Comprehensive Antiphopholipid Antibody Testing in Children with Acute Thromboembolism: Preliminary Findings from a Prospective Inceptional Cohort Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1643-1643
Author(s):  
Hannah Hathaway ◽  
Linda Jacobson ◽  
Neil A. Goldenberg ◽  
Marilyn J. Manco-Johnson
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Lupus Erythematosus ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Antibody Testing ◽  
Acute Thrombosis ◽  
Cerebral Sinovenous Thrombosis ◽  
Prothrombotic Risk Factors

Abstract BACKGROUND: The significance of the lupus anticoagulant (LA) and other antiphospholipid antibodies (APA) in children with thromboembolism (TE) has not been as clearly defined in children as among adults. OBJECTIVE: To characterize TE presentation and prothrombotic risk factors among children with TE who are positive for the LA using the dilute Russell Viper Venom Time (dRVVT) as a screening test. METHODS: Children with acute TE were consecutively enrolled in a prospective inceptional cohort study and a compehensive APA testing battery was serially employed. APA testing included StaClot-LA, as well as ELISA for IgG and IgM binding to prothrombin, protein C, protein S, cardiolipin and β2GP1. RESULTS: 34 children who were dRVVT positive within 3 months of acute thrombosis were evaluated with the entire APA battery on 1 to 5 occasions over 3 months to 4 years. Multiple APA were detected in 20 (59% of) study participants (5 tests, n=1; 4 tests, n=2; 3 tests, n=6; 2 tests, n=11; 1 test, n=14). Findings were: dRVVT (100%), anti-prothrombin (50%), StaClot (18%), anti-protein S and ACA (12% each), anti-β2GP1 (6%) and anti-protein C (3%). TE presentation and prothrombotic risk factors were compared between these 20 children with multiple APA and 14 children who were dRVVT positive only (Tables 1 and 2). Children with LA-associated TE who had multiple APA were more likely to present with parenchymal sites of thrombosis (p=0.03) and appeared less likely to have otherwise-idiopathic TE (i.e., no additional prothrombotic risk factors identified), although the latter trend was not statistically significant. CONCLUSIONS: The majority of children with acute TE and a positive dRVVT in whom a comprehensive battery of APA is performed demonstrate multiple APA, among which anti-prothrombin antibodies are the most common. When compared to children positive for dRVVT only, children with LA-associated thrombosis who have multiple APA are particularly predisposed to parenchymal thrombotic events and may be more likely to experience otherwise-idiopathic TE. Future investigations will evaluate the risk of recurrent TE in children with thrombosis relative to findings on serial comprehensive APA testing. Table 1. Thrombus Sites*, by APA Group. APA group Limb DVT Extensive PE CSVT Parenchymal thrombosis Arterial thrombosis Total * Some patients had >1 site. Abbreviations: DVT=deep venous thrombosis; PE=pulmonary embolism; CSVT=cerebral sinovenous thrombosis. Arterial thrombosis includes ischemic arterial stroke. Multiple APA 8 (40%) 6 (30%) 2 (10%) 6 (30%) 3 (15%) 20 (100%) dRVVT only 7 (50%) 4 (29%) 0 (0%) 0 (0%) 3 (21%) 14 (100%) Table 2. Prothrombotic Risk Factors, by APA Group. APA Group Infection Surgery/Trauma SLE Other* None Total * Includes anatomic anomaly, obesity, sedentary condition, oral contraceptive use, genetic thrombophilia, central venous catheter, and cardiac disease. Abbreviation: SLE=systemic lupus erythematosus. Multiple APA 4 (20%) 3 (15%) 2 (10%) 4 (20%) 7 (35%) 20 (100%) dRVVT only 2 (14%) 1 (7%) 0 (0%) 9 (64%) 2 (14%) 14 (100%)

scholarly journals The risk of arterial thrombosis in carriers of natural coagulation inhibitors: a prospective family cohort study

2021 ◽  
Author(s):  
Daniela Tormene ◽  
Franco Noventa ◽  
Elena Campello ◽  
Sabrina Gavasso ◽  
Michelangelo Marobin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Family Members ◽  
Protein S ◽  
Hazard Ratio ◽  
Thromboembolic Events ◽  
Coagulation Inhibitors ◽  
Arterial Thromboembolic Events

Abstract Background Whether the carriership of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiency increases the risk of arterial thromboembolic events (ATE) is controversial. This information has the potential to inform the management of family members of probands with inherited deficiency of natural anticoagulants. Patients/methods We conducted a large prospective family cohort study in 640 subjects (of whom 341 carriers and 299 non-carriers) belonging to 86 families with inherited deficiency of AT, PC, or PS. Results A total of 4240 and 3810 patient-years were available for carriers and non-carriers, respectively. Risk factors for atherosclerosis were similarly distributed in the two groups. Of the 26 ATE that were recorded, 19 occurred in carriers (5.6%), as compared to 7 in non-carriers (2.3%) [p = 0.07]. After adjusting for confounders, the hazard ratio (HR) for ATE was 4.9 (95% CI 1.5–16.3) in carriers as compared to non-carriers. Conclusions Among family members of probands with an inherited deficiency of natural anticoagulants, carriers exhibit a risk of ATE that is almost five times higher than in non-carriers.

Thrombophylic Profile of Fabry Patients in Argentina.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4048-4048
Author(s):  
Mario C. Aggio ◽  
Pablo A. Martinez
Keyword(s):  
Risk Factors ◽  
Gaucher Disease ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Anticardiolipin Antibodies ◽  
Nutritional Deficiencies ◽  
Lysosomal Storage ◽  
Metabolic Disturbances ◽  
Prothrombotic Risk Factors

Abstract Anderson-Fabry disease (AFD), described independently in the 1890s by William Anderson and Johann Fabry, is the second most frequent lysosomal storage disorder (after Gaucher disease). AFD is a pan-ethnic disorder due to a deficiency of the lysosomal enzime alpha-galactosidase A (alpha-GAL), with an estimated frequency of 1 in 117,000 male births, although recent studies suggest that the incidence may be underestimated, as certain patients with residual alpha-GAL activity (5 to 35% of normal levels) have disease too. Increased incidence of thrombotic events has been demonstrated in AFD. We evaluated the prevalence of prothrombotic risk factors in Argentine patients. Patients/methods: 36 patients (15 hemizygous and 21 heterozygous from 3 families) were studied for: protein C pathway (PCSys), antithrombin (AT), protein C (PC), protein S (PS), activated protein C resistance (APCR), lupus anticoagulant (LA), total plasma homocysteine (tHcy), anticardiolipin antibodies (ACA), and antiphosphatidylserine antibodies (APA). Results: The evaluation of PCSys, APCR, plasmatic levels of PC, PS, AT and APA were normal in all patients. Elevated levels of tHcy were found in 19.4% (n=7). Positive for LA were 38.9% (n=14) and for ACA 8.3% (n=3). Conclusions: 1) Our results confirm data from the literature reporting elevated homocysteinemia in AFD patients. Nutritional deficiencies, renal failure and metabolic disturbances are probable etiologic factors. 2) Thrombophilia was more frequent in hemizygous (13 patients, 86.7%) than in heterozygous (8 patients, 38.1%). Four hemizygous patients showed coexistence of two risk factors. 3) We found an unexpected high incidence of procoagulant autoantibodies. This association has also been reported and might contribute to thrombophilia in AFD: as in Gaucher disease, the accumulation of immunogenic glucocerebrosides might induce chronic immunostimulation.

Evaluation of Inherited Prothrombotic Risk Factors in Children with Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3953-3953
Author(s):  
Valerie Li Thiao Te ◽  
Remi Favier ◽  
Jeanne-Yvonne Borg ◽  
Estelle Cadet ◽  
Jacqueline Reynaud ◽  
...  
Keyword(s):  
Risk Factors ◽  
Protein C ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Protein C Deficiency ◽  
Antithrombin Deficiency ◽  
Mthfr Genotype ◽  
G20210a Mutation ◽  
Family Medical History ◽  
Prothrombotic Risk Factors

Abstract This retrospective study was designed to determine the prevalence of inherited prothrombotic risk factors (Factor V Leiden (FV) G1691A and prothrombin G20210A mutations, TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR), protein C, protein S, antithrombin deficiencies) in a population of children with ALL treated according to the FRALLE 2000 study Protocol (High Risk and Standard Risk groups). The study was performed in 5 French Centers including Amiens, Angers, Paris Trousseau, Rouen and Saint-Etienne. From December 2000 to March 2006, 354 children aged 1 to 18 years old were consecutively admitted for ALL and were enrolled in the FRALLE 2000 Protocol. Among them, 281 patients were investigated for hereditary prothrombotic defects at the time of ALL diagnosis. Informed parental consent was required for gene analysis. Abnormal test results for protein S (functional activity and free protein S antigen concentration), protein C and antithrombin were controlled on a second blood sample after induction. In the population studied, the prevalence of one established prothrombotic risk factor was 19,2%: the FV G1691A mutation was diagnosed in 10 patients (3.6%), all heterozygous, 10 patients (3.6%) showed the heterozygous prothrombin G20210A mutation, the TT677 MTHFR genotype was found in 34 children (12.7%), 1 patient showed protein C deficiency (0.4%). No antithrombin deficiency was detected. The prevalence of inherited protein S deficiency could not be evaluated because of missing data in the family medical history. Combined prothrombotic defects were found in 2 patients (0.71%): heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A mutation in 1 patient and combined with TT677 MTHFR genotype in the second patient. Except for TT677 MTHFR genotype, the prevalence of hereditary prothrombotic risk factors in children with ALL in France were found within the prevalence reported for children treated for ALL (table 1) and comparable to the prevalence in healthy Europeans (Junker et al. 1999, Margaglione et al 2001, Mueller et al. 2005). Comparison of the prevalence of inherited prothrombotic risk factors in children with ALL Country Population FV G1691A +/− ++ PT G20210A +/− +/+ MTHFR TT677 AT PC AT: antithrombin deficiency ; PC: protein C deficiency ; NE : non evaluated NowakGöttl et al 1999 (n=301) Germany ALL children 5.3% 0.3% 2% 0% 7.7% 0.7% 2.3% Mauz-Körholz et al. 2000 (n=108) Germany ALL children 5.6% 0% 2.8% 0% 5.6% 0% 2.7% Mitchell et al. 2002 (n=60) Canada ALL children 3.3% 0% 2% 0% NE NE NE Present study (n=281) France ALL children 3.6% 0% (n=277) 3.6% 0%(n=279) 2.7% (n=268) 0% 0.4%

scholarly journals Association between the Prevalence of Antibodies to β2-Glycoprotein I, Prothrombin, Protein C, Protein S, and Annexin V in Patients with Systemic Lupus Erythematosus and Thrombotic and Thrombocytopenic Complications

2001 ◽  
Vol 47 (6) ◽  
pp. 1008-1015 ◽  
Author(s):  
Junzo Nojima ◽  
Hirohiko Kuratsune ◽  
Etsuji Suehisa ◽  
Yoshiaki Futsukaichi ◽  
Hachiro Yamanishi ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Lupus Erythematosus ◽  
Arterial Thrombosis ◽  
Plasma Proteins ◽  
Protein C ◽  
Significant Risk ◽  
Fetal Loss ◽  
Annexin V ◽  
Protein S ◽  
C Protein

Abstract Background: Anti-phospholipid (aPL) antibodies (Abs) frequently found in the plasma of patients with systemic lupus erythematosus (SLE) have been associated with thrombotic complications. Our aim was to clarify the roles in thrombosis of aPL Abs that react with complexes of phospholipids and plasma proteins such as β2-glycoprotein I (β2-GPI), prothrombin, protein C, protein S, and annexin V. Methods: We determined the prevalence of aPL Abs to various phospholipid-binding plasma proteins in SLE patients with arterial thrombosis (30 cases), venous thrombosis (19 cases), thrombocytopenia (14 cases), fetal loss (14 cases), and patients without complications (91 cases). The aPL Abs were measured by an ELISA system in which human plasma proteins (β2-GPI, prothrombin, protein C, protein S, and annexin V) were immobilized on γ-irradiated or plain polystyrene plates. Results: All types of aPL Abs were frequently observed in the patients with SLE when γ-irradiated polystyrene plates were used (51 of 168 cases positive for anti-β2-GPI, 94 of 168 cases positive for anti-prothrombin, 36 of 168 cases positive for anti-protein C, 47 of 168 cases positive for anti-protein S, and 50 of 168 cases positive for anti-annexin V), whereas no Abs to these plasma proteins were detected when plain polystyrene plates were used. Multivariate analysis confirmed that both anti-β2-GPI and anti-prothrombin Abs were significant risk factors for arterial thrombosis [odds ratios (ORs), 8.8 and 14.5, respectively; 95% confidence intervals (CIs), 3.2–25 and 1.8–116, respectively] but not for venous thrombosis. The presence of anti-protein S Abs was a significant risk factor for venous thrombosis (OR, 30.4; CI, 3.3–281) but not for arterial thrombosis. The only significant risk factor for fetal loss was the presence of anti-annexin V Abs (OR, 5.9; CI, 1.4–14.8). Conclusions: Patients with SLE frequently have some aPL Abs to β2-GPI, prothrombin, protein C, protein S, and annexin V. Thrombotic complications in SLE may depend on the antigenic specificities of these Abs, alone or in combination.

Associations Between Free Protein S and Factor VIII Levels with Traditional Arterial Thrombotic Risk Factors and Their Risk On Arterial Thrombosis. Results From a Retrospective Family Cohort Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 25-25
Author(s):  
René Mulder ◽  
Inge M van Schouwenburg ◽  
Bakhtawar Khan Mahmoodi ◽  
Nic J.G.M. Veeger ◽  
André B Mulder ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Cohort Study ◽  
Factor Viii ◽  
Arterial Thrombosis ◽  
Protein S ◽  
Cumulative Distribution ◽  
Thrombotic Risk ◽  
Free Protein ◽  
Age And Sex

Abstract Abstract 25 Introduction: Accumulating evidence shows that venous and arterial thrombosis may be viewed as two diseases with similar pathophysiological entities. Both high factor VIII and low free protein S levels are risk factors for venous thrombosis, but if, and in what way, these thrombophilic factors also increase the risk of arterial thrombosis is unknown. Patients and Methods: In a single-center retrospective cohort study of families with thrombophilia, we performed a post-hoc analysis to identify if relatives with high factor VIII or low free protein S levels were at risk of arterial thrombosis. Clinical data were collected before laboratory testing. To avoid bias, all probands were excluded from the analyses. In addition, relatives with protein S deficiency type I were excluded from analysis when analyzing effects of free protein S. Factor VIII:C levels were measured by one-stage clotting assays and were considered increased at levels above 150 IU/dL. Free protein S antigen levels were measured by enzyme-linked immunosorbent assay after precipitation of protein S complexed with C4b-binding protein with polyethylene glycol. Free protein S antigen levels were considered decreased at levels below the normal range (< 65 IU/dL). Coronary and peripheral arterial disease had to be symptomatic and angiographically proven, whereas myocardial infarction was diagnosed according to clinical, enzymatic and electrocardiographic criteria. Known risk factors for arterial thrombosis were recorded and included: hypertension, hyperlipidemia, the presence of diabetes mellitus, smoking habits or obesity. Absolute risks of first arterial thrombosis in relatives with high factor VIII or low free protein S levels were calculated. Linear regression was used to determine the relation between factor VIII levels and free protein S levels, respectively, combined with traditional arterial thrombotic risk factors. Adjustments were made for age and sex. Cumulative distribution functions were constructed to visualize a possible relationship between factor VIII and free protein S levels, respectively, and BMI Results: Of 1468 relatives tested for thrombophilia, 1399 were analyzed on factor VIII and 1143 on free protein S. Forty-six percent were male. Mean age at enrollment was 45 years. Mean factor VIII level was 146 IU/dL and mean free protein S level 80 IU/dL. High factor VIII levels were observed in 39% of relatives and low free protein S levels in 23% of relatives. First arterial thrombotic events were documented in 86 relatives at a mean age of 57 years. Annual incidence of arterial thrombosis in relatives with high factor VIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal factor VIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Relatives with hypertension, diabetes mellitus, and obesity had mean factor VIII levels (age and sex adjusted) that were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher than relatives without these arterial thrombotic risk factors, which were statitically significant findings. In addition, a dose response relation could be demonstrated between increasing factor VIII and body mass index (Figure). None of these associations were shown for free protein S. Conclusions: Both high factor VIII and low free protein S levels were a risk factor for arterial thrombosis in thrombophilic families. High factor VIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors, suggesting that increase of these levels were acquired. Free protein S levels were not influenced by these arterial thrombotic risk factors which assumes that low free protein S levels were genetically determined. Disclosures: No relevant conflicts of interest to declare.

Symptomatic Onset of Severe Hemophilia A in Childhood is Dependent on the Presence of Prothrombotic Risk Factors

2001 ◽  
Vol 85 (02) ◽  
pp. 218-200 ◽  
Author(s):  
S. Halimeh ◽  
K. Kurnik ◽  
R. Schobess ◽  
C. Wermes ◽  
R. Junker ◽  
...  
Keyword(s):  
Risk Factors ◽  
Protein C ◽  
Hemophilia A ◽  
Protein S ◽  
Type I ◽  
Factor V ◽  
Severe Hemophilia ◽  
Multicenter Cohort Study ◽  
Prothrombotic Risk Factors ◽  
Reported Data

SummaryIt has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and anti-thrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.

Associations between high factor VIII and low free protein S levels with traditional arterial thrombotic risk factors and their risk on arterial thrombosis: Results from a retrospective family cohort study

2010 ◽  
Vol 126 (4) ◽  
pp. e249-e254 ◽  
Author(s):  
René Mulder ◽  
Inge M. van Schouwenburg ◽  
Bakhtawar K. Mahmoodi ◽  
Nic J.G.M. Veeger ◽  
André B. Mulder ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Factor Viii ◽  
Arterial Thrombosis ◽  
Protein S ◽  
Thrombotic Risk ◽  
Free Protein

Severe Arterial Cerebral Thrombosis in a Patient with Protein S Deficiency (Moderately Reduced Total and Markedly Reduced Free Protein S): A Family Study

1989 ◽  
Vol 61 (01) ◽  
pp. 144-147 ◽  
Author(s):  
A Girolami ◽  
P Simioni ◽  
A R Lazzaro ◽  
I Cordiano
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Free Protein ◽  
Her Family ◽  
S Deficiency ◽  
Increased Risk ◽  
Patient Reported

SummaryDeficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis.In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits.In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.

scholarly journals Isolated Protein S Deficiency - Cause of Recurrent Stent Thrombosis - A Case Report

2014 ◽  
Vol 6 (2) ◽  
pp. 175-179
Author(s):  
AK Choudhury ◽  
M Khalequzzaman ◽  
S Hasem ◽  
M Akhtaruzzaman ◽  
S Jannat
Keyword(s):  
Case Report ◽  
Stent Thrombosis ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Antiplatelet Agents ◽  
Percutaneous Coronary Interventions ◽  
Protein S Deficiency ◽  
S Deficiency ◽  
Percutaneous Coronary

Stent thrombosis (ST) is one of the major complications that occur in percutaneous coronary interventions (PCIs) with stents. Various factors have been attributed to the development of ST, and several strategies have been recommended for its management. Protein C or protein S deficiencies may uncommonly be responsible for coronary arterial thrombosis. We report a young woman with recurrent stent thrombosis due to the deficiency of protein S. After coronary stenting, stent thrombosis occurred two times despite aggressive medical therapy. This report suggests that the deficiency of protein C or S should be born in mind in a young patient with recurrent thrombotic events, and that anticoagulants in addition to antiplatelet agents considered in the presence of their deficiency DOI: http://dx.doi.org/10.3329/cardio.v6i2.18364 Cardiovasc. j. 2014; 6(2): 175-179

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