Venous Thromboembolism – what surgeons in low income countries need to know
1. Introduction
Deep venous thrombosis (DVT) and its potentially lethal acute complication,
pulmonary embolism (PE), are extremely important clinical entities, which cause
significant morbidity and mortality. It is believed that venous thromboembolism
(VTE) is the most common cause of preventable hospital death in the West. (1)
VTE is believed to affect 25% of hospital patients and PE to cause 10% of hospital
deaths. (2) Moreover, 50-80% of DVTs are asymptomatic and 70%
of PEs are undetected before death. (1) A significant percentage
of VTE events take place in post-operative patients or in those with surgical
diseases like trauma or cancer.
In the West, in recent years, important advances have taken place both in identifying
those patients at greater risk of VTE and in applying regimens to prevent its
occurrence. New pharmacologic agents have been developed to allow out-patient
management of DVT. However, in my limited experience, in low-income countries
particularly in Africa, VTE is seldom diagnosed and conscious measures for its
prevention, diagnosis and treatment are seldom instituted. The purpose of this
Review will be to summarize recent guidelines on VTE in the Western literature
and speculate to what extent these can and should be applied to the conditions
in low-income countries. In summarizing this complex literature I have relied
extensively on the guidelines developed by the Seventh ACCP Conference on Anti-Thrombotic
and Thrombolytic Therapy held in 2004.(3)
2. Epidemiology
While development of VTE in the community exceeds 1 in 1000(4),
the rate of DVT in untreated hospitalized patients depends on risk factor and
varies between 10-40% for medical or general surgical patients and 40-60% for
those undergoing major orthopedic procedures. (5) One quarter
to 1/3 of these involve proximal veins. Of patients presenting with symptomatic
DVT, 50-80% have asymptomatic PE. (6) PE has been shown to
be the cause of death in up to 30% of post-operative deaths.
As far as ethnicity is concerned, studies in the West have shown that, if anything,
Afro-Americans have a higher risk of developing VTE than Caucasians. (7)
Asians had a slightly lower risk. Parakh’s recent comprehensive review
of VTE from India suggests Asians face similar risks to those in the West. (8)
A retrospective autopsy study from Nigeria showed a PE prevalence rate of 2.9%
with increased risk for patients older than 40, males and in those with cancer,
multiple trauma, immobility and paralysis, septicemia and major surgery. (9)
An earlier study showed an alarming 78% mortality for patients admitted with
PE. (10) Despite the paucity of data from low-income countries
it is clear that there is a significant population of surgical patients in this
setting who are at risk of VTE.
3. Pathophysiology
Deep venous thrombosis most frequently affects the deep veins of the lower extremity.
It usually begins in the calf veins. In patients found to have DVT on investigation,
33% have proximal (popliteal and above) vein involvement which has an increased
risk of PE. (2) The rest have calf vein involvement alone,
which may propagate to more proximal involvement in 10-20% of cases. The differentiation
between calf and proximal vein involvement has important diagnostic, therapeutic
and prognostic implications.
The pathology of DVT has been studied since the 19th century and is based on
the seminal work of Virchow. Stasis, hypercoagulability, and endothelial damage
have long been considered the underlying etiologies. It is rational to relate
this pathogenesis to the increased risk of VTE associated with immobility, major
trauma, the thrombophilia associated with various hematologic disorders and
which can be detected in up to 50% or patients with a spontaneous DVT (11),
malignancy and other known risk factors. This theory has been questioned recently
with greater emphasis placed on sequestration of blood in the venous valve pockets
and resulting ischemia of the endothelial cells. (12) Recent
studies show that the extent of reduction in clot burden can predict the risk
of recurrence of DVT. (13) The risk of recurrent DVT may be
up to 30% at 10 years. (14) Post-thrombotic syndrome and early
death are significant consequences.
3.1. Risk Factors
The identification of risk factors has been extremely important in the development
of thromboprophylactic protocols. (5) Table
1 lists the numerous risk factors associated with increased risk of VTE.
Increasing age above 40, increasing time of surgery, malignancy and immobilization
result in progressively greater risk. Sepsis, previous VTE or thrombophilia
indicate higher risk. Hip, pelvis or leg fracture, major trauma and spinal cord
injury constitute the highest risks. More importantly, the effect of these factors
is cumulative. (1) Their number is used in the stratification
of patients into various risk categories on which intervention is based. (see
6. Prevention) Table 2 provides a simple and reproducible
system that can be used to determine risk of VTE for purposes of prophylaxis.
Patients with inherited or acquired thrombophilia are at increased risk of VTE.
(8) In Caucasians, Factor V Leiden trait is present in 20-40%
of patients with spontaneous DVT. The prevalence in the African population may
be considerably less.(7) Despite the increased risk of VTE
in trauma patients, the question of thromboprophylaxis is complicated by the
risk of bleeding. (15). Patients who are felt to be at increased
risk of bleeding might be managed by periodic leg ultrasound. An eminent American
trauma surgeon cautions against the current use of thromboprophylaxis in trauma
and recommends further study. (16)
4. Diagnosis
4.1. Clinical
Not only is the majority of DVT clinically asymptomatic, but only 25% of patients
suspected of DVT are subsequently proven to be positive. (17)
Clinical evidence may include pain, swelling and tenderness of the effected
limb. Ipsilateral edema, warmth and dilation of superficial veins are other
signs. The Wells’ scoring system (Table 3) may
be used to indicate the risk of clinical DVT. It is used with other investigations
to create diagnostic protocols.
Pulmonary embolism presents as an acute onset of dyspnea with or without hempotysis,
pleuritic chest pain or collapse with shock in the absence of other causes.
Sinus tachycardia is common as are alterations of blood gases. Abnormalities
may be seen on electrocardiogram. A scoring system similar to that for DVT has
been devised. (Table 4)
4.2. Imaging
4.2.1. Deep Venous Thrombosis (DVT)
The gold standard for the diagnosis of DVT is ascending contrast venography.
Criteria include an intraluminal filling defect in 2 views or a complete cutoff
of the contrast column in a patient with previous DVT. It may not be available
in low-income countries. Moreover, the procedure requires contrast which is
potentially thrombogenic or nephrotoxic and to which the patient may be allergic.
As a result compressive venous ultrasonography has supplanted venography in
most situations in the West. (18) The diagnosis of acute DVT
requires the disproof of venous patency, ie. the inability of the vein to collapse
under direct compression. Direct visualization of the thrombus via echogenicity
and abnormalities during color flow Doppler are other less diagnostic criteria.
The venous system should be examined from common femoral vein to the trifurcation
below the politeal vein including the proximal calf veins. This technique has
very good accuracy particularly in proximal veins when compared to venography.
However it is observer dependent, it cannot distinguish between new or old clot
and the sensitivity for calf veins is lower. It is probably more available than
venography in low-income countries.
4.2.2. Pulmonary Embolism (PE)
The gold standard for diagnosing PE is the contrast pulmonary angiogram. However
this is invasive and has a mortality of 0.5% and will be unavailable in the
vast majority of hospitals in low-income countries. The most commonly used test
in the West is the radionucleotide perfusion scan combined if necessary with
a ventilation scan. (17) This is also unlikely to be available.
The contrast enhanced helical CT scan provides an option for accurate diagnosis,
especially in the absence of nuclear medicine scans. (19)
However its value is based on the use of modern multi-detection scanners with
high resolution which may not be available in low-income countries.
4.3. D-dimer
D-dimer is a degradation product of cross linked fibrin and its levels increase
in the presence of VTE. (20) While a high level of D-dimer
>500ug/l does not confirm the presence of DVT; a low level combined with
low clinical scoring can rule out active disease. (21) It
is used with the Wells’ score to define the need for further investigation.
Although relatively inexpensive it is unlikely to be available at present in
most low-income countries.
4.4. Algorithms
Diagnostic algorithms have been developed to guide the use of various diagnostic
tests.(17) If D-dimer is unavailable or venography is used
as the gold standard these are redundant.
Figure 1 depicts the diagnostic algorithm for DVT using
a combination of Wells’ score and D-dimer to decide which symptomatic
patients are to have diagnostic venous ultrasound. Low probability patients
are submitted to D-dimer testing and only positives have ultrasound. Middle
to high probability patients have ultrasound and negatives have D-dimer testing.
Positives of this are retested. Only positive ultrasound patients are treated.
Figure 2 shows an algorithm for the management of PE.
Low Wells’ score have D-dimer and the positives of this are pooled with
moderate and high probability patients to have either V/Q scanning or CT pulmonary
angiography. Positives are treated. Negatives are not. Non-diagnostic tests
are submitted to venous ultrasound. Positives are treated, negatives have serial
ultrasounds.
5. Pharmacologic agents
A review of the pharmacologic agents used in prophylaxis and treatment of VTE
is in order. Figure 3 depicts the coagulation cascade
and the site of action of the various agents. The dosing schedules will be given
in the prevention and treatment sections.
5.1. Unfractionated Heparin (UFH)
Unfractionated heparin (UFH) is a naturally occurring mixture of polysaccharides
derived from cow or pig that has been used for over 70 years. (22)
Heparin is inactive by itself but stimulates the action of anti-thrombin III
to inactivate thrombin (IIa) as well as other proteases of the coagulation cascade.
Delivered intravenously its action is immediate; subcutaneously it has a 20-60
minute onset. Clearance is dose dependent with a T½ between 30-150 minutes.
The dose-anti-coagulant relationship is somewhat unpredictable. It is best given
through continuous intravenous infusion. Clinical anticoagulation is monitored
normally by the activated partial thromboplastin time (aPTT), but the activated
clotting time may also be used. The parameters of therapeutic aPTT, usually
1.5-2.5x control, must be established in each institution. (23)
Heparin’s anti-coagulant effect can be reversed by protamine sulfate.
1mg of protamine neutralizes 100u heparin. Bleeding and heparin-induced thrombocytopenia
are the main adverse effects. The cost of 10,000 units in my hospital in Canada
is $1.00. This would be the daily drug cost for thromoboprophylaxis in moderate
risk patients.
5.2. Low-molecular weight Heparin (LMWH)
Low molecular weight heparins (LMWH) are derived from UFH by chemical or enzymatic
reaction. (23) They have enhanced anti-Xa activity and better
pharmacokinetics. They are usually given unmonitored as they have a reduced
effect on aPTT. The T½ of LMWH is 3-6 hours and is not dose dependent.
Because of these characteristics LMWH have become widely used for both the prophylaxis
and treatment of DVT. In particular subcutaneous, unmonitored, daily injections
of LMWH have allowed outpatient treatment of DVT with proven efficacy compared
to heparin. (24) This results in substantial savings in the
Western context. Clearance is primarily via the kidneys and is delayed in renal
failure. In these patients dosages should be reduced. In a Canadian hospital
the equivalent cost is $6.00 for moderate risk thromboprophylaxis or 6x that
of heparin. Still this is not expensive in comparison with third generation
cephalosporins antibiotics.
5.3. Vitamin K antagonists (VKA)
Warfarin and other coumarins are Vitamin K antagonists that have been used for
over 50 years as oral anticoagulants. (22) They are indirect
anti-coagulants which block the production of Vitamin KH2 in the liver. VitaminKH2
is a cofactor in the production of Factors II, VII, IX, X. Its onset of action
is delayed until the inhibition of newly formed factors becomes apparent, usually
several days. Monitoring is by prothrombin time (PT) and the therapeutic level
is expressed as an international normalized ratio or INR. Moderate intensity
anti-coagulation with INR 2-3 is generally sufficient and is associated with
fewer side effects. When combined with UFH the heparin should not be discontinued
until INR is therapeutic for 2 days. Coumarins cross the placenta and are contra-indicated
in pregnancy. A daily maintenance dose of warfarin in Canada costs $0.10.
5.4. Other agents
Two other anti-coagulants need to be briefly discussed here. Aspirin is an important
agent that blocks platelet activation and aggregation by inhibiting prostaglandin
synthesis. (22) While useful in preventing myocardial infarction
and arterial platelet emboli that cause some strokes, aspirin has no significant
role in either thromboprophylaxis or treatment of VTE. (5;24)
Fondaparinux is a relatively new synthetic pentasaccharide that causes specific
inhibition of Xa. (25) It has a long half life of 15 hours
and is currently being compared to LMWH in various studies.
6. Prevention
The rationale for thromboprophylaxis rests on sound principles and scientific
evidence. (5) These include the following: 1. hospital patients
generally have one or more risk factor for VTE; 2. DVT and PE are usually clinically
silent; 3. screening is neither effective nor cost-effective; 4. VTE results
in significant adverse and often fatal consequences and 5. thromboprophylaxis
is effective and cost-effective, and with very reasonable side-effects.
Primary thromboprophylaxis in surgical patients depends on the risk classification
outlined in Table 2 above. Depending on risk level
(low to highest) appropriate prevention can be undertaken. (5)
Table 5 summarizes the recommendations. Low risk patients
receiving only minor surgery (<45min.) and <40 years of age with no other
risk factors require no specific intervention except for early mobilization.
Moderate risk patients with scores of 2 should receive UFH 5000u B.I.D or LMWH
= 3400u/daily. While mechanical methods, such as graduated compression stockings
(GCS) or intermittent pneumatic compression (IPC), are described in the guidelines;
these are inferior to and less well studied than pharmacologic agents. They
should be used alone only when these latter are contra-indicated. Patients with
high risk scores of 3-4 should receive UFH5000uQ8H or LMWH>3400u/day. Patients
with the highest risk scores, including those with hip fracture surgery, hip
or knee arthroplasty, major trauma and spinal cord injury should receive the
regime for high risk plus the addition of GCS or IPC. High dose LMWH or VKAs
may be preferable in patients undergoing high risk orthopedic surgery such as
elective hip or knee arthroplasty and hip fracture surgery.
The first dose of UFH should be given 1-2 hours prior to surgery. LMWH may be
started before or after surgery. RCTs comparing UFH and LMWH in moderate and
high risk patients show them to be equivalent. Since UFH is considerably cheaper,
it would seem to be superior. However for highest risk patients LMWHs are superior
and should be used exclusively in these cases.
The guidelines indicate that epidural and spinal anesthetic agents, while resulting
in a lower risk of VTE in general surgery patients, should be used with caution
in patients on thromboprophylaxis. Recommendations for specific surgeries are
listed in the guidelines and the interested reader is referred to these. (5)
While thromboprophylaxis for moderate and high risk patients is usually stopped
when the patients are ambulant and ready for discharge, therapy should be prolonged
for at least 10 days and possibly 35 days in patients with major orthopedic
surgery such as hip fracture. For isolated lower extremity fractures, no thromboprophylaxis
is necessary. Patients with multiple trauma are in the highest category and
should start LMWH as soon as it is considered safe. These guidelines recommend
against the use of vena caval filters as primary methods of prevention.
7. Treatment
Therapy for VTE should be based on a confirmed diagnosis derived from one of
the diagnostic algorithms above. (see 4.4 Algorithms)
7.1. DVT
The guidelines from the 7th ACCP Conference recommend, IVUFH, subcutaneous
UFH or LMWH, as the initial therapy for DVT and continued for at least 5 days.
(24) Given the fact that UFH requires laboratory monitoring
and often intravenous continuous infusion, it is reasonable to prefer LMWH,
especially in low-income countries. Unmonitored weight-adjusted doses of LMWH
(1.5mg/kg/day enoxaparin) can be given sc once or twice daily. This will result
in drug costs of about $18Can/day as opposed to $3Can/day for UFH treatment.
Because of ease of administration, scUFH may be useful in settings where this
cost differential represents a burden, if laboratory facilities to measure aPTT
can be improved. DVT therapy with scUFH should be initiated with a bolus of
5000uIVUFH and then 17,500u scUFH B.I.D with aPTT monitoring. LMWH or scUFH
give at least identical if not superior results to IVUFH, with no greater side
effects. Therapy should be initiated in high risk patients before objective
confirmation.
Unmonitored weight-adjusted doses of LMWH (1.5mg/kg/day enoxaparin) can be given
sc once daily or in 2 divided doses. Heparin can be discontinued when the INR
is stable and over 2.0. Long term VKA therapy is recommended for at least 3
months in patients with transient risk factors but should be maintained for
6-12 months or indefinitely with idiopathic spontaneous DVT. If adequate laboratory
follow-up is not available then LMWHs can be used as long term agents, but at
considerable greater cost.
The guidelines recommend against general use of systemic or catheter directed
thrombolysis unless risk of limb loss. In that case venous thrombectomy might
be preferable, particularly in ileo-femoral thrombosis. (26)
They recommend against the use of non steroidal anti-inflammatory drugs in acute
DVT. Vena caval filters should only be used when a contraindication to or major
complication of anticoagulant therapy occurs or when there is evidence of recurrent
VTE in the presence of adequate anticoagulation. Ambulation is advised. The
use of graded compression stockings with a pressure of 30-40mmHg at the ankle
is recommended for 2 years after DVT to prevent post-thrombotic syndrome.
7.2. PE
The recommendations for the acute treatment of non-massive PE are similar to
those for acute DVT except that LMWH is preferred. Indications for and duration
of VKA therapy are also similar. Thrombolytic agents are not generally recommended
except in those patients with hemodynamic instability in whom systemic rather
than catheter directed thrombolysis should be used. In these cases IVUFH should
be used as anti-coagulant because of its shorter half-life. Pulmonary embolectomy
is similarly advised against. The indications and limitations for vena caval
filters are similar to those in DVT.
8. Complications
8.1. Bleeding
The major complication of anti-coagulant therapy is bleeding. (27)
Major bleeding is defined as intracranial or retroperitoneal bleeding or that
which causes hospitalization, transfusion or death. The risk of bleeding with
thromboprophylaxis is small. (28) Minor injection site bruising
and wound hematoma may occur in 6-7% of cases. Gastrointestinal bleeding occurs
in 0.2% of cases, retroperitoneal bleeding in <0.1%. Discontinuation of therapy
due to these complications occurs in 2% of cases. Major bleeding risk with therapeutic
heparin is higher; 3% with IVUH. Bleeding risk is increased with increasing
heparin dose and age (>70 years). LMWH have a lower risk of bleeding.
The risk of bleeding with VKAs is proportional to the intensity of their anti-coagulant
effect. Major bleeding with INR<3 is ½ that when INR>3. Concomitant
use of other drugs, particularly ASA may increase the risk of bleeding. The
average annual major bleeding incidence was 1.3%, but the case fatality was
13%. The risk of bleeding is highest in the first three months of therapy.
8.2. Recurrent DVT and PE
The rate of recurrent DVT may be as high as 30% after 10 years. Risk of recurrence
depends on the risk factors involved in the original episode – patients
with transient risk factors have lower rates and those with thrombophilia defects
have higher rates – and also the duration of initial treatment. (29)
It appears that vena caval filters are of little value in reducing risk of recurrent
PE and do not lower mortality. (30) Diagnosis of recurrent
DVT may be difficult in patients with the post-thrombotic syndrome. Patients
experiencing a second episode of DVT or PE should be kept on anti-coagulants
indefinitely.
8.3. Post-thrombotic syndrome
The post-thrombotic syndrome or post-phlebitic leg is a constellation of symptoms
resulting from ongoing obstruction to the deep venous system as a consequence
of DVT. (31) It occurs in 20-50% of patients and has a significant
adverse impact on quality of life. Symptoms may include heaviness and pain on
walking or standing. Signs include leg edema, skin changes including pigmentation,
secondary varicosities and ulceration. Early use of graduated compression stockings
in the acute DVT setting has been shown to reduce the risk of these changes
by 50%. (30) Leg edema is best managed by intermittent pneumatic
compression followed by hig pressure graduated compression stockings for life.
Rutosides, which act by decreasing vascular permeability to proteins, may be
of value. (24)
8.4. Heparin-induced thrombocytopenia (HIT)
Heparin-induced thrombocytopenia is a potentially devastating complication of
heparin either UFH or LMWH. (32) HIT may occur in 5% of patients
treated with UFH. With LMWH use the risk is 1%. Two types occur. A non-immune-mediated
mild form where thrombocytopenia (defined as platelet count < 150,000/L)
usually does not drop below 100,000, where thrombosis is absent and which resolves
without heparin being discontinued. Immune-mediated HIT can result in devastating
thormboembolic complications and death. It begins 5-14 days after initiation
of therapy although it may appear more rapidly in patients with previous heparin
exposure. A relative platelet decrease of 50% may be more important than absolute
platelet count. For this reason a platelet count should always be carried out
before initiating heparin therapy, as well as weekly during therapy. Fifty percent
of patients with HIT will experience thrombosis. VTE is 4 times as common as
arterial thrombosis which usually presents as acute limb occlusion. An algorithm
for diagnosis of HIT is provided. (32) The mainstay of management
of HIT is complete removal of all heparin sources and initiation of direct thrombin
inhibitors. While warfarin is the treatment of choice in the long term management
of these patients, it should be avoided in the acute phase as it can induce
skin necrosis or venous limb gangrene.
8.5. Surgery in anti-coagulated patients
Patients receiving anti-coagulation particularly oral coumarins sometimes have
to undergo surgery. A systematic review of available studies concluded that
oral anti-coagulants do not need to be withheld for dental procedures, joint
injections, cataract surgery, and endoscopies. (33) For other
invasive procedures the anti-coagulants should be withheld or reversed in emergency
situations. Vitamin K1 10mg sc injections or fresh frozen plasma infusion will
rapidly reverse the anticoagulant effect. The decision whether to maintain peri-operative
anticoagulation with heparin in these patients depends on their risk of thromboembolic
events and should be individualized. (34) Patients with high
risk of VTE can be treated with LMWH as standard thromboprophylaxis.
9. Conclusions
Venous thromboembolism is an important cause of morbidity and mortality in the
surgical patient for which effective preventative and treatment regimens are
available. I strongly suspect that the risk is similar for patients in low-income
countries as in the West. The major recommendations in this Review have all
been found to be cost-effective in the Western context. (35)
Despite the challenges of applying these regimens in the setting of resource
restriction, I believe it can be achieved with significant improvements in patient
welfare as a result. I believe effective prevention and treatment for VTE should
be a priority once hospitals have developed adequate systems and infrastructure
for essential and emergency surgical care.
10. Recommendations
1. Surgeons in low-income countries should implement hospital-based
programs of thromboprophylaxis and treatment for VTE with the emphasis on prevention.
2. These programs should be based on clinical risk assessment and stratification
for both risk of developing VTE in asymptomatic surgical patients and likelihood
of suspected VTE being positive.
3. These programs should include standardized ultrasound examination of lower
extremity veins using compression.
4. These programs require improvement in laboratory facilities to measure aPTT
and PT levels.
5. CBC, platelet count should be performed prior to heparin thromboprophylaxis
and weekly thereafter.
6. D-dimer measurement may be of value in these settings in identifying symptomatic
patients more likely to have DVT or PE.
7. All surgical patients should be classified according to risk on admission
and receive either UFH or LMWH for thromboprophylaxis according to the guidelines
in this Review.
8. Patients with suspected DVT or PE should be submitted to diagnostic algorithms,
if appropriate, and therapy instituted only in the presence of confirmed disease.
9. Unmonitored weight-adjusted scLMWH appears more appropriate than UFH for
initial therapy of acute DVT or PE in low-income countries. Monitored scUFH
may be substituted if cost factors predominate. VKA should be initiated, unless
laboratory facilities for PT measurement are unavailable, and maintained as
preferential long term therapy for at least 3-6 months and more depending on
the risk factors surrounding the episode of DVT.
10. All case of DVT should be treated early with graduated support stocking
at 30-40mmHg at the ankle for 2 years.
Brian Ostrow MD, FRCSC
Office of International Surgery
University of Toronto
Canada
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