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Three Part Question

In [a patient with a below knee venous thrombosis], is [warfarinisation necessary] to prevent [a pulmonary embolus]?

Clinical Scenario

A 50 year old man attends the emergency department with a plethoric, swollen left calf. Ultrasound examination reveals a posterior tibial vein thrombosis. You are unsure what the risk of a pulmonary embolus is, or whether he should be anticoagulated.

Search Strategy

Using MEDLINE OVID interphase 1966 – September week 1 2005
({DVT.mp or exp venous thrombosis or deep vein thrombosis.mp} AND {below knee.mp or calf.mp or popliteal.mp or exp popliteal vein or fibular.mp or peroneal.mp or posterior tibial.mp } AND {therapy.mp or exp therapeutics or treatment.mp or exp heparin or exp heparin, low-molecular-weight or heparin.mp or exp warfarin or warfarin.mp or exp coumarins or coumarin.mp }) limited to human and English language.

Search Outcome

695 papers were found. 13 addressed the question. Some studies included other patients with PE or thigh DVTs – only the patients with calf thrombosis are described.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Philbrick JT et al, 1988, USA	All studies of sufficient quality identified from literature search over years 1944 to 1986.	Literature review	Incidence PE	6/163 patients receiving no anticoagulation (Strength of evidence weak). 9/208 patients receiving a range of anticoagulation (0/32 in only study with strong evidence, all other studies weak)
Giachino A, 1988, Canada	152 patients who died in Ottawa hospitals over a 5 year period, with PE listed as the cause of death	Retrospective study	Source of thrombosis in fatal pulmonary emboli	82 had no post mortem examination. 23 post mortems confirmed PE as the cause of death, and identified the source of the embolus. 3/23 post mortems revealed the calf veins as the source of the thrombi	No controlling of post mortem procedures – unclear if all legs veins thoroughly examined Only 23/152 considered to die from PE actually had a PM and had the source of the embolus confirmed
Lohr J et al, 1991, USA	75 patients with ultrasound diagnosed calf thrombosis Treatment left to physician's discretion	Prospective study with follow-up serial ultrasound examination	Thrombosis propagation	15% propagated to involve the popliteal or larger veins. A further 17% propagated within the calf veins	Publication bias – all of these patients may have been included in the study by Pelligrini V et al. No information regarding the length of follow-up, or the effect of varying therapies
Pellegrini VD Jr et al, 1993, USA	25 patient with isolated calf DVT and 12 patients with superficial or muscular calf thrombosis, diagnosed by venography on post-operative screening of total-hip arthroplasty patients Only 12 calf DVTs and 1 superficial/muscular calf thrombosis were anticoagulated	Prospective study following-up at 6, 12, 24 and 52 weeks	Incidence of PE	4/13 untreated calf DVT patients were diagnosed with PE. 0/1 treated calf DVT patient and none of the superficial/muscular calf thrombosis developed PE	Two of the PEs were diagnosed on the strength of sudden collapse and cardiac arrest – no post mortem carried out
Nielson HK et al, 1994, Denmark	15 patients with venographically diagnosed calf DVTs	Prospective study	VQ scan result at presentation	5/15 had positive VQ scans	No information regarding exact criteria for diagnosing PE from VQ scan alone – probable over-estimation of incidence VQ scans were performed at 10 and 60 days, however no information regarding the breakdown of subsequent PEs between proximal and isolated calf DVT groups
Lohr JM et al, 1995, USA	192 patients with ultrasound diagnosed below knee DVTs, Treatment left to physicians discretion	Prospective study with serial ultrasound for 4 weeks	Thrombus propagation	53/139 thrombi propagated	Publishing bias – the cohort appears to include all of the patients included in the previous Lohr study (see study in this table) Paper does not establish rate of PE
O'Shaughnessy AM et al, 1997, Ireland	50 patients with ultrasound diagnosed DVTs, 43 treated with anticoagulation and 7 without	Prospective study, using repeat ultrasound at one week, one month, six months and one year	'Outcome' of isolated calf thrombosis	3 patients presented initially with a 'positive' VQ scan. One fatal PE within the first month	Venography not used to diagnose initial calf DVT Apparently, no attempts were made to actively seek the diagnosis of PE throughout the follow-up period No adequate description of the positive VQ scans 10 patients lost to follow-up at 6 months No account taken of the effect of treatment
Gottlieb RH et al, 1999, USA	238 patients with ultrasound diagnosed below knee DVTs	Retrospective study	Incidence of diagnosed PE's	2/56 patients not receiving anticoagulant therapy had PE	Patients were not identified using venography Retrospective study, therefore unable to detect silent PEs or those that did not present to medical services One PE diagnosed on strength of high probability VQ scan alone. No description of frequency of follow-up ultrasound scans Therapy at the discretion of physician No information regarding anticoagulant therapy for patient with extension to thigh DVT 28 patients were not followed for the full 6 months as they died
			Incidence of extension into thigh DVT	1/227 receiving anticoagulant therapy had documented extension to thigh DVT
Pinede L et al, 2001, France	105 patients with calf DVTs treated for 6 weeks with warfarin, 92 patients with calf DVTs treated for 12 weeks with warfarin	Prospective study	Incidence of PE	1/197 (patient from 12 week warfarin group) had documented PE	Diagnosis did not always use venography No information regarding which symptoms would prompt investigations for PE Method's description implies that a VQ scan result of intermediate probability would diagnose PE – no information as to how this PE was diagnosed
Schwarz T et al, 2001, Germany	84 patients with isolated calf muscle thrombosis. 52 received LMWH for 10 days, 32 received no anticoagulation	Prospective cohort with serial ultrasound examinations	Progression to deep veins of calf	Study discontinued as 8/32 non-anticoagulated patients progressed to deep veins thrombosis, compared to 0/52 anticoagulated patients	Gold standard venography not used VQ scan results interpreted in isolation
			PE	None
Sharpe RP et al, 2002, USA	85 trauma patients with below knee DVTs	Prospective cohort	Thrombus propagation	4/85 thrombi propagated proximally	Gold standard investigations not applied for DVT or PE
			PE	1/85 did not propagate but had a PE
Lagerstedt CL et al, 1985, Sweden	52 patients admitted to medical ward with venogram confirmed below knee DVT 24 randomised to warfarin therapy, 28 randomised to no warfarin therapy	RCT	90 day incidence of recurrent DVT or PE	Warfarin group, no patient had recurrence. 5 patients had proximal extension of deep vein thrombosis and one had symptomatic PE.	Gold standard not used to diagnose PE. 5 more patients had abnormal VQ scans at 90 days, but whether they had PE remains unclear.
MacDonald PS et al, 2003, Canada	120 patients with isolated gastrocnemius or soleus muscle vein thrombosis. No patient anticoagulated. 69% inpatients.	Prospective cohort study with duplex scans at 5, 9, 14, 30 and 90 days.	Thrombus propagation	Complete resolution in 46%. Thrombus extension in 16.3%. 3% extended to level of popliteal vein or above. 90% of thrombus extensions occurred within 2 weeks.	Only 65% were followed up to 3 months. No details are available for the deaths of 22 patients. Outcomes did not include PE.

Comment(s)

All of these studies could have been more thorough in their diagnostic criteria and/or follow-up.

Clinical Bottom Line

Despite the flaws in almost all of these studies, it is clear that pulmonary emboli DO result from below knee thrombi. All patients with calf thrombosis should receive oral anticoagulation.

References

1. Philbrick JT, Becker DM. Calf deep venous thrombosis. A wolf in sheep's clothing. Arch Intern Med 1988;148(10):2131-8.
2. Giachino A. Relationship between deep vein thrombosis in the calf and fatal pulmonary embolism. Can J Surg 1988;31(2):129-30.
3. Lohr JM, Kerr TM, Lutter KS et al. Lower extremity calf thrombosis: to treat or not to treat? J Vasc Surg 1991;14(5):618-23.
4. Pellegrini VD Jr, Langhans MJ, Totterman S et al. Embolic complications of calf thrombosis following total hip arthroplasty. J Arthroplasty 1993;8(5):449-57.
5. Nielsen HK, Husted SE, Krusell LR et al. Incidence and fate in a randomised, controlled trial of anticoagulation versus no anticoagulation. J Intern Med 1994;235(5):457-61.
6. Lohr JM, James KV, Deschmukh RM et al. Calf vein thrombi are not a benign finding. Am J Surg 1995;170(2):86-90.
7. O'Shaughnessy AM, Fitzgerald DE. The value of duplex ultrasound in the follow-up of acute calf vein thrombosis. Int Angiol 1997;16(2):142-6.
8. Gottlieb RH, Widjaja J, Mehra S et al. Clinically important pulmonary emboli: does calf vein US alter outcomes? Radiology 1999;211(1) 25-29.
9. Pinede L, Ninet J, Duhaut P et al, Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf Circulation. 2001;103(20):2453-60.
10. Schwarz T, Schmidt B, Beyer J et al. Therapy of isolated calf muscle vein thrombosis with low-molecular-weight heparin. Blood Coagul Fibrinolysis 2001;12(7):597-9.
11. Sharpe RP, Gupta R, Gracias VH, et al. Incidence and natural history of below-knee deep venous thrombosis in high-risk trauma patients. J Trauma 2002;53(6):1048-52.
12. Lagerstedt CI, Olsson CG, Fagher BO, Oqvist BW, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 2:(8454):515-8, 1985.
13. Macdonald PS, Kahn SR, Miller N, Obrand D. Short-term natural history of isolated gastrocnemius and soleal vein thrombosis. Journal of Vascular Surgery. 37(3):523-7, 2003.