Original Article
Deficiencies of Coagulation-Inhibiting and Fibrinolytic Proteins in Outpatients with Deep-Vein Thrombosis
N Engl J Med 1990; 323:1512-1516November 29, 1990
- Abstract
- Abstract
Background.
Isolated deficiencies of antithrombin III, protein C, protein S, and plasminogen have been implicated as a cause of deep-vein thrombosis. It is assumed that patients with recurrent, familial, or juvenile thrombosis are very likely to have such a deficiency.
Methods.
We studied the prevalence of isolated deficiencies of these proteins in 277 consecutive outpatients with venographically proved acute deep-vein thrombosis, as compared with 138 age-matched and sex-matched controls without deep-vein thrombosis, and calculated the positive predictive value of a history of recurrent, familial, or juvenile venous thromboembolism for the presence of such a deficiency.
Results.
The overall prevalence of deficiencies of any of these proteins in the patients with venous thrombosis was 8.3 percent (23 of 277 patients) (95 percent confidence interval, 5.4 to 12.4), as compared with 2.2 percent in the controls (3 of 138 subjects) (95 percent confidence interval, 0.5 to 6.1; P<0.05 for the comparison between groups). The positive predictive values for the presence of an isolated protein deficiency in patients with recurrent, familial, or juvenile deep-vein thrombosis, defined as the proportion of patients with the clinical finding who had a deficiency of one or more of the proteins, were 9, 16, and 12 percent, respectively.
Conclusions.
The cause of acute venous thrombosis in most outpatients (91.7 percent) cannot be explained by abnormalities of coagulation-inhibiting and fibrinolytic proteins. The information obtained from the medical history concerning recurrent or familial venous thrombosis or the onset of the disease at a young age is not useful for the identification of patients with protein deficiencies. (N Engl J Med 1990; 323:1512–6.)
Media in This Article
Table 1
Plasma Levels of Antithrombin III, Protein C, Protein S, and Plasminogen in the Patients with Venous Thromboembolism and Protein Deficiencies.*Table 2
Positive Predictive Values of a History of Venous Thromboembolism, a Family History of Venous Thromboembolism, and a First Episode of Venous Thromboembolism before the Age of 41 Years for the Presence of an Isolated Protein Deficiency in Patients with Deep-Vein Thrombosis.Article Activity
- Article
DESPITE extensive progress in understanding the mechanisms of blood coagulation, the cause of deep-vein thrombosis remains obscure in the majority of cases. Acute deep-vein thrombosis is a common disorder, with an annual incidence of 1 per 1000 in the general population.1 Over the past decades, several predisposing factors have been recognized, such as recent surgery, prolonged immobilization, and the presence of malignant disease, but we are still unable to define their direct causal relation to the thrombotic event. More recently, isolated deficiencies of proteins involved in the fibrinolytic system or in the inhibition of coagulation have been described that result in a hypercoagulable state and recurrent venous thromboembolism.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 The prevalence of these protein deficiencies, including deficiency of antithrombin III, protein C, protein S, and plasminogen, in outpatients with venographically proved deep-vein thrombosis is unknown. Several retrospective prevalence studies, sometimes with inappropriate controls, have been performed in selected groups of patients, using both clinical and objective diagnostic methods to establish the presence of venous thromboembolism.16 17 18 19 20 21 22 As a result, the estimation of the prevalence of these deficiencies may be inaccurate and is probably too high. If the prevalence is indeed as high as has been found in these studies — 30 percent or more — screening of all patients with documented deep-vein thrombosis should be considered, because patients with these deficiencies might need prophylaxis with anticoagulant medication. On the other hand, if these deficiencies occur infrequently, screening will not be cost effective, and other methods to identify such patients are needed.
In the past, a history of recurrent venous thromboembolism, thrombosis in other members of the family, or thrombosis at a young age has been assumed to increase a patient's likelihood of having one of these isolated protein deficiencies.16 , 17 To assess the prevalence of isolated deficiencies of antithrombin III, protein C, protein S, and plasminogen, we undertook a prospective study in 280 consecutive outpatients with deep-vein thrombosis and compared the results with those in 140 age-matched and sex-matched control subjects without deep-vein thrombosis. Our second purpose was to determine in patients with deep-vein thrombosis the positive predictive value of a history of recurrent, familial, or juvenile thrombosis (or combinations thereof) for the presence of one of these protein deficiencies.
Methods
Patients
Between October 1984 and October 1988, 1122 consecutive patients thought to have acute deep-vein thrombosis of the leg were referred by their general practitioner to the thrombosis unit of the Academic Medical Center in Amsterdam. After a standardized medical history was obtained and a short physical examination was completed, impedance plethysmography was performed and interpreted as described elsewhere.23 If the result was abnormal, venography was performed to confirm the diagnosis. If the result was normal, no treatment was started and plethysmography was repeated one and seven days after referral. Anticoagulant treatment was withheld in patients with repeatedly normal plethysmograms. The efficacy and safety of this approach have been demonstrated earlier.24 25 26
Of the 1122 consecutive study patients, 280 (25 percent) had abnormal impedance plethysmograms and deep-vein thrombosis confirmed by contrast venography. For the control group 140 age-matched and sex-matched subjects with normal impedance plethysmograms during the initial seven days and at follow-up three and six months later were chosen at random. None of these subjects had a history of deep-vein thrombosis.
Study Design
The study was approved by the hospital ethics committee, and informed consent was obtained from all patients. On the day of referral, before impedance plethysmography, a medical history was obtained from every patient with use of a standardized questionnaire. Patients were asked whether they had had previous episodes of venous thromboembolism (recurrent thrombosis) for which they had received treatment and whether these events had been confirmed by objective tests (by venography, impedance plethysmography, 125I-labeled fibrinogen leg scanning, real-time B-mode or Doppler ultrasonography for deep-vein thrombosis and by ventilation—perfusion lung scanning or pulmonary angiography for pulmonary embolism). For the analysis of the predictive value of a history of venous thromboembolism, the patients were assigned to one of three categories: those who had had a previous episode of deep-vein thrombosis, pulmonary embolism, or both, regardless of whether it was confirmed; those who had had a previous episode of deep-vein thrombosis, pulmonary embolism, or both, confirmed by objective methods; and those with no history of venous thromboembolism.
Patients were also asked about the occurrence of venous thromboembolism in their families (familial thrombosis). A family history was considered positive if any first-degree relatives — the patient's parents, siblings, or children — had had venous thrombosis. A family history was also considered positive if any second-degree relatives — brothers or sisters of the patient's parents or the patient's grandparents — had had venous thrombosis. For the analysis of the predictive value of a family history of venous thromboembolism, the patients were assigned to one of three categories: those with a family history of venous thromboembolism in a first-degree or second-degree relative, those with a family history in a first-degree relative only, and those with no family history of deep-vein thrombosis or pulmonary embolism as defined above. Finally, patients with a history of venous thrombosis were asked at what age their first episode of venous thromboembolism had occurred, whether or not the episode was confirmed. For patients with no previous episodes of venous thromboembolism the age at presentation was recorded. For the analysis of the predictive value of the occurrence of venous thromboembolism at an early age (juvenile thrombosis), the patients were assigned to one of two categories: those with a first episode before the age of 41 years and those with a first episode at the age of 41 or later. In addition, the predictive values of the following combinations were assessed: a family history (in a first-degree or second-degree relative) and recurrent venous thrombosis in the proband; a family history (in a first-degree or second-degree relative) and a first episode of venous thromboembolism before the age of 41; and a family history (in a first-degree or second-degree relative), recurrent venous thrombosis in the proband, and a first episode of venous thromboembolism before the age of 41. Finally, these categories were used to calculate the likelihood ratios for a history of recurrent, familial, or juvenile thrombosis. Blood was collected from the patients with thrombosis at presentation, before the start of therapy with anticoagulant drugs, for the determination of coagulation-inhibiting and fibrinolytic proteins. In four patients blood was obtained after the treatment was discontinued at three months, after a washout period of at least two weeks, because venipuncture at presentation had been unsuccessful. In all the control subjects blood was drawn after the six-month follow-up period, during which the impedance plethysmograms remained normal and no signs or symptoms of venous thromboembolism occurred.
The criteria for the diagnosis of an isolated deficiency of antithrombin III, protein C, protein S, or plasminogen were plasma levels below the lower limit of normal, confirmed by at least two measurements of fresh blood samples (for normal values, see the description of laboratory studies), combined with normal levels of factors II and X (to exclude a vitamin K deficiency) and normal liver function (to exclude liver disease). Patients with acquired protein deficiencies were excluded from the analysis.
If the levels of coagulation-inhibiting and fibrinolytic proteins were within the normal range during the first measurement, they were not remeasured and were considered normal. If a low plasma level of one of these proteins was recorded during the first measurement and a normal level during the second, a third blood sample was analyzed.
Since our investigation was not intended to assess the prevalence of hereditary thrombophilia, no studies were undertaken in the family members of patients who had an isolated protein deficiency.
Laboratory Studies
Blood (9 ml) was collected from an antecubital vein with a 19-gauge butterfly needle and collected in coded plastic tubes containing 1 ml of trisodium citrate—dihydrate (3.2 percent). Plasma was separated by centrifugation at 1600×g for 20 minutes at room temperature and stored immediately at −70°C until it was assayed. All assays were performed by technicians unaware of the patients' clinical diagnosis. Antithrombin III activity was measured with an amidolytic assay as previously described27; normal values range from 0.80 to 1.40 U per milliliter. Protein C activity was also measured with a chromogenic-substrate method that has been described elsewhere28; the normal range of protein C activity is 0.70 to 1.25 U per milliliter. Total protein S antigen was assayed by an enzyme-linked immunoassay (Boehringer–Mannheim, Mannheim, Germany). Free protein S was measured by precipitating the C4b-bound fraction with polyethylene glycol 8000 and measuring the concentration of free protein S in the supernatant. The normal range is from 0.65 to 1.30 U per milliliter for total protein S and from 0.30 to 0.80 U per milliliter for free protein S. Plasminogen activity was measured by an amidolytic technique that has been described elsewhere27; normal values range from 0.80 to 1.40 U per milliliter. Normal values for the above-mentioned coagulation-inhibiting and fibrinolytic proteins were determined in 40 to 60 healthy volunteers (half of whom were men). One-stage coagulation assays for factors II and X (normal value, 80 to 140 percent for both factors) and liver-function tests (measurements of alanine aminotransferase, aspartate aminotransferase, and albumin) were carried out to exclude patients with acquired protein deficiencies.
Statistical Analysis
For the comparison of the prevalences between the two groups, the MantelHaenszel procedure was used to determine the overall odds ratio. The overall odds ratio was tested for significance according to the method of Miettinen.29 For the prediction of the presence of an isolated deficiency in the different categories, the positive predictive value was calculated. The positive predictive value was defined as the proportion of patients with a medical history of deep-vein thrombosis who had an isolated protein deficiency. The likelihood ratio was defined as the ratio of the proportion of patients with and the proportion without a protein deficiency who had a medical history of deep-vein thrombosis.
Results
The study population consisted of two groups: 280 patients with acute deep-vein thrombosis and 140 subjects without deep-vein thrombosis at presentation or during a six-month follow-up period. An acquired protein-deficiency state was found in five persons (three patients and two control subjects); two of these had documented liver cirrhosis, two had end-stage malignant disease with multiple metastases in the liver, and one had a vitamin K deficiency caused by malnutrition. All five were excluded from the analysis. Three patients with thrombosis who had initial plasma levels of one of the studied proteins that were below the lower limit of normal had normal levels of these proteins at the time of two subsequent independent investigations. These patients were considered not to have protein deficiencies.
The mean ages of the patients and the controls were 56 years (range, 17 to 91) and 57 years (range, 18 to 90), respectively. Half of each group were men.
An isolated deficiency of antithrombin III, protein C, protein S, or plasminogen was found in 23 of the remaining 277 patients with thrombosis (prevalence, 8.3 percent; 95 percent confidence interval, 5.4 to 12.4), whereas an isolated deficiency was found in 3 controls (prevalence, 2.2 percent; 95 percent confidence interval, 0.5 to 6.1). This difference was statistically significant (P<0.05). In 3 of the 277 patients with thrombosis (1.1 percent; 95 percent confidence interval, 0.2 to 3.2) an isolated deficiency of antithrombin III was detected, whereas 9 other patients (3.2 percent; 95 percent confidence interval, 1.5 to 6.2) had an isolated protein C deficiency. A protein S deficiency was found in six patients (2.2 percent; 95 percent confidence interval, 0.8 to 4.8), and a plasminogen deficiency was found in four (1.4 percent; 95 percent confidence interval, 0.4 to 3.7). A single patient (0.4 percent) had a protein C deficiency in combination with a plasminogen deficiency. Of the 138 controls, 2 had isolated protein C deficiencies (plasma levels, 0.63 U per milliliter in both) and 1 had an isolated plasminogen deficiency (plasma level, 0.66 U per milliliter) (2.2 percent; 95 percent confidence interval, 0.5 to 6.1). No other protein deficiencies were found in this group. Table 1Table 1
Plasma Levels of Antithrombin III, Protein C, Protein S, and Plasminogen in the Patients with Venous Thromboembolism and Protein Deficiencies.* shows the functional or antigenic levels of the coagulation-inhibiting and fibrinolytic proteins in the patients with deep-vein thrombosis.The second issue addressed in our study concerned the positive predictive value of a history of recurrent, familial, or juvenile deep-vein thrombosis (or combinations thereof) for the presence of one of these protein deficiencies in patients presenting with acute deep-vein thrombosis. The positive predictive values for the presence of an isolated protein deficiency in patients with a history of venous thromboembolism confirmed by objective testing and in those with a history of unconfirmed episodes were 13 and 9 percent, respectively (Table 2Table 2
Positive Predictive Values of a History of Venous Thromboembolism, a Family History of Venous Thromboembolism, and a First Episode of Venous Thromboembolism before the Age of 41 Years for the Presence of an Isolated Protein Deficiency in Patients with Deep-Vein Thrombosis.). For the patients with a family history of venous thromboembolism in either a first-degree or a second-degree relative or in a first-degree relative only, the positive predictive values for the existence of a protein deficiency were 16 and 15 percent, respectively (Table 2). The likelihood of an isolated protein deficiency in patients who had their first thromboembolic event before the age of 41 was 12 percent (Table 2). Finally, the positive predictive values of various combinations of findings in the medical history are shown in Table 3Table 3
Positive Predictive Values of a History of Familial, Recurrent, and Juvenile Venous Thromboembolism in Various Combinations for the Presence of an Isolated Protein Deficiency in Patients with Deep-Vein Thrombosis.. The combination of a familial, recurrent, and juvenile deep-vein thrombosis was present in 3 of the 23 patients with an isolated protein deficiency, whereas this combination was found in 7 patients without protein deficiencies, yielding a positive predictive value of 30 percent.Discussion
Deficiencies of proteins involved in the functioning of the coagulation and fibrinolytic system are increasingly being recognized as associated with an enhanced risk of venous thromboembolism. In several studies in selected groups of patients, isolated deficiencies of antithrombin III, protein C, protein S, or plasminogen were assumed to be responsible for a thrombophilic state in about 30 percent of the patients.16 17 18 19 20 21 22 The present investigation in a large series of consecutive outpatients with acute deep-vein thrombosis demonstrates that the overall prevalence of deficiencies of antithrombin III, protein C, protein S, or plasminogen was only 8.3 percent (95 percent confidence interval, 5.4 to 12.4). It should be noted that the prevalence of these deficiencies in a sex-matched and age-matched control group without venous thrombosis (as defined by normal results on serial impedance plethysmography tests) was 2.2 percent (95 percent confidence interval, 0.5 to 6.1), which is compatible with the observation of Miletich and colleagues,30 who found plasma levels consistent with a heterozygous deficiency of protein C in 1 in 60 healthy adults. The discrepancy between the previous studies and our investigation can probably be explained by the retrospective design or the selection of patients in the earlier studies.
Although the prevalence of isolated protein deficiencies in the patients with thrombosis was significantly higher than in the controls, it was still too low to make screening all patients with deep-vein thrombosis cost effective. Moreover, our observations indicate that the likelihood of finding a protein deficiency is not increased substantially by limiting the laboratory investigation to patients with certain findings in their medical history, such as recurrent, familial, or juvenile venous thromboembolism. In fact, of the 167 patients with a history of one of these disorders, only 16 (9.6 percent; 95 percent confidence interval, 5.7 to 15.3) had an isolated protein deficiency; thus, 7 of the 23 patients with protein deficiencies had no history of recurrent, familial, or juvenile thrombosis. On the other hand, the patients who had all three disorders did have a higher probability of having a protein deficiency (30 percent; 95 percent confidence interval, 7 to 65), but only 3 of the 23 patients with protein deficiencies would have been identified on this basis (Table 3). These observations led us to conclude that in the great majority of consecutive outpatients with acute venous thrombosis (91.7 percent), the cause of the disorder cannot be explained by an abnormality in the coagulation or fibrinolytic system — i.e., deficiency of antithrombin III, protein C, protein S, or plasminogen —and that information from the medical history with respect to the existence of recurrent, familial, or juvenile thrombosis cannot be used to distinguish patients with an isolated protein deficiency from those without such a dysfunction.
There is a possibility that we underestimated the usefulness of the medical history for the identification of patients with protein deficiencies (as reflected by the low positive predictive values we observed) because of the low prevalence of such deficiencies in our study population. Therefore, we also calculated the likelihood ratios (for the presence of any protein deficiency) of recurrent, familial, and juvenile deep-vein thrombosis, and they proved to be low as well (1.0, 2.2, and 1.5, respectively). Hence, it is unlikely that such information in a medical history will be useful in identifying patients with protein deficiencies, even in populations with higher prevalences of abnormalities of these coagulation-inhibiting and fibrinolytic proteins.
Our results do not imply that there is no relation between the presence of a deficiency of antithrombin III, protein C, protein S, or plasminogen and recurrent, familial, or juvenile venous thromboembolism. Indeed, it has repeatedly been demonstrated that these deficiencies are often hereditary, may lead to venous thrombosis at a young age, and may be associated with a tendency toward recurrent venous thromboembolism.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 However, our results indicate that this information is not useful in distinguishing patients with thrombosis who have such a deficiency from those who do not.
Patients with multiple protein deficiencies caused by impaired liver function or a vitamin K deficiency were excluded from the analysis, since the disturbances observed in the coagulation and fibrinolytic system and their inhibitors in these patients are complex, and no clear direct relation between these derangements and venous thromboembolism has been documented. One patient with thrombosis had both a protein C and a plasminogen deficiency in the absence of impaired liver function or a vitamin K deficiency; this patient was included in our analysis.
The low prevalence of deficiencies of antithrombin III, protein C, protein S, and plasminogen, and the low positive predictive value of the medical history for the presence of such a deficiency create a dilemma. If the identification of all patients with protein disorders is thought to be a prerequisite for long-term anticoagulant therapy, all patients with acute deep-vein thrombosis should be screened for the presence of a deficiency. It should be realized, however, that convincing evidence from clinical studies of the need for long-term treatment of all such patients is still lacking. We prefer to forgo screening except in patients with the combination of recurrent, familial, and juvenile deep-vein thrombosis, in view of the higher positive predictive value of such a history. Further investigations are needed, however, to explain the thrombotic events in the remaining 90 percent of patients with deep-vein thrombosis.
Dr. Büller is the recipient of a fellowship from the Royal Netherlands Academy of Arts and Sciences.
We are indebted to Mrs. Rita van Wesep, Mrs. Wil Morriën, and Mrs. Marianne van 't Hullenaar for their skilled laboratory assistance and to Mrs. Henriëtte Jagt and Mrs. Monique de Rijk for performing the impedance plethysmography and collecting the blood samples.
Source Information
From the Center for Thrombosis, Haemostasis, and Atherosclerosis Research, Academic Medical Center, Amsterdam, the Netherlands. Address reprint requests to Dr. Heijboer at the Center for Thrombosis, Haemostasis and Atherosclerosis Research, F4 Rm. 131, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
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