Doris Barcellona

Clinical course of high‐risk patients diagnosed with antiphospholipid syndrome

See also Galli M. The antiphospholipid triangle. This issue, pp 234–6.

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

Summary.  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‐β2‐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.

A Comparison of Lupus Anticoagulant–Positive Patients With Clinical Picture of Antiphospholipid Syndrome and Those Without

Among antiphospholipid antibodies, Lupus Anticoagulant (LAC) is recognized as the strongest risk factor for thromboembolic events or pregnancy morbidity.1 The presence of LAC in a subject with previously documented thromboembolism or a significant history of pregnancy loss defines the Antiphospholipid Syndrome (APS). Some patients, however, are diagnosed with LAC without ever having experienced previous vascular thrombosis or pregnancy morbidity. The antiphospholipid antibody profiles of LAC positive patients with or without associated clinical features of APS have been evaluated by us in a multicenter study. Centers affiliated with Italian Federation of Thrombosis Centers (FCSA) were invited to identify consecutive LAC positive patients diagnosed over a 1-year period. Three hundred twenty-one recruited patients were contacted and after giving informed consent they underwent testing for LAC after at least 12 weeks from the first one using routine laboratory procedures. LAC was not confirmed by Thrombosis Centers in 19 patients (6 were …

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.

Point-of-care (POCT) prothrombin time monitors: is a periodical control of their performance useful?

INTRODUCTION Point-of-care testing (POCT) prothrombin time monitors are now widely used to monitor oral anticoagulant treatment. Although portable coagulometers are extremely easy to use, checking the quality of their performance presents some difficulties. MATERIALS AND METHODS The aims of this study were to investigate on a quarterly basis the performance of 95 Coagucheck S assigned to 99 anticoagulated patients at home. This was done checking the monitors versus a reference coagulometer in the laboratory at our Thrombosis Centre (TC). The other aims were to carry out an external quality assessment employing different sets of INR certified plasmas with 5 different ranges of anticoagulation and to assess the performance of the different lots of strips employed by the patients during the study. RESULTS No difference between the PT INR obtained with both the systems at the first quarterly check was noted but a significant difference was found when the two systems were compared at the second and third quarterly checks. The Bland-Altman test showed increased disagreement between the first and the third controls. The percentage of INR values that showed a difference of more or less than 0.5 INR units in the PT values performed with both the systems was: 1.0% (first control), 7.5% (second control) and 11.5% (third control) (Chi-Square: 8.315, p=0.0156). Lots with differences higher than 10% in terms of +/- 0.5 INR Units at the first, second and third controls were 16%, 20.8% and 61%, respectively. Seven monitors (7.3%) failed to test one or two of the INR certified plasmas of one set but performed well using a second set of plasmas. Three monitors (3.1%) failed to test two sets of plasmas but performed well using a different lot of strips (from 279A to 483A). One monitor (1%) gave unsatisfactory results with different sets of plasmas and strips. All the other PT INR obtained with the monitors fell well within the different ranges of the INR certified plasmas. CONCLUSIONS Anticoagulated patient in self-testing or self-management should periodically bring their portable coagulometer to a reference Thrombosis Centre especially when the lot of strips have to be changed. The role of Thrombosis Centre appears therefore crucial in this regard.

Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis

Several studies have tried to clarify the role of polymorphism 4G/5G of the PAI-1 gene in venous thromboembolism without reaching any final conclusion. It has been demonstrated that this polymorphism may induce an increased risk for venous thromboembolism (VTE) in patients with thrombophilic defects. We studied the association of prothrombin mutation G20210A with 4G/5G polymorphism in 402 VTE patients and 466 healthy controls. Patients affected by prothrombin mutation G20210A, with or without the concomitant presence of allele 4G, had a 3.7 thrombotic risk (C.I. 95% 2.3-6.0; p<0.0001). Moreover, genotype 4G/4G is a mild risk factor for VTE, irrespectively of whether the prothrombin mutation was present. Logistic regression analysis showed that patients carrying the G20210A prothrombin mutation with allele 4G gave an odds ratio for VTE of 6.1 (C.I. 95% 3.2-11.4; p<0.001). The risk increased up to 13.0 (C.I. 95% 3.0-60.4; p<0.001) when we considered the association of the prothrombin mutation with genotype 4G/4G. The G20210A mutation without allele 4G (5G/5G) was not a risk factor for VTE. In conclusion, we believe that patients affected by VTE with concomitant presence of the G20210A prothrombin mutation could be tested for genotype 4G/4G to better define their thrombotic risk.

Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Telemedicine can improve the quality of oral anticoagulation using portable devices and self-testing at home

Point-of-care testing (POCT) devices can be used to monitor anticoagulant therapy. We compared patients being monitored at home by self-testing using a POCT device and telemedicine support with a previous period of conventional monitoring at a Thrombosis Centre. A total of 114 anticoagulated patients participated. The number of blood checks (INR) was significantly higher in the home monitoring group and the interval between checks was significantly shorter. The percentage of missed INR checks was significantly higher during the conventional monitoring period compared with home monitoring. Patients were divided into two groups on the basis of the time spent within the therapeutic range (TTR) during conventional monitoring: the unstable group had TTR<70% and the stable group had TTR ≥70%. In the unstable group there was a significant increase in TTR with home monitoring: 63% to 68% (P < 0.001) while in the stable group there was no significant change (77% to 75%). The study showed that oral anticoagulation management by means of self-testing is suitable and safe.

High frequency of inadequate test requests for antiphospholipid antibodies in daily clinical practice

Abstract Background: We have empirically noted that many physicians routinely request anti-phospholipid antibodies (aPL) without a correct clinical indication. The aim of this study was to evaluate retrospectively whether aPL testing at our Thrombosis Centre was justified. Methods: Medical records from 520 subjects for aPL screening tests for various clinical conditions were reviewed. The aPL screening tests were: lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL) and anti-β2 glycoptotein I (aβ2 GPI). Requests for aPL screening were divided into justified, potentially justified or not adequately justified. Results: aPL testing requests were considered justified in 358 (69%) patients, potentially justified in 66 (12.6%) and not adequately justified in 96 (18.4%). LA was positive in 65 (18%) of justified requests and in only one (1%) of the 96 potentially justified requests. None of the 66 not adequately justified for aPL testing was positive for LA. aβ2 GPI was positive in 63 (17.6%) of the 358 justified, in four (6%) of the 66 potentially justified and in five (5.2%) of the 96 not adequately justified requests; aCL IgG were positive in 59 (16.4%) of the 358 justified and in five (7.5%) and six (6.2%) of the potentially justified and not adequately justified requests, respectively. The presence of the triple aPL positivity was found exclusively in the justified requests. Conclusions: This study suggests that requests for aPL tests should be addressed more adequately. This work could be an example of how to focus attention on requests for laboratory tests especially on the basis of valid clinical criteria before the analyte is measured.

Inhibition of blood coagulation activation and oral anticoagulants in patients with mechanical heart valve prostheses

Oral anticoagulants are widely used for preventing thromboembolic events in many pathological conditions, such as mechanical or biological heart valve prosthesis, atrial fibrillation, deep vein thrombosis and post-myocardial infarction (1). Particularly, the intensity of anticoagulation to be induced in patients with mechanical heart prosthesis is not well established. In fact, the Dutch Thrombosis Policy recommends deep anticoagulation (3.6-4.8 INR) irrespective of whether the prosthesis is aortal or mitral (2). In contrast the Consensus Committee for antithrombotic therapy in patients with mechanical prosthetic valves, with North American thromboplastins, suggests a therapeutic range between 2.2 and 3.3 INR for both ball and tilt disk prosthesis (3). Again, the guidelines on oral anticoagulation published on behalf of the British Society for Hematology recommend a target of between 3 and 4.5 for mechanical heart valves (1). But is deeper anticoagulation more effective in the biochemical inhibition of the coagulation cascade ? Is there any difference between aortal and mitral prosthesis considering that a higher thromboembolic risk may be present in the latter due to hypercoagulability secondary to atrial fibrillation and blood stagnation ? For this purpose we chose to measure prothrombin F 1+2 peptide that is cleaved by factor Xa from the prothrombin molecule, since it has recently been shown that F 1+2 is reduced during oral anticoagulants (4).