Venous thromboembolism (VTE) is a disorder that includes deep vein thrombosis and pulmonary embolism. A deep vein thrombosis (DVT) occurs when a blood clot forms in a deep vein, usually in the lower leg, thigh, or pelvis.
43. Concept of D-Dimer
• D-dimer is a simple blood test frequently used in the diagnostic
evaluation of patients suspected to have VTE
• D-dimer is a degradation product of a fibrin blood clot and levels of D-
dimer are significantly elevated in patients with acute thrombosis.
• Although the D-dimer test is a very sensitive marker of clot formation,
it is not sufficiently specific
44. Concept of D-Dimer
• A variety of conditions can cause elevations of serum D-dimer,
including recent surgery or trauma, pregnancy, and cancer
• Therefore, a negative test can help to “rule out” a DVT or PE but a
positive test should not be used to “rule in” the diagnosis
59. FONDAPARINUX
• Fondaparinux is the first in a class of anticoagulants that selectively
inhibits factor Xa activity
• Similar to UFH and the LMWHs, fondaparinux prevents thrombus
generation and clot formation by indirectly inhibiting factor Xa activity
through its interaction with antithrombin.
60. FONDAPARINUX - Dose and Administration
• Fondaparinux is FDA-approved for the prevention of VTE following
orthopedic (hip fracture, hip replacement, and knee replacement)
surgery and for the treatment of DVT and PE
• In the setting of VTE prevention, the dose of fondaparinux is 2.5 mg
injected subcutaneously once daily starting 6 to 8 hours following
surgery
61. FONDAPARINUX - Dose and Administration
• It is important to avoid initiating fondaparinux too soon because
there is a significant relationship between the timing of the first dose
and the risk of major bleeding complications
• Patients who weigh less than 50 kg should not be given fondaparinux
for VTE prophylaxis
• The usual duration of therapy is 5 to 9 days, but may be given as
extended prophylaxis following hospital discharge for up to 21 days
62. FONDAPARINUX - Dose and Administration
• For the treatment of DVT or PE, the dose of fondaparinux is 7.5 mg
given subcutaneously once daily
• Patients who weight more than 100 kg should be given 10 mg once
daily and those who weigh less than 50 kg should receive only 5 mg
daily
• Administered into the fatty tissue of the abdominal wall (at a 90°
angle)
63. FONDAPARINUX - Therapeutic Monitoring
• CBC – Baseline & periodically
• Baseline kidney function
• Signs and symptoms of neurologic impairment (in case of neuraxial
anesthesia)
64. FONDAPARINUX - Adverse Effects
• Bleeding
• Because the risk of major bleeding appears to be related to weight, in
patients who weigh less than 50 kg, fondaparinux is contraindicated
for VTE prophylaxis and the treatment dose is only 5 mg every 24
hours
65. FONDAPARINUX - Adverse Effects
• Similar to UFH and the LMWHs, fondaparinux should be used with
extreme caution in patients with neuraxial anesthesia or following a
spinal puncture because of the risk for spinal or epidural hematoma
formation
66. IDRAPARINUX
• Idraparinux is an analog of fondaparinux that has very long duration
of effect and was developed to be administered once weekly by
subcutaneous injection
• Idraparinux is currently undergoing phase III clinical trials evaluating
its usefulness for both the acute and long-term management of VTE
67. DIRECT THROMBIN INHIBITORS
• In recent years, research has focused on the development of direct
thrombin inhibitors (DTIs) that may offer benefits over traditional
agents in the treatment and prevention of various thrombotic
disorders
• Currently four parenteral agents—lepirudin, desirudin, bivalirudin,
and argatroban—are approved for use in the United States, and
several oral compounds are in various phases of clinical development
69. DIRECT THROMBIN INHIBITORS - Therapeutic
Monitoring
• Although the DTIs produce changes in the prothrombin time, the
aPTT is used to monitor the patient’s response to lepirudin, desirudin,
and argatroban
• A complete blood count should be obtained at baseline and
periodically thereafter to detect potential bleeding.
70. DIRECT THROMBIN INHIBITORS - Adverse
Effects
• Hemorrhage is the most serious and common adverse effect related
to the DTIs
• In studies evaluating the use of lepirudin for the treatment of patients
with HIT, the incidence of major bleeding was relatively high (13% to
17%).
• A slightly lower rate of major hemorrhage was reported in HIT trials
using argatroban (approximately 5%) and, similarly, there were no
reports of fatal or intracranial bleeding
71. DIRECT THROMBIN INHIBITORS - Adverse
Effects
• Nonhemorrhagic effects such as
• fever, nausea, vomiting, and allergic reactions occur infrequently
72.
73.
74.
75.
76.
77. Use in Special Populations
• Lepirudin, bivalirudin, and argatroban are classified by the FDA as
pregnancy category B drugs but they should be used cautiously in
women of child bearing age because experience is very limited
• Desirudin is classified as pregnancy category C with no controlled
trials in pregnant women
78. UNFRACTIONATED HEPARIN
• Today, UFH and the low-molecular-weight heparins (LMWHs) are the
most commonly used therapies for the acute treatment of arterial
and venous thrombosis
79. UNFRACTIONATED HEPARIN - Dose
• The typical dose for prophylaxis is 5,000 units every 8 to 12 hours.
• When immediate and full anticoagulation is required, a weight-based
IV bolus dose followed by a continuous infusion is preferred
• Subcutaneous UFH (initial dose of 333 units/kg followed by 250
units/kg every 12 hours) also provides adequate therapeutic
anticoagulation for the treatment of acute VTE
80.
81. Practice Points
• When UFH is administered via the IV route, a continuous infusion is
preferable
• Intermittent IV boluses produce relatively high peaks in
anticoagulation activity and have been associated with a greater risk
of major bleeding
• Intramuscular administration is discouraged because of erratic
absorption and risk of large hematoma formation
82. Practice Points
• Administration of UFH has traditionally required close monitoring
because of the unpredictable anticoagulant patient response
• Several tests are available to monitor UFH therapy including whole
blood clotting time, activated partial thromboplastin time (aPTT),
activated clotting time (ACT), antifactor Xa activity, and plasma
heparin concentrations
83. Practice Points
• Long-term UFH has been reported to cause alopecia, priapism, and
suppressed aldosterone synthesis with subsequent hyperkalemia
• The use of UFH in doses ≥20,000 units/day for more than 6 months,
especially during pregnancy, is associated with significant bone loss
and may lead to osteoporosis
• Concurrent use with other antithrombotic drugs, thrombolytics, and
antiplatelet agents increases the risk of bleeding, however
84. Heparin in Pregnancy
• Heparin-related compounds such as UFH or LMWH are the
anticoagulants of choice during pregnancy
• Because UFH does not cross the placenta, it is not associated with
teratogenicity or fetal bleeding complications
• UFH should be used cautiously during the last trimester of pregnancy
and the peripartum period because of the risk of maternal
hemorrhage
85. Heparin use in children
• Advances in tertiary care for pediatric patients have resulted in
increasing numbers of children requiring antithrombotic therapy, and
UFH is commonly used in this setting
• For the treatment of acute thrombosis in children, the dosage of UFH
is an initial loading dose of 75 to 100 units/kg over 10 minutes
followed by a maintenance dose of 28 units/kg/h for infants up to 12
months of age and 20 units/kg/h for children 1 year old and older
86. LOW-MOLECULAR-WEIGHT HEPARINS
• These agents have several advantages over UFH, including
(a) predictable anticoagulation dose response,
(b) improved subcutaneous
(c) dose-independent clearance
(d) longer biologic
(e) lower incidence of thrombocytopenia, and
(f) a reduced need for routine laboratory monitoring
87.
88. LOW-MOLECULAR-WEIGHT HEPARINS
• For the prevention of VTE, the LMWHs have been studied in a variety of
high-risk circumstances, including orthopedic surgery, abdominal surgery,
acute spinal cord injury, neurosurgery, multiple trauma, and critical illness
• The effectiveness of the LMWHs has been extensively evaluated for the
treatment of VTE in hospitalized patients and used in the outpatient
management of DVT
• They are also a reasonable alternative to warfarin therapy in circumstances
when a prothrombin time (PT)/international normalized ratio (INR) can not
be routinely obtained
89.
90. Practice Points
• Prior to initiation of LMWH, a baseline PT/INR, aPTT, complete blood
cell count with platelet count, and serum creatinine should be
obtained
• Most experts recommend monitoring the complete blood cell count
every 5 to 10 days during the first 2 weeks of LMWH therapy and
every 2 to 4 weeks thereafter.
91. Safety Profile
• Several cases of epidural and spinal hematoma resulting in long-term
or permanent paralysis have been reported with the use of
enoxaparin during spinal and epidural anesthesia or spinal puncture
• The risk of these events is higher with the use of indwelling epidural
catheters and concomitant use of drugs that affect hemostasis.
92. Safety Profile
• The risk of osteoporosis appears to be substantially lower with the
LMWHs than with UFH
• The LMWHs have not caused appreciabl changes in bone mineral
density after several months of use
• They have been used in a limited number of patients with established
heparin-induced osteoporosis
93. Use in Special Populations
• Dalteparin, enoxaparin, and tinzaparin are classified as FDA
pregnancy category B
• The LMWHs are becoming the preferred agents in pediatric
populations despite the fact that the safety and effectiveness of the
LMWHs to treat VTE in children and infants has not been extensively
studied
94. WARFARIN
• Warfarin is FDA-approved for the prevention and treatment of VTE, as
well as for the prevention of thromboembolic complications
associated with atrial fibrillation, heart valve replacement, and
myocardial infarction
• Because of its narrow therapeutic index, predisposition to drug and
food interactions, and propensity to cause hemorrhage, warfarin
requires continuous patient monitoring and education to achieve
optimal outcomes
95. Dosing
• To achieve a therapeutic INR in the least amount of time, some clinicians have
used relatively high doses of warfarin (10 or 15 mg) and then adjusted the dose
based on the patient’s response
• Studies in patients with atrial fibrillation that compared a 5-mg initial dose to a
10-mg dose questioned this practice
• Although a 10-mg dose produced a more rapid response in the INR, many
patients subsequently became excessively anticoagulated.
• However, a more recent study in patients with acute venous thrombosis
demonstrated that 10-mg initial doses can be used safely when the subsequent
INR response is monitored appropriately
96.
97.
98.
99. Purple Toe Syndrome
• The “purple toe syndrome,” manifested as a purplish discoloration of
the toes, is an extremely rare event reported in a small percentage of
patients receiving warfarin
• The etiology of this unusual phenomenon is unknown, but is thought
to be the result of cholesterol microembolization into the arterial
circulation of the toes
100. Warfarin Induced Skin Necrosis
• Warfarin-induced skin necrosis is an uncommon but very serious
dermatologic reaction that is manifested by a painful maculopapular
rash and ecchymosis or purpura that subsequently progresses to
necrotic gangrene
• It most frequently appears in areas of the body rich in subcutaneous
fat, such as the breasts, thighs, buttocks, and abdomen.
101. Warfarin in Pregnancy
• Warfarin crosses the placenta and is associated with several
embryopathies, particularly CNS abnormalities, that have occurred
throughout gestation
• The FDA has designated warfarin a pregnancy category X agent
