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Monitoring of Antithrombotic Therapies in Interventional Cardiology
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Part VI
Antithrombotic Therapy in Venous
Thromboembolism
https://t.me/med1917
17 Venous Thromboembolism
Esther S.H. Kim and John R. Bartholomew
Co n t e n t s
Epidemiology And Pathogenesis
Prevention Of Venous Thromboembolism
Non-Fatal Complications Of Vte
Deep Venous Thrombosis
Pulmonary Embolism
References
Ab s t r A c t Venous thromboembolism, a clinical entity which includes deep vein thrombosis (DVT) and
pulmonary embolism (PE), is a common, lethal disease that affects both hospitalized and non-hospitalized
patients, recurs frequently, is often overlooked, and results in long-term complications. The currently avail-
able antithrombin agents, including unfractionated heparin, low molecular weight heparin, direct thrombin
inhibitors, vitamin K antagonists, and factor Xa antagonists are employed to prevent and treat this clinical
entity. Improved understanding of the optimal dosing, timing of administration, and duration of therapy of
the currently available antithrombotic therapies to treat venous thromboembolism will hopefully translate
into improved outcomes for these patients.
Key words:
Deep vein thrombosis; Pulmonary embolism; Venous; Thromboembolism; Treatment;
Prophylaxis
EPIDEMIOLOGY AND PATHOGENESIS
Venous thromboembolism (VTE), a clinical entity which includes deep vein thrombosis (DVT)
and pulmonary embolism (PE), is a common, lethal disease that affects both hospitalized and non-
hospitalized patients, recurs frequently, is often overlooked, and results in long-term complications
including chronic thromboembolic pulmonary hypertension (CTPH) and the post-thrombotic
syndrome (PTS). While VTE affects 7.1 persons per 10,000 person-years among community
residents (1), two-thirds of all VTE events are related to hospitalization, and most hospitalized
patients have at least one or more risk factors for VTE (Table 1).
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_17
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
Rudolph Virchow’s triad, formulated in 1856, still forms the best framework for understanding the
pathogenesis of VTE. The triad includes stasis, hypercoagulability, and injury to the vessel wall.
There are both inherited and acquired risk factors for hypercoagulability. The most common inherited
risk factors include: factor V Leiden (activated protein C resistance), the prothrombin gene mutation
20210A, deficiency of the natural anticoagulants proteins C, S, and antithrombin, hyperhomocystinemia,
and elevated factor VIII levels. Acquired risk factors are listed in Table 1 and include immobilization,
surgery, trauma, pregnancy, use of oral contraceptives or hormone replacement therapy, malignancy,
antiphospholipid antibody syndrome (lupus anticoagulant and/or anticardiolipin antibodies) heparin-
induced thrombocytopenia (HIT), myeloproliferative disorders, obesity (BMI
> 30), inflammatory
bowel disease, central venous catheters or pacemakers, and the nephrotic syndrome. Other emerging
risk factors include increasing age, gender, persistence of an elevated D-dimer level, and the contin-
ued presence of venous thrombosis on compression ultrasonography once anticoagulation treatment
is completed. Older patients are at higher risk for VTE (2) as are men treated for an idiopathic VTE
(compared to women) after cessation of anticoagulation therapy (3). There is also recent evidence
linking atherosclerotic arterial disease and VTE (4).
Without appropriate prophylaxis, the incidence of hospital-acquired DVT is 10–20% among
medical patients and even higher among surgical patients (15–40%) (5). Surprisingly, while PE is the
third most common cause of hospital-related death in the United States [10% of hospital deaths are
attributed to PE (6,7) and the in-hospital fatality rate for VTE is 12% (8)], only 58.5% of surgical
Table 1
Risk factors for VTE
Surgery
Trauma (major or lower extremity)
Immobility, paresis
Malignancy
Cancer therapy (hormonal, chemotherapy, or radiotherapy)
Previous VTE
Increasing age
Pregnancy and the postpartum period
Estrogen-containing oral contraception or hormone replacement therapy
Selective estrogen receptor modulators
Acute medical illness
Heart or respiratory failure
Inflammatory bowel disease
Nephrotic syndrome
Myeloproliferative disorders
Paroxysmal nocturnal hemoglobinuria
Heparin-induced thrombocytopenia
Antiphospholipid antibody syndrome
Obesity
Smoking
Varicose veins
Central venous catheterization
Inherited or acquired thrombophilia
Geerts et al. (5) Copyright©2004 by Am College of Chest Physicians.
Reproduced with permission of Am College of Chest Physicians in the format
Textbook via Copyright Clearance Center
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Venous Thromboembolism
patients and 39.5% of hospitalized medical patients at risk for VTE receive ACCP guideline-
recommended prophylaxis
(9).
PREVENTION OF VENOUS THROMBOEMBOLISM
Primary thromboprophylaxis has been shown in numerous studies to be effective in the prevention of
VTE
(10–14) and is recommended for all patients at risk for VTE (15). Monitoring for signs or symptoms
of DVT is unreliable as a method for prevention as PE can be the first manifestation of VTE. The primary
methods of thromboprophylaxis include mechanical compression devices (graduated compression
stockings, intermittent pneumatic compression devices, and venous foot pumps) and/or antithrombotic
medications including low-dose unfractionated heparin, low molecular weight heparins, fondaparinux,
and vitamin K antagonists.
Full recommendations for the prevention of VTE in a wide variety of medical and surgical
patients can be found in the report of the Eigth American College of Chest Physicians Conference
on Antithrombotic and Thrombolytic Therapy (5). Seventy to eighty percent of fatal PEs occur in
non-surgical patients
(16), and risk factors for VTE in hospitalized medical patients include (in
addition to those outlined in Table
1) advanced heart failure (NYHA Class III or IV), COPD
exacerbations, sepsis, and bed rest. The ACCP recommends the use of low-dose unfractionated
heparin or low molecular weight heparin in these individuals or those who have one or more
additional risk factors (5). The recommended dose of UFH for prophylaxis in medical and most
surgical patients is 5,000 units administered subcutaneously every 8–12 h and the recommended
dose of the LMWH, enoxaparin, is 40
mg subcutaneously given once daily unless the patient has a
creatinine clearance under 30 mL/min (Table 2). Mechanical prophylaxis with graduated compression
stockings or intermittent pneumatic compression is recommended in those medical (5) or surgical
patients for whome there is a contraindication to anticoagulation.
NON-FATAL COMPLICATIONS OF VTE
While prevention of fatal PE is a major goal of VTE prophylaxis and treatment, prevention
of the long-term sequelae of VTE is also imperative. These major complications include recur-
rent VTE, chronic thromboembolic pulmonary hypertension (CTPH), and the post-thrombotic
syndrome (PTS).
Table 2
Pharmacotherapy for the prevention of DVT in medical patients
Patient characteristics Medication Options Contraindications to Anticoagulatior
Acutely ill medical patients with
any of the following:
– Unfractionated heparin
5,000 units SC q8–12 h
– Enoxaparin (Lovenox®)
40 mg SC daily
– Enoxaparin (Lovenox®)
30 mg SC daily for
patients with severe renal
disease and creatinine
clearance < 30 mL/min
–
Dalteparin (Fragmin®)
5,000 units SC daily
–
Severe active or major bleeding
– Severe thrombocytopenia
– Heparin induced thrombocytopenia
(HIT)
– Hypersensitivity to Heparin or Low
Molecular Weight Preparations
– Congestive heart failure
– Severe respiratory disease
– Bedridden with risk factors for
development of VTE
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Antithrombotic Drug Therapy in Cardiovascular Disease
Recurrent VTE
Recurrence rates of VTE were investigated in a retrospective cohort study of 1,719 patients with
DVT or PE who were followed for a first recurrence. Overall, 404 patients developed a recurrent
event during 10,198 person-years of follow-up. The overall cumulative incidence rates of probable or
definite recurrence were 1.4% at 1 month, 4.1% at 6 months, 5.6% at 1 year, and 17.6% at 10 years.
The greatest risk for recurrence was in the first 6 months to 1 year, and the hazard rate for recurrence
never fell to zero during the median follow-up times of 7.4 years for DVT and 6.1 years for PE (17).
Potential risk factors for recurrence of VTE include male gender, increasing age, increased
BMI, neurologic disease with associated extremity paresis, active malignancy, lupus anticoagulant,
antithrombin deficiency, protein C or S deficiency, elevated D-dimer and factor VIII levels, persistent
residual DVT on ultrasound, institutionalization, inflammatory bowel disease, previous central venous
catheter or permanent pacemaker placement, and the presence of an IVC filter.
Chronic Thromboembolic Pulmonary Hypertension
Chronic thromboembolic pulmonary hypertension results from an unresolved vascular obstruction
due to pulmonary embolism and is associated with significant morbidity and mortality. The severity
of pulmonary hypertension is determined, in part, by the extent of vascular obstruction and in most
patients with CTPH, more than 40% of the vasculature is involved (18). Patients can remain asymp-
tomatic for years after their initial PE event, but the incidence of CTPH after PE without a known
prior DVT has been shown to be as high as 1.0% at 6 months, 3.1% at 1 year, and 3.8 % at 2 years
(19). Progression to CTPH may be due to recurrent VTE but similar to other forms of pulmonary
hypertension, pulmonary vascular remodeling and subsequent hypertensive arteriopathy also play a
role (20,21). The rate of survival appears to be related to the degree of pulmonary hypertension at the
time of diagnosis and survival is poor when the mean pulmonary artery pressure is >30
mmHg, or
when there is evidence of right heart failure. One observational study of 76 patients with pulmonary
thromboembolic disease found that the survival rate over a mean of 5 years of follow-up was 30% if
the initial mean pulmonary artery pressure was >40
mmHg and only 10% if it was >50 mmHg (22).
Post-thrombotic Syndrome
Post-thrombotic syndrome is caused by venous valvular incompetence due to previous DVT. It is
a cause of substantial morbidity
(23) and usually occurs within the first 2 years after DVT with a
reported incidence of 17% at 1 year and up to 28% by 5 years (24). PTS is characterized by a cluster
of signs and symptoms including extremity pain, dependent edema, and cramping which is often
worse at the end of the day. Severe manifestations of PTS (Fig. 1) are stasis hyperpigmentation,
venous ulceration, and venous claudication. One treatment modality which drastically reduces the
incidence of PTS is the use of graduated compression stockings and current ACCP guidelines recom-
mend their use at a pressure of 30–40 mmHg (at the ankle) for 2 years after an acute DVT (25).
DEEP VENOUS THROMBOSIS
Physical Examination
DVT most commonly occurs in the lower extremities but other affected sites include the upper
extremities, cerebral, mesenteric, portal, renal, and pelvic veins. Untreated proximal lower-extremity
DVTs (popliteal vein and above) have an estimated 50% risk for PE, while about 25% of calf vein
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Venous Thromboembolism
thrombi propagate (in the absence of treatment) to involve a more proximal vein. Patients with DVT may
complain of pain and swelling and physical examination may reveal warmth, tenderness, edema, or the
presence of dilated veins (collaterals). In extreme situations, cyanosis or gangrene of the limb may be
present. Phlegmasia cerulea dolens (a limb-threatening manifestation of DVT in which the thrombus
completely occludes venous outflow resulting in severe limb swelling, capillary bed hypertension, and
eventually ischemia and necrosis) occurs most frequently in patients with underlying malignancy,
heparin-induced thrombocytopenia (HIT), or other hypercoagulable conditions. It is a vascular emer-
gency and treatment includes leg elevation, anticoagulation, and in refractory cases, thrombolysis or
mechanical thrombectomy. If present, an associated compartment syndrome requires fasciotomy.
Homans’ sign (dorsiflexion of the ankle with knee at 30° flexion causing calf pain), Louvel’s sign
(worsening of pain with coughing or sneezing), and Lowenberg’s sign (pain on the affected leg after
inflation of a sphygmomanometer around each calf) may be present in patients with DVT. In general,
these signs and clinical examination are unreliable in the diagnosis of DVT
(26) because they are often
insensitive and nonspecific. Pretest probability scores have been developed to aid in the diagnosis of
DVT. For example, patients with a low pretest probability using the Wells score (27,28) (Table 3) have
a 96% negative predictive value for DVT (99% if the D-dimer is negative as well). For patients with high
pretest probability, however, the Wells score confers a positive predictive value of less than 75%,
supporting the need for further diagnostic testing to identify patients with thrombosis (29,30).
Diagnosis
While venography has been the gold standard for the diagnosis of DVT, it is an invasive test which
requires the use of intravenous contrast agents. For these reasons, it has largely been replaced as a first-line
diagnostic tool by other noninvasive tests such as duplex ultrasonography. When utilized, the presence of
DVT on venography is confirmed by the presence of an intraluminal filling defect, although several
other clues to the presence of thrombus include an abrupt cutoff, nonfilling of the deep venous sys-
tem, and/or the demonstration of collateral flow.
Duplex compression ultrasonography is a highly sensitive and specific test for the detection of
DVT in symptomatic patients (sensitivity 95% and specificity 98%); however, it is operator dependent
and is less sensitive in asymptomatic individuals and for detection of DVT in the calf veins (31,32).
Fig. 1. Venous ulceration is a severe manifestation of the post-thrombotic syndrome. There is associated stasis hyper-
pigmentation, edema, and lipodermatosclerosis. Venous ulcers usually occur around the medial malleolus where
venous pressure is greatest due to the presence of large perforating veins.
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