|Year : 2021 | Volume
| Issue : 4 | Page : 123-126
The “legacy” of the 125I-fibrinogen test and current management of isolated calf vein thrombosis: The end of a 40-year debate
Andrew N Nicolaides1, SK Kakkos2
1 Department of Vascular Surgery, Imperial College, London, England; Department of Surgery, University of Nicosia Medical School, Nicosia, Cyprus
2 Department of Vascular Surgery, University of Patras, Patras, Greece
|Date of Submission||10-Aug-2021|
|Date of Decision||17-Oct-2021|
|Date of Acceptance||24-Oct-2021|
|Date of Web Publication||21-Dec-2021|
Dr. Andrew N Nicolaides
Department of Surgery, University of Nicosia Medical School, Nicosia
Source of Support: None, Conflict of Interest: None
Prior to 1970 the true incidence of postoperative dep vein thrombosis (DVT) was unknown, although surgeons were aware that pulmonary embolism (PE) occurred in 1-4% of patients. The development of the 125I-Fibrinogen test in the 1970s provided a means of screening surgical patients and demonstrated that the incidence of silent DVT varied from 17-47% depending on age, type and duration of operation. Only 4-6% of the patients with DVT developed symptoms. It has now been realised that although symptomatic isolated calf DVT is rarely associated with fatal PE, it produces local damage to venous valves with the development of reflux and post-thrombotic syndrome in 10-23% of patients and has a recurrence rate of 14%. In recent systematic reviews and meta-analyses of patients with symptomatic isolated calf DVT anticoagulation therapy up to 3 months reduces the incidence of recurrent DVT from 7.9% to 1.65% (RR 0.25; 95% CI 0.10-0.67). When anticoagulation period of 3 months was compared with 6 weeks it reduced the incidence of DVT from 14.4% to 4.8% (RR 0.32; 95% CI 0.16-0.64) Current guidelines of European Society of Vascular Surgery are as follows: “For patients with symptomatic calf DVT 3 months therapy is recommended over shorter durations (Class 1, Level A).
Keywords: Deep Vein Thrombosis, 125I-Fibrinogen Test, Isolated calf DVT
|How to cite this article:|
Nicolaides AN, Kakkos S K. The “legacy” of the 125I-fibrinogen test and current management of isolated calf vein thrombosis: The end of a 40-year debate. Vasc Invest Ther 2021;4:123-6
|How to cite this URL:|
Nicolaides AN, Kakkos S K. The “legacy” of the 125I-fibrinogen test and current management of isolated calf vein thrombosis: The end of a 40-year debate. Vasc Invest Ther [serial online] 2021 [cited 2022 Aug 15];4:123-6. Available from: https://www.vitonline.org/text.asp?2021/4/4/123/333004
| Historical Introduction|| |
Knowledge of deep-vein thrombosis in the 1950s and 1960s
In the 1950s and 1960s, the true incidence of postoperative deep-vein thrombosis (DVT) was unknown. At that time, it had been established that the clinical diagnosis of DVT was unreliable because in the presence of classical symptoms and signs only 50% of the patients had verified DVT by venography. The available knowledge on DVT had been summarized as follows by Ian Aird in his classic monograph “A Companion in Surgical Studies” published in 1958.
”DVT occurs in 0.5%–1% of all hospital patients, in 3%–4% of surgical patients, more than 1% of obstetric patients, and in <1% of patients treated in bed without operation….There is twice as much risk of thrombosis after laparotomy as there is after other operations……It is strange that thrombosis is twice as common after bilateral herniotomy, an observation which suggests that the main causative factor, whatever it is, in the production of thrombosis acts at the time of operation and varies directly with the time spent by the patient on the operating table.” It was also stated that “Pulmonary embolism (PE) occurs in some 50%–60% of patients who have thrombosis after surgical operations, and PE kills 16%–20% of patients who have thrombosis. PE occurs in 20%–35% of obstetric patients who have thrombosis but kills only 3%–4% of them…. The age of the patient is important. Surgical and medical patients who suffer from thrombosis are normally middle aged or old…… DVT is common in some families than in others. Other factors predisposing to thrombosis are cardiac infarction, extensive lower limb varicosities, and low output cardiac insufficiency”.
Development of the 125I-fibrinogen test
The eloquent summary by Ian Aird was based on the American and Scandinavian literature of the time. Despite the observation that 80% of patients who develop postoperative PE do not have any evidence of clinical DVT, it was thought that the leg veins were the common site of origin. In 1960, John Hobbs and John Davies argued that the largest specific component of the thrombus was the fibrin network and as fibrinogen could be labeled with radioactive iodine, it should be incorporated in a forming thrombus and detected by an external scintillation counter. At the Medical Research Council in Birmingham, UK they injected intravenously131 I-Fibrinogen, in 57 rabbits, in doses of 20–77 μc before the induction of thrombosis by different methods. Twelve rabbits acted as controls. In 45 rabbits, venous thrombosis was induced in the left saphenous vein in the groin with the right leg acting also as control. Irrespective of the method used to induce thrombosis a high and persistently increased radioactivity was found at the site of every thrombus. The method was refined by further experiments at the Harvard Medical School in Boston in 1961 where John Hobbs did his fellowship, with fibrinogen being labeled by John Davies in Birmingham, UK and because of the high radiation energy, it was carried to Boston in the wings of the plane. The feasibility of the method was successfully demonstrated in a 44-year-old female patient who received 90 μc of131 I-Fibrinogen after blocking the thyroid with potassium iodide tablets and before some residual veins were treated by sclerotherapy in Boston in July 1961. Because of a coincidental epidemic of hepatitis in Boston in 1961, it was suggested that researchers had to use the patient's own fibrinogen, a task too difficult at the time and thus further studies in patients ceased.
In 1965, Atkins and Hawkins, working at Kings College Hospital Medical School, London, UK substituted the isotope125 I for 131I as the radioactive label because 125I had a longer half-life (60 days instead of 8 days) and a lower gamma radiation energy so that lighter and more mobile apparatus could be used. The accuracy of the test was confirmed by venography,,, and by using a ratemeter, it became a simple test suitable for the routine screening of large numbers of patients.
Incidence and natural history of calf deep-vein thrombosis
Several studies using the 125I-fibrinogen test demonstrated that patients who undergo general and vascular surgical procedures are at risk of developing venous thromboembolism (VTE). The findings of these early studies were summarized in a review by Hobbs and Nicolaides in 1971. In the absence of prophylaxis, the risk of silent DVT was 30% in general surgery, 17% in gynecological surgery, 47% in patients with fractured necks of femur, 30% in urological surgery, 34% in acute myocardial infarction, and 68% in medical patients in shock. It was found that the majority of the thrombi started during the operation and that 89% of thrombi started in the calf, 6.5% in the popliteal region, and 4% in the thigh. Subsequent venographic studies demonstrated that in patients with fractured neck of femur and elective hip replacement iliac vein thrombosis tended to occur de novo in the 2nd week after operation. Of the thrombi that started in the calf 20% lysed spontaneously and this was particularly so in patients who were ambulant. However, 25% extended more proximally into the popliteal, femoral or iliac veins. If the thrombosis was limited to the calf, the risk of serious PE was negligible, but if the popliteal and femoral veins became involved, the risk of PE rapidly increased reaching 50% when the iliac veins were involved.
During the 1970s, the 125I-fibrinogen test was used as a diagnostic tool in most randomized controlled trials on the efficacy of different methods of prevention, and was the tool used in randomized control trial (RCT) that established the value of low dose heparin, low-molecular-weight heparin (LMWH), elastic compression, electrical calf muscle stimulation and intermittent pneumatic compression in the prevention of postoperative DVT. These RCTs eventually demonstrated that if a method prevents calf DVT, it also prevents proximal DVT, symptomatic DVT, PE, and fatal PE., The 125I-Fibrinogen test was eventually replaced by ultrasound and with the appearance of AIDS in 1981 it became obsolete. However, its “legacy” and the problem of how to manage isolated calf DVT remained a controversial subject for over 40 years.
The finding that in the presence of isolated calf DVT fatal PE did not occur resulted in a school of thought that routine anticoagulation was unnecessary and surveillance with ultrasound would suffice, reserving anticoagulation for those in which the thrombus would extend into the popliteal or more proximal veins. However, the realisation that local damage to the venous valves with the development of reflux and skin changes, and symptoms of persistent pain and edema in 10%–23% of patients leading to CEAP C4–C6 classes and a DVT recurrence rate of up to 14%,, led to the development of another school of thought that such patients should be routinely anticoagulated unless there were serious contraindications.
| Recent Findings and Recommendations on Management|| |
Recent systematic reviews
A systematic literature review and meta-analysis of 24 studies involving 2936 patients was published in 2016. Of these, 5 studies were randomized controlled trials, 7 were prospective cohort studies, 7 were retrospective studies, and one was a combined prospective and retrospective cohort study. Four additional studies compared different durations of anticoagulation. Recurrent VTE (proximal propagation, recurrence of DVT, or PE) was reduced from 11.1% in patients not on anticoagulation to 6.5% in patients on anticoagulation (odds ratio [OR] 0.50; 95% confidence interval [CI] 0.15–0.73) without increase in major bleeding. Recurrent DVT was reduced from 6.5% to 1.5% (OR 0.23; 95% CI 0.08–0.65) and PE was reduced from 2.4% to 1.4% (OR 0.48; 95% CI 0.25–0.91). Recurrence rate of VTE was reduced from 10.7% in those receiving anticoagulation for <6 weeks to 3.2% in those receiving anticoagulation for more than 6 weeks (OR 0.39; 95% CI 0.17–0.90). The authors concluded that in patients with isolated calf DVT, anticoagulation reduces the incidence of PE and recurrent DVT without increased risk of major bleeding. Although most patients on anticoagulants in the studies included in the meta-analysis were receiving VKA, the authors suggested that direct oral anticoagulants should be considered for the treatment of isolated calf DVT, given their improved efficacy-to-safety profile.
The most recent Cochrane systematic review and meta-analysis identified eight RCTs involving 1239 patients with isolated calf DVT. In five trials, anticoagulation therapy was up to 3 months, and in three trials, anticoagulation of different periods was used in the treatment groups. Recurrence of VTE was reduced from 9.1% in the placebo/no intervention group to 2.9% in the VKA group (relative risk [RR] 0.34; 95% CI 0.15–0.77). There was not any significant difference in the risk of PE, but the risk of DVT recurrence was reduced from 7.9% to 1.65% (RR 0.25; 95% CI 0.10–0.67). There was not any significant increase in major bleeding, but there was an increase in clinically relevant nonmajor bleeding from 1.8% to 7.0% (RR 3.34 (95% CI 1.07–10.46). In three RCTs comparing treatment with VKA for three or more months to 6 weeks, treatment for 3 months or more reduced the incidence of VTE from 13.9% in the 6-week group to 5.8% in the three or more months group (RR 0.42; 95% CI 0.26–0.68). The risk of recurrent DVT was also reduced from 14.4% to 4.8% (RR 0.32; 95% CI 0.16–0.64).
Current recommendations by the European Society for Vascular Surgery 2021 on the management of venous thrombosis
In view of the high risk of recurrence, proximal extension and PE in patients with isolated calf DVT in the absence of anticoagulation and in view of the efficacy of anticoagulation demonstrated by RCTs the recommendations in the 2021 guidelines of the European Society for Vascular Surgery are as follows:
“For patients with symptomatic calf DVT 3 months therapy is recommended over shorter durations” (Class 1, Level A).
In patients in whom anticoagulation is contraindicated “…. clinical reassessment and repeat whole leg ultrasound after 1 week is recommended” (Class 1, Level B).
“For patients with symptomatic calf DVT in the presence of active cancer anticoagulation beyond 3 months should be considered” (Class IIa, Level C).
The value of direct oral anticoagulants (DOACs) in patients with isolated calf DVT has not yet been investigated. However, in view of their improved efficacy and reduced incidence of bleeding demonstrated by RCT in patients with proximal DVT or PE compared with VKA, they should be considered as preferable to VKA. Thus, the following additional recommendation is made:
“For patients with calf DVT requiring anticoagulation DOACs are recommended over LMWH followed by VKA” (Class 1, Level C).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Aird I. A Companion in Surgical Studies. Edinburgh and London: E & S Livingstone Ltd; 1958. p. 213.
Coon WW, Willis PW. Deep venous thrombosis and pulmonary embolism: Prediction, prevention and treatment. Am J Cardiol 1959;4:611-21.
Gibbs NM. Venous thrombosis of the lower limbs with particular reference to bed-rest. Br J Surg 1957;45:209-36.
Hobbs JT, Davies JW. Detection of venous thrombosis with 131 I-labelled fibrinogen in the rabbit. Lancet 1960;2:134-5.
Hobbs JT. External measurement of fibrinogen uptake in experimental venous thrombosis and other local pathological states. Br J Exp Pathol 1962;43:48-58.
Atkins P, Hawkins LA. Detection of venous thrombosis in the legs. Lancet 1965;2:1217-9.
Atkins P, Hawkins LA. The diagnosis of deep vein thrombosis in the leg using 125I-Fibrinogen. Br J Surg 1968;55:825-30.
Flanc C, Kakkar VV, Clarke MB. The detection of venous thrombosis of the legs using 125-I-labelled fibrinogen. Br J Surg 1968;55:742-7.
Negus D, Pinto DJ, Le Quesne LP, Brown N, Chapman M. 125-I-labelled fibrinogen in the diagnosis of deep-vein thrombosis and its correlation with phlebography. Br J Surg 1968;55:835-9.
Field ES, Nicolaides AN, Kakkar VV, Crellin RQ. Deep-vein thrombosis in patients with fractures of the femoral neck. Br J Surg 1972;59:377-9.
Kakkar VV, Nicolaides AN, Renney JT, Friend JR, Clarke MB. 125-I-labelled fibrinogen test adapted for routine screening for deep-vein thrombosis. Lancet 1970;1:540-2.
Hobbs JT, Nicolaides AN. The diagnosis of acute deep vein thrombosis with 125-Iodinated fibrinogen. In: Diagnostik mit Isotopenbei Arteriellen Und Venösen Durchblutungsstörungen der Extremitäten. Edited by Zeitler E, editor. Bern, Stuttgart, Vienna: Hans Huber Publishers; 1971.
Nicolaides AN, Kakkar VV, Field ES, Renney JT. The origin of deep vein thrombosis: A venographic study. Br J Radiol 1971;44:653-63.
Kakkar VV, Howe CT, Flanc C, Clarke MB. Natural history of postoperative deep-vein thrombosis. Lancet 1969;2:230-2.
Nicolaides AN. The prevention of postoperative deep venous thrombosis. In: Jacksonian Prize Essay. Deposited In library of Royal College of Surgeons of England; 1972.
Nicolaides AN, Fareed J, Kakkar AK, Comerota AJ, Goldhaber SZ, Hull R, et al
. Prevention and treatment of venous thromboembolism – International consensus Statement. Int Angiol 2013;32:111-260.
Nicolaides AN, Dupont PA, Desai S, Lewis JD, Douglas JN, Dodsworth H, et al
. Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis after major surgery. Lancet 1972;2:890-3.
Kakkar VV, Corrigan TP, Fossard DP, Sutherland I, Thirwell J. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Reappraisal of results of international multicentre trial. Lancet 1977;1:567-9.
Masuda EM, Kessler DM, Kistner RL, Eklof B, Sato DT. The natural history of calf vein thrombosis: Lysis of thrombi and development of reflux. J Vasc Surg 1998;28:67-73.
Masuda EM, Kistner RL, Musikasinthorn C, Liquido F, Geling O, He Q. The controversy of managing calf vein thrombosis. J Vasc Surg 2012;55:550-61.
Saarinen JP, Domonyi K, Zeitlin R, Salenius JP. Postthrombotic syndrome after isolated calf deep venous thrombosis: The role of popliteal reflux. J Vasc Surg 2002;36:959-64.
Franco L, Giustozzi M, Agnelli G, Becattini C. Anticoagulation in patients with isolated distal deep vein thrombosis: A meta-analysis. J Thromb Haemost 2017;15:1142-54.
Kirkilesis G, Kakkos SK, Bicknell C, Salim S, Kakavia K. Treatment of distal deep vein thrombosis. Cochrane Database Syst Rev 2020;4:CD013422.
Kakkos SK, Gohel M, Baekgaard N, Bauersachs R, Bellmunt-Montoya S, Black SA, et al
. Editor's choice – European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis. Eur J Vasc Endovasc Surg 2021;61:9-82.
Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor's choice – Efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: A systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 2014;48:565-75.