Title: DEEP VENOUS THROMBOSIS
Author: Samuel Z. Goldhaber
Last saved by: Glen Bennett
Company: DHHS

SEQUELLAE  OF  VENOUS  THROMBOEMBOLISM  PROPHYLAXIS

Samuel Z. Goldhaber, MD
Professor of Medicine
Harvard Medical School
Director, Venous Thromboembolism Research Group
Director, Anticoagulation Service
Brigham and Women’s Hospital

July 3, 2006

Cardiovascular Division
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
Phone:  617-732-7566
FAX:      617-264-5144
E-mail:  sgoldhaber@partners.org

When patients are diagnosed with deep vein thrombosis (DVT) or pulmonary embolism (PE), we tend to focus on immediate issues such as ensuring adequate and timely anticoagulation, stratifying the patient into high risk or low risk for complications, and determining whether hospitalization is necessary and, if so, for how long and for what objectives.  The diagnosis of venous thromboembolism (VTE) is rarely anticipated, so that when DVT or PE is detected, a sense of urgency and a need for immediate disposition becomes of paramount importance.  This approach is understandable and necessary, but it obscures the intermediate and long-term issues with which patients, families, and health care professionals must grapple.  

Though we tend to think of PE as a “life or death” issue, most sequellae of DVT and PE affect quality of life rather than survival.  The three most common follow-up problems are:  1) chronic venous insufficiency, 2) recurrent DVT or PE, and 3) chronic thromboembolic pulmonary hypertension.  

Patients stricken with VTE often have difficulty dealing with the psychological aftermath of their illness.  This consequence of VTE may not be apparent and often requires specific questioning to elicit.  

CHRONIC  VENOUS  INSUFFICIENCY
	The five stages of chronic venous insufficiency (also called “postthrombotic syndrome”) are outlined in Table 1.  Varicose veins may be mild or extensive.  At times they cause concern because they are cosmetically unappealing.  However, when extensive, they can cause chronic pain and burning.  Ankle and lower leg edema occurs because of permanent damage to the valves of the leg veins from the initial DVT, even if subsequent anticoagulation control is excellent.  

	Brownish skin pigmentation changes are especially common in the area of the medial malleolus.  These pigmentation abnormalities are caused by deposition of hemosiderin.  The changes tend to be permanent and irreversible.  Under the most severe circumstances, chronic venous insufficiency can progress to skin ulceration.  

	In one cohort of VTE patients followed for 10 years, more than half developed clinical evidence of at least mild venous insufficiency (1).  The likelihood of developing severe disease was 6%.  Risk factors for developing chronic venous insufficiency include proximal (as opposed to isolated calf) leg DVT, male gender, and high D-dimer levels.  Patients with chronic venous insufficiency have an increased risk of suffering recurrent VTE (2).  
RECURRENT  VENOUS  THROMBOEMBOLISM
	DVT and PE often recur following cessation of anticoagulation.  Overall, the recurrence rate is about 30% with 8-year follow-up of patients who receive 3-6 months of initial anticoagulation that is then discontinued (3).  Recurrence is more likely if the initial episode was not provoked by trauma, surgery, or hormonal changes due to pregnancy, oral contraceptives, or hormone replacement.  Therefore, the trend has been to prescribe prolonged and at times indefinite duration anticoagulation when the initial VTE is spontaneous.  

	Patients with symptomatic PE have a higher risk of recurrent VTE than those presenting with DVT symptoms alone.  Those who initially presented with PE are more likely to have a PE recurrence than a DVT recurrence (4).  For reasons that remain unclear, the risk of recurrent VTE is higher among men than women (5).  

CHRONIC  THROMBOEMBOLIC  PULMONARY  HYPERTENSION
	Chronic thromboembolic pulmonary hypertension used to be considered a rare complication of acute PE that occurred as a sequella in approximately 1 of 500 cases of PE.  However, a long-term prospective follow-up study of 223 patients has shown that this serious complication of PE is relatively common. After 2 years of follow-up, the incidence was 3.8%.  No new cases occurred after 2 years of follow-up.  Risks for developing chronic thromboembolic pulmonary hypertension included a history of prior PE, an anatomically large PE, and an initial presentation with an unprovoked spontaneous PE (6). 

	The chronic thromboembolic material is fibrous and hardens into the wall of the pulmonary artery.  It cannot be thrombolysed and requires surgical pulmonary thromboendartectomy for removal (7).  This complex operation requires median sternotomy, cardiopulmonary bypass, profound hypothermia, and circulatory arrest.  Balloon pulmonary angioplasty (8) and medical treatment with drugs such as sildenafil (9) are emerging options for inoperable patients.  

CONCLUSIONS
	Our concept of VTE has changed.  DVT and PE no longer constitute time-limited short-term illnesses.  Patients who suffer VTE are susceptible to long-term consequences, including chronic venous insufficiency, recurrent VTE, and chronic thromboembolic pulmonary hypertension.  The realization that these problems may be long-term can lead to psychological difficulty in coping with VTE as well as medical debility.

		 

REFERENCES
1.	Schulman S, Lindmarker P, Holstrom M. Larfars G, Carlsson A, Nicol P, Svensson E, Ljungberg B, Viering S, Nordlander S, Leijd B, Jahed K, Hjorth m, Linder O, Beckman M. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. 

2.	Stain M, Schonauer V, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Kyrle PA, Eichinger S. The post-thrombotic syndrome: Risk factors and impact on the course of thrombotic disease. J Thromb Haemost 2005;3:2671-2676.

3.	Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.

4.	Eichinger S, Weltermann A, Minar E, Stain M, Schonauer V, Schneider B, Kyrle PA. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med 2004;164:92-96.

5.	Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004;350:2558-2563.

6.	Pengo V, Lensing AWA, Prins MH, Marchiori A, Davidson BL, Tizzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P, for the Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-2264.

7.	Jamieson Sw, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, Channick RN, Fedullo PF, Auger WR. Pulmonary endarterectomy: Experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457-1464.

8.	Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation 2001;103:10-13.

9.	Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation 2006;113:2011-2020.

Table 1.  Stages of Chronic Venous Insufficency

1.	Varicose veins
2.	Ankle/ leg edema
3.	Stasis dermatitis
4.	Lipodermatosclerosis
5.	Venous stasis ulcer