Clinical Practice Guideline

for

Deep Venous Thrombosis and Pulmonary Embolism

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

 

Overview: That venous thromboembolic disease (VTED) is such a familiar entity to most medical personnel is to a certain extent an artifact of the training environment.  VTED is a frequent complication in hospitalized medical and surgical patients; stasis, hypercoagulability, and damage to the vascular intima (the classic Virchow’s triad) are common to a number of conditions.  VTED is considerably less common in outpatients, though hardly a rarity.  In the Longitudinal Investigation of Thromboembolism Etiology, or LITE, which combined data from two prospective cohorts, the age-standardized incidence of VTED among over 21,000 participants was 1.92 per 1,000 person-years.  Since the incidence increases with age, and the members of the study population were all over the age of 45, the incidence in the aviator population is likely to be considerably lower.  (This is truer for the military population than for the civilian one).

 

VTED manifests clinically as deep venous thrombosis (DVT), pulmonary embolism (PE), or both, but at a pathophysiologic level the disease is a single entity.  (Note that superficial thrombophlebitis is excluded from this discussion.)  In a patient presenting with PE, the probability of documenting DVT depends in large part on how thoroughly one looks, and conversely the great majority of patients with DVT can be shown to have at least subclinical evidence of PE.  Furthermore, treatment considerations vary little between the two entities.  Of more importance is the identification of the underlying etiology, or the lack of one.  Secondary VTED occurs in response to a variety of conditions, which may be acute and self-limited, or chronic.  Idiopathic VTED is that occurring in the absence of such evident risk factors.

 

Malignancy, major (especially lower extremity) surgery, and prior VTED itself constitute the major risk factors for development of VTED.  Other less potent risk factors include immobilization (e.g., bedrest, lower extremity casting, prolonged air travel), obesity, use of oral contraceptives or estrogen replacement therapy, and pregnancy.  Air travel is a risk of obvious aeromedical interest.  Two large studies conducted at major airports found that PE was very rare (0-0.01 case per million) on relatively short duration flights.  The larger study, involving passengers at Charles de Gaulle Airport, found that the rate rose to 1.5 cases per million for flights exceeding 5,000 km (3100 mi), and to 4.8 cases per million for flights exceeding 10,000 km (6200 mi).2  The other study, conducted at Madrid-Barajas Airport, determined the incidence of PE to be 0.25 cases per million for flights lasting 6-8 hours, while flights lasting longer than 8 hours were associated with an incidence of 1.65 cases per million passengers.3  Given the apparent dose-response, the association appears to be real, but the absolute risk is quite small.  Whether aviation as an occupation is attended by increased risk is unknown.  In both studies, most of the patients with PE had underlying risk factors that with rare exceptions (such as age over 40) would be absent in military aviators.  In the French study, 75% reported never having left their seats during the flight, whereas in military aviation some activity is present even in long-haul “heavy” flights.  Anecdotally, in the rare cases referred to the Aeromedical Consultation Service where aviators had developed VTED after long flights, the individuals had been passengers rather than aircrew.

 

The likelihood of developing idiopathic VTED, or that a minor risk factor such as immobilization will be complicated by VTED, depends in part on the presence of inherited or acquired disorders of the clotting cascade, i.e., thrombophilias.  (Note that the identification of an underlying thrombophilia does not change the classification of a VTE from idiopathic to secondary.)  Inherited thrombophilias currently recognized include, in roughly decreasing order of prevalence among patients presenting with thrombosis, factor V Leiden, protein S deficiency, prothrombin 20210A, antithrombin deficiency, and protein C deficiency.  The classic acquired thrombophilia is antiphospholipid antibody.  (Malignancy-associated VTED is almost certainly due to an acquired disorder of clotting factors as well, but the specific defect or defects are unknown.)

 

Since the identification of various inherited thrombophilias in the last twenty years, screening for these disorders has been frequently recommended in patients with VTED, but the value of such screening is difficult to demonstrate.  Few would advocate such screening in patients with known major risk factors, such as recent surgery, but whether or not to screen those with minor or no apparent risk factors is controversial.  Heritable defects are common in idiopathic VTED; Baglin et al. found one or more defects in 27% of such patients.  However, studies have consistently found no significant difference in recurrence rates between those with and without identifiable thrombophilias.4,5  Some authorities would recommend indefinite therapy after one unprovoked thrombotic episode in a patient with antithrombin deficiency, or possibly protein C deficiency, but these are the rarest abnormalities, and consensus does not exist.  Multiple defects do seem to increase the risk of recurrence, but combined defects are identified in only 1-2% of those with idiopathic VTED.6  Current treatment guidelines are based on idiopathic versus secondary etiologies, and primary versus recurrent episodes, and are not altered by the finding of inherited defects.

 

The major aeromedical concern is recurrence.  The likelihood of recurrence following appropriate therapy depends heavily on the reversibility of the predisposing condition.  At one extreme, underlying malignancy has been associated with a recurrence rate of over 14% per year.  At the other end of the spectrum, the risk of late recurrence after a post-operative thrombosis is minimal; in one recently published study, there were no recurrences over two years in 86 patients who had developed a postoperative thrombus.4  The recurrence rate of idiopathic VTED falls halfway between, at about 7-8% per year. 

 

Anticoagulation with a vitamin K antagonist (VKA) such as warfarin clearly reduces the risk of recurrence when employed for the first three months, which perhaps allows time for vascular remodeling, and such therapy is nearly always indicated regardless of underlying etiology.  Attempts to shorten secondary prophylaxis to less than three months have been unsuccessful.7,8  Prolongation of therapy beyond three months in those with an ongoing risk of recurrence has been shown to significantly reduce the risk of recurrence.9  However, patients who receive prolonged VKA therapy seem to be at equivalent risk of recurrence once treatment is stopped.10  Thus, a longer course of secondary prophylaxis appears to delay rather than prevent recurrence, at least for the first several years and possibly much longer.  Nonetheless, recent consensus guidelines do recommend extending secondary prophylaxis for idiopathic VTED to 6-12 months of VKA therapy.11

 

Evaluation of the aviator with VTED is complicated by the treatment itself.  Usually, waiver will be delayed until after therapy is completed, and thus any laboratory studies that were not obtained at initial presentation and that could not be obtained on VKA therapy may be delayed until therapy is concluded.  For most cases of VTED, diagnostic laboratory evaluation should consist of complete blood count, coagulation studies (PT, aPTT), hepatic and renal function tests, and urinalysis.  For reasons noted earlier, screening for inherited thrombophilia is not routinely recommended.  Evaluation for acquired thrombophilia should depend on the setting.  The identification of antiphospholipid syndrome would likely alter treatment, but confirming such a diagnosis is not as simple as a serologic study.  Anticardiolipin antibodies may be found in 5-21% of DVT cases, but it isn’t clear that the presence of the antibody per se confers any greater risk of recurrence.  Furthermore, about 10% of healthy subjects may be transiently positive for the antibody.  Screening is recommended in those with other suggestive findings, such as thrombocytopenia, abnormal baseline coagulation studies, or, in females, a history of premature deliveries or spontaneous abortions.

 

Though apparently idiopathic clots can occasionally prove to be due to underlying neoplasia, such associated thromboses usually occur in patients with known malignancies.  If a careful history and physical examination and baseline laboratory studies fail to suggest a malignant etiology for the thrombosis, further workup for occult neoplasm is rarely warranted.  One reasonable exception, because of the frequently occult and indolent nature of the carcinoma, is to obtain a prostate-specific antigen (PSA) in men over the age of 50 with an initial idiopathic thrombosis.

 

Therapy of VTED consists of acute treatment with some form of heparin followed by secondary prophylaxis with a VKA.  The internationalized normalized ratio (INR) should be maintained in the range of 2.0-3.0.  Recommended length of secondary prophylaxis is three months for those with a first episode of VTED associated with a transient risk factor; six to twelve months for those with a first episode of idiopathic VTED; and lifelong for a second episode of VTED.

 

The risks during secondary prophylaxis are primarily hemorrhage and recurrence.  Maintenance of the correct INR is vital.  The risk of bleeding correlates with the INR even within the therapeutic range, and rises steeply when the INR exceeds 5.0.12 Maintenance of the INR within the therapeutic range may be affected by concomitant illness, drugs, or food.  The patient should be followed by a specialized anticoagulation management service; such specialized care reduces the annual rate of adverse events by more than 60%.13

 

Even with the use of an anticoagulation service, hemorrhage is still a significant risk, and this is particularly true in the first three months of therapy.  A recent meta-analysis of complications of anticoagulation found annualized event rates for major bleeding of 8% in the first three months, and 2.74% thereafter.  Corresponding rates for intracranial hemorrhage (ICH) were 6% and 0.65%.  Other than ICH, it is difficult to determine the percentage of bleeds that would cause incapacitation, but it appears that only a very small proportion of extracranial bleeds would qualify.

 

Aeromedical Concerns: DVT is often accompanied by pain and localized edema.  PE causes dyspnea and hypoxia, and may rarely cause hypotension, though massive embolism is distinctly uncommon in a reasonably healthy outpatient.  Though it is difficult to define percentages, it appears that only a small minority of recurrences would present as acute incapacitation.  Anticoagulation is associated with hemorrhage, which depending on location and blood loss, can be anywhere from clinically silent to acutely incapacitating. 

 

Medical Work-up: The work-up and subsequent waiver package should be accompanied by details of the initial event, especially any pertinent risk factors.  History and physical should focus on signs and symptoms that might suggest underlying malignancy.  Lab studies should consist of complete blood count, coagulation studies (PT, aPTT), liver function tests, and urinalysis.  In a male over the age of 50 with a first episode of idiopathic thrombosis, prostate-specific antigen should be obtained.  Other workup for malignancy is not routinely indicated unless history, physical exam, or laboratory evaluation suggests pathology.  Thrombophilia workup is not routinely required, though screening for antiphospholipid antibody syndrome is indicated in patients with suggestive findings.

 

Aeromedical Disposition (military): Waiver is not allowed during the first three months of VKA therapy.  In the case of VTED associated with a temporary risk factor such as lower extremity surgery, secondary prophylaxis will be finished by the time waiver could be considered.  An aviator with idiopathic VTED will require at least six months of VKA therapy; waiver might be considered three months after initiation of treatment, subject to the restrictions listed in the following paragraph.

 

In the event of recurrence, heparin and VKA therapy must be restarted, and the latter is expected to be lifelong.  Waiver may be considered after three months, subject to the following restrictions:

1)       The individual must be followed by a specialized anticoagulation management service.  Usual care is not acceptable.

2)       Anticoagulation is incompatible with deployment.  In the unlikely event that the medical board process were to allow worldwide qualification, flying would remain proscribed; because tight control of anticoagulation would be impossible, the event rate for sudden incapacitation would considerably exceed 1% per year.

3)       A multipilot cockpit is presumed.  Unlike intracranial hemorrhage, an extracranial hemorrhage is unlikely to cause sudden incapacitation.  However, it is also unlikely to be stable enough to allow a single pilot to successfully divert the flight to a nearby airfield.

4)       High-performance aviation cannot be recommended.  Major hemorrhage by most definitions presumes a >10% loss in intravascular volume, and yet may often be clinically silent in the early stages (e.g., gastrointestinal hemorrhage).  Though unlikely to be suddenly incapacitating in routine flight, such volume loss could hardly fail to impair Gz tolerance.

 

For applicants to flying training, waiver will be considered for a history of DVT or PE which occurred in the setting of major reversible risk factors, since the risk of recurrence is minimal.

 

Aeromedical Disposition (civilian): In the civilian sector airmen with a history of PE are granted medical certification for all classes of medicals once they are discharged from the hospital, no longer have dyspnea, and can demonstrate stability of the Coumadin dosage with at least monthly INR levels. Typically the Aerospace Medical Certification Division (AMCD) would like the airman to have been taking the Coumadin for 90 days.  Eighty percent of the INR levels must be within the proscribed range of 2.0 to 3.0.  AMCD has also permitted airman who have been diagnosed with a Hypercoagulable state to fly as long as they were properly treated and followed. 

 

Waiver Experience (military): All patients with single episodes of deep venous thrombosis and 87% of those with pulmonary embolism have received waivers.  Anticoagulation was recently approved for limited waiver, and no data currently exist.

 

 

Waiver Experience (civilian): In the current pathology coding system at the Federal Aviation Administration there is no specific singular code for PE.

 

References:

 

1. Cushman M, Tsai AW, White RH, et al.  Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.  Am J Med.  2004; 117: 19-25.

 

2. Lapostolle F, Surget V, Borron SW, et al.  Severe pulmonary embolism associated with air travel.  N Engl J Med. 2001; 345:779-83.

 

3. Perez-Rodriguez E, Jimenez D, Diaz G, et al.  Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport.  Arch Intern Med 2003; 163:  2766-70.

 

4. Baglin T, Luddington R, Brown K, Baglin C.  Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.  Lancet.  2003; 362: 523-6.

 

5.  Ridker PM, Goldhaber SZ, Danielson E, et al.  Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism.  N Engl J Med.  2003; 348: 1425-34.

 

6.  Bauer KA.  Management of inherited thrombophilia.  Up To Date, accessed 9 Mar 2006.

 

7.  Schulman S, Rhedin AS, Lindmarker P, et al.  A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.  N Engl J Med.  1995; 332(25):  1661-5.

 

8.  Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.  Thromb Haemost. 1995; 74(2):  606-11.

 

9.  Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med.  1999; 340(12):  901-7.

 

10.  Agnelli G, Prandoni P, Santamaria MG, et al. Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators.  N Engl J Med.  2001 19; 345:  165-9.

 

11.  Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004; 126(3 Suppl):  401S-428S.

 

12.  Pickard JS.  Therapeutic medications in the aviator. In: Rayman RB, ed. Clinical Aviation Medicine, 4th ed. New York: Castle Connolly Graduate Medical Publishing, LLC, 2006.

 

13.  Ansell JE. Optimizing the efficacy and safety of oral anticoagulant therapy: high-quality dose management, anticoagulation clinics, and patient self-management.  Semin Vasc Med. 2003; 3(3):  261-70.

 

14.  Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis.  Ann Intern Med. 2003; 139(11):  893-900.

 

 

June 11, 2007