Management of Venous Thromboembolism
K. Pavithran*
Mathew Thomas*
* Assistant Professor in hematology
**Professor of Medicine
Medical college hospital
Thiruvananthapuram-695011
Address for Correspondence:
Dr. K. Pavithran,
Department of Hematology
Medical College Hospital,
Thiruvananthapuram-695011
Email: drkpavithran@hotmail.com
See also Thromobopoetin by Pavithran
Management of Venous Thromboembolism
Introduction
Venous thrombosis is the third most common cardiovascular disease after ischemic
heart disease and stroke.1 It is common in whites, affecting 1 in 1,000 individuals
every year, and is strongly associated with life-threatening pulmonary embolism
(PE). Though the exact incidence is not known in India it is becoming a common
clinical problem because the physicians and the surgeons are now more aware
of venous thrombosis.
In addition to circumstantial predisposing factors eg.surgery, pregnancy, or
immobilization), genetic abnormalities, molecular abnormalities of components
of the coagulation pathway leading to hypercoagulability and, in turn, to thrombophilia
have been found in subjects who have had thromboembolic disease (Table 1).2
Venous thrombosis occur most commonly in the lower limbs though it can occur
in any vein in the body. Thrombosis of superficial veins (as occurring in varicosities)
is benign and self-limiting. Thrombosis of deep vein is a serious condition.
Thrombi localized to the deep veins of the calf are less serious than those
involving the proximal veins (popliteal, femoral or iliac veins) because they
are often smaller and therefore less commonly associated with long term disability
or clinically important pulmonary embolism (PE). On the other hand PE frequently
complicates proximal vein thrmbosis. Asymptomatic PE is detected by perfusion
lung scanning in about 50% of patients with documented proximal vein thrombosis.
Asymptomatic venous thrombosis is found in 70% of patients who present with
confirmed PE.
Clinical approach -
A. Diagnosis of venous thrombosis
1. Clinical Diagnosis of venous thrombosis
Clinical diagnosis of venous thrombosis
in symptomatic patients lacks both sensitivity and specificity. It is insensitive
because many potentially dangerous thrombi do not totally obstruct the veins
nor produce inflammation of the vessel wall and therefore produce minimal clinical
manifestations. It is non-specific because none of the signs and symptoms is
unique to this condition.
Other conditions frequently confused with venous thrombosis include muscle strain
or tear, superficial thrombophlebitis, lymphangitis, lymph edema, cellulitis
and post-phlebitic syndrome.
Maneuvers formerly recommended for diagnosis of DVT, such as Homan sign (pain
provoked by forced dorsiflexion of the foot) or the Lowemberg sign (pain provoked
by the application on the calf of the sphygmomanometer cuff at relatively low
pressure) are totally useless and even dangerous as is any other maneuver exerted
on the calf at the time of a recent DVT.
2. Imaging
The standard diagnostic test for
deep-vein thrombosis of the lower extremities is ascending phlebography. Phlebography
can detect both distal thrombi (in the calf veins, a common site of inception
of deep-vein thrombosis) and proximal thrombi (in the popliteal, femoral, and
iliac veins), which are the source of most large pulmonary emboli.
Other objective diagnostic methods include impedance plethysmography 3 and various
forms of real-time B-mode ultrasonography,4 most of which are more sensitive
for the detection of proximal than distal thrombosis. With impedance plethysmography,
one measures the electrical impedance between two electrodes wrapped around
the calf. Venous obstruction proximal to the electrodes decreases the impedance
as the leg becomes engorged with blood, an electrical conductor, and delays
the characteristic increase in calf impedance when a thigh tourniquet is deflated.
The introduction of real-time B-mode ultrasonography has provided a promising
alternative to impedance plethysmography, with a sensitivity for proximal thrombi
that approaches 100 percent in patients with symptomatic deep-vein thrombosis
4,5. In symptomatic outpatients with suspected deep-vein thrombosis, serial
compression ultrasonography had a positive predictive value of 94 percent, superior
to the positive predictive value of 83 percent for serial impedance plethysmography
6.
In duplex scanning, real-time B-mode ultrasonography is supplemented by Doppler
flow-detection ultrasonic imaging, which allows detection of blood flow in any
vessel seen. In symptomatic patients with proximal deep-vein thrombosis, its
overall sensitivity in a meta-analysis of four well-designed studies was 93
percent, with a specificity of 98 percent7.
The sensitivity of d-dimer measured by enzyme-linked immunosorbent assay is
97 percent. Venous thrombosis is unlikely to be present if d-dimer concentrations
are not elevated, but a positive result requires confirmation by more specific
tests based on imaging.
Magnetic resonance venography has 100% sensitivity and over 96% specificity
for diagnosis of deep vein thrombosis but this is done only in exceptional cases.
Radio nucleotide venography is under development.
B. Etiology
1. Detailed clinical history: One should suspect thrombophilia in the following situations8 (Table.2).Age - young vs old. In most patients
with inherited thrombophilia, thrombotic event occurs before the age of 45 years.
In the elderly except Factor V Leiden all others are rare.
Race - Factor V Leiden and prothrombin gene mutation (G20210A) are common among
healthy whites but are extremely rare among Asians and Africans.
Arterial vs venous: In addition to venous thrombosis occurrence arterial thrombosis
is also seen with Protein S deficiency and hperhomocystinemia and antiphospholipd
antibody syndrome.
Site - unusual site, multiple sites occurs more often with inherited thrombophilia.
Drugs - history of oral contraceptive and tamoxifen use.
Hereditary thrombophilia
The term "thrombophilia" refers to a tendency to have recurrent venous
thromboembolism. Hereditary abnormalities that are associated with initial and
recurrent venous thromboembolism include congenital deficiencies of antithrombin
III, protein C, protein S, or plasminogen; congenital resistance to activated
protein C (APC resistance or Factor V Leidin defect), mutation of prothrombin
and hyperhomocysteinemia. The most common hereditary condition is APC resistance.
Lifetime prevalence of venous thromboembolism in patients with antithrombin
III, protein C, protein S is over 50 percent. Initial episodes of venous thromboembolism
are rare before the age of 18 years and uncommon after the age of 50.
Acquired thrombophilias
As with the hereditary thrombophilias, acquired disorders vary widely in their
propensity to cause venous and arterial thrombotic disease. Mucin secreting
carcinomas have very high potential for thrombosis. Antiphospholipid antibody
syndrome may manifest solely as a laboratory abnormality or present with venous
and arterial thrombosis, stroke or recurrent abortion. Patients with myeloproliferative
disorders and paroxysmal nocturnal hemoglobinuria may present with thrombosis
at unusual sites9.
Management
General:
The main objectives of treatment of DVT are 1) to prevent (both fatal and non-fatal)
PE and thrombus extension in the acute phase of the disease 2) to prevent recurrences
of venous thromboembolism (VTE) 3) to prevent late sequelae (post phlebitic
syndrome)
In highly selected cases of deep vein thrombosis it may be possible to restore
the venous patency by surgical thrombectomy with dramatic early results.
Antithrombotic regimens modify one or more of these abnormalities. These regimens
include drugs that inhibit blood coagulation, such as the various heparins and
heparinoids; warfarin; direct thrombin inhibitors; drugs that inhibit platelet
function, such as aspirin and dextran; and techniques that counteract venous
stasis, such as compression stockings and pneumatic compression devices.
Once venous thromboembolism is diagnosed, heparin should be given for four to
seven days and warfarin therapy should be initiated. Thrombolytic therapy is
reasonable in selected patients with extensive proximal-vein thrombosis or pulmonary
embolism. In patients with acute venous thromboembolism and active bleeding
or a high potential for bleeding, those who are noncompliant, and those with
a history of heparin-induced thrombocytopenia, a filter should be inserted in
the inferior vena cava. After an initial bolus of 5000 U, at least 30,000 U
per day of UFH should be infused. Lower doses result in higher rates of recurrence10,
11. An APTT value 1.5 to 2.5 times the control value is commonly recommended
as a target therapeutic range for heparin. To ensure a continuous antithrombotic
effect in patients with venous thromboembolism, heparin should be given for
at least four days and not discontinued until the INR has been in the therapeutic
range for two consecutive days. In patients with extensive proximal-vein thrombosis
or pulmonary embolism, a longer course of heparin should be considered12,13.
LMW Heparin or Unfractionated Heparin?
Both unfractionated (UFH) and low
molecular weight heparins have been found to be equally effective for the management
of VTE. Data from four meta-analyses suggest that low-molecular-weight heparins
are more effective than unfractionated heparin in preventing recurrence (risk
reduction, 34 to 61 percent) and cause less major bleeding (risk reduction,
35 to 68 percent) 14- 17. LMWH are also found to provide a survival advantage
in those with malignancy.
LMW heparin is effective in most patients when given in weight-based doses (anti-Xa
U/kg body weight) without subsequent laboratory monitoring or dose adjustment.
The kidneys clear all LMW heparins and caution should be exercised when the
creatinine clearance is < 30 mL/min. The correct dose for massively obese
persons has not been established, and laboratory monitoring (plasma anti-Xa
activity) may be useful in such patients.
Doses of various LMWH preparations are dalteparin sodium 200 anti-Xa IU/kg/d
subcutaneous, enoxaparin sodium 1 mg/kg q12h subcutaneous or enoxaparin sodium
1.5 mg/kg/d subcutaneous, nadroparin calcium 86 anti-Xa IU/kg bid subcutaneous
or nadroparin calcium 171 anti-Xa IU/kg subcutaneous daily, tinzaparin sodium
175 anti-Xa IU kg/d subcutaneous daily.
Warfarin or other coumarins should be started within 24 hours after the initiation
of heparin therapy, with a target INR of 2.0 to 3.0; higher values are associated
with more bleeding but no greater efficacy 18. Therapy should be continued at
least for 3 to 6 months. Patients with metastatic cancer are candidates for
long-term therapy because they probably have high rates of recurrence. Patients
with recurrent disease should receive long-term therapy - for those who had
two episodes one year and life long for those who had three episodes or having
multiple risk factors.
Other newer antithrombotic drugs.
Hirudin a new molecule is a potent inhibitor of thrombin but unlike heparin
its action is independent of AT III and it has very little effect on platelets.
Other newer molecules are 7 E3 a murine monoclonal antibody fragment that competes
with fibrinogen for its platelet receptor and recombinant human Factor Xa. Drugs
that target factor VIIa/tissue factor (tissue factore pathway inhibitor and
NAPc2), block factor Xa (synthetic pentasaccaride and DX9065a), inhibitors of
factor VA and VIIIa oral formulation of heparin. Anisoylated plasminogen-streptokinase
activator complex or single chain urokinase like plasminogen activator is under
investigation.
Management of complications of anticoagulant therapy
Bleeding
The management of bleeding associated with anticoagulant treatment should be
individualized, with therapy depending on the location and severity of bleeding,
laboratory-test results, and the risk of recurrent venous thromboembolism. If
urgent treatment is needed, vitamin K and plasma or factor IX concentrates should
be administered to warfarin-treated patients; protamine should be administered
to heparin-treated patients who have a prolonged APTT. In patients who have
bleeding while receiving a low-molecular-weight heparin, protamine should be
given because it neutralizes the heparin molecules thought to be most responsible
for bleeding.
Heparin Induced thrombocytopenia
Frequency of heparin-induced thrombocytopenia (HIT) is < 1% when either unfractionated
heparin or LMW heparin is given for no more than 5 to 7 days. Because of this
finding, a platelet count should be checked between day 3 and day 5 of therapy.
When the platelet count falls precipitously or in a sustained fashion, heparin
therapy should be stopped. The syndrome of HIT is unusual after 14 days of heparin
therapy. Recombinant hirudin (lepirudin) has been specifically approved for
HIT accompanied by thrombosis. In this setting, lepirudin should be used for
temporary anticoagulation and warfarin therapy delayed until the platelet count
has risen to > 100,000/muL20.
Failure of Anticoagulation
The failure of anticoagulant therapy results in symptomatic recurrent venous thromboembolism. Treatment failure despite adequate anticoagulation occurs in patients with overt or occult cancer and possibly in patients with antiphospholipid antibodies.Post-phlebitic syndrome.
This is a syndrome occurring in patients after acute deep vein thrombosis. It occurs in about one third of patients during long-term follow up. This is usually due to valve destruction but can also be due to large proximal vein thrombi that block the overflow. As a result the venous pressure increases during exercise and blood flow is directed from deep to superficial veins resulting in edema, impaired viability of subcutaneous tissue and venous ulcerations. Use of graduated compression stockings may reduce the risk of the syndrome.Venous Thromboembolism during Pregnancy
The risk of venous thromboembolism is five times higher in a pregnant woman than in a nonpregnant woman of similar age. Unfractionated and low-molecular-weight heparins do not cross the placenta and are very safe for the fetus, 21,22 whereas coumarin derivatives can cause fetal bleeding and are teratogenic. Low-molecular-weight heparins are suitable substitutes for unfractionated heparin and probably cause less bleeding and osteoporosis, but they are more expensive and the clinical experience with the drug is still limited. Some authorities recommend the use of warfarin during pregnancy for specific patients, such as women with mechanical heart valves, those who have a recurrence while receiving heparin, and those with contraindications to heparin therapy. If venous thrombosis is diagnosed during pregnancy intravenous heparin is given for 5-10 days followed by subcutaneous heparin for the rest of pregnancy. After delivery, warfarin, which is safe for infants and nursing mothers, should be given (with initial heparin overlap) for four to six weeks23,24.Prognosis of venous thrombosis
Untreated or inadequately treated
venous thrombosis is associated with the high complication rate, which can be
reduced by adequate anticoagulant therapy. About 30% of untreated silent or
symptomatic calf thrombi extend into popliteal vein and is associated with 40-50%
risk of clinically detectable PE. Patients with proximal vein thrombosis who
are inadequately treated have a 47% frequency of recurrent thrombo embolism
over three months. If properly treated the recurrence rate is only 2% in the
first 3 months and 5-10% in the subsequent year.
Prevention of Venous Thromboembolism
The goal of prophylactic therapy in patients with risk factors for deep-vein
thrombosis is to prevent both its occurrence and its consequences. Detection
of deep-vein thrombosis is likely to be delayed, as many of the affected patients
are asymptomatic. Preventing deep-vein thrombosis in patients at risk is clearly
preferable to treating the condition after it has appeared, a view that is supported
by cost-effectiveness analysis. The presence of clinical risk factors identifies
patients with the most to gain from prophylactic measures, as well as patients
who should receive antithrombotic prophylaxis during periods of increased susceptibility,
such as postoperatively or post partum. For example a patient with Homocysteinemia
should get folic acid supplements as a preventive measure and antithrombotic
prophylaxis during surgery.
For prophylactic treatment the following
risk categories are identified for inpatients.
Risk category Risk of VT % Calf vein T Proximal vein T PE
High risk
1.Gen. Surgery-patient >40 years withrecent DVT or PE
2.Extensive pelvic or abd surgery for 40-80 10-20 1-5
malignant disease
3. Major ortho surgery of lower
limbs
Low risk
1.General surgery-patient >40 yearslasting 30 minutes or more
2.Immobilization with medical illness 10-40 2-10 0.1-0.7
cardiac disease, stroke, chronic resp
disease, bowel disease & malignancy
VT- venous thromboembolism, PE - pulmonary embolism, DVT- deep vein thrombosis
The methods used for prophylaxis in these patients are early ambulation, low dose unfractionated heparin, intermittent pneumatic compression, graduated compression stockings, oral anticoagulants, dextran and low molecular weight heparin. These methods are used alone or in combination, the choice depending upon the risk stratification. A simple regimen of low dose unfractionated heparin is 5000 U given 2 hours prior to surgery and is continued post operatively at a dose of 5000 U for every 12 hours.
6th ACCP Recommendations24
Treatment of VTE
1 Patients with DVT or PE should be treated acutely with LMW heparin, unfractionated
IV heparin, or adjusted-dose subcutaneous heparin.
2. When unfractionated heparin is used, the dose should be sufficient to prolong
the APTT to a range that corresponds to a plasma heparin level of 0.2 to 0.4
IU/mL by protamine sulfate or 0.3 to 0.6 IU/mL by an amidolytic anti-Xa assay.
3. LMW heparin offers the major benefits of convenient dosing and facilitation
of outpatient treatment. LMW heparin treatment may result in slightly less recurrent
VTE and may offer a survival benefit in patients with cancer.
Initial Anticoagulation With Heparin
1. Treatment with heparin or LMW
heparin should be continued for at least 5 days and that oral anticoagulation
should be overlapped with heparin or LMW heparin for at least 4 to 5 days. For
most patients, treatment with warfarin can be started together with heparin
or LMW heparin. The heparin product can be discontinued on day 5 or day 6 if
the INR has been therapeutic for 2 consecutive days.
2. For massive PE or severe iliofemoral thrombosis, longer period of heparin
therapy of approximately 10 days is required.
Long-term Anticoagulation
1. Oral anticoagulant therapy should be continued for at least 3 months to prolong
the prothrombin time to a target INR of 2.5 (range, 2.0 to 3.0). When oral anticoagulation
is either contraindicated or inconvenient, a treatment dose of LMW heparin or
unfractionated adjusted-dose heparin to prolong the APTT to a time that corresponds
to a therapeutic plasma heparin level for most of the dosing interval should
be used.
2. Patients with reversible or time-limited risk factors should be treated for
at least 3 months.
3. Patients with a first episode of idiopathic VTE should be treated for at
least 6 months.
4. Patients with recurrent idiopathic VTE or a continuing risk factor such as
cancer, antithrombin deficiency, or anticardiolipin antibody syndrome needs
treatment for 12 months or longer.
5. Symptomatic isolated calf vein thrombosis should be treated with anticoagulation
for at least 6 to 12 weeks.
Thrombolytic Therapy
Patients with hemodynamically unstable
PE or massive iliofemoral thrombosis, who are at low risk to bleed, are the
most appropriate candidates.
Inferior Vena Caval Procedures
Placement of an inferior vena caval filter when there is a contraindication or complication of anticoagulant therapy in an individual with or at high risk for proximal vein thrombosis or PE. Placement of an inferior vena caval filter is also useful for recurrent thromboembolism that occurs despite adequate anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with the concurrent performance of surgical pulmonary embolectomy or pulmonary thromboendarterectomy.
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