High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there?

BACKGROUD: COVID-19 coagulopathy linked to increased D-dimer levels has been associated with high mortality (Fei Z et al. in Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England) 395(10229):1054-62, 2020). While D-dimer is accepted as a disseminated intravascular coagulation marker, rotational thromboelastometry (ROTEM) also detects fibrinolysis (Wright FL et al. in Fibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection. J Am Coll Surg (2020). Available from https://pubmed.ncbi.nlm.nih.gov/32422349/ [cited 14 Jun 2020]; Schmitt FCF et al. in Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care 9(1):19, 2019). We describe the ROTEM profile in severely ill COVID-19 patients and compare it with the standard laboratory coagulation test. METHODS: Adult patients diagnosed with COVID-19 admitted to the ICU were prospectively enrolled after Ethics Committee approval (HCB/2020/0371). All patients received venous thromboembolism prophylaxis; those on therapeutic anticoagulation were excluded. The standard laboratory coagulation test and ROTEM were performed simultaneously at 24-48 h after ICU admission. Sequential organ failure assessment (SOFA), disseminated intravascular coagulation (DIC) and sepsis-induced coagulopathy (SIC) scores were calculated at sample collection. RESULTS: Nineteen patients were included with median SOFA-score of 4 (2-6), DIC-score of 1 (0-3) and SIC-score of 1.8 (0.9). Median fibrinogen, D-dimer levels and platelet count were 6.2 (4.8-7.6 g/L), 1000 (600-4200 ng/ml) and 236 (136-364 109/L), respectively. Clot firmness was above the normal range in the EXTEM and FIBTEM tests while clot lysis was decreased. There was no significant correlation between ROTEM or D-dimer parameters and the SOFA score. CONCLUSION: In COVID-19 patients, the ROTEM pattern was characterized by a hypercoagulable state with decreased fibrinolytic capacity despite a paradoxical increase in D-dimer levels. We suggest that, in COVID-19 patients, the lungs could be the main source of D-dimer, while a systemic hypofibrinolytic state coexists. This hypothesis should be confirmed by future studies.

Total circulating microparticle levels are increased in patients with deep infiltrating endometriosis.

STUDY QUESTION: Are the levels of total circulating cell-derived microparticles (cMPs) and circulating tissue factor-containing microparticles (cMP-TF) increased in patients with endometriosis? SUMMARY ANSWER: The levels of total cMP, but not cMP-TF, were higher in patients with endometriosis, and these were attributed to higher levels in patients with deep infiltrating endometriosis (DIE). WHAT IS KNOWN ALREADY: Previous studies have reported elevated levels of total cMP in inflammatory conditions as well as higher levels of other inflammatory biomarkers in endometriosis. Increased expression of tissue factor (a transmembrane receptor for Factor VII/VIIa) in eutopic and ectopic endometrium from patients with endometriosis has been described. There is no previous data regarding total cMP and cMP-TF levels in patients with endometriosis. STUDY DESIGN, SIZE, DURATION: A prospective case-control study including two groups of patients was carried out. The E group included 65 patients with surgically confirmed endometriosis (37 with DIE lesions) and the C group comprises 33 women without surgical findings of any form of endometriosis. Patients and controls were recruited during the same 10-month period. Controls were the next patient without endometriosis undergoing surgery, after including two patients with endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Venous blood samples for total cMP and cMP-TF determinations were obtained at the time of surgery, before anesthesia at a tertiary care center. To assess total cMP, an ELISA functional assay was used and cMP-TF activity in plasma was measured using an ELISA kit. MAIN RESULTS AND THE ROLE OF CHANCE: Total cMP levels in plasma were higher in the E group compared with the C group (P < 0.0001). The subanalysis of endometriosis patients with DIE or with ovarian endometriomas without DIE showed that total cMP levels were higher in the DIE group (P = 0.001). There were no statistically significant differences in cMP-TF levels among the groups analyzed. LIMITATIONS, REASONS FOR CAUTION: This is a preliminary study in which the sample size was arbitrarily decided, albeit in keeping with previous studies analyzing cMP in other inflammatory diseases and other biomarkers in endometriosis. The control group included patients with other pathologies as well as healthy controls, and blood samples were taken at different phases of the cycle. WIDER IMPLICATIONS OF THE FINDINGS: Elevated total cMP levels in DIE patients may reflect an inflammatory and/or procoagulant systemic status in these patients. Further studies are warranted to confirm our findings and to assess the role of cMP levels in the pathophysiology of DIE. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by a grant from FIS-PI11/01560 and FIS-PI11/00977 within the 'Plan Nacional de I + D + I' and co-funded by the 'ISCIII-Subdirección General de Evaluación' and 'Fondo Europeo de Desarrollo Regional (FEDER)' and by the grant 'Premi Fi de Residència Emili Letang 2015' from the Hospital Clínic of Barcelona. The authors have no competing interests to disclose.

Higher levels of procoagulant microparticles in women with recurrent miscarriage are not associated with antiphospholipid antibodies.

STUDY QUESTION: Are the levels of circulating cell-derived microparticles (cMPs) in patients with recurrent miscarriage (RM) associated with the antiphospholipid syndrome (APS)? SUMMARY ANSWER: cMPs in women with RM are not associated with antiphospholipid antibodies (aPLs). WHAT IS KNOWN ALREADY: Previous studies have focused on cMP levels in RM patients. Most studies have shown higher levels of cMPs in RM patients whereas others have reported lower levels. Data regarding cMPs in patients with the APS are scanty in the literature. STUDY DESIGN, SIZE, DURATION: A case-control study including three groups of patients. A total of 154 women were prospectively recruited from September 2009 to October 2013. Four patients refused to participate. The APS group consisted of 50 women that had been previously diagnosed with primary APS and had had ≥3 consecutive first trimester miscarriages. The uRM group included 52 couples with ≥3 consecutive first trimester miscarriages of unknown etiology. The fertile control (FER) group was composed of 52 healthy fertile women with no history of pregnancy losses. Miscarriage was defined as intrauterine pregnancy loss at <10 weeks' size on ultrasound. PARTICIPANTS/MATERIALS, SETTING, METHODS: Venous blood samples for coagulation studies and cMP determinations were obtained. All patients underwent a thrombophilia study. MAIN RESULTS AND THE ROLE OF CHANCE: cMP levels were significantly higher in the APS and uRM groups versus the FER group (P < 0.0001 and P = 0.009, respectively) (cMP number × 10(3)/ml plasma [mean ± SD]: APS: 18.5 ± 13.6; uRM: 16.3 ± 13.8; FER: 9.7 ± 4.6). There were no statistically significant differences in cMP levels between the APS and uRM groups. LIMITATIONS, REASONS FOR CAUTION: The sample size was arbitrarily decided according to previous studies analyzing cMPs in RM patients. Different cMP subtypes were not investigated. WIDER IMPLICATIONS OF THE FINDINGS: The present study adds further data on the subject showing that patients with RM, irrespective of testing positive for aPLs, have increased levels of cMPs compared with healthy fertile controls. The presence of elevated cMPs in RM women may reflect an ongoing systemic pathological, albeit asymptomatic, status that can become deleterious in the setting of pregnancy. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by grant from FIS-PI11/01560 within the 'Plan Nacional de I+D+I' and co-funded by the 'ISCIII-Subdirección General de Evaluación' and the 'Fondo Europeo de Desarrollo Regional (FEDER)'. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Reduced ADAMTS13 activity is associated with thrombotic risk in systemic lupus erythematosus.

BACKGROUND: Severe deficiency of ADAMTS13 activity leads to von Willebrand factor (VWF) ultralarge multimers with high affinity for platelets, causing thrombotic thrombocytopenic purpura. Other pathological conditions with moderate ADAMTS13 activity exhibit a thrombotic risk. We examined the ADAMTS13 activity in systemic lupus erythematosus (SLE) and its value as a thrombotic biomarker. METHODS: ADAMTS13 activity, VWF antigen and multimeric structure, and vascular cell adhesion molecule 1 (VCAM-1) were measured in plasma samples from 50 SLE patients and 50 healthy donors. Disease activity (systemic lupus erythematosus disease activity index; SLEDAI) and organ damage (systemic lupus international collaborating clinics) scores, thrombotic events, antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPLs) were registered. RESULTS: SLE patients showed decreased ADAMTS13 activity and high VWF levels compared with controls (66 ± 27% vs. 101 ± 8%, P < 0.01, and 325 ± 151% vs. 81 ± 14%, P < 0.001). VCAM-1 levels were higher in SLE patients (P < 0.05). Considering three groups of SLE patients depending on ADAMTS13 activity (>60%, 60-40% and <40%), comparative analysis showed significant association between ADAMTS13 activity and SLEDAI (P < 0.05), presence of aPLs (P < 0.001), APS (P < 0.01) and thrombotic events (P < 0.01). Reduced ADAMTS13 activity together with increased VWF levels were especially notable in patients with active disease and with aPLs. CONCLUSION: ADAMTS13 activity, in combination with other laboratory parameters, could constitute a potential prognostic biomarker of thrombotic risk in SLE.

Serological autoimmune profile of systemic lupus erythematosus in deep and non-deep endometriosis patients.

OBJECTIVE: Several studies have reported a high prevalence of autoimmune diseases such as systemic lupus erythematosus (SLE) in endometriosis patients. The aim of this study was to evaluate the SLE autoimmune antibody profile in patients with deep (DE) and non-deep endometriosis (Non-DE). MATERIALS AND METHODS: Four groups of premenopausal patients were evaluated: patients with DE (n = 50); patients with ovarian endometriomas (Non-DE; n = 50); healthy patients without endometriosis (C group; n = 45); and SLE patients without endometriosis (SLE group; N = 46). Blood samples were obtained and the standard SLE autoimmune profile was evaluated in all patients. Pain symptoms related to endometriosis and clinical SLE manifestations were also recorded. RESULTS: The DE group presented a statistically significant higher proportion of patients with antinuclear antibodies (ANA) (20%) compared to the Non-DE group (4%) and C group (2.2%). Levels of complement were more frequently lower among DE and Non-DE patients although differences did not reach statistical significance. Similarly, anti-dsDNA antibodies and anticoagulant lupus were positive in more patients of the DE group but did not reach statistical significance. The DE group complained of more arthralgia and asthenia compared to the Non-DE and C groups. CONCLUSIONS: The results of this study showed higher positivity of ANA and greater arthralgia and asthenia in patients with DE compared with Non-DE patients and healthy controls, suggesting that they may have a higher susceptibility to autoimmune diseases and present more generalized pain.

Idiopathic sudden sensorineural hearing loss: classic cardiovascular and new genetic risk factors.

BACKGROUND: The main causative process in idiopathic sudden sensorineural hearing loss (iSSNHL) has yet to be explained or demonstrated. The clinical picture supports vascular involvement, but obvious limitations of inner ear study make this difficult to corroborate. OBJECTIVES: To determine the role of thrombophilic genetic variants that may affect platelet function and to assess the cardiovascular risk profile in a cohort of patients with iSSNHL. PATIENTS AND METHODS: 118 Caucasian patients with iSSNHL were recruited from the same geographical area and enrolled prospectively in this study. Clinical data were obtained for each patient. Polymorphisms of the platelet glycoprotein subunit IIIa gene, ITGB3 (PLA1/A2, rs5918), and of the platelet glycoprotein subunit Ia gene, ITGA2 (C807T, rs1126643) were analyzed. A control group of 161 age- and gender-matched healthy individuals from the same geographical area was recruited for genetic comparisons. In order to determine the cardiovascular risk profile of each patient and of our cohort, a cross-sectional assessment was performed by means of a calibrated Framingham coronary heart disease risk scale. Risk factor proportions were compared to those recommended in European guidelines for coronary prevention, which are also based on the Framingham function. RESULTS: A significantly high prevalence of the 807T allele of platelet glycoprotein subunit Ia was found in patients compared to controls. There was a significant correlation between the 807TT homozygous genotype and a low probability of recovery. The PLA1/A2 polymorphism of platelet glycoprotein subunit IIIa was not associated with recovery, with a similar genotype prevalence being found in patients and controls. In terms of cardiovascular risk profile, patients did not present an excess of baseline coronary risk factors compared to the general population in the same geographical area. CONCLUSIONS: Patients with iSSNHL had a higher prevalence of the 807T thrombophilic polymorphism of platelet glycoprotein Ia/IIa. Patients homozygous for this polymorphism are less likely to recover from iSSNHL. Classical cardiovascular risk factors were not related to iSSNHL.

Incidental versus symptomatic venous thrombosis in cancer: a prospective observational study of 340 consecutive patients.

BACKGROUND: The clinical significance of incidental venous thrombosis (IVT) is uncertain. The objective of this study was to compare the clinical characteristics and the outcome of cancer patients with IVT with those of patients with symptomatic venous thrombosis (SVT). PATIENTS AND METHODS: Prospective observational study enrolling consecutive cancer patients newly diagnosed with venous thromboembolism (May 2006-April 2009). Diagnosis of IVT was based on vascular filling defects in scheduled computed tomography scans in the absence of clinical symptoms. Anticoagulant therapy was routinely prescribed regardless of SVT or IVT. RESULTS: IVT was diagnosed in 94 out of 340 (28%) patients. Patients with IVT were older (63.7 ± 10.5 versus 60.8 ± 10.5 years, P = 0.035), more frequently had metastatic cancer (82% versus 65%, P = 0.01) and were less likely to be receiving chemotherapy at the time of the thrombotic event (53% versus 67%, P = 0.018). Mean follow-up was 477 days. A lower risk of venous rethromboses was observed in patients with IVT (log-rank P = 0.043), with no differences in major bleeding and overall survival compared with SVT patients. CONCLUSIONS: A high proportion of venous thrombotic events in cancer patients are diagnosed incidentally during scheduled imaging. Prospective controlled trials evaluating the optimal therapy in this setting are required.

Is there an overlap between sudden neurosensorial hearing loss and cardiovascular risk factors?

INTRODUCTION: Sudden sensorineural hearing loss (SSHL) has been proposed as a symptom of underlying vascular problems. The purpose of this work is to evaluate the genetic and acquired risk factors. METHODS: Ninety-nine patients were tested for the presence of common polymorphisms related to thrombophilia (prothrombin and factor V Leiden) in order to assess genetic risk factors, and several parameters classically associated with vascular disorders (cardiovascular events, brain stroke and antiphospholipid syndrome) were evaluated. Additional assessments of personal and familial history risk factors for vascular disorders were performed in each patient. RESULTS: Thrombophilia studies did not demonstrate statistically relevant differences between the patients and control group. However, lipidemia profile and directed personal and familial histories showed positive trends for SSHL. CONCLUSION: The lack of clear relationships between SSHL and other vascular risk factors suggests multicausality as a predominant disease profile. Although preliminary results point at a vascular involvement in SSHL, a long-term prospective study is necessary to demonstrate that SSHL represents an early vascular symptom.

Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus.

OBJECTIVE: We analysed the genetic polymorphisms in platelet glycoproteins (GP) Ib-alpha, Ia/IIa and IIb/IIIa and their correlation with the development of arterial thrombosis and preclinical arteriosclerosis in patients with antiphospholipid syndrome (APS) or with systemic lupus erythematosus (SLE). METHODS: We included 131 patients with APS (86 with primary APS and 45 with APS associated with SLE), 102 patients with SLE and 160 healthy controls. GP Ib-alpha VNTR polymorphism, GP Ia/IIa 807 C/T polymorphism and GP IIb/IIIa PlA1/2 polymorphism were determined by polymerase chain reaction. Thrombotic events were assessed clinically and confirmed by objective methods. The presence of preclinical arteriosclerosis was evaluated by a carotid ultrasound study in a subgroup of 70 patients with SLE measuring the intima-media wall thickness and the presence of arteriosclerotic plaque. RESULTS: A total of 50 episodes of arterial thrombosis in 36 patients with APS have been registered. We found a significant correlation between the 807 T/T genotype of GP Ia/IIa and arterial thrombosis (22% vs 7%, p = 0.04; OR 3.59, 95% CI 1.20 to 10.79). The VNTR Ib-alpha and P1A1/2 IIb/IIIa polymorphisms were not associated with arterial thrombosis in patients with APS when individually analysed. The coexistence of both 807 T and PlA2 alleles increased the arterial thrombosis risk (28% vs 7%, p = 0.005; OR 4.84, 95% CI 1.67 to 13.96). In patients with SLE, no relationship was found between the presence of carotid arteriosclerotic plaque and separate polymorphisms of platelet GP. The coexistence of alleles 807 T of GP Ia/IIa and PlA2 of GP IIb/IIIa was associated with the presence of carotid plaque (35% vs 4%, p = 0.002; OR 12.92, 95% CI 2.39 to 69.81). CONCLUSIONS: The T/T genotype of 807 C/T polymorphism of GP Ia/IIa may be an additional risk for the development of arterial thrombosis in APS. The coexistence of both 807 T and PlA2 alleles increased the arterial thrombosis risk in patients with APS and preclinical arteriosclerosis in patients with SLE.

Combined type-1 plasminogen activator inhibitor and NOD2/CARD15 genotyping predicts complicated Crohn's disease behaviour.

BACKGROUND: NOD2/CARD15 gene variants have not been universally associated with stricturing behaviour in Crohn's disease. Other behaviour modifying genes could explain these results. AIM: To study the combined influence of NOD2/CARD15 variants and 4G/4G genotype of type-1 plasminogen activator inhibitor (PAI-1) gene on Crohn's disease behaviour. METHODS: One hundred and seventy Crohn's disease patients were studied prospectively, with a mean follow-up of 7+/- 6 years. Disease behaviour was registered by using two criteria: the Vienna classification and a non-hierarchical classification based on the behavioural Vienna categories. RESULTS: In the multivariate analysis for stricturing behaviour according to the Vienna categories, only absence of colonic disease (OR, 4.0; 95% CI: 1.49-11.1; P = 0.006) was an independent predictive factor. However, in the multivariate analysis for stricturing disease applying a non-hierarchical criteria, ileal disease (OR, 4.19; 95% CI: 1.30-13.5; P = 0.01), and carrying both NOD2/CARD15 variants and the 4G/4G PAI-1 genotype (OR, 5.02; 95% CI: 1.44-17.48; P = 0.01) were independent predictive factors. In the multivariate analysis for penetrating behaviour, the 4G/4G PAI-1 (OR, 3.10; 95% CI: 1.54-6.23; P = 0.001) and male sex (OR, 2.44; 95% CI: 1.30-4.60; P = 0.005) were independent predictive factors irrespective of criteria applied. CONCLUSIONS: Combined PAI-1 and NOD2/CARD15 genotyping predict complicated Crohn's disease. Patients with these variants could benefit from early interventions.

Pharmacogenetics of antithrombotic drugs.

Antithrombotic therapy has improved the prognosis of patients with venous or arterial thrombosis. However, there is substantial interindividual variability in the response to antithrombotic drugs. This variability is due, in part, to genetics, which may affect the efficacy and safety of drugs used in the treatment and prevention of thrombosis. Pharmacogenetics studies the genetic factors related to interindividual variability in the response to drugs. Various polymorphisms in genes of the hemostatic system that have been reported to be markers of susceptibility to thromboembolic disease also seem to be implicated in the response to antithrombotic therapy. These include polymorphisms in platelet receptors (platelet glycoproteins) and coagulation factors (factors II, V, XII, XIII). There is also growing evidence on genetic polymorphisms affecting the metabolism (cytochrome P450), disposition, transporter proteins or cellular receptors of antithrombotic drugs. This review summarizes current knowledge on the pharmacogenetics of antithrombotic therapy, paying special attention to four therapeutic groups: antiplatelet agents, anticoagulants (vitamin K antagonists and heparin), fibrinolytics and other drugs used for the prevention of cardiovascular risk, such as statins and hormone replacement therapy in the menopause. The potential relevance of pharmacogenetics in the future of antithrombotic therapy and the design of clinical trials is also explored.

Effect of plasma from patients with primary antiphospholipid syndrome on platelet function in a collagen rich perfusion system.

The effect on platelet function of plasma from 9 patients with primary antiphospholipid syndrome (PAS) with previous thrombotic episodes was investigated under flow conditions. Five asymptomatic individuals with antiphospholipid antibodies (aPL) (A-aPL) and 14 normal controls were also studied. Patients and controls plasmas were added (1:20 v/v) to anticoagulated blood and perfused through annular chambers containing collagen rich vessel segments. The interaction of platelets with vessel subendothelium was morphometrically evaluated in thin sections. An increase in both covered surface and thrombi formation was observed in perfusions in the presence of PAS-plasma (mean +/- SD: 34.2% +/- 9.6% and 23.2% +/- 10.0% respectively) compared with control plasmas (21.4% +/- 7.3% and 10.1% +/- 7.7%, p < 0.01). Affinity purified anticardiolipin antibodies from one PAS patient showed a similar effect when added to normal blood. In contrast, A-aPL plasma had no effect on platelet-subendothelium interaction. In parallel studies, the same plasmas were incubated with isolated normal platelets before and after activation with ADP or collagen and the binding of immunoglobulins (Ig) was determined by flow cytometry. A significantly increased binding of Ig was observed in 8 out of 9 plasmas from PAS patients when platelets had been activated with collagen but not when resting or ADP activated platelets were used. No increased Ig binding to platelets was seen using A-aPL individuals plasma. These observations might help to explain the pathophysiology of the thrombotic events occurring in patients with PAS.

Myelomonocytic antigens in B-cell chronic lymphocytic leukemia.

The clinical significance of myelomonocytic (MyMo) antigens in B-cell chronic lymphocytic leukemia (B-CLL) is unclear. We have analyzed the expression of MyMo antigens (CD13, CD14 (LeuM3, My4, Mo2), CD15, CD11b, CD11c, CD33 and CD68) on B-lymphocytes (CD19+) in 105 B-CLL patients and in 35 controls. A double direct staining technique and flow cytometric analysis was performed. The expression of MyMo antigens on the control group did not exceed 4% B-lymphocytes. A MyMo antigen was considered as positive when present in > or = 10% of B-lymphocytes. Among the B-CLL patients, 28 (26.7%) were positive for CD11c, 21 (20.0%) for CD11b, nine (8.6%) for CD15, five (4.8%) for CD13, two (1.9%) for Mo2, and one (1.0%) for My4. No patient was positive for LeuM3, CD33 or CD68. CD11c was more frequently expressed in patients with a short lymphocyte doubling time (< 12 months) (P = 0.05) and CD11b in the group with a higher number of lymphoid areas involved (P = 0.02). No correlation was found between lymphoid morphology and MyMo antigen expression. Fourteen of the 80 patients at risk subsequently progressed to a more advanced stage. Multivariate analysis identified hemoglobin (P = 0.004) and CD11b positivity (P = 0.009) as independent variables for disease progression. Fifteen patients died during evolution. Seven out of the 21 CD11b positive patients and eight of the 84 CD11b negative patients died (LR: P = 0.02, BG: P = 0.05). In the multivariate analysis, only CD11b positivity (> or = 10%) added prognostic value to clinical stages.

Antiphospholipid antibodies and thrombophilic factors in giant cell arteritis.

OBJECTIVES: To evaluate the prevalence of thrombophilic risk factors known to induce intravascular clotting and to assess their relationship with ischemic manifestations in giant cell arteritis (GCA). METHODS: Eighty consecutive patients with established GCA were included: 36 with isolated temporal arteritis (TA), 14 with isolated polymyalgia rheumatica (PMR), and 30 with TA and PMR. Forty-four patients (67%) had ischemic phenomena due to GCA. Twelve patients (15%) had thrombotic events unrelated to GCA (6 strokes, 5 deep venous thrombosis, and 1 myocardial infarction). A control group of 100 age- and sex-matched individuals without autoimmune disease, bleeding disorders, thrombosis, or clinical picture of TA or PMR also was analyzed. All participants were tested for the antiphospholipid antibody (aPL) profile, protein C, protein S, antithrombin activity, factor V Leiden mutation, and prothrombin gene G20210A mutation. We also studied fibrinolysis parameters: plasminogen, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, type-1 plasminogen activator inhibitor (PAI-1) antigen, PAI-1 activity, and the 4G/5G polymorphism of the promoter region of the PAI-1 gene. RESULTS: Eleven patients (18%) tested positive for lupus anticoagulant, 24 (30%) for anticardiolipin antibodies, 9 (11%) for anti-beta 2-glycoprotein I antibodies, and 29 (36%) for antiprothrombin antibodies. No relationship was found between these autoantibodies and ischemic manifestations. None of the patients had decreased protein C, protein S or antithrombin activity. Two patients and 2 controls were heterozygous for factor V Leiden, and only 1 patient and 2 controls were heterozygous for the prothrombin gene G20210A mutation. No statistically significant correlation was found between any thrombophilic factor and GCA-related or GCA-unrelated ischemic events. CONCLUSION: GCA patients have a high prevalence of aPL that is not related to ischemic manifestations. Moreover, GCA-related or GCA-unrelated ischemic manifestations do not appear to be due to congenital thrombophilic risk factors. Semin Arthritis Rheum 31:12-20.

Clinical study and follow-up of 100 patients with the antiphospholipid syndrome.

OBJECTIVES: To study the clinical characteristics at diagnosis and during follow-up of patients with the antiphospholipid syndrome (APS) and to analyze the influence of treatment on their outcome. PATIENTS: One hundred patients with APS were included (86% female and 14% male; mean age, 36 years). Sixty-two percent had primary APS and 38% had APS associated with systemic lupus erythematosus (SLE). The median length of follow-up was 49 months. RESULTS: Fifty-three percent of the patients had thromboses, 52% had thrombocytopenia, and 60% of the women had pregnancy losses. Patients with APS associated with SLE had a higher prevalence of hemolytic anemia (P = .02), thrombocytopenia (platelet count lower than 100 x 10(9)/L) (P = .004), antinuclear antibodies (P = .0002), and low complement levels. Fifty-three percent of the patients with thrombosis had recurrent episodes (86% in the same site as the previous thrombotic event). Recurrences were observed in 19% of the episodes treated with long-term oral anticoagulation, in 42% treated prophylactically with aspirin, and in 91% in which anticoagulant/antiaggregant treatment was discontinued (P = .0007). Multivariate analysis showed that prophylactic treatment and older age had an independent predictive value for rethrombosis. Prophylactic treatment during pregnancy (usually with aspirin) increased the live birth rate from 38% to 72% (P = .0002). CONCLUSIONS: Patients with APS have a high risk of recurrent thromboses. Long-term oral anticoagulation seems to be the best prophylactic treatment to prevent recurrences. Prophylactic treatment with aspirin during pregnancy reduced the rate of miscarriages remarkably.

The 4G/4G genotype of the 4G/5G polymorphism of the type-1 plasminogen activator inhibitor (PAI-1) gene is a determinant of penetrating behaviour in patients with Crohn's disease.

BACKGROUND: Crohn's disease is a heterogeneous disorder with polygenic inheritance. AIM: To assess the effect of the 4G/5G polymorphism of the type-1 plasminogen activator inhibitor (PAI-1) gene, the major inhibitor of fibrinolysis, on Crohn's disease susceptibility and phenotype. METHODS: One hundred and fifty-seven patients with Crohn's disease and 350 controls were included prospectively. Medical records were reviewed to determine changes in the Crohn's disease phenotype. The 4G/5G polymorphism was assessed by polymerase chain reaction techniques. RESULTS: The frequencies of the 4G/4G, 4G/5G and 5G/5G genotypes were similar in patients with Crohn's disease and controls. The 4G/4G genotype (P < 0.0001; odds ratio, 4.84) and male sex (P = 0.009; odds ratio, 2.63) were independent risk factors for penetrating behaviour in Crohn's disease. Most Crohn's disease patients had a non-penetrating phenotype at diagnosis. The probability of development of a penetrating phenotype within 5 years of diagnosis was higher in patients with the 4G/4G genotype (72% vs. 19%, P < 0.0001). CONCLUSIONS: The 4G/4G genotype of the PAI-1 gene does not influence Crohn's disease susceptibility, but increases by five-fold the probability of penetrating behaviour. Most patients with the 4G/4G genotype have a non-penetrating phenotype at diagnosis, but develop a penetrating behaviour within 5 years. Genotyping the 4G/5G polymorphism may be useful for the identification of a sub-group of patients with aggressive Crohn's disease, who might benefit from specific therapy.

Cardiac hemangioma with papillary endothelial hyperplasia: report of a resected case and review of the literature.

A case of left atrial hemangioma with papillary endothelial hyperplasia in a 42-year-old man is reported. With the aid of cardiopulmonary bypass, the tumor was resected, and the patient is well 22 months after operation. The clinical symptoms at initial examination, operative procedure, and pathological findings are reported, and the diagnostic and therapeutic approaches to cardiac tumors are described briefly. A review of surgically treated hemangiomas is also given.

Large-cell lymphoma: a study of prognostic factors and assessment of five recently proposed predictive systems.

The main initial and evolutive variables of 133 patients with large-cell lymphoma treated with adriamycin-containing regimens were evaluated for prognostic significance. At the time of analysis, 66 patients had died with the median survival of the series being 48.9 months. Variables associated with poor prognosis in the univariate study were: lymphoma of immunoblastic subtype, advanced Ann Arbor stage, presence of B-symptoms, poor performance status, bulky disease (> or = 10 cm), involvement of two or more extranodal sites, bone marrow infiltration, and high serum LDH levels. In the multivariate analysis, Ann Arbor stage (p < 0.001), bulky disease (p = 0.004), performance status (p = 0.018), and histologic subtype (p = 0.021) retained their prognostic value. After excluding those patients with localized disease (stage I), the Ann Arbor staging system lost prognostic significance in favor of bone marrow infiltration (p = 0.009) and serum LDH (p < 0.001). However, when response to treatment was included in the regression model, it proved to be the most important prognostic factor (p < 0.001), followed by serum LDH (p = 0.004). On the other hand, when the analysis was restricted to complete responders, serum LDH at diagnosis was the only parameter useful to predict survival (p = 0.008). Finally, five recently proposed prognostic classifications were useful to separate different risk-groups of patients when applied to the series.

Increased induced monocyte tissue factor expression by plasma from patients with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To investigate whether monocyte expression of tissue factor is increased by plasma from patients with severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective longitudinal study. SETTING: Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting. PATIENTS: Nine IVF patients with severe OHSS. INTERVENTIONS: Pretreatment with leuprolide acetate was followed by gonadotropin treatment for ovarian follicular stimulation. After administration of hCG, a standard IVF-ET procedure was performed. MAIN OUTCOME MEASURES: Measurement during the syndrome and 4 to 5 weeks after recovery of induced monocyte tissue factor expression. RESULTS: In each of the nine patients, plasma obtained during the syndrome induced a significantly higher proportion of monocytes expressing tissue factor and a significantly higher intensity of tissue factor expression on monocytes than plasma obtained after recovery and control plasma. CONCLUSIONS: Procoagulant activity of blood monocytes, which is mediated principally by tissue factor expression, is increased in patients with severe OHSS. This fact may be important in thrombotic events associated with the syndrome.