Up Close and Personal with Deep Vein Thrombosis

   Clinicians often are so focused on their patients’ needs and symptoms they overlook their own health. If an elderly, hospitalized, or immobilized patient presented in a healthcare facility, clinicians would automatically check for deep venous thrombosis (DVT) but how frequently would an otherwise healthy, fairly young, busy medical professional acknowledge those symptoms and conduct self-screening? Typically, we are always on the go, giving up meals, exercise, or sleep when duty calls without a second thought. Sometimes, however, a second thought might help preserve our health so we can continue contributing to our patients’ well being.

My personal experience with DVT underscores the need for clinicians to be aware and proactive about their own, as well as their patient’s, health.

Personal Experience

   I was attending a conference on the West Coast, alternating sitting for extended times and walking long distances in high-heeled shoes. At some point during the conference, my left foot began to hurt. Walking became difficult but the discomfort could be endured. After the conference, I immediately went on a planned vacation. Two weeks after my vacation, I finally had my foot examined; the x-ray revealed a probable stress fracture. Naproxen and crutches eased the pain and my normal gait returned.

   I did not have time to slow down — the back-to-back trips meant I had to tackle accumulated work, face looming deadlines, and assimilate the next batch of speaking materials before I left again to address another conference, barely 2 weeks later. During the conference, my foot and calf began to bother me. I awakened with leg cramps during the night. Thinking the pain and cramps were the result of too much walking, I elevated the leg more often.

   When I returned to my office a few days later, my foot felt better but pain began to radiate into my knee and thigh. Soon, the calf became grossly swollen and hard. The back of the knee also was swollen and sore. I felt extreme pain in the leg almost instantaneously whenever my leg was not elevated. I called the nurse manager and my doctor; something was wrong.

   A history was taken and clinical examination was followed by compression ultrasound that revealed thrombi occluding the saphenous and popliteal veins. Thankfully, I experienced no chest pain nor did the chest x-ray show any signs of pulmonary embolism. But I was stunned. Were my circumstances actually that conducive to DVT? I was traveling frequently (10 flights in 6 weeks), restricting my foot movement, and attending numerous conferences, but I am also a young mother with two preschoolers — wasn’t chasing them around enough to counteract periods of inactivity?

   My doctor offered a choice: hospitalization or self-treatment as an outpatient with home health visits for venipuncture. Although outpatient treatment for DVT is not right for everyone, it helped me avoid potential nosocomial infections and maintain a sense of normalcy. I learned how to inject a low molecular weight heparin (LMWH), combining this blood-thinning regimen with oral warfarin. Until the pain medication took effect, I did not realize the extent of my discomfort. I had no choice but to slow down and comply with the imposed bedrest.

   Trying to avoid the whiplash from the sudden change in pace was difficult at first but my body seemed to enjoy the new priority: rest. The forced down time allowed me to research DVT and related issues. I discovered why I had become vulnerable to the condition and decided to share my newfound knowledge with the hope that clinicians will be better able to recognize the risks and symptoms of DVT and, in turn, provide the appropriate timely care that can relieve the discomfort and the potential for complications.

DVT Background

   Approximately 2 million Americans develop DVT each year.¹ The majority of DVT cases occurs in the legs, although cases of upper extremity DVT have been reported. The development of DVT involves damage to the endothelium of the vein wall, venous stasis, and hypercoagulability — Virchow’s triad.² The presence of these factors precipitate the formation of a blood clot. Until a clot obstructs a major blood vessel, usually no symptoms are noticed. Once obstruction occurs, the patient may present with pain, swelling, warmth, muscle cramps, and redness.³ Compression ultrasonography and duplex ultrasound are the only noninvasive, fast, and reliable diagnostic tests available to provide confirmation of DVT in the deep veins.^2,4

Complications

   Venous thromboembolism (VTE) is the most serious and potentially fatal complication that can arise from DVT. If the blood clot breaks off and travels in the blood stream, it can cause stroke, cardiac failure, or pulmonary failure depending on where it lodges. In 1 year, approximately 600,000 Americans will develop pulmonary embolism, resulting in more than 60,000 deaths.^1,5 Long-term complications of DVT include recurrent DVT, VTE, and postthrombotic syndrome of continued leg pain and swelling in absence of DVT.^2,6

   Venous conditions are implicated in compromised wound healing. Postthrombotic syndrome is caused by venous hypertension.¹ Venous hypertension can be caused by persistent outflow occlusion, scarred or incompetent valves, and dependent positioning of lower extremities.^1,7 Both venous ulceration and chronic venous insufficiency are exacerbated by increased venous hypertension; thus, often postthrombotic syndrome is demonstrated even in the absence of DVT.^1,7 Consequently, patients with venous ulcers should have their venous disease carefully evaluated to determine if past or present increased venous hypertension is contributing to delayed healing.⁷ One study⁸ demonstrated the most important factor affecting ulceration and ambulatory venous pressure in post DVT patients was valvular incompetence. Ulceration did not occur in patients with persistent occlusion and competent valves. Similar findings of the importance of valvular competence were reported in another study assessing long-term sequelae of DVT.⁹ Because 80% to 85% of all leg ulcers are associated with venous hypertension, compression and leg elevation remain key factors in alleviating symptoms and promoting healing.⁷

Management

   Once a definitive diagnosis of DVT is made, treatment goals include preventing 1) the thrombus from enlarging, 2) a venous embolic event from occurring, and 3) new DVT from forming.^2,3 Treatment also should allow for clot dissolution and resolution of symptoms.

   Anticoagulation therapy. Anticoagulation therapy is the treatment of choice. Treatment time ranges from 3 to 6 months or even up to a lifetime depending on bleeding and recurrence risks.^2-4 Deep vein thrombosis induced by major surgery is considered a transient risk; thus, treatment is usually only 3 months. A person with low-risk thrombophilia such as a genetic mutation usually requires 6 months of treatment. Indefinite or lifetime therapy with anticoagulants is reserved for persons with multiple DVT recurrences or high-risk thrombophilia.²

   Anticoagulation therapy consists of warfarin use; however, a short-acting anticoagulant such as a heparin formulation must be used in conjunction until acceptable prothrombin time/International Normalized Ratio (PT/INR) levels are reached due to differences in action onset.² Low-molecular weight heparins have been available for DVT prevention for several years and have advantages over unfractionated heparin, including better bioavailability, longer half-life, more predictable dose-response relationship, and the fact that intravenous administration and monitoring are not required.^1,2,10 A meta-analysis by Gould¹¹ suggested that LMWH may be associated with lower mortality in the treatment of DVT when compared to unfractionated heparin and appears to be as effective in preventing thromboembolitic recurrences. A study¹⁰ of subcutaneous enoxaparin with doses adjusted for the patient’s weight found that administration at home is as safe and effective as standard heparin therapy administered in the hospital when treating acute proximal DVT in appropriately selected patient populations.

   Using LMWH for DVT at home increases the convenience for the patient. Had I been admitted to the hospital, I would have subjected myself to potential nosocomial infections, a higher anxiety level, and a sense of helplessness. By treating myself with LMWH, I avoided the disadvantages of hospital stay and enjoyed the comfort of my home. Maintaining a sense of normality was important to me and my family.

   Use of LMWH for DVT in outpatient settings substantially reduces the cost to the healthcare system.^1,12,13 A landmark Canadian randomized clinical trial¹⁰ demonstrated the safety and efficacy of home treatment of acute DVT with LMWH compared to unfractionated heparin. O’Brien¹³ followed subsets of patients — an economic analysis demonstrated substantially lower average cost of treatment for LMWH. A retrospective, replicate of the Canadian trial using a US managed care organization demonstrated similar safety, efficacy, and economic results¹²; outpatient treatment with LMWH resulted in a cost savings for total care of $2,583 per patient. This cost savings may actually be somewhat higher as the study included patients with minimized inpatient stays.

   Thrombolytic therapy. Thrombolytic therapy is employed when an active embolic event affecting areas such as the heart, brain, lung, or limbs has occurred.² During the initial phase of treatment, bedrest often is prescribed to reduce the risk of VTE. Bedrest helps alleviate the symptoms of DVT, decrease venous hypertension, and reduce bloodflow volume past the thrombosis.^3,7 Analgesics should be chosen carefully to avoid interference with or increase the effects of anticoagulant therapy.¹⁴ If the patient is receiving warfarin or other coumarins, he/she also must maintain a strict diet, avoiding foods containing high levels of vitamin K, which also interferes with anticoagulant therapy.¹⁴ Later in the treatment regimen, compression hose can be worn to assist venous return and to help avoid postthrombotic syndrome.^2,5,6,15-18

Risk Factors

   General risks. Virchow’s triad for DVT development is a multifactoral combination of acquired, congenital, reversible, and irreversible factors (see Table 1).^1,2,19 Unlike normal blood vessels, damaged endothelium cannot inhibit coagulation and initiate local fibrinolysis. Damage often occurs when the blood flow is altered and the vessel interior is “roughed up.”² Venous stasis occurs when the limb is immobile or venous obstruction is present. Blood pooling can be caused by everyday occurrences such as sitting at the computer or on an airplane for many hours. Venous stasis slows the clearance and dilution of activated coagulation factors, increasing the risk for clotting, especially if pooling occurs over damaged vessel walls.^2,16-18

   Hypercoagulability is caused by genetic mutation or by acquired thrombophilia as a result of estrogen therapy.^2,5,15,18 Each factor has a different relative rate of risk; the presence of multiple factors increases the estimated risk.^5,15 For example, estrogen contraception alone raises the risk of DVT and Factor V Leiden mutation is associated with twice as high a risk as estrogen contraception; the combination of these two risk factors substantially raises the risk more than 30-fold.¹⁵

   Oral contraceptive risk. Many epidemiologic and clinical studies were performed after the introduction of high estrogen concentration birth control pills (BCPs) and subsequent increased reports of thrombosis.⁵ Study results appeared to indicate that lower estrogen levels were safer. This led to the second- and third-generation BCPs that contain lower estrogen levels in combination with different levels and types of progestins.⁵ Evidence obtained in the last 10 years suggests that progestins also may have an associated risk of thrombosis.^5,20 Results of a meta-analysis²⁰ comparing the risk of venous thrombosis development between second- and third-generation BCPs indicated that patients who used third-generation contraceptives were 70% more likely to develop VTE than patients using second-generation BCPs (odds ratio 1.7, 95% confidence interval 1.4–2.0).²⁰ The risk of VTE also was higher with first-time users. Other studies in the literature^5,19 estimate that the risk of developing VTE when using third-generation BCPs is 1.4 to four times as high as when using second-generation BCPs.

   Because epidemiological and clinical evidence indicates that some oral BCPs are more thrombogenic, package inserts accompanying third-generation BCPs in the US and UK state that these drugs are associated with a higher risk of thrombosis.⁵ Although the estimated risk for oral contraceptive VTE appears to increase with the third generation, the risk remains small. Third-generation BCP risk for VTE is still only 1.5 per 10,000 women per year. Risk for death is 1 per 25,000 women taking these products for 10 years.

   Factor V Leiden risk. Factor V Leiden is a single point dominate mutation in the gene for factor V. The resulting factor Va is resistant to degradation by activated protein C; thus, increases hypercoagulation.^1,15 It is the most common genetic prothrombotic defect.¹⁹ Although Factor V Leiden is prevalent in approximately 6% of the population, the mutation is detected in 20% of all patients with venous thrombosis and up to 50% of thrombophilic patients.^15,19 Unless a family history that includes thrombotic events is documented and testing is performed, genetic risks often go undetected. As mentioned previously, the risk impact for DVT varies; a strong association between Factor V Leiden mutation and VTE exists. Preventive screening for Factor V Leiden before issuing a BCP prescription has been discussed but not performed due to cost, small at-risk population, and potential legal ramifications.^5,15 Although insurance policies by law should not be biased against certain medical conditions, thrombophilia disorders or required screening conceivably could be used to prevent policy purchase. In addition, routine screening for a prothrombotic defect, case finding, and increased use of long-term anticoagulant therapy for prevention could result in a lifetime of substantial risks.

   In order to prevent one death, estimates indicate that approximately one-half million people would require screening.^5,15 A study²¹ that examined screening and the financial implications of lifetime treatment in VTE patients showed only a marginal reduction in costs, primarily due to the small at-risk population; when multiple high risk factors or an increased recurrence rate were present, the screening was more cost effective. One study⁵ suggested that if the price of testing was less than $9, the cost could be justified. For these reasons, only patients who have family or personal history of DVT are currently routinely screened for relevant genetic mutations.

Prevention Strategies

   The most commonly recommended prevention strategy for DVT development is to avoid sitting for long periods. When sitting, people should refrain from crossing the legs or ankles to ensure blood flow is not impeded.³ Elevating the legs when sitting also will enhance circulation. Leg exercises and walking help keep blood circulating, reducing the risk of venous stasis. Of course, maintaining a healthy body weight through regular exercise and not smoking also will help prevent DVT, as well as a myriad of other problems.^2,3 However, people with certain comorbidities such as protein C deficiency will need to take additional measures to prevent DVT. Prophylactic use of LMWH should be implemented in thrombophilic patients entering high-risk situations.¹

   When traveling, people should stay hydrated and avoid alcohol to reduce hypercoagulability.^3,16 Wearing compression hose to assist circulation can help prevent DVT.^2,17,18 People should be alert to symptoms and continue other preventative measures vigilantly for 2 weeks following travel — this is when DVT is most likely to develop.¹⁶ Prophylactic anticoagulant therapy is recommended for patients with high risk thrombophilia that cannot be avoided.^2,15

Conclusion

   Personally, a visit with a hematologist revealed several risk factors of which previously I had been unaware. An arthritic knee infection from childhood, old sports-related injuries, past pregnancies, previous pelvic surgery, extensive travel, a foot fracture, and a recent change in medication to a third-generation oral contraceptive appeared to have taken their toll. However, the most surprising revelation was the presence of a Factor V Leiden mutation, a common congenital cause of thrombophilia. Based on the current literature,^1,15,19 I did not present as a typical thrombophilic patient. The lack of significant personal and family history for clotting disorders did not indicate potential problems. Fourteen years of BCP usage and two successful pregnancies with no thrombotic symptoms gave no indication of the upcoming DVT.^5,15,19 After the DVT episode, the multiple risk factors were more evident.^1,2 As one author states,¹⁹ “Venous thrombosis is a multicausal disease, caused by the simultaneous presence of genetic and acquired risk factors. The genetic defects that were known to cause venous thrombosis a decade ago were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors. Black and white has become a grayscale, and no longer is thrombophilia a rare disorder: all are at risk for thrombosis, but some are more at risk than others.”

   As I navigate the road to wellness, I am thankful. I can recover. I am now aware of and willing to take preventive measures. Hopefully, my experience will alert others who may be unaware of the risks to themselves and their patients.

Acknowledgments

   I am grateful to my excellent medical team, church, family, and friends who took care of me when I was incapacitated. Special thanks to Geraldine Gossard, MD, for overseeing my medical care and assisting in the preparation of this article.

1. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals. Circulation. 1996;93(12):2212–2245.

2. Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med. 2004;351(3):268–277.

3. Deep vein thrombosis. Clinical Reference Systems: Adult Health Advisor. Windows Software. San Francisco, Calif: McKesson Health Solutions LLC;2004.

4. Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet. 2005;365(9465):1163–1174.

5. Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001;344(20):1527–1535.

6. Markel A. Origin and natural history of deep vein thrombosis of the legs. Semin Vasc Med. 2005;5(1):65–74.

7. Simon DA, Dix FP, McCollum CN. Management of venous ulcers. BMJ. 2004;328: 1358–1362.

8. Shull KC, Nicolaides AN, Fernandes e Fernandea J, et al. Significance of popliteal reflux in relation to ambulatory venous pressure and ulceration. Arch Surg. 1979;114(11):1304–1306.

9. Standness Jr. DE, Langlois Y, Cramer M, et al. Long-term sequelae of acute venous thrombosis. JAMA. 1983;250(10):1289–1292.

10. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334(11):677–681.

11. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med. 1999;130(10):800–809.

12. Spyropoulos AC, Hurley JS, Ciesla GN, et al. Management of acute proximal deep vein thrombosis: pharmacoeconomic evaluation of outpatient treatment with enoxaparin vs. inpatient treatment with unfractionated heparin. Chest. 2002;122:108–114.

13. O’Brien B, Levine M, William A, et al. Economic evaluation of outpatient treatment with low-molecular weight heparin for proximal vein thrombosis. Arch Intern Med. 1999;159:2298–2304.

14. Bristol-Meyers Squibb Company. Coumadin (Warfarin sodium tablets, USP) Crystalline full prescribing information. Available at: http://www.coumadin.com/coumadin/home/hcp_index. Accessed October 20, 2005.

15. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thrombotic disease. Ann Intern Med. 1997;127(10):895–903.

16. Watson HG. Travel and thrombosis. Blood Rev. 2005;19(5):235–241.

17. Hsieh HF, Lee FP. Graduated compression stockings as prophylaxis for flight-related venous thrombosis: systemic literature review. J Adv Nurs. 2005;51(1):83–98.

18. Martinelli I, Taioli E, Battaglioli T, et al. Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives. Arch Intern Med. 2003;163(22):2771–2774.

19. Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematol. 2005;2005:1–12.

20. Kemmermen JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ. 2001;323(7305):131–134.

21. Eckman MH, Singh SK, Erban JK, Kao G. Testing for Factor V Leiden in patients with pulmonary or venous thromboembolism: a cost-effective analysis. Med Decis Making. 2002;22(2):108–124.