The diagnosis of acute recurrent deep-vein thrombosis

643

IJC 013XA

News and Views

The diagnosis of acute recurrent deep-vein thrombosis * The patient with clinically suspected recurrent deep-vein thrombosis presents a diagnostic challenge for the clinician because the clinical diagnosis of recurrent deep-vein thrombosis is highly non-specific, and because each of the objective diagnostic tests for deep-vein thrombosis has potential limitations in this context [l]. Recurrent leg symptoms following deep-vein thrombosis may be caused by acute recurrent deep-vein thrombosis, the post-phlebitic syndrome, or a variety of nonthrombotic disorders. Differentiation between these three causes for recurrent leg symptoms is important because anticoagulant therapy is not required in patients with either the post-phlebitic syndrome or a non-thrombotic cause for leg symptoms. Venography alone has the limitation that the diagnostic hallmark, a constant intraluminal filling defect, may be masked because of obliteration and recanalization leading to impaired visualization. Consequently, the venographic findings may be inconclusive in patients with previous disease. Impedance plethysmography (IPG) may be falsely positive because of persistent venous outflow obstruction due to a previous episode of venous thrombosis, or falsely negative because of large collateral channels which have developed consequent to the first episode. Leg scanning with [‘x Ilfibrinogen is useful for detecting active calf and distal thigh-vein thrombi, but is relatively insensitive in the upper thigh and cannot detect external and common iliac-vein thrombi. Evaluation of Objective Testing for Suspected Recurrent Deep-vein Thrombosis We have recently completed a cohort analytic study incorporating long-term follow-up of 270 patients with clinically suspected acute recurrent deep-vein thrombosis who were evaluated by combined impedance plethysmography and [‘251]fibrinogen leg scanning, plus venography [l]. The results of this study are of considerable clinical relevance because, for the first time, the clinician is provided with a practical approach to the patient with clinically suspected recurrent deep-vein thrombosis. Conventional methods could not be used to assess the accuracy of this diagnostic approach in this condition because of the lack of an acceptable reference standard * From the Departments University, Hamilton, Ontario,

of Medicine Canada.

and

Clinical

Inrernational Journal of Cardiology, 5 (1984) 643-648 0 Elsevier Science Publishers B.V.

Epidemiology

and

Biostatistics,

McMaster

644

for the diagnosis of acute recurrent venous thrombosis. In our study, this problem was overcome by establishing a priori diagnostic criteria for the presence or absence of acute recurrence, and then testing their validity by recording outcome on long-term follow-up. At the onset of the study, we decided to withhold anticoagulant therapy in patients with negative results by IPG and leg scanning, irrespective of the severity or extent of the clinical findings. The diagnostic approach which we evaluated is outlined in Fig. 1. Impedance plethysmography was performed immediately on referral; if the results were negative, the patient was injected with [“‘I]fibrinogen and leg scanning was performed one and three days later, at which time the IPG was also repeated. Anticoagulant therapy was withheld in all patients who remained negative by non-invasive testing. If the initial IPG was positive, venography was performed. Anticoagulant therapy was commenced in all patients positive by impedance plethysmography in whom venography detected a constant intraluminal filling defect. If a constant intraluminal filling defect was not detected by venography, the patient was injected with [‘251]fibrinogen, and leg scanning was performed 1 and 3 days later. Anticoagulant therapy was commenced if the [“‘I]fibrinogen leg scan result was positive. All patients were then followed-up long term at 3 months and 12 months. One hundred and eighty-one of 270 patients (67%) had negative IPG and leg scan results; 89 patients had positive IPG or leg scan results (Fig. 1) [l]. Anticoagulant

270 PATIENTS WITH CLINICALLY SUSPECTED ACUTE RECURRENT DEEP VEIN THROMBOSIS

POSITIVE -IMPEDANCE (70 patients)

I-VENOGRAPHY-1

I

INTRALUMINAL FILLING

DEFECT

NEGATIVE (200 pa(hts)

PLkTHYSMOGRAPM-

LEG SCAN

I

I

NEGATIVE

INDETERMINATE

(2 patients)

(23 patients)

I TREATMENT

REPEAT

/ POSITIVE

(45 patients)

i

\ LEG SCAN

(19 patients)

r

1 LEG SCAN

POSiTlVE

(10 patients)

IPG

NEGATIVE (lS1

pationtr)

I TREATMENT

1 NEGiTlVE (13 patients)

I TREATMENT

Fig. 1. Diagnostic process deep-vein thrombosis.

and outcome

on entry in 270 patients

with clinically

suspected

acute recurrent

645

therapy was withheld in all 181 patients negative by non-invasive testing. On long-term follow-up, none of the 181 patients died from pulmonary embolism, and only 3 patients (1.7%) returned with objectively documented recurrent venous thromboembolism. In contrast, 18 of 89 patients (20%) with positive IPG or leg scan results had new episodes of objectively documented venous thromboembolism, including four deaths (4.5%) from massive pulmonary embolism (P -c 0.001). The results on long-term follow-up indicate that a combined approach of non-invasive testing and venography can be used to separate patients with clinically suspected recurrent deep-vein thrombosis into two groups: a negative cohort in whom it is safe to withhold anticoagulant therapy and a positive cohort who require anticoagulant therapy [I]. Clinical Utility. Our diagnostic approach has high clinical utility, as definitive management was established in 95% of the 270 patients. Sixty-seven percent of the 270 patients (181 patients) were spared the need for anticoagulant therapy [l]. A definitive indication for anticoagulant therapy was established in 28% (76 patients). In the remaining 5% (13 patients) with a positive IPG, an indeterminate venogram result, and a negative leg scan, acute recurrent venous thromboembolism could not be confidently ruled out. It can be argued that these patients should be treated because leg scanning is insensitive in the upper thigh and cannot detect external and common iliac-vein thrombi. Given the infrequency of this combination of test results, it would be prudent to err on the side of treating these patients rather than to risk death from massive pulmonary embolism. Differential Diagnosis. In patients with recurrent leg symptoms in whom the diagnosis of acute recurrent deep-vein thrombosis has been ruled out by objective testing, the differential diagnosis includes the post-phlebitic syndrome and a variety of nonthrombqtic causes. The presence of the post-phlebitic syndrome is suggested by the presence of venous insufficiency. Incompetence of the valves of the deep veins resulting in venous insufficiency can be demonstrated by Doppler ultrasonography or by a variety of plethysmographic techniques. If recurrent deep-vein thrombosis and the post-phlebitic syndrome have been ruled out, the following alternate diagnoses should be considered: muscle strain (usually associated with unaccustomed exercise), muscle tear, direct twisting injury to the leg, internal derangement of the knee, hematoma, vasomotor changes in a paralyzed leg, lymphangitis. lymphatic obstruction, Baker’s cyst, cellulitis, and congestive cardiac failure [2]. In our experience, having ruled out acute recurrent venous thrombosis by objective testing and having ruled out the possibility of the post-phlebitic syndrome. it is often possible to determine the cause of symptoms by careful follow-up. In some patients, however, the cause of pain, tenderness and swelling remains uncertain even after careful follow-up and is presumably due to inflammation of other soft tissues of the leg. Cost Effectiveness. Although the study algorithm was test-intensive and complex, it was highly cost-effective as 67% of the 270 patients (181) were spared the need for anticoagulant therapy and management in hospital.

646

A Practical Approach to the Diagnosis of Acute Recurrent Venous Thrombosis A diagnosis of acute recurrent venous thrombosis can be made by impedance plethysmography if it can be demonstrated that the test result was negative prior to presentation, and is positive at the time of presentation. The presence of a previously normal impedance plethysmograph result greatly simplifies the practical diagnostic approach in patients subsequently presenting with clinically suspected acute recurrence. Recurrent venous thromboembolism on adequate anticoagulant therapy is rare (2%) [3-51, and the majority of patients who recur do so after discontinuation of 3 months of anticoagulant therapy [3-51. In our experience, 60% of patients with their first episode of extensive proximal deep-vein thrombosis have a normal impedance plethysmograph result at the time of discontinuation of 3 months of anticoagulant therapy [6]. For this reason, we perform a baseline impedance plethysmograph evaluation at the time of discontinuation of long-term anticoagulant therapy in all patients with deep-vein thrombosis. Diagnostic Approach in Patients with a Previously Normal Impedance Plethysmograph Result. The diagnostic algorithm for the diagnosis of clinically suspected recurrent deep-vein thrombosis in patients with a previously normal impedance plethysmograph is shown in Fig. 2. We perform impedance plethysmography anticoagulant therapy is withheld. immediately on referral and, if negative, [‘251]fibrinogen leg scanning is performed daily for 72 hr together with impedance plethysmography. If the results of both IPG and leg scanning remain negative, the diagnosis of acute recurrence is excluded and the need for anticoagulant therapy avoided. If the result of either IPG or leg scanning becomes positive in the absence of conditions known to produce false-positive test findings, a diagnosis of acute recurrent venous thrombosis is established and the patient is treated accordingly. A positive leg scan result in the presence of conditions known to produce a false-positive scan (e.g. hematoma) should be confirmed by venography. Venography should also be performed in patients with a concurrent condition that is known to produce a false-positive IPG result (e.g. congestive cardiac failure). Diagnostic Approach in Patients with a Previously Abnormal or Unknown Impedance Plethysmograph Result. The diagnostic algorithm for the diagnosis of suspected recurrent venous thrombosis in patients with a previously abnormal or unknown IPG result is shown in Figs. 2 and 3. If, on referral, the result of IPG is positive in a patient in whom the IPG was previously abnormal, or if the result of the previous IPG is unknown, then venography should be performed (Fig. 2) because the abnormal IPG does not distinguish between acute recurrent deep-vein thrombosis and chronic venous outflow obstruction. If the venogram demonstrates a new, constant. intraluminal filling defect at a site not involved on the previous venogram, the diagnosis of acute recurrent deep-vein thrombosis is established (Fig. 3). If the findings of venography are unchanged or indeterminate, but the common

641 CLINICALLY SUSPECTED ACUTE DEEP-VEIN THROMBOSIS

RECURRENT

I IPG

NEGATIVE

LEG .&AN

IPG NEdATlVE PRIOR TO REFERRAL

AND REPEAT IPG

A

EITHER POSITIVE*

TREATMENT

BOTH NEGATIVE

IPG PRi-VIOUSLY

I

ABNORMAL OR UNKNOWN

I

VENOGRAPHY

J

TREATMENT

**

NO TREATMENT RECURRENTDVTEXCLUDED

Fig. 2. Practical diagnostic approach in patients with clinically suspected acute recurrent thrombosis. * In the absence of conditions known to produce a false-positive test result. management of the results by venography is shown in Fig. 3.

venous ** The

femoral and iliac are well visualized and normal, the patient should be injected with [ ‘251]fibrinogen and leg scanning performed for 72 hr. If the results of leg scanning remain negative, acute recurrent venous thrombosis can be excluded and anticoagulant therapy withheld (Fig. 3). VENOGRAPHY

ILiD*

INDETEdh’llNATE

TREAiMENT

FEMORAL AND ILIAC VEINS NORMAL BY VENOGRAPHY

FEMORAL AND ILIAC VEINS ABNORMAL OR NON-VISUALIZED

LEG &-JAN

NEGATIVE

NO TREATMENT RECURRENCE EXCLUDED

TREAiMENT

POSiTlVE

NO TREATMENT

Fig. 3. Management deep-vein thrombosis.

NEGiTlVE

TREAiMENT

of results by venography in patients ILFD* = intraluminal filling defect.

with

clinically

suspected

acute

recurrent

648

Patients with a positive IPG result, indeterminate findings by venography which include the common femoral or iliac veins (but in whom no new intraluminal filling defects can be seen), and a negative leg scan result present a diagnostic dilemma. In these patients, acute recurrence cannot be confidently excluded and given the infrequency of this combination of test results, we prefer to err on the side of treatment rather than risk death from massive pulmonary embolism (Fig. 3). The management of patients with negative test results on referral in whom the previous IPG result was abnormal or unknown is the same as outlined above for patients with a previously negative IPG (Fig. 2).

Acknowledgements I am indebted to Dr. J. Leclerc, Dr. R. Jay, and Mr. Gary assistance in the preparation of this article. Department of Medicine McMaster University Hamilton. Ontario, Canada

Raskob,

B.Sc. for

Russell Hull

LSN 325

References Hull RD. Carter CJ. Jay RM. et al. The diagnosis of acute recurrent deep-vein thrombosis: a diagnostic challenge. Circulation 1983;67:901-906. Hull RD. Hirsh J, Sackett DL. et al. Clinical validity of a negative venogram in patients with clinically suspected deep-vein thrombosis. Circulation 1981;64:622-625. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979;301:855-858. Hull R. Delmore T. Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982;306:189-194. Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal vein thrombosis. N Engl J Med 1982;307:1676-1681. Jay R. Hull R. Carter C, et al. Outcome of abnormal impedance plethysmography results in patients with proximal vein thrombosis: frequency of return to normal. Thromb Hemostasis 1983;50:152a.

IJC 0138B

Myocardial P-adrenergic receptor downregulation in heart failure * One of the major challenges facing cardiologists and basic scientists is to elucidate a molecular basis for heart failure. Extensive studies of cardiac morphology and biochemistry have failed to yield a satisfactory explanation of the primary pathophysiology of the failing heart. * From the Cardiology Division, University of Utah School of Medicine, Salt Lake City, Utah, and the Department of Cardiovascular Surgery, Stanford University Medical Center. Stanford. California. Internntional Journal of Cardiology, 5 (1984) 648-652 0 Elsevier Science Publishers B.V.