Antiphospholipid syndrome: long-time research on pathogenic mechanisms has finally lead to new therapeutic strategies.

The antiphospholipid syndrome is characterized by the presence of arterial or venous thrombosis or recurrent miscarriages in a patient with positive laboratory tests for antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant and/or anti-beta2-glycoprotein I). Despite the strong association between antiphospholipid antibodies and thrombosis and obstetric morbidity, their pathogenic role in the development of these clinical features has not been fully elucidated. However, the knowledge of new pathogenic mechanisms might identify novel therapeutic targets and therefore may improve the management of these patients.

Circulating microparticles, lupus anticoagulant and recurrent miscarriages.

Pregnancy is a pro-inflammatory/hypercoagulable state. Impairment of trophoblastic invasion and placental microthrombi are involved mechanisms in the pathogenesis of recurrent miscarriages (RM). Although in RM related to antiphospholipid antibodies (aPL) non-thrombotic mechanism seems to play an important role as well, we focused this review on the thrombotic mechanisms of RM related to aPL. Thus, in cases of RM related to aPL, placental injury produces inflammatory changes in endothelial cells. Endothelial dysfunction has been shown by increased plasma levels of ICAM-1/VCAM-1 and E-selectin. In RM associated with aPL, the thrombogenic mechanisms included different pathways: protein C inhibition, annexin-5 displacement, blocking of beta(2)GP1 anticoagulant activity and tissue factor upregulation. A new marker/causative agent of RM by itself or in relation to lupus anticoagulant (LA) has risen: circulating microparticles. Microparticles are a heterogeneous group of small, membrane-coated vesicles with a diameter of 0.1-1 microm. Microparticles are released from the cellular membrane during cell activation/apoptosis. Exposition of phospholipids in the outer membrane leaflet could explain the role of microparticles in the thrombotic events. Microparticles have been associated with RM. Microparticles are increased in women with RM when compared with healthy pregnant women. A relationship between aPL and activated endothelial cells (EC) occurs, as well as between EC and circulating microparticles. Interestingly, microparticles induced coagulation in vitro via tissue factor, especially in plasmas with LA. Finally, the relationship between EC, microparticles, LA and RM is revised.

Antiphospholipid antibodies: paradigm in transition.

OBJECTIVES: This is a critical review of anti-phospholipid antibodies (aPL). Most prior reviews focus on the aPL syndrome (APS), a thrombotic condition often marked by neurological disturbance. We bring to attention recent evidence that aPL may be equally relevant to non-thrombotic autoimmune conditions, notably, multiple sclerosis and ITP. ORGANIZATION: After a brief history, the recent proliferation of aPL target antigens is reviewed. The implication is that many more exist. Theories of aPL in thrombosis are then reviewed, concluding that all have merit but that aPL may have more diverse pathological consequences than now recognized. Next, conflicting results are explained by methodological differences. The lupus anticoagulant (LA) is then discussed. LA is the best predictor of thrombosis, but why this is true is not settled. Finally, aPL in non-thrombotic disorders is reviewed. CONCLUSION: The current paradigm of aPL holds that they are important in thrombosis, but they may have much wider clinical significance, possibly of special interest in neurology.

Correlation between the potency of a beta2-glycoprotein I-dependent lupus anticoagulant and the level of resistance to activated protein C.

The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies in plasma of patients. It has been published that antibeta2-glycoprotein I (beta2-GPI) antibodies, with lupus anticoagulant activity (LAC), highly correlate with thrombosis. Resistance related to antiphospholipid antibodies against activated protein C (APC) is one of the proposed mechanisms responsible for thrombosis. We investigated a possible correlation between a beta2-GPI-dependent LAC (titration of cardiolipin into an activated partial thromboplastin time-based assay) and increased APC resistance in a population of 22 plasma samples with LAC activity. Eleven plasma samples that displayed a beta2-GPI-dependent LAC also showed increased APC resistance. In contrast, only one of the 11 plasma samples with a beta2-GPI-independent LAC displayed increased APC resistance. In addition, a monoclonal antibeta2-GPI antibody and patient-purified immunoglobulin G (both with LAC activity) were diluted in plasma with/without protein C. Both antibodies only displayed a beta2-GPI-dependent LAC in plasma in the presence of protein C. This indicates that the principle of the beta2-GPI LAC-assay was based on increased resistance against protein C. Surface plasmon resonance analysis was used to investigate binding between APC and beta2-GPI. We observed that beta2-GPI was able to bind APC directly, especially in the presence of a monoclonal antibeta2-GPI antibody. In conclusion, our observations show a direct correlation between a major clinical symptom of antiphospholipid syndrome (thrombosis), a diagnostic assay (beta2-GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC resistance).

The effect of platelet activation on the hypercoagulability induced by murine monoclonal antiphospholipid antibodies.

BACKGROUND: To identify the mechanisms of the hypercoagulability associated with antiphospholipid antibodies, we investigated antibody-mediated platelet activation and interference of antibodies with phospholipid-dependent reactions. DESIGN AND METHODS: We used two murine monoclonal antibodies, one against beta(2)-glycoprotein I (7F6G), the other against prothrombin (28F4). Platelet activation was assessed by phospholipid-related platelet procoagulant activity. Endogenous thrombin potential without activated protein C (ETP(0)) and the activated protein C concentration that reduced the ETP(0) by 50% (IC(50)-APC) were determined by calibrated automated thrombography. RESULTS: Both monoclonal antibodies mimicked the effect of IgG in 11 out of a series of 40 patients with antiphospholipid antibodies in thrombography. In the presence of their target, 7F6G and 28F4 at 200 microg/mL exhibited comparatively low and high binding to platelets and elicited low and high levels of procoagulant phospholipids on platelet surface, respectively. In platelet-poor plasma, these antibodies induced a 1.6 and >12-fold increase in IC(50)-APC, respectively, thus providing evidence for a procoagulant effect independent of platelet activation. The 84% decrease in ETP(0) indicated that 28F4 also displayed an anticoagulant effect. In platelet-rich plasma, this anticoagulant effect was significantly less (23% decrease in ETP(0)), demonstrating that a high increase in procoagulant surfaces by platelet activation significantly antagonizes the anticoagulant effect of antiphospholipid antibodies. In both types of plasma, the inhibition of thrombin generation (reduced ETP(0)) was less than the inhibition of activated protein C activity (increased IC(50)-APC). CONCLUSIONS: Our findings show that platelet activation reinforces the hypercoagulability induced by competition between antiphospholipid antibodies/target complexes and pro- and anticoagulant complexes for phospholipid surfaces.

Laboratory evaluation of the antiphospholipid syndrome.

Antiphospholipid syndrome (APLS) is among the most common acquired blood protein defects that have been identified as leading to thrombosis. This article describes the laboratory diagnosis of APLS, including the detection of lupus anticoagulants, anticardiolipin antibodies, and subtypes of antiphospholipid antibodies.

Postoperative parkinsonism and lupus anticoagulant: a model of autoantibody-mediated neurotoxicity in stress.

PRIMARY OBJECTIVE: Nigrostriatal hypodopaminergism is the fundamental basis in parkinsonism. It may arise secondarily from a variety of disorders but is rarely mentioned shortly after surgery. METHODS AND PROCEDURES: To report the clinical course of five patients who had had symptomatic parkinsonism developed shortly after surgery (lumbar laminectomy, prostatectomy and cholestectomy). Appropriate investigations were done to elucidate their pathogenesis. MAIN OUTCOMES AND RESULTS: There was no remarkable finding of their anesthetic agents, duration of surgery, type of surgery, medical conditions or preoperative screening test. Extensive investigations did not reveal consistent abnormality. However, an abnormal presence of lupus anticoagulant was detected in four patients; primary antiphospholipid antibody syndrome was fulfilled in two of them. The lupus anticoagulant restored to the reference range in another two patients later. Catastrophic antiphospholipid antibody syndrome was not seen. Initially, their parkinsonian symptoms rapidly progressed but slowed down after six months. CONCLUSION: Lupus anticoagulant possesses neurotoxic property and has been found in cases of movement disorder involving with the central dopaminergism. Surgery, a form of traumatic stress, has been reported to bring on lupus anticoagulant and catastrophic antiphospholipid antibody syndrome. These relationships remind a generation or an enhancement of pathognomic autoantibody vulnerable for dopaminergic toxicity, such as lupus anticoagulant or other antiphospholipid antibody.

Life-threatening bleeding in a patient with a lupus inhibitor and probable acquired factor VII deficiency.

We report the case of a 71-year-old man on warfarin for chronic atrial fibrillation presenting with a massive spontaneous soft tissue bleed. Despite reversing the effects of warfarin with large doses of intravenous vitamin K and fresh frozen plasma, bleeding continued, and his prothrombin time and activated partial thromboplastin time remained prolonged. The prothrombin time and activated partial thromboplastin time failed to correct with 50% normal plasma. Further investigations confirmed a lupus inhibitor with low levels of factors II, V, VII and XI. Factor II, V and XI levels normalized, however, when the patient's plasma was diluted 1:16 in buffer, suggesting the lupus inhibitor may have been interfering with these factor assays causing artefactual low results. Factor VII levels remained consistently low at all dilutions. The patient subsequently died following a massive left haemothorax despite surgical intervention and treatment with activated recombinant factor VII concentrate. We presumed the primary problem was bleeding from a local vascular lesion but the patient was never well enough to undergo confirmatory angiography. This case highlights the fact that patients with lupus inhibitors can develop severe haemorrhagic complications, and illustrates the complexities involved in both the investigation and treatment of abnormal bleeding in these patients.

Long-term remission from life-threatening hypercoagulable state associated with lupus anticoagulant (LA) following rituximab therapy.

Rituximab, a chimeric monoclonal CD20 antibody, is useful in the treatment of B-cell lymphomas and certain autoimmune diseases. We report a successful outcome of rituximab for life threatening hypercoagulable state associated with lupus anticoagulant (LA). A 30-year-old woman initially presented 10 years ago with DVT and positive serology for SLE and LA. While on Coumadin, she suffered from recurrent DVT in the legs and arms, pulmonary emboli, Budd-Chiari syndrome, mesenteric vein thrombosis, bone infarcts, recurrent strokes, and chronic ITP. All measures including plasmapheresis and monthly IV cyclophosphamide were of no benefit. She was recently admitted with spontaneous subdural hematoma with INR of 3.8. Upon discontinuation of anticoagulation for surgical drainage, she developed acute abdomen from thrombosis and recurrent DVT. Because she had failed prior standard measures, 4 weekly infusions of rituximab (375 mg/m2) were given following 2 rounds of plasmapheresis. Subsequently, she made a remarkable recovery over the next month and has been free of thrombosis on Coumadin for over 15 months. LA, IgM antibodies to cardiolipin, and B2GP1 were consistently positive. After rituximab therapy, LA became negative and IgM antibodies to cardiolipin decreased and ITP went into remission. Rituximab induced a lasting remission in a woman suffering from life-threatening hypercoagulable state associated with LA. Her clinical remission was associated with disappearance of LA.

[The effects of lupus anticoagulant on pulmonary thromboembolism].

OBJECTIVE: To evaluate the effects of lupus anticoagulant (LA) on pulmonary thromboembolism (PTE). METHODS: Thirty-eight patients with PTE (17 massive and 21 submassive) and 30 healthy adults were studied. Russell's viper venom time (RVVT) was used to examine the ratio of LA (LAR), and a colorimetric method was used to detect the activity of plasma protein C (PC:A) and radioimmunoassay (RIA) was employed to measure the level of plasma thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). RESULTS: Compared with the normal group, LAR, TXB(2) and TXB(2)/6-keto-PGF1alpha showed significant increase in the massive PTE and the submassive PTE groups (P < 0.01), and the levels were higher in the massive group than in the submassive group (P < 0.01). Both groups showed significant decrease in PC:A and 6-keto-PGF1alpha compared with the normal group (P < 0.01). CONCLUSIONS: LA can increase TXB(2)/6-keto-PGF1alpha and decrease PC:A in patients with PTE. It is suggested that there may be an association between the increase of LAR and the presence of PTE.

Transient lupus anticoagulant: an unusual cause of bruising in children.

A child presented with excessive bruising and prolonged activated partial thromboplastin time. Mixing studies in plasma were positive for phospholipid dependence of the anticoagulant, confirming a diagnosis of lupus anticoagulant. Factor II level was reduced. Laboratory findings normalised after three months, with spontaneous resolution of bruising. This case demonstrates a transient antiphospholipid antibody syndrome as a rare presentation of bleeding diathesis in a previously healthy child, and should be considered in children with new onset bruising and prolonged activated partial thromboplastin time.

Lupus anticoagulant associated with transient severe factor X deficiency: a report of two patients presenting with major bleeding complications.

Acquired factor X (FX) deficiency is rare, but has been reported in diverse disease states, including systemic amyloidosis and respiratory infections. FX deficiency associated with lupus anticoagulant (LA) and a bleeding diathesis has not been previously reported. We report two patients both of whom presented with a severe bleeding diathesis after a preceding respiratory infection due to isolated FX deficiency associated with a LA. The FX deficiency and LA were transient. We conclude that patients with LA may rarely present with severe acquired FX deficiency. This may be another mechanism whereby patients with antiphospholipid antibodies present with bleeding complications.