Protein Z Levels Could Help To Predict Obstetrical Complications and Arterial Thrombosis in Patients with Antiphospholipid Antibodies.

Abstract Introduction: Protein Z (PZ) is a vitamin K dependant plasma protein synthesized by the liver. The precise physiological function of PZ is still unclear: - anticoagulant, the PZ-dependant protease inhibitor complex inhibits factor Xa and acts as a naturally occurring anticoagulant; - procoagulant, PZ promote the assembly of thrombin with PL vesicles- and promote coagulation. In clinical situations, low PZ plasma levels have been associated with bleeding and thrombotic tendency while elevated PZ plasma levels have been linked with ischemic stroke. Antiphospholipid syndrome (APS) is a complex autoimmune thrombotic disorder. Despite specific clinical and laboratory criteria, diagnostic and prognostic tools in patients with APS are limited in their ability to predict adverse outcome in patients with antiphospholipid antibodies (aPLA). Therefore, we hypothesized that PZ could play a role in the thrombotic tendency. Study: to evaluate our hypothesis, we measured PZ plasma concentrations in a case control study including 61 patients with confirmed aPLA with or without APS versus 53 controls. Among the group of patients with APS, 15 had obstetrical complications (OC), 16 had arterial thrombosis (AT) and 11 venous thrombosis (VT). Nineteen patients had aPLA without APS defining the APS(−) group. Plasma PZ antigen concentrations were measured on citrated plasma using the commercial ELISA kit, Asserachrom protein Z, (Diagnostica Stago). Results: PZ plasma levels were normally distributed. Normal PZ concentrations defined as mean ±2 SD were contained between 0.4 and 2.6 μg/mL. No difference was found in mean+ SD between male and female. Two per cents of controls and 18% of patients with venous thrombosis had PZ under 0.4 μg/mL. Forty per cents of patients with OC, 25% with AT and 18% with VT had PZ above 2.6 μg/mL. Plasma protein Z levels measured at least 6 month after any clinical event were significantly higher in APS patients than in controls and APS(−) patients [mean ± SD μg/mL, 2.0 ± 0.9 vs 1.5 ± 0.5 and 1.3 ± 0.5 respectively). According to the clinical complications, PZ concentrations were significantly greater in the group with OC (2.4+0.6 μg/mL) and AT (2.05+0.8 μg/mL) than in controls (1.5+0.5 μg/mL), VT(1.3+0.9 μg/mL) and APS(−) (1.3+0.5 μg/mL) patients [OC vs Controls: p<0.0001; AT vs Controls: p= 0.0047; OC vs AT: p= NS; OC vs APS(−):p< 0.0001; OC vs VT: p= 0.0016, APS(−) vs controls: NS; APS(−) vs VT: NS; VT vs Controls: NS; APS(−) vs AT: p=0.0034; AT vs VT: p= 0.05]. We found an increased relative risk of OC and AT with increasing PZ levels with odds ratios of 7.1 [95% CI: 2.1–23.7] for OC and 2.4 [95% CI: 1.1–5.4] for AT. Conclusion: our study retrospective on a small size sample, indicates that high protein Z plasma could be a high risk for obstetrical complications and a lower risk for arterial thrombosis in aPLA patients. Measure of PZ could help to evaluate obstetrical and thrombotic risk of patients with aPLA. Further prospective studies are needed to confirm our results.

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Phospholipid inhibitors

Hämostaseologie ◽

10.5482/ha-1165 ◽

2011 ◽

Vol 31 (04) ◽

pp. 243-250 ◽

Cited By ~ 3

Author(s):

M. Galli

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Anticardiolipin Antibodies ◽

Low Molecular Weight ◽

Obstetrical Complications ◽

Glycoprotein I ◽

Long Duration ◽

Activity Dependent ◽

Cerebral Arterial Thrombosis

SummaryThe antiphospholipid syndrome (APS) is defined by the association of arterial and/or venous thrombosis and/or pregnancy complications with the presence of at least one among the main antiphospholipid antibodies (aPL) (i. e., Lupus anticoagulants, LA, IgG and/ or IgM anticardiolipin antibodies, aCL, IgG and/or IgM antiβ2-glycoprotein I antibodies, aβ2-GPI). Several clinical studies have consistently reported that LA is a stronger risk factor for both arterial and venous thrombosis compared to aCL and aβ2-GPI. In particular, LA activity dependent on the first domain of β2-GPI and triple aPL positivity are associated with the risk of thrombosis and obstetrical complications.Asymptomatic aPL-positive subjects do not require primary thromboprophylaxis. Venous thromboembolism is the most common initial clinical manifestation of APS. To prevent its recurrence indefinite anticoagulation is recommended. Long duration treatment with warfarin or aspirin is used after a first cerebral arterial thrombosis. Low molecular weight heparin (LMWH) with or without aspirin is recommended to reduce the rate of obstetrical complications of APS pregnant women.

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Arterial and Venous Thrombosis as a Symptom of Antiphospholipid Syndrome – A Noticeable Analysis from the Past.

Medical Research Archives ◽

10.18103/mra.v9i3.2359 ◽

2021 ◽

Vol 9 (3) ◽

Author(s):

Agata Kopydłowska ◽

Ewelina Wojtasińska ◽

Jolanta Kurosz ◽

Krystyna Zawilska ◽

Lidia Gil

Keyword(s):

Risk Factors ◽

Autoimmune Diseases ◽

Venous Thrombosis ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Protein C ◽

Fibrinogen Concentration ◽

Thrombotic Risk ◽

Asymptomatic Patients

Antiphospholipid syndrome (APS), defined as combination of venous and/or arterial thrombosis as well as obstetric complications with antiphospholipid antibodies presence in blood, is an example of acquired thrombophilia. The thrombotic episodes in the APS course are highly recurrent, with an increasing incidence with years after secondary anticoagulant prophylaxis cessation. In between 2005-2011 a study was conducted in Poznań, Poland, with the aim to find a correlation between actual APS diagnostic guidelines (criteria from Sydney’2006) and the clinical feature of thrombosis in this syndrome with coexistence of inherited thrombophilia and risk factors for cardio-vascular disease included. Additionally, a selection of the highest thromboembolic risk group was made among asymptomatic patients with antiphospholipid antibodies (APA) detected to compare with APS patients. An association between a type of laboratory test confirming the longtime APA presence and thrombotic risk was analyzed as well. The follow up had lasted for meanly 47 months and included 75 patients (50 females and 25 males) at the mean age of 43, divided into three groups (25 persons each): I – with asymptomatic APA, IIA – with arterial episodes in the history and IIB – with past venous complications in the course of APS. The majority of them comprised persons with primary APS or with asymptomatic APA (aAPA) - without any other autoimmune diseases. The laboratory tests included: lupus anticoagulant (LA) according to the 3-step procedure recommended by ISTH (International Society on Thrombosis and Hemostasis), anticardiolipin (ACA) – of IgG and IgM class and anti-β2-glycoprotein I (aβ 2 GPI) – of IgG class, both with the cut-off value of 99 percentile. D-dimer and fibrinogen concentration, protein C and antithrombin activity, activated protein C resistance, free protein S concentration, factor VIII were further analyzed. Among comorbidities and risk factors for venous and arterial thrombosis, there was significantly more frequent incidence of autoimmune diseases in the asymptomatic group of people compared to patients after thromboembolic episodes. Most often the aAPA presence was confirmed in the LA tests – the majority of positive results appeared among patients with asymptomatic course and with past venous thrombosis as well and less frequently - in the group of arterial episodes in the history. Any significant differences were found in the reference to the incidence of thrombotic episodes in the retrospective assessment of symptomatic patients and prospective – in the whole investigated group, although the time of their occurrence after beginning of observation period almost doubled in people with past thromboembolic episodes, comparing to the earlier asymptomatic persons.

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Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030520 ◽

2003 ◽

Vol 88 (12) ◽

pp. 5723-5729 ◽

Cited By ~ 125

Author(s):

A. W. F. T. Toorians ◽

M. C. L. G. D. Thomassen ◽

S. Zweegman ◽

E. J. P. Magdeleyns ◽

G. Tans ◽

...

Keyword(s):

Venous Thrombosis ◽

Plasma Protein ◽

Plasma Levels ◽

Protein C ◽

Ethinyl Estradiol ◽

Protein S ◽

Hormone Treatment ◽

Moderate Increase ◽

Thrombotic Risk ◽

Apc Resistance

Abstract The incidence of venous thrombosis associated with estrogen treatment in male-to-female (M→F) transsexuals is considerably higher with administration of oral ethinyl estradiol (EE) than with transdermal (td) 17-β-estradiol (E2). To find an explanation for the different thrombotic risks of oral EE and td E2 use, we compared the effects of treatment of M→F transsexuals with cyproterone acetate (CPA) only, and with CPA in combination with td E2, oral EE, or oral E2 on a number of hemostatic variables [activated protein C (APC) resistance and plasma levels of protein S, protein C, and prothombin], all of which are documented risk factors for venous thrombosis. APC resistance was determined by quantification of the effect of APC on the amount of thrombin generated during tissue factor-initiated coagulation; plasma levels of total and free protein S were determined by standard ELISA; and levels of prothrombin and protein C were determined with functional assays after complete activation of the zymogens with specific snake venom proteases. CPA-only, td-E2+CPA, or oral-E2+CPA treatment produced rather small effects on hemostatic variables, whereas oral EE treatment resulted in a large increase in APC resistance from 1.2 ± 0.8 to 4.1 ± 1 (P < 0.001), a moderate increase in plasma protein C (9%; P = 0.012), and a large decrease in both total and free plasma protein S (30%; P < 0.005). The large differential effect of oral EE and oral E2 indicates that the prothrombotic effect of EE is due to its molecular structure rather than to a first-pass liver effect (which they share). Moreover, these differences may explain why M→F transsexuals treated with oral EE are exposed to a higher thrombotic risk than transsexuals treated with td E2. Testosterone administration to female-to-male transsexuals had an antithrombotic effect.

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Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis

Thrombosis and Haemostasis ◽

10.1160/th04-03-0138 ◽

2004 ◽

Vol 92 (12) ◽

pp. 1312-1319 ◽

Cited By ~ 11

Author(s):

Jeannine Kassis ◽

Carolyn Neville ◽

Joyce Rauch ◽

Lambert Busque ◽

Erika Chang ◽

...

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Protein C ◽

Complete Blood Count ◽

Tertiary Care ◽

Activated Protein C ◽

Factor V Leiden ◽

Activated Protein C Resistance ◽

Increased Risk

SummaryAlthough antiphospholipid antibodies (aPL) are associated with thrombosis, it is not known who with aPL is at higher risk for thrombosis. It was the aim of this cross-sectional study to investigate how thrombophilic factors contribute to venous or arterial thrombosis in aPL-positive individuals. In outpatient test centres at two tertiary care hospitals, two hundred and eight (208) persons requiring aPL testing were matched by age, gender and centre to 208 persons requiring a complete blood count. Persons were classified as aPL-positive (having anticardiolipin, lupus anticoagulant and/or anti-β2-glycoprotein I antibodies) or aPL-negative. Several thrombophilic factors were studied using logistic regression modelling. Results showed that the aPL-positive group had three-fold more events (37%) than the aPL-negative group (12%). In unadjusted analyses, clinically important associations were observed between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35-11.91; 4.79, 2.03-11.33; and 2.03, 1.03-3.97, respectively). After adjusting for recruitment group, persons with both APCR and aPL had a three-fold greater risk (OR, 95% CI = 3.31, 1.30-8.41) for venous thrombosis than those with neither APCR nor aPL. Similarly, after adjusting for hypertension, family history of cardiovascular disease, gender and recruitment group, persons with both hyperhomocysteinemia and aPL had a five-fold increased risk (OR, 95% CI = 4.90, 1.37-17.37) for arterial thrombosis compared to those with neither risk factor. In conclusion, APCR phenotype and hyperhomocysteinemia are associated with a higher risk of venous and arterial thrombosis, respectively, in the presence of aPL.

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Determinants of Risk for Venous and Arterial Thrombosis in Primary Antiphospholipid Syndrome and in Antiphospholipid Syndrome with Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.081194 ◽

2009 ◽

Vol 36 (6) ◽

pp. 1195-1199 ◽

Cited By ~ 105

Author(s):

ADRIANA DANOWSKI ◽

MARIO NEWTON LEITÃO de AZEVEDO ◽

JOSE ANGELO de SOUZA PAPI ◽

MICHELLE PETRI

Keyword(s):

Systemic Lupus Erythematosus ◽

Venous Thrombosis ◽

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Pregnancy Loss ◽

Fold Increase ◽

Systemic Lupus ◽

Hereditary Thrombophilia

Objective.Antiphospholipid syndrome (APS) is characterized by thrombosis (venous and arterial) and pregnancy loss in conjunction with the lupus anticoagulant, IgG or IgM anticardiolipin, or IgG or IgM anti-ß2-glycoprotein I. In most series, only a minority of patients with antiphospholipid antibodies develop a clinical manifestation.Methods.A cross-sectional study of consecutive patients in the Hopkins Lupus Center was performed. Interviews were done and records were reviewed for the following variables: gender, ethnicity, hypertension, triglycerides, cholesterol, smoking, diabetes mellitus, homocysteine, cancer, hepatitis C, hormone replacement therapy/oral contraceptives, hereditary thrombophilia, anticardiolipin antibodies IgG, IgM and IgA, and lupus anticoagulant (LAC). Our aim was to identify risk factors associated with thrombosis and pregnancy loss in patients with antiphospholipid antibodies.Results.A total of 122 patients (84% female, 74% Caucasian) were studied. Patients were divided into 3 groups: primary APS, APS associated with systemic lupus erythematosus, and patients with systemic lupus erythematosus (SLE) with antiphospholipid antibodies but no thrombosis or pregnancy loss. Venous thrombosis was associated with high triglycerides (p = 0.001), hereditary thrombophilia (p = 0.02), anticardiolipin antibodies IgG > 40 (p = 0.04), and LAC (p = 0.012). Hypertriglyceridemia was associated with a 6.4-fold increase, hereditary thrombophilia with a 7.3-fold increase, and anticardiolipin IgG > 40 GPL with a 2.8-fold increase in the risk of venous thrombosis. Arterial thrombosis was associated with hypertension (p = 0.008) and elevated homocysteine (p = 0.044). Hypertension was associated with a 2.4-fold increase in the risk of arterial thrombosis. No correlations were found for pregnancy loss.Conclusion.The frequency of thrombosis and pregnancy loss is greater in APS associated with SLE than in primary APS. Risk factors differ for venous and arterial thrombosis in APS. Treatment of hypertension may be the most important intervention to reduce arterial thrombosis. Elevated triglycerides are a major associate of venous thrombosis, but the benefit of treatment is not known. Hereditary thrombophilia is an associate of venous but not arterial thrombosis, making it cost-effective to investigate only in venous thrombosis.

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Plasma protein Z deficiency is common in women with antiphospholipid antibodies

British Journal of Haematology ◽

10.1046/j.1365-2141.2003.04151_5.x ◽

2003 ◽

Vol 120 (5) ◽

pp. 913-914 ◽

Cited By ~ 21

Author(s):

M. D. McColl ◽

A. Deans ◽

P. Maclean ◽

R. C. Tait ◽

I. A. Greer ◽

...

Keyword(s):

Plasma Protein ◽

Antiphospholipid Antibodies ◽

Protein Z

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Neutrophil-to-Lymphocyte Ratio (NLR) Is a Risk Factor for Venous Thrombosis in Polycythemia Vera

Blood ◽

10.1182/blood-2021-146793 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1499-1499

Author(s):

Alessandra Carobbio ◽

Alessandro Vannucchi ◽

Paola Guglielmelli ◽

Giuseppe Gaetano Loscocco ◽

Ayalew Tefferi ◽

...

Keyword(s):

Risk Factor ◽

Venous Thrombosis ◽

Polycythemia Vera ◽

Board Of Directors ◽

Arterial Thrombosis ◽

Research Funding ◽

Multivariate Model ◽

Advisory Committees ◽

Thrombotic Risk ◽

Lymphocyte Ratio

Abstract Background. The tendency towards thrombosis in myeloproliferative neoplasms (MPNs) is linked to the JAK2-mutant clone which leads to hypercellularity and functional interplay between abnormal erythrocytes, platelets, leukocytes and dysfunctional endothelium. The resulting cell activation that also involves stromal cells in their microenvironment, has been shown associated with chronic, systemic, subclinical pro-inflammatory state, and has been implicated in the pathogenesis of thrombosis in MPN. Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory marker found to be associated with the severity and prognosis of cardiovascular diseases but there is little evidence for its prognostic significance in MPN. We investigated whether NLR could predict the onset of arterial and venous thrombosis in polycythemia vera (PV). Methods. Subjects of this study were 1508 patients included in the ECLAP trail with NLR evaluation available. In addition to standard statistical methods, we used proportional hazards additive models (GAM) as they can provide an excellent fit in the presence of nonlinear relationships, for the prediction of total, arterial and venous thrombosis as smooth functions with cubic splines of different blood parameters. Results. After a median follow-up of 2.76 years, 169 thrombotic events (10.3%) were objectively diagnosed and analyzed: 87 arterial (MI, Stroke, TIA, PAT) and 88 venous thrombosis (DVT±PE, superficial thrombophlebitis). In univariate analysis, arterial thrombosis was associated with age (p=0.003) and previous thrombosis, especially if arterial (p<0.001), and with the presence of at least one cardiovascular risk factor (p=0.009). No association between baseline platelet and leukocyte counts and NLR with arterial events was found. Conversely, in venous thrombosis, beside age (p=0.039) and history of venous thrombosis (p<0.001), additional risk factors were low hemoglobin (p=0.039) and increasing values of NLR (p=0.002) resulting from a simultaneous increase of neutrophils (p=0.002) and to a decrease of absolute number lymphocytes (p=0.002).To predict outcomes, we tested total leukocytes, neutrophils, lymphocytes, platelets and NLR by GAM to evaluate their trend in continuous scale of thrombotic risk. A significant association between the risk of venous thrombosis and the progressive lower counts of lymphocytes (p=0.002) emerged, leading to increase the NLR values (p=0.005). However, given the greater precision of the NLR estimates and the markedly wide confidence interval of lymphocyte counts estimates, NLR was used in multivariate model. Conversely, neither absolute values of neutrophils and lymphocytes nor NLR were found associated with arterial events.In multivariate model, adjusted for age, gender and treatments at baseline, the risk of venous thrombosis was independently associated with previous venous events (HR=5.48, p ≤0.001) and NLR values ≥5 -the best cut-off resulted applying the Liu's method (HR=2.13, p=0.001). NLR effect for total venous thrombosis was not modified by excluding superficial venous thrombosis (HR=2.90, p=0.001) in a sensitivity analysis. Older age (i.e., ≥65 years, HR=1.88, p=0.005) and previous arterial thrombosis (HR=1.92, p=0.003) retained the prognostic statistical significance for arterial thrombosis.Our learning cohort findings, indicating a correlation between NLR values and venous thrombosis, have been validated in two Italian independent external cohorts (Florence, n=282 and Rome, n=173) of contemporary PV patients (Figure 1). Conclusions. The NLR is an inexpensive and easily accessible test compared to other inflammatory markers. We found that NLR-alone is an independent predictor of venous thrombosis and could be included in a new scoring system. In addition to guiding the stratification of thrombotic risk, these data confirm that inflammation is a relevant target of antithrombotic therapy in PV. Figure 1 Figure 1. Disclosures Vannucchi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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No Thrombotic Risk in Patients with Asymptomatic Antiphospholipid Antibodies

Blood ◽

10.1182/blood.v118.21.5254.5254 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5254-5254

Author(s):

Krystyna M Zawilska ◽

Agata M Kopydlowska

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Study Group ◽

Hemorrhagic Diathesis ◽

Thromboembolic Events ◽

Systemic Lupus ◽

Thrombotic Risk ◽

Abnormal Results

Abstract Abstract 5254 Aim of the study. Antiphospholipid antibodies (APA) are well known risk factor for thromboembolic events and/or obstetric complications. They may be found incidentally in patients without thrombotic complications (asymptomatic APA), and they often lead to an incorrect suspicion of hemorrhagic diathesis, as well as to an unnecessary disqualification from surgical procedures or withdrawal from a proper antithrombotic prophylaxis during these procedures. The aim of the study was to register venous and/or thrombotic events in a group of patients with asymptomatic APA, diagnosed according to the international guidelines (Myakis et all. 2006). Material and methods. The study group consisted of 25 patients (18 women and 7 men) of the mean age of 46 years (20 – 75 years). Concomitantly 9 of them had other autoimmune disorders (no systemic lupus erythematosus) and 4 had neoplasms. Among risk factors for arterial thrombosis 5 patients had hypercholesterolemia, 5 – hypertension, 4 were smokers and 4 were obese (BMI >30 kg/m2). None of the patients had hereditary thrombophilia (antithrombin, protein C or protein S deficiency, factor V Leiden, prothrombin G20210A mutation, increased activity of factor VIII). Family history of venous thromboembolic disease has been noticed in 4 patients and of arterial thrombosis in 6 patients. The observation lasted for 3 to 127 months (mean 35 months). Results. The number and percent of patients (n = 25) with abnormal results 997337of different laboratory diagnostic assays for APA: aPTT-activated partial thromboplastin time; dRVVT - diluted Russell viper venom time; ACA-anticardiolipin antibodies; β2-GPI – anti-β2–glycoprotein I antibodies Abnormal results of more than one assay in any combination were found in 16 patients, lupus anticoagulant alone in 9 patients. Only 4 out of 25 patients have taken aspirin - 75mg daily, in the other 4 a prophylactic dose of low molecular weight heparin was administered temporarily because of surgery. During observation time no venous or arterial thrombotic events occurred in the study group. On a basis of a limited number of previous studies that predominantly included systemic lupus erythematosus patients, aPL-positive patients without previous thrombosis have a 0% to 3.8% annual incident thrombosis risk (Barbhaiya M, Erksan D. Curr Rheumatol Rep. 2011; 13: 59–69). In two patients asymptomatic APA disappeared. Conclusion: independently of the type and quantity of asymptomatic antiphospholipid antibodies, there were no venous or arterial thromboembolic events in the group of patients observed for meanly 35 months. Disclosures: No relevant conflicts of interest to declare.

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A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

Blood ◽

10.1182/blood-2005-08-3249 ◽

2006 ◽

Vol 108 (1) ◽

pp. 177-183 ◽

Cited By ~ 43

Author(s):

Javier Corral ◽

Rocio González-Conejero ◽

Jose Manuel Soria ◽

Jose Ramón González-Porras ◽

Elena Pérez-Ceballos ◽

...

Keyword(s):

Protease Inhibitor ◽

Venous Thrombosis ◽

Stop Codon ◽

Anticoagulant Activity ◽

Low Frequency ◽

Protein Z ◽

Antithrombin Deficiency ◽

Thrombotic Risk ◽

Genetic Modifications ◽

History Of

The protein Z-dependent protease inhibitor (ZPI) is a hemostatic serpin with anticoagulant activity. As for antithrombin, deficiency of ZPI could have relevant thrombotic consequences. We have studied 6 genetic modifications affecting the ZPI gene, identifying 5 haplotypes. Haplotype H5 is featured by a stop codon at position 67. The relevance of these genetic modifications and haplotypes in venous thrombosis was evaluated in a case-control study including 1018 patients and 1018 age- and sex-matched controls. Surprisingly, the H5 haplotype was found in 0.9% of controls, supporting that the Arg67Stop change is a low frequency nonsense polymorphism. The prevalence of this haplotype increased significantly in patients (3.0%), one of whom was in a homozygous state. Multivariate analysis confirms that carriers have a 3.3-fold risk of developing venous thrombosis (P = .002; 95% CI: 1.5-7.1). Moreover, we observed a significant association of this polymorphism with familial history of thrombosis (P < .001). Our study supports that the ZPI Arg67Stop nonsense polymorphism might be an independent genetic risk factor for venous thrombosis. This polymorphism has slightly lower prevalence but similar thrombotic risk than the FV Leiden or prothrombin 20210A. Although further studies are required, all available data support that the ZPI is a candidate to play a significant role in thrombosis and should be evaluated in thrombophilic studies. (Blood. 2006;108:177-183)

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Identifying additional risk factors for arterial and venous thrombosis among pediatric antiphospholipid antibodies carriers

Lupus ◽

10.1177/09612033211002256 ◽

2021 ◽

pp. 096120332110022

Author(s):

Elizabeth Sloan ◽

Tracey Wright ◽

Yu Zuo

Keyword(s):

Risk Factors ◽

Connective Tissue ◽

Venous Thrombosis ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Pediatric Patients ◽

Univariate Analysis ◽

Connective Tissue Diseases ◽

Additional Risk ◽

Potential Predictor

Background Antiphospholipid antibodies (aPL) have been extensively reported in children, but investigations into thrombotic risks associated with aPL positivity in pediatric patients is scarce. Positive aPL are not uncommon in pediatric connective tissue diseases (CTD), but identification and management of these patients is challenging due to lack of validated criteria and a paucity of data. In this study, we identify potential additional risk factors for thrombosis in a unique cohort of pediatric aPL positive carriers. Methods Retrospective chart review was performed on 491 pediatric patients with CTD seen in our institution from 2001 to 2019. Patients without persistently moderate to high titer aPL at least 12 weeks apart were excluded. Univariate analysis was performed to evaluate correlation between different risk factors and thrombotic events. Results Seventy-one aPL positive children with underlying CTD are included in this cohort. The majority (87%) are female and of Hispanic ethnicity (56%). Mean age of the cohort at the diagnosis of connective tissue disease is 12.7 (SD 2.6) years, and mean age of first positive aPL is 13.3 (SD 2.5) years. Average length of follow-up is 4.3 (SD 2.5) years. Four (5.6%) patients experienced arterial thrombosis, and 11 (15.5%) had venous thrombosis. Fifty-seven (80.3%) patients did not have any thromboembolic events. Among traditional risk factors and signs of endothelial injury, only Raynaud’s phenomena demonstrated significant association with arterial thrombosis (OR = 8.4, 95%CI 1.13–111, P = 0.039), and hypertension or anti-hypertensive use demonstrated significant association with venous thrombosis (OR = 8.387, 95%CI 1.2 – 94, P = 0.02). Conclusion Data from our cohort suggest that Raynaud’s phenomenon is a potential predictor of arterial thrombosis while the presence of hypertension or anti-hypertensive medication use is a potential predictor of venous thrombosis in aPL positive pediatric carriers. Further studies investigating pediatric aPL profiles and risk factors for development of thrombosis are needed to help guide clinicians in caring for these challenging patients.

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