Inferior Vena Caval (IVC) Filters

The two principal indications for insertion of an IVC filter are (1) active bleeding that
precludes anticoagulation, and (2) recurrent venous thrombosis despite intensive
anticoagulation. Prevention of recurrent PE in patients with right heart failure who
are not candidates for fibrinolysis or prophylaxis of extremely high-risk patients are
"softer" indications for filter placement. The filter itself may fail by permitting the
passage of small to medium-sized clots. Large thrombi may embolize to the
pulmonary arteries via collateral veins that develop. A more common complication
is caval thrombosis with marked bilateral leg swelling.
Paradoxically, by providing a nidus for clot formation, filters double the DVT rate
over the ensuing 2 years following placement. Therefore, if clinically safe, patients
receiving IVC filters should also receive concomitant anticoagulation.
Retrievable filters can now be placed for patients with an anticipated temporary
bleeding disorder or for patients at temporary high risk of PE, such as individuals
undergoing bariatric surgery with a prior history of perioperative PE. The filters can
be retrieved up to several months following insertion, unless thrombus forms and is
trapped within the filter. The retrievable filter becomes permanent if it remains in
place or if, for technical reasons such as rapid endothelialization, it cannot be
removed.
Maintaining Adequate Circulation
For patients with massive PE and hypotension, the most common initial approach is
administration of 5001,000 ml of normal saline. However, fluids should be used
with extreme caution. Excessive fluid administration exacerbates RV wall stress,
causes more profound RV ischemia, and worsens LV compliance and filling by
causing further interventricular septal shift toward the LV. Dopamine and
dobutamine are first-line inotropic agents for treatment of PE-related shock. There
should be a low threshold to initiate these pressors. However, a "trial and error"
approach may be necessary with other agents such as norepinephrine, vasopressin,
or phenylephrine.
Fibrinolysis
Successful fibrinolytic therapy rapidly reverses right heart failure and leads to a
lower rate of death and recurrent PE. Thrombolysis usually (1) dissolves much of the
anatomically obstructing pulmonary arterial thrombus; (2) prevents the continued
release of serotonin and other neurohumoral factors that exacerbate pulmonary
hypertension; and (3) dissolves much of the source of the thrombus in the pelvic or
deep leg veins, thereby decreasing the likelihood of recurrent PE.
The preferred fibrinolytic regimen is 100 mg of recombinant tissue plasminogen
activator (tPA) administered as a continuous peripheral intravenous infusion over 2

h. Patients appear to respond to fibrinolysis for up to 14 days after the PE has

occurred.
Contraindications to fibrinolysis include intracranial disease, recent surgery, or
trauma. The overall major bleeding rate is about 10%, including a 13% risk of
intracranial hemorrhage. Careful screening of patients for contraindications to
fibrinolytic therapy (Chap. 239) is the best way to minimize bleeding risk.

The only FDA-approved indication for PE fibrinolysis is massive PE. For patients with
preserved systolic blood pressure and submassive PE, guidelines recommend
individual patient risk assessment of the thrombotic burden versus bleeding risk. I
concur with these guidelines. Younger patients with submassive PE but without
comorbidities are generally excellent candidates for fibrinolysis. For older patients
(>70 yrs) with risk of intracranial hemorrhage, a "watch and wait" approach is
suitable, with frequent serial evaluation of RV function by echocardiography;
fibrinolysis should be considered in those with deterioration of RV function.

Low Molecular Weight Heparins

These fragments of UFH exhibit less binding to plasma proteins and endothelial cells
and consequently have greater bioavailability, a more predictable dose response,
and a longer half-life than UFH. No monitoring or dose adjustment is needed unless
the patient is markedly obese or has renal insufficiency.

Enoxaparin 1 mg/kg twice daily and tinzaparin 175 units/kg once daily have
received U.S. Food and Drug Administration (FDA) approval for treatment of patients
who present with DVT. The weight-adjusted doses must be adjusted downward in
renal insufficiency because the kidneys excrete LMWH.

Fondaparinux

Fondaparinux, an anti-Xa pentasaccharide, is administered by once-daily

subcutaneous injection and has been approved by the FDA to treat DVT and PE. No
laboratory monitoring is required. Patients weighing <50 kg receive 5 mg, 50100
kg patients receive 7.5 mg, and patients weighing >100 kg receive 10 mg. The dose
must be adjusted downward for patients with renal dysfunction because the drug is
excreted by the kidneys.

Warfarin

This vitamin K antagonist prevents carboxylation activation of coagulation factors II,

VII, IX, and X. The full effect of warfarin requires at least 5 days, even if the
prothrombin time, used for monitoring, becomes elevated more rapidly. If warfarin is
initiated as monotherapy during an acute thrombotic illness, a paradoxical
exacerbation of hypercoagulability can increase the likelihood of thrombosis rather
than prevent it. Overlapping UFH, LMWH, or fondaparinux with warfarin for at least
5 days can counteract the early procoagulant effect of unopposed warfarin.

Dosing

In an average-sized adult, warfarin is usually initiated in a dose of 5 mg. Doses of

7.5 or 10 mg can be used in obese or large-framed young patients who are
otherwise healthy. Patients who are malnourished or who have received prolonged
courses of antibiotics are probably deficient in vitamin K and should receive smaller
initial doses of warfarin, such as 2.5 mg. The prothrombin time is standardized with
the INR, which assesses the anticoagulant effect of warfarin (Chap. 59). The target
INR is usually 2.5, with a range of 2.03.0.

The warfarin dose is titrated to achieve the target INR. Proper dosing is difficult
because hundreds of drug-drug and drug-food interactions affect warfarin
metabolism. Furthermore, variables such as increasing age and comorbidities such
as systemic illness, malabsorption, and diarrhea reduce the warfarin-dosing
requirement.

No reliable nomogram has been established to predict how individual patients will
respond to warfarin. Therefore, dosing is adjusted according to an "educated
guess." Centralized anticoagulation clinics have improved the efficacy and safety of
warfarin dosing. Based upon a meta-analysis of trials comparing anticoagulation
clinic care versus self-monitoring, patients benefit if they can self-monitor their INR
with a home point-of-care fingerstick machine. The subgroup with the best results
also learns to self-adjust warfarin doses.

Pharmacogenomics may provide the gateway to rational dosing of warfarin. A

recent discovery is that five polymorphisms of the vitamin K receptor gene explain
25% of the variance in warfarin dosing. These polymorphisms can stratify patients
into low, intermediate, and high-dose warfarin groups. An additional 10% of dosing
variance can be explained by allelic variants of the cytochrome P-450 enzyme 2C9.
These mutations decrease warfarin dosing because they impair the metabolism of
the S-enantiomer of warfarin. In the future, if rapid turnaround of genetic testing
becomes possible, warfarin could be dosed according to specific pharmacogenomic
profiles.

Complications of Anticoagulants

The most important adverse effect of anticoagulation is hemorrhage. For lifethreatening or intracranial hemorrhage due to heparin or LMWH, protamine sulfate
can be administered. There is no specific antidote for bleeding from fondaparinux.

Major bleeding from warfarin is traditionally managed with cryoprecipitate or freshfrozen plasma (usually 24 units) to achieve rapid hemostasis. Recombinant human
coagulation factor VIIa (rFVIIa), FDA-approved for bleeding in hemophiliacs, is widely
used off-label to manage catastrophic bleeding from warfarin. The optimal dose
appears to be 40 mcg/kg. The greatest risk of this therapy is rebound
thromboembolism. For minor bleeding, or to manage an excessively high INR in the
absence of bleeding, a small 2.5 mg dose of oral vitamin K may be administered.

Heparin-induced thrombocytopenia (HIT) and osteopenia are far less common with
LMWH than with UFH. Thrombosis due to HIT should be managed with a direct
thrombin inhibitor: argatroban for patients with renal insufficiency or lepirudin for
patients with hepatic failure. In the setting of percutaneous coronary intervention,
administer bivalirudin.

The most common nonbleeding side effect of warfarin is alopecia. A rare

complication is warfarin-induced skin necrosis, which may be related to warfarininduced reduction of protein C.

During pregnancy, warfarin should be avoided if possible because of warfarin

embryopathy, which is most common with exposure during the 6th through 12th
week of gestation. However, women can take warfarin postpartum and breast-feed
safely. Warfarin can also be administered safely during the second trimester.

Duration of Hospital Stay

Acute DVT patients with good family and social support, permanent residence,
telephone, and no hearing or language impairment can often be managed as
outpatients. They or a family member or a visiting nurse can administer a
parenteral anticoagulant. Warfarin dosing can be titrated to the INR and adjusted on
an outpatient basis.

Acute PE patients, who traditionally have required 5-7 day hospital stays for
intravenous heparin as a "bridge" to warfarin, can be considered for abbreviated
hospitalization if they have an excellent prognosis. The latter are characterized by
clinical stability, absence of chest pain or shortness of breath, normal right
ventricular size and function, and normal levels of cardiac biomarkers.

Duration of Anticoagulation

Patients with PE following surgery or trauma ordinarily have a low rate of recurrence
after 36 months of anticoagulation. For DVT isolated to an upper extremity or calf

that has been provoked by surgery or trauma, 3 months of anticoagulation suffices.

For provoked proximal leg DVT or PE, 6 months of anticoagulation is sufficient.

However, among patients with "idiopathic," unprovoked DVT or PE, the recurrence
rate is surprisingly high after cessation of anticoagulation. VTE that occurs during
long-haul air travel is considered unprovoked.

Current American College of Chest Physicians (ACCP) guidelines recommend

anticoagulation for an indefinite duration with a target INR between 2.0 and 3.0 for
patients with idiopathic VTE. However, I recommend that the intensity of
anticoagulation be tailored to the patient's risk of recurrent VTE versus risk of
bleeding. For a patient at high risk of recurrent VTE (for example, someone with
multiple thrombophilic disorders) and a low risk of bleeding (for example, young age
and no comorbidities), I recommend standard intensity anticoagulation. However,
for a patient with a high bleeding risk (for example, older age and a prior history of
gastrointestinal bleeding), I advise low-intensity anticoagulation (INR 1.52.0) after
6 months.

Several years ago, the presence of genetic mutations such as factor V Leiden or
prothrombin gene mutation was thought to markedly increase the risk of recurrent
VTE. Now, however, the clinical circumstances in which the DVT or PE occurs rather
than underlying thrombophilia are considered much more important in deciding the
risk of recurrence and the optimal duration of anticoagulation. However, patients
with moderate or high levels of anticardiolipin antibodies probably warrant indefinite
duration anticoagulation, even if the initial VTE was provoked by trauma or surgery.