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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Hematology/Oncology, Hannover
Medical School, Hannover, Germany; Department of
Pediatrics, Westphalian Wilhelms- University, Münster, Germany;
Center of Internal Medicine I, University Hospital Frankfurt,
Frankfurt, Germany; Clinical Chemistry, Hannover Medical
School, Hannover, Germany.
Elevation of serum lipoprotein (a) (Lp[a]) is a known risk factor
predisposing to cardiovascular and cerebrovascular disease. However,
little is known about the role of increased Lp(a) in venous
thromboembolism (VTE). This study evaluated the role of Lp(a) among a
panel of established hereditary thrombogenic defects in patients with
VTE. A total of 685 consecutive patients with at least one episode of
VTE and 266 sex- and age-matched healthy controls were screened with
regard to activated protein C resistance, protein C, protein S,
and antithrombin deficiency, elevated serum levels of Lp(a), and the
factor V G1691A, MTHFR C677T, and prothrombin G20210A mutations.
Elevated Lp(a) levels above 30 mg/dL were found in 20% of all
patients, as compared to 7% among healthy controls (P < .001, odds ratio [OR] 3.2, 95% confidence
interval [CI], 1.9-5.3). The coexistence of FV G1691A and elevated
Lp(a) was significantly more prevalent among patients with VTE than in
the control group (7% versus 0.8%; P < .001, OR 9.8, 95% CI, 2.4-40.7). No other established prothrombotic risk factor was
found to be significantly combined with increased Lp(a). These data
suggest that Lp(a) concentrations greater than 30 mg/dL are a frequent and independent risk factor for VTE. Furthermore, elevated Lp(a) levels
might contribute to the penetrance of thromboembolic disease in
subjects being affected by other prothrombotic defects, such as FV
G1691A mutation.
(Blood. 2000;96:3364-3368) The most common risk factor for hereditary
thrombophilia is the factor V (FV) G1691A mutation, which is in the
majority of cases responsible for resistance against activated protein
C (APC), and which is present in 20% to 50% of patients with
venous thrombosis, depending on criteria of cohort
selection.1-4 Other known markers of hereditary
thrombophilia are the G20210A variant of the prothrombin gene5 and deficiencies of protein C, protein S, and
antithrombin. Furthermore, the thermolabile variant of the 5,10 methylenetetrahydrofolate reductase due to the 677 CT transition, which
appears to facilitate hyperhomocysteinemia especially in malnutrition
with folic acid, has been discussed as a genetic risk factor for
vascular disease and venous thromboembolism (VTE).6-8
High serum lipoprotein (a) (Lp[a]) concentrations are associated with
coronary heart disease,9-15 ischemic cerebrovascular disease,16-19 and chronic thromboembolic pulmonary
hypertension.20 The major protein component of Lp(a) is
apolipoprotein (a), which is disulfide-linked to apolipoprotein
B-100.21 Because of the close structural homology of
apolipoprotein (a) to plasminogen and of in vitro22-24 as
well as in vivo25 data, it seems reasonable that Lp(a)
competes with plasminogen for fibrin binding leading to impaired
fibrinolysis. Lp(a) can be found abundantly in atheromatous plaques26 and is therefore regarded to be a direct link
between thrombogenesis and atherosclerosis. Although strong evidence
suggests that Lp(a) is an independent risk factor for atherosclerotic
vascular disease, little is known about the role of Lp(a) in VTE.
Recently, in 2 pediatric case-control studies elevated Lp(a) was
demonstrated to be an independent risk factor for childhood
VTE27 and spontaneous stroke.28 Because the
role of increased Lp(a) is unclear in venous thrombosis of adults, we
evaluated Lp(a) as a single defect and in combination with established
prothrombotic abnormalities of blood coagulation factors in patients
with VTE and assessed its impact on the clinical manifestation of VTE.
The present multicenter study was approved by the medical ethics
committee at the Hannover Medical School, Hannover, Germany, and
conducted in accordance to the ethical standards of the 1995 Declaration of Helsinki. All patients had given informed consent prior
to study enrollment.
Patients
Controls were 266 healthy, age- and sex-matched white individuals
(blood or potential bone marrow donors) from the same geographic areas
as the patients. The criterion for recruitment of control subjects was
the lack of any history of thromboembolic events.
Blood sampling
Lipoprotein (a) measurement In all subjects Lp(a) serum concentration was measured with a photometric "sandwich enzyme immunoassay" using mouse monoclonal antiapolipoprotein (a)-coated microtiter plates and peroxidase-coupled Fab fragments of mouse monoclonal antiapolipoprotein B-100 antibodies including human standards and controls (Roche Diagnostics, Mannheim, Germany). The lower detection limit of the assay was 5 mg/dL. A threshold value of Lp(a) more than 30 mg/dL was considered as the cut-off value, which is widely accepted as the cut-off in the assessment of increased risk for cerebrovascular and cardiovascular events.29,30Assays of hemostatic factors Determination of APC resistance was done using a commercially available kit (Chromogenix, Mølndal, Sweden). Activities of protein C and antithrombin were measured by means of a chromogenic assay (Chromogenix). Total and free protein S antigen and protein C antigen were measured using a commercially available enzyme-linked immunosorbent assay kit (Asserachrom, Diagnostica Stago, Asnières, France). In patients treated with oral anticoagulants, no protein C and protein S were measured. Antithrombin and protein C deficiency were defined as reduction of the functional plasma activity below the lower limit alone or along with a reduced antigen concentration. Protein S deficiency was diagnosed when free protein S antigen levels were reduced below the lower limit combined with decreased or normal total protein S antigen levels, respectively.DNA-based assays The FV G1691A mutation, prothrombin (PT) G20210A variant, and the MTHFR C677T variant were determined. DNA was prepared from buffy coat using standard techniques, amplified by polymerase chain reaction, and detected by allele-specific hybridization.31 The tests are based on a 3-step procedure consisting of DNA isolation, DNA amplification, and finally allele-specific hybridization and detection of amplified target DNA with 2 sequence-specific oligonucleotide reporter molecules in 2 separate cavities of a microwell plate. The labeling of the target DNA was done during amplification. Detection was done by binding of horseradish peroxidase-labeled specific antibodies against fluorescein. All analyses of FV G1691A mutation were consistent with analyses of APC resistance.Statistical analysis Data are expressed as means and standard deviations (SD) and compared by using the Student t test or as medians and ranges and compared by Mann-Whitney U test where appropriate. The significance of differences of the frequency of prothrombotic risk factors were tested using the 2 test.
Odds ratios (OR), 95% confidence intervals (CI) and P
values (2 test, corrected for multiple testing according
to Bonferroni) were calculated as a measure for relative risk. P
values less than .05 were considered significant. In addition, the
multifactorial role of prothrombotic risk factors was assessed using
multivariate logistic regression analysis. All calculations were made
with the SPSS for Windows Release 9.0.0 statistical package (SPSS, Chicago, IL).
Characteristics of thromboembolic manifestations At the first episode of VTE, patients' ages ranged between 11 and 77 years, with a median age of 34 years (women 33 years, range 11-77; men 36 years, range 14-76). Of 685 patients, 476 (84%) suffered from juvenile thrombosis occurring before the age of 50 years. Of all patients, 333 (49%) suffered from one thromboembolic episode; the other 352 patients (51%) had recurrent VTE with a total of up to 6 thromboembolic events. Seventeen patients suffered from arterial thromboembolism as the second thromboembolic event (5%; myocardial infarction, n = 6; cerebral infarction, n = 5; and peripheral arterial thromboembolism, n = 6). Nine additional patients had arterial thromboembolism as their third thromboembolic event.The first thrombotic onset consisted of lower extremity deep vein thrombosis in 427 patients (62%), thrombosis of the pelvic region in 77 (11%), thrombosis in the splanchnic region in 37 (5%), deep vein thrombosis of the upper limb in 36 (5%), retinal venous thrombosis in 25 (4%), cerebral vein thrombosis in 16 (2%), and thrombosis of the superior or inferior caval vein in 4 patients (0.6%). Pulmonary embolism without detectable deep venous thrombosis was found in 63 cases (9%). In 355 patients (52%) the first VTE developed spontaneously; in 147 patients (21%) VTE occurred immediately after trauma or surgery or while bedridden. Thirty-two patients (5%) suffered from obesity, 110 female patients (16%) used oral contraceptives, and 41 women (6%) developed VTE during pregnancy or immediately after delivery. Seventy-eight patients (11%) had more than one of the mentioned exogenous risk factors. Lipoprotein (a) levels In patients the mean Lp(a) level was 21.6 mg/dL (SD 40.6), whereas the mean level in controls was 11.9 mg/dL (SD 16.4; P < .01, t test). Elevated Lp(a) levels above 30 mg/dL, considered to be the atherosclerotic cut-off value as well as the threshold for venous thrombosis in the young,28 were diagnosed in 135 of 685 patients (20%), whereas the prevalence of elevated Lp(a) levels was significantly lower in healthy controls (19 of 266, 7%,2 test, P < .001). The OR of
VTE associated with Lp(a) elevation was 3.2. (95% CI, 1.9-5.3, Table
1). If the cut-off level was set to more
than 20 or more than 10 mg/dL, there was still a significantly higher
proportion of Lp(a) elevation among patients compared to controls with
a significantly raised OR (Table 2).
Patients with no additional exogenous risk factor and Lp(a) more than 30 mg/dL had a slightly lower OR compared to controls (OR 2.8, 95% CI 1.6-4.8, P < .001). A similar OR was calculated for patients who suffered from trauma or surgery or were immobilized (OR 2.9, 95% CI 1.6-5.5, P = .001). Women using oral contraceptives had the highest risk of all patient subgroups (OR 4.0, 95% CI 2.1-7.6, P < .001), which was comparable to patients with a combination of several exogenous risk factors versus controls (OR 3.9, 95% CI 1.9-7.9, P < .001). Patients with recurrent VTE had a similar OR (2.9, 95% CI 1.6-5.5, P = .001) compared to controls. There were no differences of increased Lp(a) levels according to patients' gender and age at first onset of VTE. Established prothrombotic risk factors Analysis of the FV G1691A gene was performed in 683 patients; 205 were heterozygotes (29%) and 26 homozygotes (4%). Among the controls (n = 256) we found no homozygotes and 19 (7%) heterozygotes, which was significantly lower compared to patients (Table 1). Because we found no homozygous FV G1691A mutations among our controls, the OR could not be calculated.In 664 patients and 235 controls gene analysis of the PT G20210A
genotype was performed. Forty-five of 664 patients (7%) were heterozygotes compared to 6 controls (2.6%). Thus, the prevalence was
significantly higher in patients ( The MTHFR 677TT genotype was found in 49 of 486 patients tested (10%)
and in 22 of 161 controls (14%). Among the patients, 212 tested
heterozygous for the MTHFR C677T variant (44%) as did 71 controls
(44%); 225 (46%) of the patients and 68 (42%) of the controls were
negative (none of the differences were statistically significant,
Coexistence of Lp(a) more than 30 mg/dL and FV G1691A was found in 49 of 683 patients (7%), but only in 2 of 256 (0.8%) of the control
group ( Multivariate analysis To identify independent risk factors for VTE, multivariate logistic regression was performed including all parameters that proved to be statistically significant in univariate analysis. Lp(a) more than 30 mg/dL (OR 2.8, 95% CI 1.6-4.9, P < .001), FV G1691A mutation (OR 5.4, 95% CI 3.2-9.0, P < .001), as well as PT G20210A mutation (OR 3.1, 95% CI 1.3-7.6, P < .01) could be identified as independent risk factors for VTE. In addition, Lp(a) levels more than 20 mg/dL still proved to be an independent risk factor with an OR of 2.0 (95% CI 1.3-3.1, P < .001) as well as Lp(a) levels of more than 10 mg/dL (OR 1.5, 95% CI 1.0-2.0, P < .05).
In this multicenter study we evaluated the prevalence of elevated Lp(a) levels and their association with VTE. Our data on consecutive white patients suggest that Lp(a) elevation is an independent risk factor for VTE. Lipoprotein (a) inhibits the activation of plasminogen by streptokinase and tissue plasminogen activator in vitro and competes with plasminogen for binding to fibrin as well as for binding to annexin II and the plasminogen/tissue plasminogen activator receptor on endothelial cells and on platelets.23,29,32-35 Recently, a French study provided the first quantitative evidence that binding of Lp(a) to lysine residues of fibrin and cell surfaces is directly related to circulating levels of both plasminogen and Lp(a) and that these glycoproteins may interact as competitive ligands for these biologic surfaces in vivo.36 They observed an association of low plasminogen concentrations and high Lp(a) levels with an increased Lp(a) binding ratio onto fibrin and cells in nephrotic children during a flare-up of the disease.36 Thus, because Lp(a) shares striking similarities with human plasminogen,37 it is suggested that Lp(a) competitively interferes with plasminogen without exhibiting the proteolytic activity of plasminogen. Therefore, Lp(a) might interact with fibrin, platelets,34 and cell surface receptors and might impair fibrinolysis and promote thrombosis.22,38-41 In addition, Lp(a) is able to bind and inhibit tissue plasminogen activator.33 This possible prothrombotic potential confers on Lp(a) the direct link between thrombogenesis and atherosclerosis. High plasma concentrations of Lp(a) are associated with the development of atherosclerosis in coronary heart disease,9,11-13 restenosis, and ischemic stroke.16,18,27,42,43 However, there is only little information on the role of Lp(a) in venous thrombosis. In a small scale study Atsumi and coworkers25 analyzed Lp(a) levels in patients with antiphospholipid antibody syndrome (APAS). They found significantly increased plasma Lp(a) levels in patients with APAS with arterial thrombosis as well as in patients with venous thrombosis. März and colleagues,44 who investigated the apolipoprotein (a) levels of 203 patients with venous thrombosis before the age of 45 years, did not find a relevant association of apolipoprotein (a) levels and juvenile VTE. However, it should be taken into account that they measured apolipoprotein (a) levels using a sandwich radioimmunoassay. It is recommended to use a combination of antibodies against apolipoprotein (a) for capture with antiapolipoprotein B antibodies for detection to avoid cross-reactions to apolipoprotein (a), which may be present in free form in plasma as full-length and truncated apolipoprotein (a).45 On the other hand, it has recently been shown that increased Lp(a) is a risk factor for VTE in childhood.28 In the consecutively recruited patients investigated here we could identify elevated Lp(a) concentrations as a frequent and independent risk factor of VTE associated with an OR of 2.8 in multivariate logistic regression analysis. For recurrent disease the OR was similar. The OR is lower compared to other established risk factors of hereditary thrombophilia such as heterozygous FV G1691A mutation. On the other hand, it is higher than elevated prothrombin levels exceeding 1.15 U/mL with an OR of 2.1,5 which is similar to the OR of Lp(a) elevation if the cut-off level is set to 20 mg/dL. Lp(a) levels above 30 mg/dL are considered to be the atherosclerotic threshold. However, our study suggests that the thromboembolic risk associated with Lp(a) elevation in the cohort presented is concentration dependent, starting at Lp(a) levels well below the established cut-off (Table 2). It is now widely accepted that thrombophilia is a multifactorial disorder.46 In our study, the combination of Lp(a) elevation and the FV G1691A mutation revealed a high prevalence among patients. In 7.2% of the patients but only in 0.8% of the control subjects, Lp(a) levels more than 30 mg/dL were coincident with the FV G1691A mutation, increasing the OR to about 10. Thus, it is likely that the simultaneous presence of Lp(a) elevation and FV G1691A mutation in a patient enhances the risk of VTE. Similar findings could be demonstrated in children with VTE.27 However, other than the coexistent FV G1691A mutation, no further combinations of genetic defects with elevated Lp(a) were found. Additional exogenous risk factors are likely to modify the thrombogenetic risk caused by Lp(a) elevation depending on the kind and number of the exogenous risk factors. Our data indicate that the strongest enhancing effect might be caused by intake of oral contraceptives. Although Lp(a) levels seem to be genetically determined, a reduction of Lp(a) has been achieved in postmenopausal women receiving hormone replacement therapy.47,48 However, little is known on the effect of oral contraceptives on lipoprotein metabolism.49,50 Thus, our results warrant further investigations. In conclusion, our data indicate that the elevation of serum or plasma Lp(a) concentration significantly increases the risk of venous thromboembolic disease, especially with the coexistence of the FV G1691A mutation or further exogenous risks, thereby underlining the multifactorial genesis of thromboembolism. The exact pathogenic mechanism of elevated Lp(a) leading to VTE remains to be clarified.
Submitted February 17, 2000; accepted July 19, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Mario von Depka, Hannover Medical School, Department of Hematology/Oncology, 30623 Hannover, Germany; e-mail: depka.mario{at}mh-hannover.de.
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© 2000 by The American Society of Hematology.
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  H. Jana, L. Vaclav, M. Hynek, C. Zdenek, and T. Vladislav Portal and Mesenteric Vein Thromboses in a Patient With Prothrombin G20210 Mutation, Elevated Lipoprotein (a), and High Factor VIII Clinical and Applied Thrombosis/Hemostasis, October 1, 2008; 14(4): 481 - 485. [Abstract] [PDF]
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U. Nowak-Gottl, R. Junker, W. Kreuz, A. von Eckardstein, A. Kosch, N. Nohe, R. Schobess, and S. Ehrenforth Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors Blood, February 15, 2001; 97(4): 858 - 862. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
20°C not longer than 3 weeks
until analysis. For measurement of Lp(a), serum was obtained from
venous blood following centrifugation at 1500g for 10 minutes and stored at