and massive PE
Cont’d
• Alteplase has a very short half-life (5 to 30 minutes),
and therefore, 10% of the total dose is injected IV bolus,
remaining administered over 60 minutes.
• Both reteplase and tenecteplase have longer half-lives
and, therefore, may be administered as an IV bolus.
Alteplase may cause orolingual angioedema, increased
risk of this effect when combined with angiotensin-
converting enzyme (ACE) inhibitors.
B. Streptokinase:
• Extracellular protein purified from culture broths of
group C B-hemolytic streptococci
• Forms an active one-to-one complex with plasminogen.
• This enzymatically active complex converts un-
complexed plasminogen to the active enzyme plasmin
• In addition to the hydrolysis of fibrin plugs, the complex
also catalyzes the degradation of fibrinogen, as well as
clotting factors V and VII
C. Urokinase:
• Urokinase produced naturally in the body by the kidneys
• Isolated from cultures of human kidney cells and has low
antigenicity.
• Directly cleaves the arginine-valine bond of plasminogen
to yield active plasmin
• Only approved for lysis of pulmonary emboli
• Off-label uses include treatment of acute MI, arterial
thromboembolism, coronary artery thrombosis, and DVT. Its
use has largely been supplanted by other agents with a
more favorable benefit-to-risk ratio.
A. Abciximab, eptifibatide, tirofiban:
(anti platelet)
Mechanism of action: The GP lIb/Illa receptor plays a key role in
stimulating platelet aggregation
A chimeric monoclonal antibody, abciximab inhibits the GP lIb/Illa
receptor complex.
By binding to GP lIb/Illa, abciximab blocks the binding of fibrinogen
and von Willebrand factor, aggregation does not occur
Eptifibatide & tirofiban act similarly to abciximab, by blocking the GP
Iib/llla receptor
Eptifibatide is a cyclic peptide that binds to GP Ilb/Illa at the site that
interacts with the arginine glycine- aspartic ecid sequence of
fibrinogen Tirofiban is not a peptide, but it blocks the same site as
eptifibatide.
Therapeutic use:
• These agents are given intravenously, along with
heparin and aspirin, as an adjunct to PCI for the
prevention of cardiac ischemic complications.
Abciximab is also approved for:
• patients with unstable angina not responding to
conventional medical therapy when PCI is planned within
24 hours.
Pharmacokinetics:
• Abciximab is given by IV bolus, followed by IV infusion, achieving
peak platelet inhibition within 30 minutes
• Metabolism of abciximab is unknown.
• After cessation of abciximab infusion, platelet function gradually
returns to normal, with the antiplatelet effect persisting for 24 to
48 hours.
• When IV infusion of eptifibatide or tirofiban is stopped, both
agents are rapidly cleared from the plasma.
• Eptifibatide and its metabolites are excreted by the kidney
• Tirofiban is excreted largely unchanged by the kidney and in the
feces
Adverse effects:
• The major adverse effect of these agents is bleeding,
especially if used with anticoagulants