Diagnosis of Established Deep Vein Thrombosis with the 125I Fibrinogen Uptake Test

One hundred and two patients with clinical signs indicating a possible diagnosis of deep vein thrombosis were studied with the fibrinogen uptake test and phlebography to assess the reliability of the test as a means of diagnosing established venous thrombosis. The test gave a correct diagnosis in 78% of the 85 legs shown to contain thrombus by phlebography and only 19 (10%) false-negative results in the 195 legs examined. The duration of the symptoms, the administration of anticoagulants, and mild leg swelling did not affect the accuracy of the test. Very old thrombus, phlebographically more than 11 days old, was associated with an increased false-negative rate.The fibrinogen uptake test is accurate enough to make it a valuable method of clinical investigation.     

Effect of intravenous dextran 70 and pneumatic leg compression on incidence of postoperative pulmonary embolism.

The incidence of pulmonary embolism and deep vein thrombosis was measured in 50 matched pairs of patients undergoing common surgical procedures with preoperative and postoperative ventilation-perfusion lung scans and the fibrinogen uptake test. One patient in each pair was treated with intravenous dextran 70 and pneumatic leggings. The incidence of pulmonary embolism among the treated patients was significantly reduced from 24% to 8%, but the incidence of deep vein thrombosis was not significantly reduced (34% to 24%).     

Puerperal Thromboembolic Disease in “High Risk” Cases

One hundred obstetric patients were studied for evidence of puerperal thromboembolic disease. Only one case of deep vein thrombosis was detected in patients thought to be in a “high risk” category because of age or operative intervention. Clinical findings were unreliable compared with measurements of ¹²⁵I-labelled fibrinogen uptake. Doppler ultrasound flow detection proved a simple screening technique but produced no abnormal findings in this series.     

Incidence of early post-operative iliofemoral thrombosis.

The doppler ultrasound probe was used to study 138 patients after major surgery to assess the incidence of iliofemoral thrombosis in the early postoperative period. The patients were simultaneously studied with the 125-I-fibrinogen uptake test. The accuracy of the ultrasonic technique was assessed concurrently by comparing its results with those of ascending phlebography in a separate group of patients. The ultrasound probe detected thrombus proximal to the calf but was inaccurate in locating its exact site. Of the 138 patients studied postoperatively 28 developed calf vein thrombosis detected istopically, but there was no evidence of iliofemoral thrombosis in any patient. Thus, spontaneous iliofemoral thrombosis in the early postoperative period is rare.     

Prevention of postoperative deep vein thrombosis with dipyridamole and aspirin.

One hundred and sixty patients have been studied in a controlled trial of two drugs which have been in combination to prevent postoperative-deep-vein thrombosis. Both the drugs, dipyridamole (Persantin) and aspirin, were given by mouth from the evening before operation and for seven days after operation. The radioactive fibrinogen test was used to diagnose thrombosis. Of the 85 patients in the control group 24 developed thrombosis (28%). Twelve out of 85 patients (14%) in the test group were found to have thrombosis. Similar significant differences in incidence were found in the various subgroups.     

Deep Vein Thrombosis in a Queensland Hospital

Investigation in the postoperative period of 75 patients by means of the radioiodinated fibrinogen uptake method, by the use of the Doppler ultrasonic flow detector, and by clinical assessment revealed an incidence of deep vein thrombosis of only 12%. This is distinctly lower than has been reported by other investigators using the same techniques both in Australia and elsewhere. It appears from this study and associated work that the Doppler ultrasonic technique is sufficiently accurate to be of value in the clinical diagnosis of significant deep vein thrombosis.     

Heparin in the Prevention of Deep Vein Thrombosis after Myocardial Infarction

A trial of continuous intravenous heparin in the prevention of deep vein thrombosis was undertaken in 48 patients who had suffered a myocardial infarction. Of the 24 control patients who did not receive heparin seven (29%) developed calf vein thrombosis as detected by the radioactive fibrinogen technique. None of the 24 heparinized patients had any evidence of venous thrombosis. This difference is significant at the 1% level.     

Prevention of Postoperative Leg Vein Thrombosis by Electrical Muscle Stimulation. An Evaluation with 125I-Labelled Fibrinogen

In a prospective trial of preventing deep vein thrombosis electrical stimulation of the calf muscles of one leg was used in 110 patients undergoing major surgery. Deep vein thrombosis was detected by means of the ¹²⁵I-fibrinogen uptake test in nine of the stimulated legs and in 23 of the unstimulated legs. It is suggested that this technique, which is both simple and effective, should be used on all patients undergoing major surgery.     

The endocytic adaptor protein Disabled-2 is required for cellular uptake of fibrinogen

Endocytosis is pivotal for uptake of fibrinogen from plasma into megakaryocytes and platelet α-granules. Due to the complex adaptor and cargo contents in endocytic vehicles, the underlying mechanism of fibrinogen uptake is not yet completely elucidated. In this study, we investigated whether the endocytic adaptor protein Disabled-2 (DAB2) mediates fibrinogen uptake in an adaptor-specific manner. By employing primary megakaryocytes and megakaryocytic differentiating human leukemic K562 cells as the study models, we found that fibrinogen uptake is associated with the expression of integrin αIIbβ3 and DAB2 and is mediated through clathrin-dependent manner. Accordingly, constitutive and inducible knockdown of DAB2 by small interfering RNA reduced fibrinogen uptake for 53.2 ± 9.8% and 59.0 ± 10.7%, respectively. Culturing the cells in hypertonic solution or in the presence of clathrin inhibitor chlorpromazine abrogated clathrin-dependent endocytosis and diminished the uptake of fibrinogen. Consistent with these findings, 72.2 ± 0.2% of cellular DAB2 was colocalized with clathrin, whereas 56.4±4.1% and 54.6 ± 2.0% of the internalized fibrinogen were colocalized with clathrin and DAB2, respectively. To delineate whether DAB2 mediates fibrinogen uptake in an adaptor-specific manner, K562 stable cell lines with knockdown of the adaptor protein-2 (AP-2) or double knockdown of AP-2/DAB2 were established. The AP-2 knockdown cells elicited normal fibrinogen uptake activity but the uptake of collagen was diminished. In addition, collagen uptake was further reduced in DAB2/AP-2 knockdown cells. These findings thereby define an adaptor-specific mechanism in the control of fibrinogen uptake and implicate that DAB2 is the key adaptor in the clathrin-associated endocytic complexes to mediate fibrinogen internalization.     

Prevention of Early Postoperative Deep Vein Thrombosis by Passive Exercise of Leg during Surgery

A clinical trial assessed the effect of passive exercise of the lower limb during surgery on the incidence of early postoperative deep vein thrombosis. Thrombosis was diagnosed by means of the ¹²⁵I-fibrinogen uptake test. Passive exercise of the lower limb during the operation was achieved by using a motorized foot mover designed for use on supine subjects, and by pedalling only one leg each patient acted as his own control.In a sequential statistical analysis, 47 patients were required to reach the 5% level of significance. Thrombosis was detected in 11 control (unpedalled) legs alone, and in only one pedalled leg alone. Two patients developed thrombosis bilaterally. The investigation shows that the incidence of early thrombosis in legs which were exercised during surgery was reduced by 77%.     

Prophylaxis of postoperative leg vine thrombosis by low dose subcutaneous heparin or peroperative calf muscle stimulation: a controlled clinical trial.

In a randomized, controlled clinical trial of two methods of preventing postoperative leg vein thrombosis patients undergoing major surgery were divided into three groups. One received intermittent electrical calf muscle stimulation during surgery, the second subcutaneous heparin calcium 5000 IU every eight hours for six days, and the third no specific prophylaxis. Leg vein thrombosis was detected by the 125-I-fibrinogen uptake test. Neither method was effective in patients undergoing open bladder or prostatic surgery. Stimulation did not reduce the incidence of leg vein thrombosis in patients with malignant disease undergoing laparotomy, but heparin calcium was highly successful in this group (P smaller than 0-001). When the laparotomy was for a benign condition, however, both heparin calcium (P smaller than 0-001) and stimulation (P smaller than 0-01) were effective.     

Failure of low-dose heparin to prevent significant thromboembolic complications in high-risk surgical patients: interim report of prospective trial. Groote Schuur Hospital Thromboembolus Study Group.

The efficacy of low-dose subcutaneous heparin (5000 IU eight-hourly) is being studied in a single-centre, prospective randomised trial of patients aged over 40 submitted to major elective intra-abdominal surgery. The trial end-points are the objectively defined incidence and extent of deep vein thrombosis (as seen on uptake of 125I-labelled fibrinogen, Doppler ultrasonography, and bilateral ascending phlebography) and non-fatal pulmonary embolus (as measured by preoperative spirometry and preoperative and postoperative chest radiography and perfusion lung scanning performed on a routine, unselected basis). An interim analysis of the first 200 patients indicates that low-dose heparin significantly reduces the incidence of calf-vein thrombosis but does not reduce the incidence of proximal segment thrombosis or non-fatal pulmonary embolism. Thus the routine use of low-dose heparin prophylaxis in all major surgical procedures in patients aged over 40 may not be advisable.     

Some haemostatic parameters in patients with deep and superficial venous thrombosis.

Some haemostatic parameters (AT III, alpha 2-AP, C1-INH, kallikrein, F.XII, fibrinogen, plasminogen, euglobulin lysis time, FDP and ethanol test) were studied in patients with deep (DVT) and superficial (SVT) venous thrombosis. The patients with DVT revealed significantly decreased AT III activity, increased alpha 2-AP, C1-INH activity, fibrinogen and FDP concentrations and prolongation of euglobulin lysis time. Ethanol gelation test was positive in 61% in DVT group. Plasminogen level was unchanged in patients with DVT. No significant changes in these parameters were found in SVT group. Only the ethanol gelation test was positive in 21% in this group. These results show a markedly expressed phenomenon of hypercoagulability in the group of patients with DVT and suggest that in the treatment different therapeutic procedures should be considered which influence these specific changes in these coagulation parameters.     

Prevention of Early Postoperative Deep Vein Thrombosis by Intermittent Compression of the Leg during Surgery

A clinical trial is described in which the effect of intermittent compression of the lower limb during surgery on the incidence of early postoperative deep vein thrombosis was assessed. Deep vein thromboses were diagnosed by the ¹²⁵I-fibrinogen uptake test. Peroperative intermittent compression was achieved by means of an inflatable plastic splint coupled to a pneumatic controller. By compressing only one leg of each patient, each patient acted as his own control.With a sequential statistical analysis, 39 patients were required to pass the 5% level of significance. Eleven thrombi were detected in the control (uncompressed) legs and two occurred in the compressed legs; one of the latter was bilateral. The investigation shows that increasing the pulsatility of the venous flow in the leg is a potent prophylactic against postoperative deep vein thrombosis.     

Coagulation abnormalities and cardiovascular disease.

In patients with excessive venous thrombosis, genetic defects predisposing to thrombosis can be found in 60-80%. Increased plasma levels of coagulation proteins such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of myocardial infarction. However, despite the presence of polymorphisms that regulate plasma levels of factor VIII, PAI-1, and fibrinogen the association between common polymorphisms of these coagulation protein and ischemic cardiac disease remains ambiguous. Up to 10% of the population have defects that predispose them to excessive venous thrombosis. In spite of the essential role of thrombosis in coronary ischemic syndrome, no convincing evidence has implicated the two most common venous hypercoagulable states in ischemic heart disease. Pathogenic polymorphisms in the platelet fibrinogen and collagen receptors remains an area of intense research interest. Finally, it has been shown that lipoproteins can act as mediators of coagulation processes.     

Detection and Management of Deep Vein Thrombosis

The accuracy of diagnosis of deep venous thrombosis is significantly improved by combining clinical evaluation with other adjunctive methods, especially fibrinogen uptake tests, technetium scans, Doppler techniques and phlebography. Using these studies, early treatment with intravenous administration of heparin can be begun and in selected cases with long-term risks, warfarin is often useful. These same drugs, in different dosage schedules, may also be helpful as prophylaxis. With these methods of treatment, thrombectomy and caval interruption are required less often. If interruption of inferior vena cava flow becomes necessary, several new methods utilizing intracaval filters are proving to be very useful.     

Treatment of Deep Vein Thrombosis. A Trial of Heparin,Streptokinase, and Arvin

Thirty patients with deep vein thrombosis of the legs of less than four days'' duration were allocated at random to treatment with heparin, streptokinase, or Arvin under laboratory control. When the fate of the thrombi was assessed by objective techniques—phlebography and the ¹²⁵I-labelled fibrinogen test—the incidence of complete thrombolysis was greatest in the streptokinase group. Complications arose during treatment in each group but were least with Arvin. The natural history of the disease favours clinical but not always anatomical recovery.     

Symptomless postoperative thrombosis of the deep calf veins--treatment and prognosis

Deep calf vein thrombosis in the rule can be diagnosed by objective methods like 125I fibrinogen up take test only. But if the diagnosis is done, we have to cure because the risk of the single case is not calculable prospectively. After our therapy we never saw neither progressive development of the thromboembolic process, nor haemorrhagic complications.     

Criteria in Radioisotope Detection of Venous Thrombosis

Forty-one patients out of a larger series undergoing elective surgery were examined for the presence of venous thrombosis in the legs by means of the ¹²⁵I-fibrinogen technique. The radioisotope data were analysed by three different methods. The percentage uptake was calculated and, by the generally accepted difference of 15%, 22 patients had evidence of thrombosis. The statistical index, which takes account of the errors due to radioactivity counting inherent in the percentage uptake calculation, indicated thrombosis in 36 patients. The relative uptake index, which allows for the errors due to unequal distribution of radioactivity throughout the normal limb as well as the errors due to radioactivity counting, provided evidence of thrombosis in a total of 34 patients, compared with only 22 patients when assessed by the “15%” criterion.     

Fibrinolysis in Cholestatic Jaundice

The fibrinolytic system was studied in primary biliary cirrhosis (16 patients) and large bile duct obstruction (10 patients, nine of whom had carcinoma). Plasma fibrinolysis (plasminogen activator activity) was decreased and fibrinogen increased in both groups of patients, particularly in those with large duct obstruction. These changes were related to the degree of cholestasis. Plasminogen activator activity was inversely related to serum triglyceride levels in patients with primary biliary cirrhosis. Urokinase inhibitors were decreased in both groups and antiplasmins increased in patients with large duct obstruction; fibrin/fibrinogen degradation products were normal in primary biliary cirrhosis and moderately increased in large duct obstruction. None of these fibrinolytic indices was related to the degree of cholestasis. Fibrinolytic activity and fibrinogen returned almost to normal levels after palliative surgery in the three patients with large duct obstruction who were studied. The decreased plasma fibrinolysis and increased fibrinogen may be due to altered lipid metabolism in cholestatic jaundice. In patients undergoing surgery for large duct obstruction there may be an increased risk of thrombosis.