Antiphospholipid antibodies and hyperhomocysteinaemia in patients with vascular occlusive disease.

Hyperhomocysteinemia (HHcy), lupus anticoagulant (LA) and anticardiolipin antibodies (ACA) are independent risk factors for thrombosis. Even though risks are cumulative, the clinical impact of the association is unknown. Preliminary data suggested that HHcy might be associated with transient LA and ACA, disappearing after lowering HHcy. We prospectively evaluated the association of HHcy and LA/ACA, the effect of lowering HHcy with folic acid in LA behavior, and the correlation of the initial dRVVT with LA behavior after folic acid in 210 patients with thrombosis and adverse pregnancy outcomes. Prevalence of HHcy among patients with LA/ACA was 40%. Thirty-one patients exhibited only HHcy (15%; Group 1), 106 (50%; Group 2) had only LA/ACA, while 73 (35%; Group 3) had both. After therapy, 63% and 64% of LA/ACA remained positive in Group 3 and 2, respectively. We observed a trend towards a more positive dRVVT in persistent LA after lowering HHcy. No differences in clinical presentation or in outcomes after two years of followup were observed among the groups. Even though the association of HHcy and LA/ACA is common in patients with thrombosis, it might have no prognostic implications if Hcy levels are lowered. Currently, no laboratory findings correlate with LA behavior, which is independent of homocysteine levels and vitamin treatment.

Endogenous or exogenous coagulation factor level and the response to activated protein C.

BACKGROUND: The abnormal response to activated protein C could be the mechanism to explain the prothrombotic role of elevated coagulation factor levels. OBJECTIVE: We evaluated the effect of factor VIII, II, or X (FVIII, FII, or FX) levels on activated protein C resistance technique and its association with the resistant phenotype. MATERIALS AND METHODS: The correlation between APCR and FVIII was assessed in 36 samples, after Desmopressin infusion and the correlation between FII or FX and APCR in 15 patients with plasma levels between 100-125 U/dl. Also, the effect of the addition of purified human factors (FII, FX) to a normal plasma pool (final concentration: 100, 120, 140, 180, 220 U/dl) was estimated on the APCR technique. RESULTS: APCR values correlated with FVIII increase (r(Spearman) = 0.839; p < 0.001); APCR was abnormal (<2.4) in 9/36 samples, showing higher FVIII values in the abnormal group (VIII(abnormalAPCR) = 176.7 +/- 14.2; VIII(normalAPCR) = 103.5 +/- 8.0). APCR did not correlate with endogenous FII (r(Spearman) = 0.423) or FX (r(Spearman) = -0.169). However, the addition of human FII or FX to the normal plasma pool caused a decrease in APCR (r(SpearmanFII) = -0.843; r(SpearmanFX) = -0.958) without reaching abnormal (<2.4) results. FVIII levels may be associated with a resistant phenotype at values >153.0 U/dl, according to the linear regression analysis. Exogenous FII or FX levels greater than 120 U/dl would affect the APCR, without obtaining abnormal results. CONCLUSIONS: The data do not allow the direct association of the FII or FX increase with a defect in the protein C system in the current conditions.

Mechanical heart valve prostheses and persistent lupus anticoagulant: is the thrombotic risk increased?

The risk of thrombosis in patients with mechanical heart valve prostheses in spite of life-long adequate anticoagulation is 1-2% per year. Current recommendations for anticoagulation take into account the prosthesis itself and the co-morbid conditions that enhance the thrombotic risk. Lupus anticoagulant is diagnosed in many thrombotic recurrences. We designed an ambispective case-control study to evaluate thrombotic events in patients with mechanical heart valve prostheses and persistent lupus anticoagulant. Our objectives were to determine whether persistent lupus anticoagulant increased the risk of embolism in that population and thus, if a more intense anticoagulation would be recommended, even at the risk of increasing bleeding episodes. We included 16 patients and 16 controls with more than 80 patient-years of follow-up and with other risk factors for embolism. We observed no increased rate of thromboembolic events in patients than in controls, even during high-risk situations (i.e. bacterial endocarditis). Our population spent most of the time within the intended anticoagulation range. We conclude that adequate anticoagulation is the most important issue to prevent events, protecting against thrombosis without increasing the bleeding risk.

Morbidity of lupus anticoagulants in children: a single institution experience.

INTRODUCTION: The lupus anticoagulant (LA) and the anticardiolipin antibodies (ACA) are the antiphospholipid antibodies more relevant clinically. Their clinical manifestations are diverse with most patients being asymptomatic while others present venous or arterial thrombosis, and more rarely, bleeding. Our objectives were to evaluate clinical presentation of LA in children and to correlate it to LA behavior. PATIENTS AND METHODS: A retrospective cohort of patients (under 18 years old) who had a positive determination of LA followed by at least another determination of LA at a variable period was evaluated. Personal and family history, including infectious diseases temporally related to the event, were recorded. The screening of other coagulation disorders was performed according to symptoms, family history or laboratory results. RESULTS: Thirty-six patients were evaluated, median age was 10.8 years old, and 52.8% were female. Asymptomatic patients were 19.4% (7/36) of study population. Bleeding and thrombosis were found in 52.8% and 27.8%, respectively. Median LA determinations per patient were 3. von Willebrand disease was diagnosed in 66.7% of patients consulting for bleeding. A concomitant hemostatic defect was found in 8/10 patients with thrombosis (p = 0.003). LA behavior was not uniform and not correlated to symptoms. CONCLUSIONS: Most LA found in children is incidental and asymptomatic. In children with bleeding, LA might be a fortuitous finding associated with VWD. The persistence of LA does not imply a higher risk of thrombosis.

Primary upper-extremity deep vein thrombosis: high prevalence of thrombophilic defects.

Primary deep venous thrombosis of the upper extremity (UEDVT) is an unusual disorder. Limited data are available on the contribution of hypercoagulable status in the pathogenesis of this disease. This study aims to report the prevalence of inherited and acquired thrombophilic risk factors (TF) in patients with primary (effort-related and spontaneous) UEDVT. From 1993 to 2002, 31 patients (17 females, median age 38.8 years, range 16-60 years; and 14 males, median age 31.4 years, range 20-56 years) with primary UEDVT (n = 15 effort-related and n = 16 spontaneous) were referred for screening of hypercoagulable status. Nineteen (61.3%) patients had at least one coagulation abnormality. The most common acquired TF were antiphospholipid antibodies (31% lupus anticoagulant and 12.9% anticardiolipin antibodies). Factor V Leiden (12.9%) and prothrombin G20210A mutation (20%) were the most prevalent genetic risk factors. Five patients (16.1%) had high plasma homocysteine levels, and one patient (4.7%) had protein S deficiency. Effort-related UEDVT was associated with male gender (P = 0.04) and younger age (P = 0.02). There was no significant difference in the prevalence of acquired or inherited TF between patients with effort-related or spontaneous UEDVT. A local anatomic abnormality was detected in seven patients (22.5%), and the prevalence of TF was significantly lower within this group (P = 0.006). The incidence of TF in patients without an anatomic abnormality was 75% (RR 5.25). This study found a high prevalence of an underlying thrombophilic status in spontaneous and effort-related UEDVT. Hypercoagulable status may play a significant role in both groups. Screening for local anatomical abnormalities and thrombophilia should be included in the evaluation of primary UEDVT.

Antiphospholipid antibodies impact the protein C (PC) pathway behavior.

Antiphospholipid antibodies may interfere with the PC pathway, displaying a resistance to the activated PC (resistant phenotype). This effect was evaluated by the APCR and the ProCG systems in 36 lupus anticoagulant samples, yielding abnormal results in 47% of APCR(original), 17% of APCR(modified), and 22% of ProCG test. ProCG values correlated with APCR(original) but not with APCR(modified). Most of lupus anticoagulants affecting the PC pathway showed abnormal APCR(original) results but not abnormal ProCG values. The different behavior between both systems may be due to the heterogeneity of the antibodies or could be attributed to the fact that, in the ProCG, a PC activator is added, while the APCR employs already activated exogenous PC.

A chromogenic substrate method for detecting and titrating anti-factor VIII antibodies in the presence of lupus anticoagulant.

BACKGROUND AND OBJECTIVES: The development of neutralizing anti-factor VIII antibodies (a-fVIII) is a major clinical complication. Lupus anticoagulant (LA) might affect detection of a-fVIII, since both inhibitors may act on the same coagulation pathway. Our aim was to accomplish unequivocal detection and titration of a-fVIII even in the presence of LA. DESIGN AND METHODS: We evaluated a-fVIII activity by a chromogenic substrate (CS) method in samples with a-fVIII (n=6), LA (n=12) and presumably both LA+a-fVIII (n=5). The inhibition index before (Ii) and after incubation at 37 C (Ii(37)) was estimated. We also performed factor VIII assays (one-stage and CS) and titration methods (Bethesda and CS) in parallel. RESULTS: Inhibition in the a-fVIII group (Ii=5-3200) was potentiated by incubation (Ii(37)=27-5200) as it was in LA+a-fVIII (Ii=9-21; Ii(37)=50-903). LA samples showed no or meaningless inhibitory effect (Ii=0-7; Ii(37)=0-4) or a-fVIII activity (0.00-0.06 CSU/ml) by the CS method; on the contrary, very low to moderate (0.52-7.00 BU/ml) a-fVIII activity was recorded by the Bethesda method. The two titration methods did not correlate (p>0.100) in the presence of LA, or LA+a-fVIII. Differences between factor VIII:C and factor VIIIcs were significant only in LA samples (p=0.005); however, patients with residual factor VIII activity from the LA+a-fVIII group also showed higher factor VIIIcs values than factor VIII:C ones. INTERPRETATION AND CONCLUSIONS: Results indicate the possibility of detecting and titrating a-fVIII without interference of LA by the CS method. This marks a difference with respect to the Bethesda method, in which a measurable effect can be expected in the presence of a strong LA.