[Show abstract][Hide abstract] ABSTRACT: To characterize the first type II protein S (PS) deficiency affecting the epidermal growth factor (EGF)4 domain, a calcium-binding module with a poorly defined functional role.
The proband suffered from recurrent deep vein thrombosis and showed reduced PS anticoagulant activity (31%), and total, free PS antigen and C4bBP levels in the normal range.
Reverse transcription-polymerase chain reaction analysis showed the presence of the IVSg-2A/T splicing mutation that, by activating a cryptic splice site, causes the deletion of codons Ile203 and Asp204. Free PS, immunopurified from proband's plasma, showed an altered electrophoretic pattern in native condition or in the presence of Ca2+. The recombinant PS (rPS) mutant showed reduced anticoagulant (<10%) and activated protein C-independent activities (24-38%) when compared with wild-type rPS (rPSwt). Binding of the rPS variant to phospholipid vesicles (Kd 235.7 +/- 30.8 nM, rPSwt; Kd 15.2 +/- 0.9 nM) as well as to Ca2+-dependent conformation-specific monoclonal antibodies for GLA domain was significantly reduced.
These data aid in the characterization of the functional role of the EGF4 domain in the anticoagulant activities of PS and in defining the thrombophilic nature of type II PS deficiency.
Full-text · Article · Jan 2006 · Journal of Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: The last few years have clarified the tight link between inflammation and coagulation. In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways. Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed. Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant. Increased tissue factor expression results in increased thrombin formation within the microcirculation. Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C. Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure. However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition. Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia. The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling. This system is markedly depressed in severe sepsis. The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.
No preview · Article · Jun 2004 · Minerva anestesiologica
[Show abstract][Hide abstract] ABSTRACT: In vitro studies have shown that the rate of prothrombin activation is linearly related to the concentration of factor II (FII) in the assay system, suggesting a key role of prothrombin levels in the expression of the antithrombotic activity of oral anticoagulant treatment (OAT). We investigated the in vivo relationship between prothrombin activation and vitamin K-dependent clotting factor levels during the early and steady phases of OAT in patients and in healthy volunteers.
The changes in international normalizezd ratio (INR) and in the plasma levels of FVII, FX, FII, protein C (PC) and prothrombin fragment 1.2 (F1+2) induced by OAT were monitored over 9 days in 10 patients not on heparin starting warfarin after heart valve replacement (HVR) and in 9 healthy volunteers submitted to an 8-day course of warfarin treatment. FII and F1+2 plasma levels were also measured in 100 patients on stable oral anticoagulant treatment with INRs ranging from 1.2 to 6.84.
Because HVR patients had subnormal FVII, FX and FII levels after surgery, INR values > 2.0 were attained already 24 hours after the first warfarin dose. In healthy volunteers, INR values greater than 2.0 were first observed after 72 hours. Nadir levels of FVII, PC, FX and FII were reached between 40 and 88 hours in HVR patients and between 72 and 192 hours in healthy volunteers. The FII apparent half-disappearance time (t/2) was 99 hours in HVR patients and 115 hours in healthy volunteers (p = ns). In HVR patients there was no normalization of initially elevated F1+2 levels until day 7 with an apparent t/2 of 132 hours. In healthy volunteers, a decrease to subnormal F1+2 levels was observed by day 8 of treatment (apparent t/2 = 107 hours). In both HVR patients and healthy volunteers, FII and PC levels were independent predictors of the changes in F1+2 levels (p = 0.0001). In patients on stable OAT, only FII levels were independent predictors of the variation in F1+2 levels (p = 0.0001).
During the early phase of oral anticoagulant treatment in vivo prothrombin activation is a function of the balance between FII and PC levels and is not significantly prevented until nadir levels of FII are obtained. This provides an explanation for the requirement of overlapping heparin and oral anticoagulant treatment for at least 48 hours after the achievement of therapeutic INR values in patients with thromboembolic diseases. In addition, in vivo prothrombin activation is a function of FII levels rather than INR values also in patients on stable oral anticoagulant treatment.
[Show abstract][Hide abstract] ABSTRACT: Delayed thrombus regression after a first episode of deep vein thrombosis (DVT) of the inferior limbs has been implicated in the development of the post-thrombotic syndrome. Whether normalization of vein segments involved in the index DVT has prognostic significance with respect to the probability of DVT recurrence or new thrombosis is currently unknown. In this study, we prospectively monitored thrombus regression in consecutive patients with symptomatic and asymptomatic DVT. Factors affecting normalization rates and the relationship between previous normalization and DVT recurrence or new thrombosis were explored.
One hundred and seventy-nine patients with a first episode of symptomatic DVT of the lower limbs (38 with cancer) and 104 patients with DVT occurring after hip replacement surgery were serially monitored by real time B-mode compression ultrasonography (C-US) over a period of 12 months (months 1, 3, 6 and 12). C-US normalization of popliteal and femoral venous segments was arbitrarily assigned to be residual thrombus occupying, at maximum compressibility, less than 40% of the vein area in the absence of compression.
In patients with no DVT recurrence or new thrombosis, C-US normalization was observed at 12 months in 100% of 99 patients with post-operative DVT, in 59% of 134 cancer-free symptomatic DVT outpatients and in 23.3% of 30 symptomatic DVT outpatients with cancer (p = 0.0001). Independent negative effects on the probability of C-US normalization were observed for younger age (p <0.05), for the outpatient presentation of the index DVT (p 0.017), for DVT involving the entire femoro-popliteal axis (p 0.05), and for the presence of cancer (p 0.05). DVT recurrence or new thrombosis was observed in 5 patients with post-operative DVT (4.8%), in 7 cancer-free patients with symptomatic DVT (5.0%) and in 8 patients with cancer (21.1%). Only 4 of these patients had shown normalization of their index DVT prior to the event. The presence of cancer was the only significant predictor of DVT recurrence and/or new thrombosis occurring within 3 months from the index DVT (OR = 4.90, p = 0.002). The absence of previous C-US normalization was the only predictor of recurrence or new thrombosis occurring after 3 and 6 months from the index DVT (OR 5.26, p 0.027).
Absence of C-US normalization after a first episode of DVT appears to be a factor favoring recurrence or new thrombosis and may be relevant to the optimal duration of oral anticoagulant treatment.
[Show abstract][Hide abstract] ABSTRACT: The role of blood tests in identifying patients at high risk for post-operative venous thromboembolism is undefined. The aim of this study was to evaluate the correlation between pre-operative plasma levels of soluble fibrin polymers (SFP), as determined by a recently developed enzyme-linked immunosorbent assay (ELISA) assay (TpP), and the incidence of deep vein thrombosis (DVT) after elective neurosurgery. Blood samples for SFP assay were withdrawn on the day before surgery from 157 consecutive patients undergoing elective neurosurgery for brain or spinal tumour. Patients were randomized to subcutaneous enoxaparin (40 mg once daily) or placebo given for at least 7 days. All patients wore compression stockings. DVT was assessed by bilateral venography, performed on day 8 +/- 1. Thirty-four patients (21.7%) were found to have a DVT, proximal in 11 (7%) and isolated distal in 23. Patients with and without DVT had a plasma pre-operative SFP levels of 6.2 +/- 4.6 and 1.9 +/- 1.5 mg/ml respectively (mean +/- SD) (P < 0.001). SFP levels in patients with proximal and isolated distal DVT were 7.6 +/- 5.1 and 5.5 +/- 4.4 microg/ml, respectively (P = 0.22). SFP cut-off levels categorized patients into three classes of DVT incidence. The incidence of DVT was 7.4% (6 of 81) for SFP levels < 2 microg/ml, 20.4% (11 of 54) for levels between 2 and 4.5 microg/ml, and 77.3% (17 of 22) for levels > 4.5 microg/ml (P= 0.001, Cochran-Mantel-Haenszel test). We conclude that pre-operative SFP levels correlate with post-operative DVT in elective neurosurgery patients. Further studies are required to define whether pre-operative SFP measurement could be useful in patient management.
No preview · Article · Jan 2000 · Blood Coagulation and Fibrinolysis
[Show abstract][Hide abstract] ABSTRACT: Prolonged anticoagulation aiming at International Normalized Ratio (INR) values > 3.0 has been recommended for patients with thrombosis and the antiphospholipid-antibody syndrome. We evaluated the influence of anticoagulant antibodies in two different prothrombin time (PT) assays carried out on plasma from lupus anticoagulant patients on oral anticoagulation.
INR values obtained with a combined (final test plasma dilution 1:20) and a recombinant (final test plasma dilution 1:3) thromboplastin were compared in 17 patients with persistent lupus anticoagulants (LA) receiving oral anticoagulant treatment and monitored for 69.8 patient-years. Doses of anticoagulant drugs were always assigned based on the results obtained with the combined thromboplastin, aiming at a target INR of 2.5 or 3.0 for patients with venous or arterial thromboembolic disease. Paired determinations with both reagents were also obtained throughout the study period in 150 patients on stable oral anticoagulation but free of antiphospholipid antibodies. Total IgG fractions were purified from selected patients to evaluate effect in the two PT assay systems.
No patient experienced recurrence of thrombosis or major bleeding complications (95% confidence interval: 0.1-6.5 per 100 patient-years). INR values with the recombinant reagent were significantly higher than with the combined reagent in 8 LA patients (mean DINR ranging from 0.17 to 0.54) of the degree of anticoagulation was overestimated in all but one LA patients with the recombinant reagent when compared to the DINR observed in non-LA patients (-0.64 +/- 0.42). The anti-cardiolipin IgG titer (r(2) = 0.43, p = 0.004) and the anti-b(2)GPI IgG titer (r(2) = 0.30, p = 0.023) were positively associated with the mean deltaINR observed in LA patients. When added to plasmas with different levels of vitamin K-dependent factors, total IgG fractions from 6 LA patients with significant overestimation of the INR with the recombinant reagent (mean DINR ranging from 0.17 to 0.54, group 1) and from 7 LA patients with mean deltaINR < or = 0.0 (ranging from -0.25 to 0.04, group 2) reproduced the effects observed ex vivo in the two assay systems. However, when total IgG fractions were tested at the same final concentration in the two PT assay systems, there was no difference in the clotting times determined with total IgG fractions from group 1 and group 2 LA patients. Addition of negatively charged liposomes (0.4 and 0.8 mg/mL final concentrations) to platelet free plasma from LA-free patients on stable oral anticoagulation caused a 20% to 48% prolongation of the prothrombin time determined with the recombinant reagent. In contrast, no significant prolongation of the prothrombin time determined with the recombinant reagent was observed upon addition of negatively charged liposomes to plasma from group 1 LA patients.
These results confirm previous suggestions of assay-dependency of INR values in LA patients on oral anticoagulation. For these patients, accurate INR values may be obtained using combined thromboplastin reagents that permit testing at high plasma dilution.
[Show abstract][Hide abstract] ABSTRACT: Autoantibodies to beta(2)-glycoprotein I (beta(2)-GPI) and/or prothrombin (FII) have been involved in the expression of lupus anticoagulant (LA) activity, an in vitro phenomenon associated with an increased risk of arterial and/or venous thromboembolic events. However, LA activity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-beta(2)-GPI antibodies. Because assays aimed at detecting LA activity are now commercially available, we evaluated the relative sensitivity to anti-FII and anti-beta(2)-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clinical suspicion of anti-phospholipid antibody (APA) syndrome.
One hundred and ten consecutive patients with the clinical suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot, Stago), anticardiolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG binding to solid-phase and/or phospholipid (PL)-bound beta(2)-GPI and FII by ELISA assays developed an optimized in our laboratory. Odds ratios for the association of IgG binding activity with LA and the aCL IgG status were calculated. In LA patients, dependency of LA potency (as assessed by clotting time prolongation in absence or presence of hexagonal phospholipid) on autoantibody titers was analyzed by the generalized linear model. Total IgG fractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration.
Anticardiolipin antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-beta(2)-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 standard deviations the mean values observed in control subjects were found in 46 and 47 patients and in 56 and 30 patients respectively, with the highest titers detected in the subgroup of patients with both LA and aCL IgG. The relative risk of LA for patients free of anti-FII and/or anti-beta(2)-GPI IgG was 0.03 after stratification for the aCL IgG status. Anti-beta(2)-GPI (solid-phase and PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phase) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-FII and anti-beta(2)-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including anti-beta(2)-GPI IgG. Anti-beta(2)-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in absence phospholipid (anti-beta(2)-GPI IgG) or in presence of hexagonal phospholipid (aCL IgG). Total IgG fractions purified from 12 patients (6 with anti-FII IgG) did not significantly inhibit factor II activity up to a 150-fold molar excess.
These results highlight the high prevalence of anti-FII and anti-beta(2)-GPI IgG in patients with the clinical suspicion of APA syndrome and particularly in the subgroup of patients with LA activity. The fraction of LA activity which can be quenched by addition of hexagonal phospholipid is, however, only dependent on IgG directed to PL-bound beta(2)-GPI. Other antibodies associated with anticardiolipin IgG may explain residual clotting time prolongation observed in the presence of hexagonal phospholipid.
[Show abstract][Hide abstract] ABSTRACT: In a prospective longitudinal study, 130 primigravidae at risk for preeclampsia were examined and plasma sampling performed in 45 of them. Plasma thrombomodulin (pTM) was sequentially measured at weeks 12, 24 and 32 of gestation and after delivery in 20 primigravidae who developed either mild preeclampsia (n = 8) or gestational hypertension (n = 12) between weeks 32 and 39 of gestation and in 25 (age-matched) primigravidae who had uneventful pregnancies. pTM elevations were not observed until week 32 in uneventful pregnancies, but were present by week 24 (p = 0.002) in patients who later developed hypertensive complications. A net individual pTM increase > or = 4.2 ng/ml between weeks 12 and 24 (more than 8 times that of normotensive primigravidae) and/or pTM level > or = 47.5 ng/ml at week 32 predicted the development of hypertensive complications with 80% accuracy. Serial pTM determinations can be useful to select pregnancies who may benefit from early pharmacological intervention.
No preview · Article · Jun 1998 · Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: The potential utility of D-dimer measurements for the diagnosis of deep vein thrombosis became evident soon after the development of reliable commercial assays. The purpose of this review is to outline some critical aspects affecting cost-effectiveness of D-dimer measurements in the diagnosis of deep vein thrombosis (DVT).
The authors have been working in this field contributing original papers whose data have been used for this study. In addition, the material analyzed in this article includes papers published in the journals covered by the Science Citation Index and Medline.
D-dimer levels are very sensitive to the process of fibrin formation/dissolution occurring with ongoing thrombosis. However, they may not be highly specific for venous thromboembolism as they are influenced by the presence of comorbid conditions potentially elevating plasma D-dimer (cancer, surgery, infectious diseases). In addition, commercially available ELISA assays, although quantitative and reproducible, cannot be used under emergency conditions because they are time-consuming and suited for batch-processing of plasma samples. Recently, new assays have been introduced which permit fast and quantitative D-dimer estimations in individual patients. We have evaluated the utility of two new rapid assays (LPIA D-dimer. Mitsubishi, and VIDAS D-DIMER, bio-Merieux) in combination with compression real-time-B-mode ultrasonography for the detection of deep vein thrombosis in asymptomatic patients following elective hip replacement and in patients with clinically suspected deep vein thrombosis. In both settings, we identified cut-off values with optimal sensitivity which allow exclusion of deep vein thrombosis in a considerable percentage of patients, with substantial sparing of economic resources. In fact, based on a cost-effectiveness analysis, a diagnostic algorithm combining D-dimers measurement and compression ultrasonography would result in cost-savings ranging from 5% to 55% in patients with high or low clinical pretest probability respectively. However, the specificity of D-dimer measurements for deep vein thrombosis was much higher in symptomatic than in asymptomatic patients. Choice of the cut-off value proved to be dependent on the method as well as on the patient populations studied.
The cost-effectiveness of D-dimers measurement in the diagnosis of asymptomatic DVT remains questionable. Conversely, our data strongly support the utility of D-dimers determinations in the diagnosis of symptomatic DVT. In terms of sparing economic resources, the introduction in the clinical laboratory of the rapid quantitative assays would be highly convenient, because they avoid a source of bias in the interpretation of D-dimers results, are easy to perform and do not require dedicated personnel or instrumentation. Prospective management studies validating the utility of D-dimer measurement in the diagnosis of deep vein thrombosis are urgently needed.
[Show abstract][Hide abstract] ABSTRACT: In spite of the large number of reports showing that hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and arterial occlusive disease, this metabolite of the methionine pathway is measured in relatively few laboratories and its importance is not fully appreciated. Recent data strongly suggest that mild HHcy is also involved in the pathogenesis of venous thromboembolic disease. The aim of this paper is to analyze the most recent advances in this field.
The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition the authors of the present article have been working in the field of mild HHcy as cause of venous thromboembolic disease.
The studies examined provide very strong evidence supporting the role of moderate HHcy in the development of premature and/or recurrent venous thromboembolic disease. High plasma homocysteine levels are also a risk factor for deep vein thrombosis in the general population. Folic acid fortification of food has been proposed as a major tool for reducing coronary artery disease mortality in the United States. Vitamin supplementation may also reduce recurrence of venous thromboembolic disease in patients with HHcy. At the present time, however, the clinical efficacy of this approach has not been tested. In addition, the bulk of evidence indicates that fasting total homocysteine determinations can identify up to 50% of the total population of hyperhomocysteinemic subjects. Patients with isolated methionine intolerance may benefit from vitamin B6 supplementation. Homocysteine-lowering vascular disease prevention trials are urgently needed. Such controlled studies, however, should not focus exclusively on fasting homocysteine determinations and folic acid monotherapy.
[Show abstract][Hide abstract] ABSTRACT: The major improvements obtained in the quality of commercial reagents and in the accuracy of coagulometers has rendered comparabilty of the results among different laboratories a major task of the bodies devoted to standardization of coagulation testing. Commutability of results is of major importance especially in the monitoring of anticoagulant therapy. Critical aspects relate to the preanalytical phase, the anaytical phase and to the expression of results with the adoption of proper correction factors - like the international sensitivity index (ISI) for thromboplastin reagents. Problems with the APTT in the monitoring of heparin treatment include the variable sensitivity of commercially available APTT reagents to clinically insignificant deficiencies of factors involved in the contact phase of coagulation and to the presence of lupus anticoagulants, which - in addition to the different sensitivity of the reagents to the anticoagulant effect of heparin - render commutability of results unworkable in practice.
No preview · Article · Oct 1996 · Pure and Applied Chemistry
[Show abstract][Hide abstract] ABSTRACT: We describe a case of central retinal vein and branch artery occlusion associated with inherited type I plasminogen deficiency (68%) and permanent elevation of Lp(a) (460 mg/l, S2 phenotype) in a 45 year old white woman with no associated local or systemic risk factors. Pedigree analysis revealed inheritance of plasminogen deficiency from the deceased father and of high Lp(a) levels from the mother. Both the patient's sons had plasminogen deficiency, but they had normal Lp(a) levels. In a series of 40 consecutive patients with central retinal vein occlusion we previously reported the observation of high Lp(a) levels — consistently associated with the S2 phenotype — in 30% of the patients as compared to a 10% incidence in controls. This case emphasizes the importance of screening patients with occlusion of the retinal vessels and no associated risk factors for coagulation abnormalities predisposing to thrombosis.
No preview · Article · Dec 1995 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: To determine their ability to diagnose postoperative deep vein thrombosis (DVT) D-dimer - by three methods -, fibrinogen degradation products (FgDP) and fibrinogen levels were measured in 68 consecutive patients before elective surgery for hip replacement and on postoperative day 1, 3, 6, and 10. All patients received prophylaxis and underwent compression real-time B-mode ultrasonography (C-US) on postoperative day 5 and 9, and bilateral ascending venography on day 10. Twenty-two out of 68 patients developed asymptomatic postoperative DVT, which was limited to the calf veins in 14 and involved the proximal veins in 8 patients. C-US was negative in all patients on day 5. On day 9, C-US sensitivity and specificity for proximal DVT were 63% (95% confidence interval: 26%-90% and 98% (89%-100%) respectively. Postoperative changes in the laboratory parameters evaluated were not different in patients with or without DVT until day 10. On day 10, mean D-dimer, FgDP and fibrinogen levels were significantly higher in patients with DVT than in those without DVT (p values between 0.006 and 0.032), but only D-dimer was higher with DVT involving two or more venous segments than with thrombosis involving one venous segment only (p < 0.05). Stepwise logistic regression analysis identified D-dimer and fibrinogen on day 10 as predictors of postoperative DVT. In a receiver operator curve and after weighing for the coefficients generated by logistic regression analysis, the combination of a latex photometric immuno-assay and of PT-derived fibrinogen yielded-at a cut-off value of 7.0 a sensitivity of 100% (73%-100%) and a specificity of 58% (39%-75%) for DVT, with a negative predictive value of 100% (78%-100%), a positive predictive value of 52% (32%-71%) and an overall accuracy of 71% (55%-83%). These results suggest that two simple, fast and reproducible tests may permit the identification of patients at low risk of having postoperative DVT and that a combination of sensitive laboratory assays and of the highly specific C-US may select patients requiring anticoagulant treatment. Efficacy and cost-effectiveness of this approach should be evaluated in large clinical management studies.
No preview · Article · Nov 1995 · Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: To evaluate the prevalence of moderate hyperhomocysteinemia and inherited thrombophilia disorders (congenital defects of the natural anticoagulant or fibrinolytic mechanisms) in patients with early-onset venous or arterial thromboembolic disease.
Cross-sectional 2-year evaluation of consecutive unrelated patients with a history of venous or arterial occlusive disease occurring before the age of 45 years or at unusual sites, in the absence of local predisposing factors.
Thrombosis research unit of a community hospital.
107 patients with venous thromboembolism (mean age at event, 32.9 +/- 11.9 years) and 50 patients with arterial occlusive disease (mean age at event, 31.1 +/- 10 years) who did not have acquired coagulation defects, overt cancer, or acquired conditions affecting methionine metabolism.
Total plasma homocysteine (fasting levels), antithrombin III, protein C, protein S, activated protein C resistance, plasminogen, and heparin cofactor II were measured at least 3 months after the event. In 87 patients, total plasma homocysteine levels were also measured 8 hours after an oral methionine load was administered (L-methionine, 0.1 g/kg body weight). Ninety-fifth percentiles of the distribution of these variables were established in 60 apparently healthy persons; sex-specific ranges were used for protein S and total plasma homocysteine. Relatives of patients with laboratory abnormalities were studied to confirm inheritance of the defects.
Moderate hyperhomocysteinemia was detected in 13.1% (95% CI, 7.6% to 21.3%) and in 19.2% (CI, 9.0% to 31.9%) of patients with venous or arterial occlusive disease. The prevalence of hyperhomocysteinemia was almost twice as high when based on homocysteine measurements done after oral methionine load as when based on fasting levels. The remaining defects were detected only in patients with venous occlusive disease (activated protein C resistance in 11.2% of patients, protein S or C deficiency in 6.6%, and plasminogen deficiency in 0.9%), with an overall prevalence of 18.7% (CI, 12.1% to 27.6%). Inheritance of hyperhomocysteinemia and of the other defects was confirmed in 26 of the 30 families studied. Event-free survival analysis showed that the relative risk for occlusive disease in patients with moderate hyperhomocysteinemia and other defects was 1.70 times (CI, 1.19 to 2.42; P < 0.01) greater than in patients without defects. After adjustment for the presence of predisposing factors (for example, use of contraceptive drugs, pregnancy, surgery, prolonged bedrest, smoking, mild hypertension or dyslipidemia) and a family history of thrombosis, the age at first event of patients with moderate hyperhomocysteinemia was similar to that of patients with the other defects (26.4 +/- 11.2 years compared with 25.2 +/- 10.6 years), and the 43 patients with defects were significantly younger at first event than the 114 patients without defects (25.5 +/- 11.1 years compared with 31.0 +/- 12.3; P < 0.005). Patients with mild hyperhomocysteinemia had a higher rate of recurrence than those without defects (52% compared with 25%; P = 0.01); among the 56 patients who had their first event more than 1 year before observation, the recurrence rate was higher (80% [CI, 51% to 95%]) in patients with defects than in patients without defects (41% [CI, 26% to 57%] P = 0.01).
Moderate hyperhomocysteinemia may have pathogenic significance in premature venous and arterial occlusive disease and should be included among the (inherited) disorders of venous and arterial thrombophilia.
No preview · Article · Nov 1995 · Annals of internal medicine