Drugs For Venous Emboli

Front 1

Formation of prothrombin

Back 1

a. Decarboxy prothromin is biologically
inactive unless it is carboxylated.
b. The reaction requires carbon dioxide,
molecular oxygen, and reduced vitamin
K. It is catalyzed by γ-glutamyl
carboxylase.
c. In the process of carboxylation
vitamin K is oxidized to its
corresponding epoxide.
d. Reduced vitamin K is regenerated
from the epoxide by the enzyme
vitamin K epoxide reductase.
e. In addition to coagulation factor II
(prothromin), factors VII, IX,
and X and the anticoagulant
proteins C and S are
biologically activated by the
same mechanism.

Front 2

Vessel wall and platelets

Back 2

Platelet membrane receptors
include the glycoprotein (GP) Ia
receptor, binding to collagen (C);
GP Ib receptor, binding von
Willebrand factor (vWF); and GP
IIb/IIIa, which binds fibrinogen
and other macromolecules.
Antiplatelet prostacyclin (PGI2) is
released from the endothelium.
Aggregating substances released from the degranulating platelet include
adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin
(5-HT).

Front 3

Fibrinolysis

Back 3

a. Plasmin is generated by the proteolytic cleavage of plasminogen, a
plasma protein that is synthesized in the liver.
b. The proteolytic cleavage is catalyzed by tissue plasminogen activator
(t-PA), which is synthesized and secreted by the endothelium.
c. Plasmin exerts its anticoagulant effect by proteolytically cleaving fibrin
into fibrin degradation products.

Front 4

Venous thromboembolism

Formation and risks

Back 4

1. Results from clot formation in the venous circulation; manifested as deep
vein thrombosis (DVT) or pulmonary embolism
2. A number of factors increase the risk of developing VTE including age,
history of VTE, venous stasis, vascular injury, and drug therapy.

Front 5

Once formed a venous thrombus may either...

Back 5

a. remain asymptomatic
b. spontaneously lyse
c. obstruct the venous circulation
d. propagate into more proximal veins
e. embolize
f. act in any combination of these
4. VTE can be debilitating or fatal so it is important to treat it quickly and
aggressively. Because the antithrombotic drugs can cause major bleeding,
the diagnosis must be made with reasonable certainty.

Front 6

Mechanism of action

Unfractionated heparin (part 1)

Back 6

(1) derived from bovine lung or porcine intestinal mucosa
(2) made up of repetitive units of D-glycosamine and uronic acid
(3) heparin and LMWH (and fondaparinux below) have no intrinsic
anticoagulant activity. Instead, they bind to antithrombin and
accelerate the rate at which it inhibits various coagulation proteases
(e.g., thrombin and Xa).
(4) pentasaccharide on the heparin molecule binds antithrombin
provoking a conformational change-the heparin-antithrombin
complex is 100x-1000x more potent as an anticoagulant compared
to antithrombin alone

Front 7

Mechanism of action

Unfractionated heparin (part 2)

Back 7

(5) IXa, Xa, XIIa, and thrombin are inhibited; inasmuch as thrombin is
inhibited, the activation of factors V and VIII is inhibited as well
(6) the unfractionated heparin molecule contains enough saccharides
(>18) to form a ternary complex bridging antithrombin and thrombin
inactivating thrombin
(7) inactivation of factor Xa does not require the bridging between
antithrombin and thrombin; it requires only the binding of
antithrombin to the pentasaccharide
(8) the anti-Xa to anti-IIa ratio is 1:1
(9) heparin uncouples from antithrombin after it has produced its effect
and quickly recouples with another antithrombin
(10) the heparin-antithrombin complex is too large to inactivate Xa and
thrombin within a formed clot
(11) heparin prevents growth and propagation of a formed thrombus
allowing the patient’s own thrombolytic system to degrade the clot

Front 8

Enoxaparin

Mechanism

Back 8

(1) The mechanism is the same as for heparin but it is less effective in
inhibiting thrombin
(2) the low-molecular-weight heparins (enoxaparin) have a shorter
chain length which limits their activity against thrombin
(3) the anti-Xa to anti-IIa ratio is up to 4:1

Front 9

Pharmacokinetics
a. Heparin

Back 9

(1) can be administered subcutaneously or intravenously; the
bioavailability after subcutaneous administration is variable
(2) eliminated by two mechanisms
(a) heparinases and desulfatases enzymatically inactivate heparin
molecules - the process is zero order (saturable)
(b) heparin is also eliminated renally (first order) but this process
is slower
(3) heparin is administered subcutaneously in abdominal fat for
prophylaxis or for acute treatment but the intravenous route is preferred for acute treatment (bolus dose followed by continuous
infusion)
(4) the aPTT is used to assess anticoagulation with heparin; it is
determined before administration and 6 hours later or after a dose
change

Front 10

Enoxaparin

Pharmacokinetics

Back 10

(1) bioavailability and anticoagulant response after subcutaneous
administration is better than with heparin and is the route of
administration
(2) it is eliminated renally so half-life may be prolonged in patients with
renal impairment
(3) because the anticoagulant effect is more predictable, routine
laboratory monitoring is usually not necessary; when it is,
measurement of anti-factor Xa is used

Front 11

Heparin/Enoxaparin

Adverse Effects

Back 11

a. Bleeding
(1) can occur at any site
(2) when it occurs, heparin should be discontinued immediately and
protamine administered; it forms a stable salt with heparin with loss
of anticoagulant activity
(3) major bleeding with enoxaparin less than with heparin but when it
occurs protamine can be use; because the low-molecular-weight
heparins have shorter chains, protamine does not bind as well so it
cannot completely neutralize anticoagulation
b. Heparin-induced thrombocytopenia
(1) more commonly seen with heparin (LMWH do not bind platelets
and PF-4 to the same degree as heparin)
(2) because of cross-reactivity with heparin antibodies, LMWH should
not be use in patients diagnosed or have a history of HIT
(3) more details are provided below

Front 12

Heparin/Enoxaparin

Drug interactions

Back 12

Other anticoagulants can increase the risk of bleeding

Front 13

Drug that reverses heparins effect

Back 13

Protamine
binds heparin>enoxaparin

Front 14

Fondaparinux
a. Mechanism of action

Back 14

Xa inhib
(1) consists only of the
pentasaccharide
(2) causes a permanent
conformational change
in antithrombin
(3) it is not destroyed but
released to interact with other antithrombin molecules
(4) it has no direct effect on thrombin

Front 15

Fondaparinux

Pharmacokinetics/use

Back 15

(1) It is rapidly and completely absorbed (100% bioavailabilty) after
subcutaneous administration
(2) eliminated renally and thus should not be used in patients with
severe renal impairment
(3) it is used for prevention and acute treatment of VTE

Front 16

Fondaparinux

Adverse Effects

Back 16

bleeding - no specific antidote

Front 17

Rivaroxaban
a. Mechanism of action

Back 17

Direct Factor Xa inhibitor not requiring antithrombin

Front 18

Rivaroxaban

admin/elim

Back 18

(1) Oral administration; rapidly and well-absorbed from the
gastrointestinal tract
(2) Eliminated in the urine and is a substrate for P-gp and CYP3A4
(see below Drug Interactions)

Front 19

Rivaroxaban

Adverse effects

Back 19

bleeding--no specific antidote

Front 20

Rivaroxaban

Drug interaxn

Back 20

a. Inducers and inhibitors of the transporter P-glycoprotein (P-gp) will have
corresponding effects (decreased and increased, respectively) serum
concentrations of rivaroxaban.
b. Inducers (e.g., rifampin) and inhibitors (e.g., ketoconazole) of the
CYP3A4 will have corresponding effects (decreased and increased,
respectively) serum concentrations of rivaroxaban.
c. Other anticoagulants (warfarin, heparin, low-molecular weight heparin,
anti-thrombin agents) can increase the risk of bleeding
d. Anti-platelet drug (aspirin, clopidogrel) can increase the risk of bleeding

Front 21

Rivaroxaban

Clinical Use

Back 21

a. Thromboprophylaxis in patients
undergoing hip or knee replacement
surgery
b. Treatment and secondary prevention
of VTE (DVT or pulmonary embolism)

Front 22

Direct thrombin inhibitors
1. Mechanism of action

Back 22

a. Directly interact with the thrombin
molecule
b. Able to inhibit circulating and clotbound
thrombin
c. Lepirudin is the most potent since it
binds to both the active site and a
second site on the thrombin molecule
d. Argatroban and dabigatran bind only to the active site of thrombin

Front 23

Pharmacokinetics
a. Lepirudin

Back 23

(1) administered via continuous intravenous infusion or subcutaneously
(2) eliminated renally; adjust dose in patients with impaired renal
function
(3) monitor therapy using aPTT

Front 24

Pharmacokinetics

Dabigatran

Back 24

(1) Dabigatran etexilate is rapidly absorbed from the gastrointestinal
tract and converted by serine esterases to dabigatran, which is the
active form
(2) Eliminated in the urine; Use with caution in patients with mild to
moderate renal impairment, Should not be used in severe renal
impairment

Front 25

Pharmacokinetics
Argatroban

Back 25

(1) administered via continuous intravenous infusion
(2) eliminated by hydroxylation and aromatization in the liver; reduce
dose in patients with impaired liver function
(3) monitor therapy using aPTT

Front 26

Direct thrombin inhibitors
(dabig, argatro, lepirudin)

Uses

Back 26

a. Lepirudin and argatroban - used in patients with HIT to prevent further
thromboembolic complications
b. Dabigatran - Primary and secondary prevention of thromboembolism in
patients with nonvalvular atrial fibrillation

Front 27

Direct thrombin inhibitors
(dabig, argatro, lepirudin)

Adverse Effects

Back 27

Bleeding - no specific antidotes

Front 28

Direct thrombin inhibitors
(dabig, argatro, lepirudin)

Drug interaxns

Back 28

Other anticoagulants can increase the risk of bleeding

Front 29

Vitamin K antagonist - Warfain
1. Mechanism of action

Back 29

a. The drug inhibits vitamin K epoxide reductase which is the enzyme that
regenerates reduced vitamin K. Warfarin’s action occurs in the liver
b. Warfarin has no effect on the activity on the clotting factors that are
already formed. Therefore the onset of warfarin activity depends upon
the rate of metabolism of the performed factors. (Factor II: 60 hrs, Factor
VII: 8 hrs, Factor IX: 24 hrs, Factor X: 40 hrs, Protein C: 14 hrs)
c. There is a delay of several days between the drug administration and the
peak anticoagulant effect.

Front 30

Vitamin K antagonist - Warfain

admin/elim

Back 30

a. Warfarin is well absorbed orally
b. The drug is metabolized in the liver

Front 31

Vitamin K antagonist - Warfain

adverse effects

Back 31

a. Bleeding (It can occur at any site and is related to dosage, length of therapy, patient’s underlying disorder and concomitant use of other
drugs.)
b. Skin necrosis (Lesions are characterized by widespread thrombosis of
the microvasculature and can spread rapidly, sometimes becoming
necrotic and requiring debridement or amputation.)
c. Fetal toxicity: it includes abortion, fetal bleeding and a characteristic
pattern of malformations called fetal warfarin syndrome

Front 32

Vitamin K antagonist - Warfain

drug interaxns: decreased effect

Back 32

Drug interactions associated with decreased effect of oral anticoagulants
(shortened PT)
(1) Reduced absorption of drug caused by binding to cholestyramine in
the gastrointestinal tract
(2) Increased metabolic clearance of drug secondary to induction of
hepatic enzymes (e.g., barbiturates)
(3) Ingestion of large amounts of vitamin K-rich foods or supplements

Front 33

Vitamin K antagonist - Warfain

Contraindications

Back 33

a. Any disease that increases the risk of hemorrhage (e.g., aplastic
anemia, leukemia, thrombocytopenia, thrombotic thrombocytopenic
purpura, infective endocarditis, inflammatory bowel disease, peptic ulcer,
gastrointestinal neoplasms, active pulmonary tuberculosis, etc.)
b. Concomitant use of drugs that enhance the anticoagulant effect of
warfarin
c. Pregnancy

Front 34

Vitamin K antagonist - Warfain

Clinical use

Back 34

a. Prevention and treatment of VTE
b. In patients with atrial fibrillation and a presumed cardiac source of
embolism, warfarin is the antithrombotic agent of first choice for primary
and secondary prevention of ischemic stroke.

Front 35

Vitamin K antagonist - Warfain

Dosing

Back 35

a. Genetic variations in the CYP2C9 isozyme (responsible for metabolizing
warfarin) and vitamin K epoxide reductase (VKOR) have been shown to correlate with warfarin dose requirements.
b. The dose of warfarin is patient specific based on the desired intensity of
anticoagulation and the patient’s individual response.
c. There is tremendous intrapatient variability so it is necessary to
continually monitor clinical response and laboratory values.
d. Routine monitoring of the INR (International Normalized Ratio) is used to
assess anticoagulation; the goal range is determined by the therapeutic
indication; usually a target of 2.5 with an acceptable range of 2.0-3.0.
e. Bleeding or high INR
(1) Vitamin K administered orally or intravenously can be used to lower
the INR rapidly
(2) In cases of serious or life-threatening bleeding, vitamin K should be
administered with fresh-frozen plasma, clotting factor concentrates,
or recombinant factor VIII.

Front 36

Vitamin K antagonist - Warfain

Drug interactions associated with increased effects

Back 36

Drug interactions associated with increased effects of warfarin and thus
hemorrhage (excessive PT prolongation)
(1) Decreased metabolism due to P450 inhibition (e.g., cimetidine)
(2) Elimination of intestinal flora by antimicrobial agents. Gut bacteria
synthesize vitamin K and thus are an important source of this
vitamin.
(3) Hormone replacement therapy for hypothyroid patients.
Hypothyroid patients catabolize coagulation factors more slowly
than euthyroid patients. When thyroid function is normalized,
anticoagulant effects can increase due to increased rate of
catabolism of coagulation factors.

Front 37

Prophylaxis of VTE

Back 37

1. Prophylaxis therapy is given throughout the period of risk
2. Drugs used
a. Low-dose heparin subcutaneous administration
b. Enoxaparin
c. Fondaparinux
d. Warfarin
e. Rivaroxaban
f. Dabigatran is currently indicated only for prevention of stroke and
systemic embolism in patients with nonvalvular AF but further studies
may establish its value in preventing VTE

Front 38

Treatment of acute venous thromboembolism (DVT or pulmonary embolism)

Back 38

1. Confirm diagnosis
2. Initiate therapy with rapid-acting injectable anticoagulant (heparin,
enoxaparin, fondaparinux)
a. Stable patients who have low bleeding risk and no other comorbid
conditions can be discharged early or treated entirely on an outpatient
basis; in these cases, enoxaparin is used
b. Rivaroxaban is indicated for treatment of DVT but it does not have the
long-term history for use in DVT as the injectable agents have
3. Begin warfarin therapy concurrently with rapid-acting injectable
anticoagulant therapy
a. Therapy should overlap for at least 5 days and until the INR is $2.0
b. The warfarin dose should be periodically adjusted to maintain an INR
between 2.0 and 3.0.
c. The minimum duration of warfarin therapy for an acute first episode of
VTE is 3 months
4. Rivaroxaban (and probably eventually dabigatran) is an alternative to the
use of warfarin and has several advantages including convenience, it does
not require routine monitoring. NO antidote for newer drugs

Front 39

Pregnancy
1. Use of anticoagulation therapy for the treatment of DVT or PE in pregnant women

Back 39

1. Use of anticoagulation therapy for the treatment of DVT or PE in pregnant
women is common.
2. Low-molecular weight heparins (e.g., enoxaparin) is preferred for prevention
and treatment of VTE
3. Fondaparinux and parenteral direct thrombin inhibitors can be used in
pregnant patients with severe allergic reactions to heparin (e.g., HIT).
4. Oral direct thrombin inhibitors (dabigatran) and factor Xa inhibitors
(rivaroxaban) should be avoided since their effects on the fetus are not fully
known.
5. Warfarin should be avoided because it is toxic to the embryo and fetus.
Enoxaparin can be substituted

Front 40

Management of heparin-induced thrombocytopenia
1. Pathophysiology

Back 40

a. Heparin binds PF4 (released from activated platelets) forming a
negatively charged polysaccharide molecule that is highly antigenic
b. IgG antibody production is stimulated and IgG complexes with heparin-
PF4
c. The IgG-heparin-PF4 complexes bind to Fc receptor on platelets leading
to further activation of platelets and release of PF4
d. PF4 and heparin-like molecules bind to the surface of endothelial cells
resulting in antibody-induced endothelial cell damage and the release of
tissue factor
e. Net result: increased risk of thrombotic events secondary to platelet
activation, endothelial damage, and thrombin generation

Front 41

Management of heparin-induced thrombocytopenia

Clinical presentation

Back 41

a. Thrombotic complications
(1) VTE is most common including DVT and pulmonary embolism;
arterial thrombosis is less common
(2) Skin lesions, venous limb gangrene and anaphylactic-type
reactions after intravenous heparin are atypical manifestations
b. Mortality may be as high as 50% in patients with acute thrombosis

Front 42

Management of heparin-induced thrombocytopenia

Treatment

Back 42

a. Goal of therapy is to reduce the risk of thrombosis
b. All sources of heparin, including flushes, should be discontinued
c. Direct thrombin inhibitors (argatroban or lepirudin) are the drugs of
choice in patients with or without thrombosis
d. Patients without thrombosis receive therapy until the platelet count
normalizes
e. Patients with thrombosis should receive therapy with direct thrombin
inhibitors and transition to warfarin after platelet counts recover. Warfarin
therapy is then maintained for at least 6 months
f. Patients with a history of HIT should receive alternative anticoagulant
agents