Prevalence and significance of anti-prothrombin (aPT) antibodies in patients with Lupus Anticoagulant (LA).

OBJECTIVE: Anti-prothrombin (aPT) antibodies have been found in Lupus Anticoagulant (LA) positive patients. Their prevalence and relative contribution to thromboembolic risk in LA-positive patients is not well defined. The aim of this study was to determine their presence and association with thromboembolic events in a large series of patients with confirmed LA. METHODS: Plasma from LA-positive patients was collected at Thrombosis Centers and sent to a reference central laboratory for confirmation. Positive plasma was tested using home-made ELISA for the presence of aPT and anti-beta(2)GPI antibodies. RESULTS: LA was confirmed in 231 patients. Sixty-one of 231 (26%, 95%CI 22-33) LA positive subjects were positive for IgG aPT and 62 (27%, 95% CI 21-33) were positive for IgM aPT antibodies. Clinical features of Antiphospholipid Syndrome (APS) were not associated with the presence of IgG aPT [43 APS in 61 (70%) positive and 109 APS in 170 (64%) negative IgG aPT subjects, p=ns] or IgM aPT. Rate of positivity of IgG and IgM a beta(2)GPI was significantly higher than that of IgG and IgM aPT. Clinical events accounting for APS occurred in 97 of 130 (75%) IgG a beta(2)GPI positive and in 55 of 101 (54%) IgG a beta(2)GPI negative patients (OR 2.4, 95% CI 1.4 to 4.3, p=0.002). No significant association with clinical events in patients positive for both IgG aPT and IgG a beta(2)GPI as compared to those positive for one or another test was found. When patients negative for both IgG aPT and IgG a beta(2)GPI (LA positive only) were compared with remaining patients, a significantly lower association with clinical events was found (OR=0.4, 95% CI: 0.2 to 0.7, p=0.004). CONCLUSIONS: As compared to IgG a beta(2)GPI, the prevalence of IgG aPT in patients with LA is significantly lower and not associated with the clinical features of APS.

Survey of lupus anticoagulant diagnosis by central evaluation of positive plasma samples.

OBJECTIVE: To determine whether the diagnosis of lupus anticoagulant (LAC) in a large cohort of positive patients was confirmed at a reference laboratory. METHODS: Over a 1-year period, each participating center collected samples from LAC-positive patients. Plasma was filtered and kept deep-frozen until it was sent on dry ice to the reference laboratory by express courier. Centers returned detailed laboratory information and clinical data from each patient. The reference laboratory screened plasma samples by diluted Russell viper venom time (dRVVT) and kaolin clotting time (KCT). When these were prolonged, 1:1 mixing studies were carried out, and confirmatory tests were performed as appropriate. Positive samples were further tested by thrombin time (TT). The presence of heparin was checked by measuring antifactor Xa activity when TT was prolonged. Negative samples were tested by activated partial thromboplastin time using hexagonal phospholipids. RESULTS: Plasma samples from 302 patients from 29 anticoagulation clinics were analyzed. LAC was excluded in 71 samples (24%), because dRVVT and KCT screening test results were normal (34) or reversed to normal by mixing studies (35). The remaining two samples were considered negative because they contained heparin. LAC-negative patients showed different characteristics from those in whom diagnosis was confirmed. They were significantly older (49.7 vs. 45.0 years, P < 0.03), were more often first diagnosed (66% vs. 41%, P < 0.001), and were more frequently judged as mild in LAC potency (60% vs. 25%, P < 0.0001). Moreover, anticardiolipin and anti-beta(2)-glycoprotein I antibody values were more often normal in LAC-negative (82%) than in LAC-positive (42%) samples (P < 0.0001). LAC-positive samples identified by both dRVVT and KCT (146/231, 63%) showed a LAC potency that was significantly stronger than that in samples in which LAC diagnosis was made by a single test. CONCLUSIONS: A false-positive LAC diagnosis is not uncommon across specialized centers. Patients' characteristics and a complete antiphospholipid antibody profile may help to identify these individuals.

Clinical outcome of orthopaedic patients with negative lower limb venography at discharge.

Pharmacological prophylaxis for postoperative venous thromboembolism is generally restricted to the hospital stay. A high incidence of deep vein thrombosis (DVT) and pulmonary embolism presenting after hospital discharge has been reported and thus it has been claimed that pharmacological prophylaxis should be continued after discharge. The aim of this study was to perform a prospective survey to assess the prevalence of clinically overt thromboembolic events in hip surgery patients discharged with a negative venography without further pharmacological prophylaxis. We followed-up 213 patients with negative venography at discharge (105 elective hip replacement and 108 hip fracture patients). 186 patients (87.3%) were re-examined as outpatients one to two months after discharge. Five patients reported symptoms of DVT but the diagnosis was not confirmed by objective testing. The remaining 27 patients (12.7%) were followed up through their family doctor or by telephone call; in these patients the follow-up period ranged from 60 days to 2 years. Twenty-two patients (10.3%) were still alive and reported no signs or symptoms of venous thromboembolism. Three patients (1.4%) died for reasons not correlated with venous thromboembolism. Two patients could not be traced due to geographical inaccessibility; they were still alive after 1 year according to the records of their health care district. The results of our study suggest that in hip surgery patients with negative venography the prevalence of clinically overt thromboembolic events after hospital discharge ranges from 0 to 2.2% (95% C.I.). It is conceivable that the majority of late presenting postoperative DVT actually develop during the hospital stay and become symptomatic after hospital discharge.

Features of thrombi and diagnostic accuracy of impedance plethysmography in symptomatic and asymptomatic deep vein thrombosis.

Impedance plethysmography (IPG) has high sensitivity and specificity in patients with symptomatic deep vein thrombosis (DVT) while it fails to detect asymptomatic DVT. The aim of this study was to determine whether the features of thrombi such as location, size and occlusiveness could explain the different accuracy of IPG in symptomatic and asymptomatic DVT patients. One-hundred and seventeen consecutive outpatients with a clinical suspicion of DVT and 246 consecutive patients undergoing hip surgery were admitted to the study. In symptomatic patients IPG was performed on the day of referral, followed by venography, while in asymptomatic patients IPG was performed as a surveillance programme, followed by bilateral venography. A venography proved DVT was observed in 37% of the symptomatic patients and 34% of the asymptomatic limbs. A significantly higher proportion of proximal DVTs was found in symptomatic patients than in asymptomatic patients (78% vs 46%; p = 0.001). The mean Marder score, taken as an index of thrombus size, was significantly higher in symptomatic patients than in asymptomatic patients (19.0 vs 9.6; p = 0.0001). A significantly higher proportion of occlusive DVTs was observed in symptomatic than in asymptomatic patients (69% vs 36%; p = 0.001). We conclude that the unsatisfactory diagnostic accuracy of IPG in asymptomatic DVT is due to the high prevalence of distal, small and non occlusive thrombi. Such thrombi are unlikely to cause a critical obstruction of the venous outflow and therefore to produce a positive IPG.

Detection of asymptomatic deep vein thrombosis by real-time B-mode ultrasonography in hip surgery patients.

The aim of this study was to prospectively evaluate the accuracy of real-time B-mode ultrasonography in the diagnosis of asymptomatic proximal deep vein thrombosis (DVT) in hip surgery patients. Venography was adopted as the gold standard. We studied 100 consecutive patients undergoing hip surgery: 60 patients for hip fracture and 40 patients for elective hip replacement. Bilateral real-time B-mode ultrasonography was performed prior to bilateral venography. The two diagnostic procedures were performed on the same day by different investigators unaware of the assigned prophylatic regimen for DVT. Compressibility of the vein segment was adopted as the single criterion for DVT. Venography was performed and judged by radiologists unaware of the ultrasonography results. In 13 limbs venography was either impossible to perform or not adequate for judgement. Ultrasonography and an adequate venography was obtained in 187 limbs. A venography proven DVT was observed in 49 limbs (26.2%) and a proximal DVT in 21 limbs (11.2%). All the patients were asymptomatic for DVT. The sensitivity and specificity of real time B-mode ultrasonography for proximal DVT were 57% (95% confidence interval: C.I. 36-80) and 99% (C.I. 99-100), respectively and the positive and negative predictive values were 93% (C.I. 73-100) and 95% (C.I. 91-97), respectively. The sensitivity and specificity for overall DVT were 25% (C.I. 11-38) and 99% (C.I. 97-100), respectively and the positive and negative predictive values were 92% (C.I. 73-100) and 79% (C.I. 76-85), respectively. Our data indicate that real-time B-mode ultrasonography for its high specificity could make venography unnecessary in patients with positive results.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomised, double-blind, placebo-controlled trial of dermatan sulphate for prevention of deep vein thrombosis in hip fracture.

Dermatan sulphate (MF 701) is a natural glycosaminoglycan that catalyses thrombin inhibition by heparin cofactor II. The aim of the study was to evaluate the efficacy and safety of MF 701 for prevention of deep vein thrombosis (DVT) in patients with hip fracture. A randomised, double-blind, placebo-controlled design was used to assess two dose regimens of MF 701 in two consecutive study phases. Treatment was started within 48 h from the trauma and continued for 14 days for non-operated patients or until the 10th postoperative day. Bilateral mandatory venography was used to assess the end-point. Eighty patients were included in the first phase (40 MF 701, 40 placebo). MF 701, 100 mg IM b.i.d., did not reduce incidence of DVT from that on placebo and did not induce any bleeding. In the second phase 126 patients were included, with a randomisation ratio of 2:1 (84 MF 701, 300 mg IM b.i.d., 42 placebo). Bilateral venography was obtained for 110 patients. The incidence of DVT was 64% (23/36) in the placebo group and 38% (28/74) in the MF 701 group (p = 0.01; odds ratio [OR] = 0.34, 95% confidence limits [CL] = 0.15-0.80p; proximal DVTs were 42% (15/36) and 20% (15/74), respectively (p = 0.02; OR = 0.36, CL = 0.15-0.89). No significant differences were found in haemorrhagic complications (2.4% in each group), blood loss from drains, blood transfusions, haemoglobin and haematocrit values. This study is the first demonstration that dermatan sulphate is a clinically effective antithrombotic agent without bleeding effects. It also provides evidence of the biological role of heparin cofactor II.