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Volume 330:517-522 February 24, 1994 Number 8 Next

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ABSTRACT

Background In three families with various forms of venous thrombosis, we observed an apparently inherited poor response to the anticoagulant activated protein C (APC). The condition was due to a deficiency in a previously unrecognized anticoagulant factor that functioned as a cofactor to activated protein C.

Methods We conducted the present study to determine the prevalence of resistance to APC in patients with venous thrombosis. We compared 104 consecutive patients with venous thrombosis confirmed by objective tests with 130 controls. In addition, 211 members of 34 families of persons with resistance to APC were studied. The anticoagulant response to APC was measured with a modified version of the activated partial-thromboplastin time test; the results were expressed as APC ratios.

Results Forty-five percent of patients had a family history of thrombosis. A significant (P<0.001) difference in APC ratios was observed between the controls and the patients with thrombosis. For 33 percent of patients, the APC ratio was below the 5th percentile of the control values, although the results of the family studies suggested that the prevalence of APC resistance may be even higher (approximately 40 percent) in the patients with thrombosis. The inherited nature of the defect was confirmed in a majority of cases, and the family studies suggested the mode of inheritance to be autosomal dominant. The thrombosis-free survival of APC-resistant family members was significantly less than that of non-APC-resistant family members.

Conclusions There was a high prevalence of APC resistance among young persons with a history of venous thrombosis, and this resistance appeared to be inherited as an autosomal dominant trait.

Protein C, a vitamin K-dependent plasma protein, is the key component in a physiologically important anticoagulant system^3,6. After its activation on the surface of endothelial cells by a complex of thrombin with thrombomodulin, activated protein C (APC) inhibits coagulation by selectively degrading coagulation factors Va and VIIIa. During the neonatal period, a life-threatening disease called purpura fulminans develops in infants homozygous for protein C deficiency, illustrating the physiologic importance of the protein⁹. The condition is characterized by generalized microvascular thrombosis. Young and middle-aged adults heterozygous for protein C deficiency have an increased risk of venous thrombosis^10,11. Protein S, another vitamin K-dependent plasma protein, is thought to function as a cofactor to APC,^3,12 and heterozygosity for protein S deficiency is also associated with thrombosis^13,14,15.

Young people with thrombosis frequently have a family history of thrombosis, indicating the involvement of genetic factors. However, only a minority of patients are found to be heterozygous for deficiencies of anticoagulant proteins,^16,17,18 suggesting the presence of unidentified genetic defects that predispose them to thrombosis. We recently described a relation between familial thrombosis and an inherited defect in the anticoagulant response to APC that we termed APC resistance¹⁹. Since possible recognized mechanisms had been excluded, such as functional protein S deficiency, APC inhibitors, and APC-resistant molecules of factor VIIIa and Va, we hypothesized the molecular background to be an inherited deficiency of a hitherto unknown anticoagulant functioning as a cofactor to APC. This hypothesis has recently gained support²⁰. We report here an investigation of the prevalence of inherited APC resistance in a cohort of patients with thromboembolic disease, and the results of a more extensive study of 34 families with inherited APC resistance. We found APC resistance to be highly prevalent in patients with thrombosis and to be much more common than other genetic defects known to occur in these patients.

Methods

Patients with Thrombosis

The study population comprised 104 consecutive patients with thromboembolic disease (72 women and 32 men) who were referred during a 15-month period (September 1991 through November 1992). The presenting thrombotic events were deep venous thrombosis in a leg (83 patients), pulmonary embolism (17 patients), or thrombosis in cerebral vessels (4 patients, 2 with sagittal-sinus thrombi and 2 with retinal-vein thrombi). Thirty-one percent of the patients had previous thrombotic events. Only patients whose diagnoses had been objectively verified were included. Deep venous thrombosis was diagnosed by phlebography or ultrasonography, pulmonary embolism by scintigraphy or angiography, thrombosis in intracerebral vessels by computed tomographic scanning or angiography, and retinal-vein thrombosis by ophthalmologic examination. The mean age of the cohort at the time of the study was 37 years (range, 14 to 74); the mean age of the female patients was 35 years (range, 15 to 74), and that of the male patients 41 years (range, 14 to 71). The mean age at the time of the first thrombotic episode was 34 years (range, 14 to 71) in the cohort, 33 years (range, 14 to 71) in the female patients, and 38 years (range, 14 to 71) in the male patients. Factors predisposing the patients to thrombosis were identified for 60 percent of the cohort, the most common factors being pregnancy (in 28 percent of the female patients) and the use of oral contraceptives (in 24 percent of the female patients). Forty-five percent of the patients had a family history of thrombosis; 29 percent reported a thrombotic event in at least one first-degree relative (a parent, sibling, or child), and 16 percent reported such an event in at least one second-degree relative (a grandparent, aunt, uncle, or cousin).

The laboratory investigation was performed at least three months after the most recent thrombotic episode. Patients taking oral anticoagulants were excluded from the study, because we found APC-dependent prolongation of clotting time to be excessive in persons receiving such therapy, even when previous examination had demonstrated APC resistance (no clot after 300 seconds). None of the patients received heparin during the investigation. New blood samples were obtained from 30 of the 40 patients thought to have APC resistance. In 14 families, samples were obtained from at least one additional family member.

Family Studies

Forty-five families were studied in which the index patient had thrombosis and APC resistance, defined as an APC ratio less than 1.7. (The APC ratio is described below, under Assays.) Fourteen of the index patients were recruited from the thrombosis study described above; the others were examined before or after the 15-month period of that study. APC resistance was found in at least one first-degree relative in 34 families (76 percent). In all, 211 persons (123 female and 88 male family members) were studied, including the 34 index patients (22 female and 12 male patients). Among these 34, 14 had had one thrombotic episode, 14 had had two episodes, and the remaining 6 had had three episodes; the mean age at the time of the first episode was 32 years.

Controls

The control group comprised 130 healthy volunteers (72 men and 58 women) with a mean age of 40 years (mean age of the women, 39 [range, 21 to 60]; of the men, 40 [range, 22 to 64]).

APC-Resistant Plasma Used in Mixing Studies

During the screening of healthy adults for APC resistance, we identified one woman (born in 1947) with pronounced APC resistance (APC ratio, <1.3). Plasma from this woman was used in the mixing studies. Her mother was also APC-resistant.

Blood Sampling

Blood (4.5 ml) was collected in Vacutainer tubes containing 0.5 ml of 0.12 M sodium citrate and centrifuged at 2000 x g for 20 minutes to obtain platelet-poor plasma, which was frozen and stored at -70 °C until it was analyzed. Many of the samples were collected at local hospitals and sent to the laboratory on dry ice.

Assays

The laboratory investigation included an automated measurement of activated partial-thromboplastin time (APTT automated, Organon Teknika); a prothrombin-complex assay to measure factors II, VII, and X (SPA 50, Stago); and assays for antithrombin III (Coatest Antithrombin III, Chromogenix) and plasminogen (Coatest Plasminogen, Chromogenix); the manufacturers' directions were followed. Proteins C and S were measured as described elsewhere²¹. The APC-resistance test (formerly called APC-APTT), a modified activated partial-thromboplastin time test that measures the anticoagulant response to the addition of a standard amount of APC, was performed as described elsewhere¹⁹.

The APC ratio was calculated by dividing the clotting time obtained with the APC-calcium chloride solution by the clotting time obtained with calcium chloride alone. This ratio correlated well with the APC-dependent prolongation of clotting time (r = 0.97). The APC-calcium chloride solution was stable in small aliquots at -70 °C, a crucial factor because small changes in APC activity affect the results. Each batch used in the analysis included a pool of plasma samples (obtained from approximately 30 healthy donors and stored in aliquots at -70 °C) that served as a normal control. The interassay coefficient of variation for these controls was 6.4 percent, and the mean APC ratio was 2.3 (for 25 controls).

Statistical Analysis

In the case of unpaired samples, Student's t-test and the Mann-Whitney U test, respectively, were used to compare populations with normal and non-normal distributions. Pearson's correlation coefficients were calculated. Thrombosis-free survival curves were constructed with the method of Kaplan and Meier,²² and the log-rank test was used to compare them. Confidence intervals for rates of thrombosis-free survival were calculated on the basis of a binomial distribution. Values are reported as means ±SD.

Results

APC Resistance in Patients with Thrombosis

The patients' APC ratios were significantly lower than those of the controls (P<0.001). Few patients had high APC ratios, and the values for the group showed a distinctly bimodal distribution; 33 percent were below the 5th percentile of the control values, and 83 percent were below the 50th percentile of the control values (Figure 1).

View larger version (6K): [in this window] [in a new window]   Figure 1. Anticoagulant Response to APC in Controls, Patients with Thrombosis, and Members of Study Families. The response to APC was determined by the APC-resistance test, and the results were plotted as APC ratios, with each person represented by a circle. The 5th, 25th, 50th, 75th, and 95th percentiles are indicated. The 34 propositi with APC resistance are not included among the members of study families. The difference in APC ratios between patients with thrombosis and controls was significant (P<0.001).

 
New blood samples were requested from patients who had a poor APC response, and low or borderline APC ratios were found in all the new samples. The APC ratio in control subjects was also reproducible. The correlation between APC ratios in samples obtained on two occasions was high (r = 0.90, P<0.001, for 56 controls and patients combined). Studies of 14 families were possible, and in 9 (64 percent) inheritance of APC resistance was confirmed. In the families without confirmed inheritance, the number of family members studied was small (one to three people). Four patients had intracerebral thrombosis, two of whom had APC resistance (one with sagittal-sinus thrombosis and one with retinal-vein thrombosis).

The mean (±SD) activated partial-thromboplastin time was significantly shorter in the patients (28.7 ±3.3 seconds) than in the controls (32.6 ±4.1 seconds), and the APC-dependent prolongation of clotting time correlated significantly with the basal activated partial-thromboplastin time obtained by the APC-resistance test (r = 0.72, P<0.001; values for controls and patients were combined in this calculation). The results of the APC-resistance test and the levels of free protein S were not correlated. A weak inverse correlation was found between the APC ratio and the prothrombin-complex level (r = -0.27, P = 0.005); the APC response was higher at low concentrations of vitamin K-dependent proteins, a finding consistent with the high APC ratios associated with oral anticoagulant therapy. Among both patients and controls, there was no significant difference between men and women with respect to the APC ratio and no correlation with age, weight, or height.

That APC-resistant plasma samples from different patients were deficient in the same anticoagulant factor was shown by retesting them in a 1:1 mixture with plasma known to have resistance. In none of the mixtures did the APC ratio increase significantly (Figure 2).

View larger version (15K): [in this window] [in a new window]   Figure 2. Results of Plasma-Mixing Experiments. Plasma from each of 19 patients with low APC ratios was mixed in a 1:1 ratio with plasma from a person with pronounced APC resistance. The plasma samples from the patients and the mixtures were then tested with the APC-resistance test.

 
Protein C deficiency was found in two patients, and protein S deficiency in three. The three patients with protein S deficiency had normal APC responses. None of the patients had a lupus anticoagulant or an antithrombin III deficiency.

Family Studies

Forty-five families of propositi with thrombosis and APC resistance were studied. Inheritance of APC resistance from the propositus was confirmed in 34 families (76 percent). In all, 211 persons were included, and of the 177 relatives studied, 15 (from 13 families) had a history of thrombosis. Thus, a total of 49 family members had such a history, and 45 of them had APC ratios less than 2.0 (Figure 3). At an APC ratio of less than 2.0, the odds ratio for thrombosis was 10.4. Approximately 45 percent of the 177 relatives had APC ratios below 2.0 (Figure 1), which was consistent with autosomal dominant inheritance. Two people with a history of thrombosis (both from the same family) had protein S deficiency. Their APC ratios were normal, indicating that protein S deficiency is not linked to APC resistance.

View larger version (5K): [in this window] [in a new window]   Figure 3. Relation between Thrombosis and APC Response. The APC ratio was determined in 211 members of 34 families, each of which included a propositus with thrombosis and APC resistance. The relation between the APC ratio and the cumulative frequency of thrombosis is plotted. In all, 49 of the 211 family members (23 percent) had a history of thrombosis.

 
The curves for thrombosis-free survival (Figure 4) suggested that the probability that an APC-resistant person in these families would be free of thrombosis at the age of 45 was approximately 59 percent (95 percent confidence interval, 49 to 70 percent), as compared with 97 percent (95 percent confidence interval, 93 to 100 percent) for a relative without APC resistance. The results suggest that APC resistance is associated with an increased risk of thrombosis, but inclusion of the index patients introduced a bias into the analysis. After the 34 index patients with APC resistance and the 2 patients with protein S deficiency were excluded, however, the difference in survival curves remained significant (P<0.002), supporting the suggestion that people with APC resistance are at higher risk of thrombosis.

View larger version (8K): [in this window] [in a new window]   Figure 4. Thrombosis-free Survival in Persons with APC Resistance and Normal Relatives. The upper panel shows the probability of freedom from thrombosis in a Kaplan-Meier analysis of 104 persons with APC resistance and 107 relatives who did not have APC resistance (P<0.001). Each step in the curves indicates a thrombotic event. The lower panel shows the same curves after the exclusion of the 34 propositi from the APC-resistant group and of the 2 people with protein S deficiency from the non-APC-resistant group (chi-square = 10.1, P<0.002).

 
Discussion

Although a family history of thrombotic events is frequent in young adults with venous thrombosis, inherited deficiencies of anticoagulant proteins are found in only a small proportion of patients. Additional unknown genetic risk factors must therefore be involved. Linkage studies of DNA polymorphisms in families with venous thrombosis have been proposed²³ as an approach to uncover these factors. A new and potentially important genetic risk factor was suggested by the identification of three families with thrombosis and inherited APC resistance¹⁹. In the present study, we found this anticoagulant defect to be highly prevalent in a cohort of patients with thromboembolic disease, and the results suggest that inherited resistance to APC is a major risk factor for venous thrombosis. It is not yet known whether such resistance is also a risk factor for arterial thrombosis.

It may appear surprising that persons deficient in protein S did not have resistance to APC and that the plasma levels of protein S did not correlate with the response to APC. However, the activity of human protein S as a cofactor of APC is relatively weak in vitro,¹² and we have found that protein S does not affect the APC-resistance test to any major degree¹⁹. Moreover, the addition of purified human protein S to plasma from APC-resistant persons does not correct the defective response to APC, and patients resistant to human APC are also resistant to a mixture of APC and protein S of bovine origin (unpublished data). Thus, although the importance of protein S is underscored by the association between protein S deficiency and thrombosis, its mechanism of action is not clear.

The APC-resistance test appears to be a satisfactory screening test, but careful standardization is of the utmost importance. The response to APC is affected by the level of APC activity, the reagent used in determining the activated partial-thromboplastin time, the instrumentation, and the handling of the sample. If these variables are carefully controlled, the results are consistent and reproducible.

We have routinely analyzed the APC response in patients referred to us with a history of thromboembolic events. The present population of patients was similar to a larger cohort we recently described, in which inherited deficiencies of protein C, protein S, or antithrombin III were found in approximately 5 percent¹⁸. In 33 percent of the patients in our study, the APC ratio was below the 5th percentile of the control values. Using the 2.5th or 5th percentile of a control population underestimates the prevalence of the genetic defect, as was suggested by the results of the family studies, which showed an APC ratio of less than 2.0 to be associated with thrombosis. Approximately 45 percent of the relatives had an APC ratio below 2.0, which was consistent with an autosomal dominant mode of inheritance. Approximately 40 percent of the patients had APC ratios below this limit; among patients with a family history of thrombosis, approximately 50 percent had APC ratios below 2.0. Among the controls, the corresponding figure was 7 percent. The overlap in APC ratios between persons with the genetic defect and those without it complicated the determination of a lower limit of normal. A recent study of families with hereditary heterozygosity for protein C deficiency²⁴ clearly showed the existence of a wide overlap in protein C activity between family members with the genetic defect and those without it. The investigators observed that on the basis of determinations of protein C levels, 15 percent of the heterozygotes and 5 percent of the normal subjects would be misclassified. The prevalence of APC resistance in the general population is unknown, but its high prevalence in patients with thrombosis suggests that it may be common. Data in agreement with those presented here were recently reported by Griffin et al.,²⁵ who found APC resistance in 52 to 64 percent of patients with juvenile or recurrent venous thromboembolism, or both, that was unexplained by other causes.

Persons with APC resistance tend to have a shorter activated partial-thromboplastin time than do those with a high level of APC response, and a short activated partial-thromboplastin time has been reported to be a significant risk factor for postoperative thrombosis²⁶. Protein C is known to circulate at low concentrations in its active form,²⁷ and this low level may be enough to prolong the activated partial-thromboplastin time a few seconds, provided that the levels of APC cofactors are normal.

APC resistance may be caused by an inherited deficiency of an anticoagulant factor that functions as a cofactor to APC. In support of this concept, we have fractionated normal plasma and obtained a fraction that corrects APC resistance fully; corresponding fractions from plasma with pronounced APC resistance contained no such activity²⁰. APC resistance appears to be inherited as an autosomal dominant trait, suggesting that a single gene is involved. It is possible that people with severe APC resistance are homozygous for the genetic defect, whereas an APC response closer to the normal range indicates heterozygosity. In this respect, it is noteworthy that we found both parents in one family to be APC-resistant.

These results suggest that a genetically determined defect in anticoagulation characterized by resistance to APC is highly prevalent in patients with venous thrombosis. This defect appears to be at least 10 times more common in such patients than any of the other known inherited deficiencies of anticoagulant proteins.

Supported by a grant (B93-13X-07143) from the Swedish Medical Council, the Alfred Osterlund Trust, King Gustaf V's 80th Birthday Trust, the King Gustaf V and Queen Victoria Trust, the Magnus Bergwall Trust, the Albert Pahlsson Trust, the Johan and Greta Kock Trust, and research funds from Malmo General Hospital.

We are indebted to the staff of the Department for Coagulation Disorders for their expert technical assistance and to Jan Ake Nilsson for his help with the statistical evaluation.

Editor's note: After this manuscript was accepted for publication, the authors reported²⁸ that they had isolated the anticoagulant cofactor that corrects inherited APC resistance and found it to be identical to unactivated factor V. Because APC-resistant plasma contains normal levels of factor V procoagulant, the authors suggest that APC resistance may be due to a selective defect in an anticoagulant function of factor V.

Source Information

From the Department for Coagulation Disorders (P.J.S., B.D.), the Department of Medicine (P.J.S.), and the Department of Clinical Chemistry (B.D.), University of Lund, Malmo General Hospital, Malmo, Sweden. Presented in part at the 14th Congress of the International Society on Thrombosis and Haemostasis, New York, July 4-9, 1993.

Address reprint requests to Professor Dahlback at the Department of Clinical Chemistry, Malmo General Hospital, S-214 01 Malmo, Sweden.

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