Impaired fibrinolysis as an essential contribution to thrombosis in patients with lupus anticoagulant

Lupus anticoagulants (LA) are IgG or IgM antibodies against phospholipids which in vivo represent an important thrombophilic factor despite their in vitro anticoagulant activity. We investigated the fibrinolytic system of 20 patients with connective tissue disease and positive LA, compared to a control group of 24 age- and disease-matched patients without LA. There was no statistically significant difference of alpha 2-antiplasmin, plasminogen, fibrinogen, t-PA activity, D-dimers and heparin cofactor II, between the two groups. Although t-PA was uniformly low in both groups, plasminogen activator inhibitor activity (PAI) was significantly higher in LA cases (p less than 0.001). Increased PAI levels represent an inhibitory factor of the fibrinolytic defense mechanism, which together with other functional deviations may contribute to the thrombophilic tendency of LA patients.     

Neurology and the lupus anticoagulant

The lupus anticoagulant, an immunoglobulin of the IgG or IgM class, is one of a group of antiphospholipid antibodies. Although an anticoagulant in vitro, its action in vivo is that of a procoagulant. This procoagulant activity may involve many organ systems including the nervous system. Thus far cerebral thrombosis, spinal thrombosis, chorea and Guillain-Barré syndrome have been described in association with the lupus anticoagulant. Although the lupus anticoagulant is an uncommon cause of neurological disease, it must be considered, especially in a setting of a prolongation of the common pathway of coagulation, thrombosis and other autoimmune phenomena.     

Impairment of the protein C anticoagulant pathway in a patient with systemic lupus erythematosus, anticardiolipin antibodies and thrombosis

We have identified an inhibitor of the protein C anticoagulant pathway in the plasma of a patient with systemic lupus erythematosus and a history of recurrent deep vein thrombosis, fetal wastage, and seizures. The patient's plasma contained anticardiolipin antibodies as well as a weak lupus anticoagulant. Examination of this patient's plasma revealed normal levels of protein C and protein S antigen, normal levels of functional protein C, as well as essentially normal levels of every blood coagulation factor. In a modified prothrombin time assay, the activated protein C-mediated prolongation of the clotting time observed in normal plasma was not observed in this patient's plasma. Gel permeation chromatography of the patient's plasma revealed that the inhibitory material was a high molecular weight protein that coeluted with the IgM peak. The inhibitor did not appear to circulate as a complex with protein C, since the inhibitor could easily be separated from protein C during fractionation procedures, and did not interfere with the activation of protein C in plasma as assessed by a functional amidolytic assay. Our findings suggest that the recurrent thrombotic episodes observed in this patient may have occurred as a result of the patient's antiphospholipid antibody neutralizing specific phospholipids essential for the full expression of the anticoagulant activity of activated protein C.     

Cerebrovascular ischemia associated with lupus anticoagulant

The lupus anticoagulant, an acquired circulating serum gamma-globulin, prolongs all phospholipid-dependent coagulation tests. Recent associations of the lupus anticoagulant and focal cerebral and/or ocular ischemia have been made. We present 5 cases of lupus anticoagulant-associated cerebrovascular ischemia and review all reported cases for the first time. Clinical spectra, cerebral angiographic findings, associated conditions, and response to therapy are presented. Typical features include a relatively young age (mean 39 years), female preponderance, transient ischemic attacks (including amaurosis fugax) or stroke, and normal or large vessel occlusions on angiography. Commonly associated conditions were systemic lupus erythematosus (34%), noncerebral venous thrombosis (31%), hypertension (28%), false-positive VDRL (28%), and spontaneous abortions (22%). Four of our 5 patients (all without systemic lupus erythematosus) and 11 of the 20 (55%) patients in the literature without systemic lupus erythematosus had other definite stroke risk factors coexisting. Response to therapy was highly variable, with no clear beneficial effect of corticosteroids.     

Epilepsy associated with lupus anticoagulant.

INTRODUCTION: Lupus anticoagulant (LA) is commonly present in patients with systemic lupus erythematosus (SLE) who present with an ischemic cerebral stroke. Reports have noted the presence of LA in patients with epilepsy who do not have SLE. These patients are usually elderly, and it has been postulated that their epilepsy is due to subclinical ischemic infarcts. METHODS: Two cases are presented in young patients (age < 35 years) who developed epileptic seizures and were LA positive. These patients did not have SLE or have cerebral infarcts that could explain the presence of their seizures.RESULTS: A 28-year-old woman was admitted for aortic insufficiency and new onset seizures. The clinical history, physical examination and magnetic resonance imaging did not reveal an antecedent cortical ischemic event. Serological testing revealed the presence of LA. The second patient was a 33-year-old man with medically intractable epilepsy in whom serological testing revealed the presence of LA. The clinical history, physical examination, and MRI did not reveal any evidence of an antecedent ischemic event. Neither patient had SLE. CONCLUSIONS: In young patients without SLE and cerebral infarcts, LA may be associated with epileptic seizures.     

Ischemic pituitary apoplexy associated with the lupus anticoagulant

PURPOSE: To report a case of ischemic pituitary apoplexy secondary to a hypercoagulable state following elective orthopedic surgery. DESIGN: Observational case report. METHODS: A 48-year-old Caucasian man underwent an uneventful, left-sided total hip replacement and corrective osteotomy of the proximal femur. Two days post-operative, he developed a frontal headache and blurred vision in both eyes. RESULTS: Ophthalmic examination revealed right VIth cranial nerve palsy. Imaging studies indicated pituitary apoplexy with a large hypodense pituitary lesion with widening of the sella turcica. Laboratory findings included positive lupus anticoagulant, a normal prothrombin time (PT), and an elevated activated partial thromboplastin time (aPTT). Five days after the initial symptoms, a transsphenoidal pituitary resection was performed. At a 6 months follow-up, the VIth nerve paresis was completely resolved. CONCLUSIONS: This case describes ischemic pituitary apoplexy associated with a pre-operatively elevated aPTT and positive lupus anticoagulant. This is the first report, to our knowledge, of atypical apoplexy concurrent with antiphospholipid (aPL) antibodies following an uneventful surgery. The results we obtained on this patient suggest that an associated hypercoaguable state may increase the risk of thrombosis following elective orthopedic surgery.     

Ischemic stroke in a girl with lupus anticoagulant

A 16-year-old girl developed right middle cerebral artery infarction and deep venous thrombosis of the lower extremities in association with circulating lupus-like anticoagulant. Currently, she is functionally independent with no further vascular insults and is being treated with sodium warfarin. This patient illustrates that cerebral ischemia can occur in association with lupus anticoagulant in the pediatric population. This entity should be considered and appropriate screening tests performed in young patients with unexplained ischemic stroke or transient ischemic attack.     

Prolonged bleeding time in patients with lupus anticoagulant.

Platelet adhesion to collagen under flow conditions was studied in 18 patients with lupus anticoagulant, seven of which showed a prolonged bleeding time in the presence of a normal platelet count. The effect of patient plasma, IgG and purified anticardiolipin antibodies on platelet adhesion was also examined. We found a significant reduction of platelet adhesion in patients with lupus anticoagulant, which was more evident in patients with prolonged bleeding time. This platelet adhesion defect could be attributed to a plasma factor. In fact, patients' platelets regained normal adhesion when mixed with normal plasma, whereas controls' platelets showed abnormal adhesion in the presence of patient plasma. A causative role of antiphospholipid antibodies was demonstrated in experiments using purified immunoglobulins and anticardiolipin antibodies.     

Increased monocyte procoagulant activity independent of the lupus anticoagulant in patients with systemic lupus erythematosus

Monocytes can play a role in the activation of coagulation via increased procoagulant activity (PCA). We investigated the level of monocyte PCA in 19 patients with systemic lupus erythematosus (SLE), given the high rate of thrombotic events in this condition. Nine of these subjects also presented the lupus anticoagulant (LA). The PCA generated by patient monocytes was significantly higher than control values and was identified as tissue factor-like. Moreover, the number of monocytes with membrane-associated D dimer, a parameter which we have shown to be correlated with the PCA expressed in vitro by endotoxin-activated monocytes, was also significantly increased. Serum from both groups of patients (i.e. SLE and SLE + LA) stimulated the generation of PCA by control monocytes. By contrast, purified IgG from both patient groups had the same effect as control IgG on PCA generation by control monocytes. The nature of the stimulating agent in the serum was not identified. In conclusion, increased monocyte PCA may account for the increased incidence of thrombosis in SLE patients, although other, superimposed, factors would appear to exist in SLE + LA patients, given the higher incidence of thrombosis in this subgroup.     

Cardiogenic brain embolism and lupus anticoagulant

The lupus anticoagulant, an acquired immunoglobulin associated with an increased tendency for thrombosis, has been linked to the occurrence of cerebral ischemia presumably related to in situ thrombosis. Cardioembolic cerebral ischemic events have rarely been reported. We encountered 2 patients with focal cerebral ischemia, substantial mitral valvular masses, and a circulating lupus anticoagulant. In each, diagnostic evaluation supported a cardioembolic etiology. These findings illustrate the need for evaluating patients with cerebral ischemic events for a cardioembolic source when a circulating lupus anticoagulant is present.     

Antibodies to factor XII associated with lupus anticoagulant

Falsely low levels of factor XII (FXII) have been documented in patients who are lupus anticoagulant positive (LA+). In addition, we have previously noted a surprisingly high incidence (20.9%) of apparently true FXII deficiency in patients who were LA+. We have hypothesised that this may be partly due to the presence of antibodies to FXII. The aim of the present study was to investigate whether LA+ patient plasmas contain antibodies directed either against FXII or FXII in association with phospholipids. Plasma samples from 60 blood donors, all LA negative, and 51 LA+ patients were tested using ELISA assays employing purified FXII, phosphatidylserine (PS) and phosphatidylethanolamine (PE). We have identified seven patients whose plasma contained either IgG or IgM that reacted with purified FXII in the absence of PS or PE. When PS was included in the assay system four additional patient plasmas were shown to contain either IgG or IgM that reacted with FXII. The plasma of one patient contained IgG that reacted with FXII both in the presence and absence of PS. There was no reactivity to FXII with either IgG or IgM when PE was included in the assay system. Affinity purified IgG from three patients whose plasma reacted with FXII in the ELISA assay in the absence of PS, gave a positive reaction in an immunoblot assay. These results suggest that FXII antibodies are present in a significant proportion of LA+ patients and may lead to an erroneous diagnosis of FXII deficiency.     

Cerebral ischemia in the presence of lupus anticoagulant

Two patients with manifestations of cerebral ischemia were found to have a circulating coagulation inhibitor. This immunoglobulin, termed lupus anticoagulant, results in a prolonged partial thromboplastin time. Paradoxically, it is usually associated with a thrombotic tendency rather than a bleeding diathesis. It is most commonly found in systemic lupus erythematosus, which our patients did not have. These two patients represent the interesting phenomenon of cerebral ischemia in the presence of an endogenous inhibitor of coagulation.     

Premature stroke in a family with lupus anticoagulant and antiphospholipid antibodies

Lupus anticoagulant and antiphospholipid antibodies are associated with thromboembolic phenomena in individuals both with and without systemic lupus erythematosus. A 32-year-old woman (the index case) with lupus anticoagulant, multiple cerebrovascular events, and a family history of premature stroke raised the possibility of a familial diathesis. Histories or interviews, examinations, and blood tests were obtained for 23 members of four generations of her family. Four individuals had suffered strokes and three more had suffered neurologic symptoms. Two living individuals who had suffered strokes, two individuals with neurologic symptoms, and five asymptomatic individuals had antiphospholipid activity in their blood. In addition, a cousin of the index case was found to have systemic lupus erythematosus and antiphospholipid activity. Elevated concentrations of von Willebrand factor antigen were found associated with some positive lupus anticoagulant assays, the highest concentrations in the two individuals with stroke. The characteristic presentation of the index case and her good response to treatment suggests that further studies of families in whom antiphospholipid antibodies may represent a risk factor for stroke is worthwhile.     

Recurrent ischemic attacks in two young adults with lupus anticoagulant

Two young adults with lupus anticoagulant had multiple attacks of cerebrovascular ischemia in different arterial territories. Cerebral angiography was normal. One patient had a new episode during anticoagulant therapy, but has remained asymptomatic on antiplatelet treatment. In the other, further events occurred during treatment with platelet-inhibiting drugs, but there have been no recurrences with adequate anticoagulant therapy. Lupus anticoagulants are possible causes of otherwise unexplained thromboembolic events. Due to the variable mode of action of these immunoglobulins, platelet-inhibiting drugs may in some cases be considered as a prophylactic alternative to anticoagulant treatment.     

Lupus anticoagulant and thrombosis following Henoch-Schonlein purpura

A male adolescent developed a sinovenous thrombosis 4 weeks following a Henoch-Schonlein purpura episode. A hypercoagulation evaluation revealed a positive lupus anticoagulant. This suggests an association between Henoch-Schonlein purpura and antiphospholipid antibody syndrome and is the first report of sinovenous thrombosis after Henoch-Schonlein purpura that was likely due to elevated antiphospholipids. Children who develop Henoch-Schonlein purpura with neurologic features including headache should be evaluated for sinovenous thrombosis and a hypercoagulable state.     

Brain stem infarction, systemic lupus erythematosus and circulating lupus anticoagulant

A 30 year old man admitted with a brain stem infarct presented with intellectual deterioration. A diagnosis of systemic lupus erythematosus (S.L.E.) was based on the presence of five A.R.A. criteria :photosensitivity, arthralgia, leukopenia and thrombopenia, false positive syphilitic serology, antinuclear factors on immunofluorescence. A lupus type circulating anticoagulant (L.C.A.) was no longer detected after corticotherapy. This appears to be a case of the "hematologic" form of S.L.E. in which the presence of L.C.A. predisposes towards thrombosis, not only of veins--which is typical--but also of arteries. These may be isolated and reveal the underlying disease as in the present case. The L.C.A. is an antibody possessing antiphospholipid specificity which explains the anticoagulant action in vitro and the thrombogenic effect in vivo. Some authors consider this to be sufficient justification for administration of anticoagulants and/or antiplatelet agents, but corticotherapy may be effective.