COAGULATION AND TRANSFUSION MEDICINE
Original Article
An Evaluation of 200 Consecutive Patients
With Spontaneous or Recurrent Thrombosis
for Primary Hypercoagulable States
ROWAN G. DOIG, MB, BS, FRACP, CINDY J. O'MALLEY, BAPPSCI, RAY DAUER, BAPPSCI,
AND KATHERINE M. McGRATH, MB, BS, FRCPA
Two hundred consecutive patients who were referred for evaluation of
spontaneous or recurrent thrombosis were investigated for possible hypercoagulable states to determine the relative frequencies of these conditions in the Australian population and to identify features that would
indicate which patients should be investigated with the expensive battery of tests for hypercoagulable states. Thirty-two percent were found
to have prolongation of the postvenous occlusion euglobulin clot lysis
time (PVO-ELT), 32% were found to have elevated levels of plasminogen activator inhibitor-1 (PAI) and 66% were found to have reduced
release of tissue plasminogen activator (tPA). Antiphospholipid antibodies were found in 12%. Hereditary antithrombin III deficiency was
found in 2%. Hereditary deficiency of the naturally-occurring anti-
coagulant factors protein C and protein S was found in 2%. Age, sex,
site of thrombosis (venous or arterial), or presence of a family history
was not helpful in predicting a group more likely to have abnormal
investigation results.
Reduced fibrinolytic activity and the presence of antiphospholipid
antibodies are the most common findings in patients with thromboembolic disease. Further prospective studies are required to assess the
natural history and appropriate management of patients with these abnormalities. (Key words: Thromboembolism; Fibrinolysis; Lupus anticoagulant; Anticardiolipin antibody; Protein C; Protein S; Antithrombin III) Am J Clin Pathol 1994;102:797-801.
Thromboembolic disease is a major cause of morbidity and
mortality in Western society. There has been much interest in
evaluating patients for underlying defects of the hemostatic
system that may predispose patients to thromboembolic dis-
ary cause were studied. Evaluation of the hemostatic system
was directed at the fibrinolytic system and naturally occurring
anticoagulant proteins as abnormalities in these systems have
been shown to be common in patients with primary hypercoagulable states.2
1-4
ease.
The detection of an underlying hemostatic abnormality may
be helpful in deciding on the nature and duration of therapy in
patients with thromboembolic disease.4
The term "hypercoagulable state" is a poorly defined condition that encompasses inherited or acquired disorders associated with an increased risk of thrombosis. Such factors may
be long-standing or transient factors, such as immobilization,
inflammation, or tissue injury. Examples of the long-standing
factors include hereditary disorders, such as deficiency of a
naturally occurring anticoagulant protein and acquired disorders (ie, malignancy, etc.) The hypercoagulable state may be
considered secondary, in which a clearly identifiable nonhemostatic disorder carries an attendant risk of thrombosis, or
primary in which a primary hemostatic disorder or no apparent disorder is present.4
In this study, patients with a history of thrombosis, either
spontaneous or recurrent, in the absence of any overt second-
MATERIALS A N D METHODS
Patient
Population
Patients included in this analysis were referred for investigation of a possible underlying hypercoaguable state in the absence of any obvious secondary cause (ie, malignancy, postoperative state, etc.). All patients had at least one documented
thrombotic episode, but otherwise there were no specific requirements before investigation. Specifically, there were no exclusions on the basis of age, absence of a family history, or
whether the documented thrombosis was venous or arterial.
The results from 200 consecutive patients are presented in this
study. Patients were excluded if results of more than one investigation, such as tests of fibrinolysis, lupus anticoagulant, and
anticoagulant factor levels, were not obtainable.
Collection
From the Department ofDiagnostic Haematology, Royal Melbourne Blood Sample
Hospital. Parkville. Australia.
Blood samples were collected in the morning after resting for
10 minutes in the supine position. Two samples were obtained,
Manuscript received October 20, 1993; revision accepted February
one before and one after 10 minutes of venous occlusion (per21, 1994.
formed with a sphygmomanometer inflated midway between
Address correspondence to Dr. Doig: Department of Diagnostic
systolic and diastolic pressure). Specimens were collected into
Haematology, Royal Melbourne Hospital, Grattan Street, Parkville,
sodium citrate containers and transported on ice. Studies have
3050, Australia.
797
COAGULATION AND TRANSFUSION MEDICINE
798
Original Article
o
o
o
o
0 0 oo
oo
ooo
oo ooo
ooooooooo
r
100
0
200
300
400
PVO-ELT (mins) Controls n=30
FIG. I. Post-venous occlusion euglobulin clot lysis time: Controls.
shown that PAI can behave like other acute phase reactants, 5 so
tests of fibrinolysis generally were performed at a minimum of
10 days after the thrombotic event. Fibrinolytic tests were not
performed if the patient was on heparin. For patients receiving
coumarin therapy, tests of the coagulation system were repeated after cessation of therapy and rest period of 4 weeks.
Hereditary deficiency was confirmed by family studies when
appropriate.
Investigation
Profile
Fibrinolysis
1. Euglobulin clot lysis time (ELT) pre- and post-venous occlusion was performed according to methods previously described.6 A normal range was established from healthy volunteers (Fig. 1).
2. Plasminogen activator inhibitor-1 (PAI) functional assay
prevenous occlusion (Stachrom PAI, Stago, Asnieres,
France) was determined.
3. Tissue plasminogen activator (t-PA) functional assay preand post-venous occlusion (Stachrom PA, Stago) was assessed. t-PA release was calculated by subtracting the prevenous occlusion value from the post-occlusion value.
tPA release was assessed only in the first 100 patients. In
the next group of 100 patients, identical PVO-ELT and PAI
results were obtained. In this study, only the first 100 patients, in whom all three fibrinolytic parameters were obtained, are analyzed.
Coagulation
I. Prothrombin time (PT), activated partial thromboplastin
time (APTT), thrombin clotting time (TCT) and plasma
fibrinogen were measured. The 1-stage prothrombin time
was performed on either an MLA-1000 or MLA-700 instrument (Medical Laboratory Automation, Pleasantville, NY)
using Dade Thromboplastin IS (a rabbit thromboplastin).
The ISI of each reagent was determined by comparison with
an Australian reference thromboplastin. The APTT was
performed on either of the above instruments using Actin
FSL (Baxter-Dade, Miami, FL). TCT measurements were
performed as previously described.7 The thrombin concentration was adjusted to give a clotting time of a normal
control (Citrol I, Baxter-Dade) of 12 to 15 seconds. Plasma
fibrinogen was determined by two methods. Initially a derived fibrinogen from the PT obtained from the MLA-1000
instrument was used. Any abnormal results were then
checked using a Clauss-based method (Baxter-Dade).
2. Antithrombin III (ATIII) functional assay (ATIII Assay Kit,
Baxter-Dade) was performed. If abnormal, antigen levels
(ATIII RID plate, Behring, Marburg, Germany) were performed.
3. Protein C functional levels were determined by a 2-stage
APTT-based assay (personal communication Prof. H. Salem).
4. Protein S total antigenic level was measured (Assera-Plate
Protein S, Stago).
5. Protein S free antigen level was determined according to
method of Woodhams. 8
6. Plasminogen functional assay was measured (Plasminogen
Chromogenic Assay Kit, Baxter-Dade).
Miscellaneous
1. Full blood examination was done.
2. Lupus anticoagulant (LAC) assays were performed on platelet-free plasma obtained by centrifugation of citrated
plasma at 1,700 g for 15 minutes and then filtered. A filtered
APTT was performed as a screening test. If prolonged a
further APTT was performed using a 50/50 mix with filtered pooled normal plasma (FPNP) to exclude clotting factor deficiencies. The following confirmatory assays were
performed: (1) Tissue thromboplastin inhibition test9 was
performed and the result in seconds was compared to that of
normal plasma. A ratio of greater than 1.3 (patient to control) was considered abnormal. (2) Dilute Russell Viper
Venom level was determined. 10 A ratio of greater than 1:3
(patient to control) was considered abnormal. (3) Kaolin
clotting time (KCT) was measured." A 1:4 mix of patient
plasma and filtered pooled normal plasma (FPNP) was
compared to FPNP alone. A ratio of greater than 1:3 (patient to control) was considered abnormal.
The criteria for a positive lupus anticoagulant were a prolonged filtered APTT not corrected by a 50/50 mix plus an
abnormality in 2 of the 3 tests (TTI, D R W , KCT), and
were used to diagnose the presence of a lupus anticoagulant.
If a patient was on coumarin therapy these tests were performed on a 50/50 mix of patient and FPNP. If a patient
was on heparin, an anion exchange resin was used to remove heparin from the system before performing the assays. Confirmatory tests, such as phospholipid or platelet
neutralization, were not performed because they were not
available at the start of patient accrual and because they had
not proved useful beyond the assays already outlined above
in this laboratory's experience.
3. Anticardiolipin antibody (ACL) assays were performed
courtesy of Dr. Russell Buchanan, Repatriation General
Hospital, Heidelberg, Victoria, Australia.
RESULTS
Patient
Characteristics
There was an equal sex ratio with a broad age distribution
(median 43, range 15-91 years) (Table 1). Two-thirds of the
patients presented with a venous event. One-third of the patients had a family history of thromboembolic disease. A family history was considered positive if any first or second degree
relative had a history of a thromboembolic event. Of patients
with venous events, there was a positive family history in 32
patients, but in only 3 patients were hereditary disorders of
A.J.C.P. • December 1994
799
DOIG ET AL.
Primary Hypercoagulabl States in Thrombosis
TABLE 1. PATIENT CHARACTERISTICS
Age
<20 years
20-40 years
41 -60 years
>61 years
5
63
75
57
Male
Female
imily history
Present
Absent
Unknown
103 (50%)
96 (50%)
Venous
Arterial
Both
Unknown
142(71%)
38(19%)
2(1%)
18(9%)
40 (20%)
107 (54%)
53 (26%)
coagulation identified (vida infra). Of the patients with arterial
events, eight had a positive family history (of both arterial and
venous events), but none of these were found to have hereditary coagulation disorders. Forty-four patients were on oral
anticoagulant therapy at the time of investigation. Because of
the known effect of coumarin drugs on protein C activity,12
assays were only considered abnormal if they remained low
after cessation of therapy for at least 1 month and no other
clinical factors (eg, liver disease) could account for the low
activity.
Abnormalities
Detected
Coagulation. Fifteen cases of reduced antithrombin III activity were found in 197 patients that were tested. In 12 cases
repeat levels performed 3 to 6 months after the presenting
thrombotic event were normal. In 3 cases, persistent reduction
in activity was detected. Comparable reduction of activity was
found in family members confirming hereditary deficiency of
ATIII. All of these three patients were women and presented
with venous thrombosis at the ages of 23,43, and 52 years. One
patient had a positive family history of venous thrombosis.
Five cases of reduced plasminogen activity were identified in
192 patients tested. All cases were detected in patients who had
received streptokinase therapy in the preceding 3 to 6 months.
Repeat testing using a tPA-based activation system in the assay
showed normal plasminogen activity in all cases.
Two cases of hereditary protein C deficiency were documented although 19 cases of transient reduced activity were
attributed to the coumarin effect. Two cases of protein S deficiency were found. In both cases there was deficiency of free
protein S with normal total protein S levels. All of these patients presented with venous thromboses. In one patient, family testing confirmed hereditary deficiency. In the other patient, family testing was normal. Nineteen cases of reduced
levels were attributed to oral anticoagulant therapy.
Fibrinolysis. The distribution of fibrinolytic parameters is
shown in Figure 2. A normal PVO-ELT of less than 120 minutes was established from a group of 28 normal controls. On
the basis of this distribution, 32 patients were found to have a
prolonged PVO-ELT (Table 2). This finding was more common in men (male to female ratio was 1.4:1), and present in all
age groups (range 15-91 years). A family history of thrombosis
was present in 8 of 28 (29%). Twenty-seven patients were found
8o 800088 8008 888 o 000 o
0
100
200
00
300
400
PVO-ELT (mins) n=100
FIG. 2. Post-venous occlusion euglobulin clot lysis time: Patients.
to have elevated PAI levels and 66 were found to have reduced
t-PA release (Table 2).
The relationship between these parameters is shown in Table
3. In 32 patients with prolonged PVO-ELT, 19 were found to
have elevated PAI levels and 13 had normal levels. All of the
normal group had "primary" reduced tPA release (ie, reduced
release of tPA in the presence of normal PAI levels). In the 68
patients with normal PVO-ELT, 8 patients had elevated PAI
levels. Of the remaining 60 patients, 27 patients had primary
reduced tPA release. Thus, a prolonged PVO-ELT often was
reflected by an increase in PAI (ie, 19 of 32, [60%]). In those
with normal PAI levels, always by primary, reduced tPA release (ie, 13 of 13, [100%]). However, in patients with normal
PVO-ELT, elevation of PAI was seen in 8 of 68 (12%) and
primary reduced tPA release in 27 of 60 (45%).
In 17 of 32 patients with prolonged PVO-ELT, repeat testing
was performed on 1 to 5 occasions over a 3- to 24-month period from the time of initial testing. Three patients subsequently had normal tests, but in two of these, the initial results
were borderline. The remaining 14 patients had consistently
abnormal testing.
Anliphospholipid Antibodies. Eighteen patients were found
to have a positive test for a lupus anticoagulant (LAC) (Table
2). There was a preponderance of men (male to female ratio
2:1), and a broad age distribution (median 52 years, range 2993 years). A family history of thrombosis was obtained in 5 of
18 patients. Most of the thromboses in this group were venous
(13 of 18). Fourteen patients had no clinical or laboratory evidence of SLE. Three patients had no clinical evidence of SLE,
but laboratory tests for antinuclear factor were not performed.
TABLE 2. ABNORMALITIES DETECTED
Hereditary antithrombin III deficiency
Hereditary protein C deficiency
Hereditary protein S deficiency
Plasminogen deficiency
PVO-ELT
Prolonged
Normal
PAI
Elevated
Normal
tPA release
Reduced
Normal
Lupus anticoagulant (LAC)
Anticardiolipin antibody (ACL)
LAC and ACL
No. 6
3(1.5%)
2(1%)
2(1%)
0 (0%)
32
68
27
73
66
34
18(9%)
3 (1.5%)
2(1.0%)
800
COAGULATION AND TRANSFUSION MEDICINE
Original Article
TABLE 3. FIBRINOLYTIC PARAMETERS (100 PATIENTS)
PAI Normal (<J5.0 IU/mL)
PAI Increased (>15.0 IU/mL)
tPA Normal
(<0.5 IU/mL)
tPA Reduced
(<0.5 IU/mL)
tPA Normal
tPA Reduced
Total
PVO-ELT normal
(< 120 minutes)
PVO-ELT prolonged
33
27
1
7
68
(> 120 minutes)
0
13
0
19
32
Total
73
27
One patient had HIV infection. Three patients were found to
have positive tests for ACL antibodies, and 2 patients had a
positive test for both ACL and LAC.
DISCUSSION
Impaired fibrinolytic activity has been described as the most
common abnormality in patients with idiopathic venous
thrombosis, 613 " 17 postoperative venous thromboembolism, 18
recurrent idiopathic venous thrombosis, 19 and young survivors
of myocardial infarction.20 In these series, reduced fibrinolytic
activity was seen in 30% to 35% of patients.
In this study, the fibrinolytic system was assessed by overall
plasma fibrinolytic activity (PVO-ELT values), as well as assays
for tPA and PAI activity that are the two major components of
the fibrinolytic pathway. There has been some suggestion that
overall activity assessment (ELT) may be prone to day-to-day
variation,21 although in this study 14 of 17 (89%) patients retested were found to have reproducibly abnormal results over 3
months to 5 years. The majority of patients with prolonged
PVO-ELT were found to have elevated PAI levels (19 of 32,
[60%]), whereas all the remainder had normal PAI activity with
defective tPA release. Other series,' 31417 have reported similar
findings with PAI elevation accounting for 65% to 75%. Defective tPA release accounted for the rest of patients with impaired
fibrinolytic activity. A few patients with normal PVO-ELT had
elevated PAI levels (8 of 68, [12%]), but primary defective t-PA
release was seen in 27 of 60 (45%) of this group. PVO-ELT may
be considered a global, or overall, assessment of plasma fibrinolytic activity. tPA and PAI are the principal opposing components of the fibrinolytic pathway. In this study, abnormal
PVO-ELT was specific for an underlying fibrinolytic defect,
but was insensitive given that 12 of 27 (44%) of elevated PAI
values, and 27 of 66 (40%) of primary defective tPA release
were not detected by it. Prospective studies to examine the
natural history of patients with abnormalities in one or a combination of these parameters are lacking. Several studies suggest
that the absolute PAI level may be an important marker for
thrombotic disease. In one study, PAI levels were found to be
elevated in young survivors myocardial infarction.20 PAI is an
acute phase reactant,' 4,22,23 so that repeat reevaluation after an
acute thrombotic event is important to determine if persistent
elevation is present. In this study, an interval of at least 10 days
was allowed between the thrombotic event and measurement
of fibrinolytic parameters. Although some groups have reported transient abnormalities of fibrinolysis due to a reactive
process that persisted for up to 3 months, 5,21 in 14 of 17 patients
with prolongation of the PVO-ELT, the results were reproducibly abnormal at 3 months to 3 years as previously explained.
This indicates a primary disturbance in the fibrinolytic system,
rather than a reactive process, is present in these patients. Such
persistence has been suggested to represent a fundamental endothelial cell disturbance because this is the main site of PAI
synthesis and storage.14 Evidence also exists that indicate PAI
synthesis can be inhibited by the use of the anabolic steroid
stanazalol.24 Randomized controlled studies of this agent in
patients with recurrent thrombosis and PAI elevation are not
yet available, but the results of such studies may have therapeutic implications.
Deficiency of a naturally occurring anticoagulant protein
was seen in only 3.5% of patients. This is marginally lower than
that reported in other series that report 5% to 9% of patients
will have an inherited abnormality. Protein C and protein S
deficiency are the most common findings.21,25"28 This difference probably is explained by difference in the population studied. In the series with the highest incidence of protein C deficiency and protein S deficiency,27 only young patients with
recurrent venous thrombosis were evaluated. In this series, the
age range was much broader, and there was no requirement for
recurrent episodes. Although young age and family history often are cited as pointers to the presence of hereditary deficiency, other studies have suggested that these clinical factors
are not helpful in identification of such patients. 25 In the 7
patients reported in this study, only three had a family history
and two presented at a relatively late age (43 and 52 years,
respectively). Hereditary deficiency of these factors should be
assessed in all patients with putative hypercoaguable states and
not confined to a young group with a positive family history.
Hereditary hypoplasminogenemia and dysplasminogenemia
have been associated with an increased risk of thrombosis. In
this series, five patients with reduced plasminogen activity were
identified. However, all had received streptokinase therapy in
the preceding 6 months. When the assay was repeated using
tPA instead of streptokinase as the activator in this assay, normal plasminogen activity was detected. It may be speculated
that antistreptokinase antibodies, induced by previous therapy,
may interfere with commercially available plasminogen assay
systems. This should be taken into account when performing
plasminogen assays.
Twelve percent of the cohort was found to have a positive
test for antiphospholipid antibodies (APL). Nine percent had
LAC, 1.5% had ACL and 1% had LAC and ACL. Other series
have reported a generally lower incidence of LAC positivity
from 2% to 4%.21,28,29 In the studies of Malm 21 and Ben-Tal,30
the study populations were restricted to patients with venous
thrombosis, and the age distribution was generally younger.
Neither of these groups evaluated ACL. The study of Bick and
colleagues28 found a striking level of ACL positivity (24%) with
LAC positivity of 4%. This high rate of ACL positivity may be
A.J.C.P.-December 1994
DOIG ET AL.
801
Primary Hypercoagulable States in Thrombosis
due to the large number of patients (55%) with "secondary"
causes for hypercoagulability, including malignancy, diabetes,
recent trauma, etc. Such patients were excluded from the group
in this study. Of the patients with LAC positivity, none had
evidence of systemic lupus erythematosus. One patient had
asymptomatic HIV infection, which is associated with LAC
positivity.31 Series of patients with LAC have suggested that up
to one-third of patients may have a thrombotic event.32 In this
study, there was a preponderance of men with LAC, but site of
thrombosis, age, and family history were not helpful in identifying this group. Thus, it is recommended that evaluation of
LAC and ACL should be routine in the evaluation of all patients with primary hypercoaguable states.
SUMMARY
In patients with primary hypercoaguable states, the presence
of antiphospholipid antibodies and impaired fibrinolytic activity are the most common abnormalities, which occur in about
10% and 30%, respectively. The prognostic significance of
overall fibrinolytic impairment compared to elevated PAI levels or primary defective tPA release is unclear. Because of this
and the relative expense in performing al of these assays, assessment should be restricted to patients enrolled in prospective
longitudinal studies. Routine evaluation does not appear justified at this time. The presence of antiphospholipid antibodies
may be more common than expected and should be routinely
evaluated. Hereditary deficiency of anticoagulant proteins is
uncommon, but should be assessed because of their prognostic
significance and therapeutic implication. In all of the previous
cases, age at presentation and family history were not useful in
identifying a group at high risk of having an underlying abnormality.
Acknowledgments. The authors thank Dr. Russell Buchanan for providing anticardiolipin antibody assays and Deb Porter for preparation
of the manuscript.
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