Antiphospholipid Antibodies in Iraqi Women with Recurrent Mid-Trimester Abortions

ABSTRACT Purpose: Antiphospholipid antibodies are often associated with recurrent pregnancy loss, and although many studies have addressed this association in Western countries, such studies are not so frequent from developing countries. The current study aims to determine the frequency of Antiphospholipid antibodies (Anticardiolipin antibodies and Lupus anticoagulant) among Iraqi women with recurrent mid-trimester abortions and to evaluate various tests used for their detection. Materials and Methods: Two hundred women with recurrent mid-trimester abortions were randomly enrolled from a main referral center in Baghdad-Iraq. The enrollees had their IgG and IgM anticardiolipin antibodies assayed by ELISA, and Lupus anticoagulant by a combination of the following screening tests: Activated Partial Thromboplastine Time (APTT), and Partial Thromboplastine Time-LA (PTT-LA), Kaolin Clotting Time (KCT) and confirmation was made by Hexagonal phospholipid neutralization test. Results: The women were aged between 19 and 45 years (median 30 years). Fifty three (26.5%) had one or both anticardiolipin antibodies present, while 27 (13.5%) were positive for lupus anticoagulant. The KCT and KCT index appeared to be the most sensitive tests, while the KCT index and APTT were the most specific for Lupus anticoagulant. Patients with antiphospholipid antibodies had higher rates of history of thrombosis, thrombocytopenia and family history of recurrent abortion (P = 0.0009, 0.0056 and 0.0003 respectively). Conclusions: Antiphospholipid antibodies constitute an important cause of recurrent mid-trimester abortion in Iraqi women, with frequencies intermediate between Western and Indian reports. While thrombocytopenia and thrombosis are well documented associations of antiphospholipid antibodies, the significant association with family history of recurrent fetal loss is intriguing and requires further scrutiny.

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The Influence of Antiphospholipid Antibodies on the Pregnancy Outcome of Patients With Recurrent Spontaneous Abortion

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602960100700405 ◽

2001 ◽

Vol 7 (4) ◽

pp. 281-285 ◽

Cited By ~ 9

Author(s):

L. Heilmann ◽

G.-F. v. Tempelhoff ◽

S. Kuse

Keyword(s):

Pregnant Women ◽

Intravenous Immunoglobulin ◽

Spontaneous Abortion ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Standard Therapy ◽

Loss Rate ◽

Fetal Loss ◽

Negative Group ◽

History Of

Several therapeutic regimens have been proposed for women with recurrent spontaneous abortion (RSA) and antiphospholipid antibodies (APA). Conflicting results have been reported about women with history of RSA, positive APA, and failure of standard therapy. To evaluate the use of intravenous immunoglobulin in RSA patients with APA and history of treatment failure, we initiated a study with standard therapy (aspirin and low-molecular- weight heparin) and intravenous immunoglobulin. We used an enzyme-linked immunosorbent assay (ELISA)test to screen IgG and IgM anticardiolipin antibodies, and a diluted Russel viper venom time assay for the lupus anticoagulant activity. Altogether. 66 pregnant women with positive APAs at the first visit could be included. Patients with hereditable thrainbaghilic factors were excluded. After confirmation of the pregnancy, women received a basis immunization of 0.3 g/kg immunoglobulin in a 4-week cycle until the 28th to 32nd week of gestation. All patients received 100 mg/d aspirin and 3,000 anti-Xa U/d certoparin. Among the 66 pregnant women, 17 were persistently autoantibody positive (25.8%), of whom 11 (16.7%) were ACA positive alone, 2 (3%) were lupus anticoagulant positive, and 4 (6.4%) had both antibody types. A total of 49 patients had positive APAs at the initial test, but were negative for ACA and lupus anticoagulant at the second test administered approximately 5 weeks after the start of therapy. We described this group in our following observation as "antibody negative." Sixteen of the 17 autoantibody-positive patients (94.1 %) were delivered of live infants compared with 40 patients (81.6%) in the antibody-negative group (odds ratio [OR]: 1.2; 95% CI: 0.98 to 1.4). The overall miscarriage rate was 12.1% and the fetal loss rate was 15.2%. Four patients (25%) in the antibody-positive group developed symptoms of preeclampsia and fetal growth retardation compared with four patients (9.8%) in the antibody-negative group. In conclusion. we see a reduction of the fetal loss rate in patients with RSA and positive APA (5.8%) compared with APAnegative (18.4%) women with the same therapy (OR: 0.3; 95% CI: 0.04 to 2.3).

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Anticardiolipin Antibodies Block the Inhibition by β2-Glycoprotein I of the Factor Xa Generating Activity of Platelets

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649577 ◽

1993 ◽

Vol 70 (02) ◽

pp. 342-345 ◽

Cited By ~ 88

Author(s):

Wei Shi ◽

Beng H Chong ◽

Philip J Hogg ◽

Colin N Chesterman

Keyword(s):

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Fetal Loss ◽

Factor Xa ◽

Anticardiolipin Antibodies ◽

Recurrent Fetal Loss ◽

Glycoprotein I ◽

Activated Platelets ◽

Inhibit Factor

SummaryAntiphospholipid antibodies, defined either by lupus anticoagulant (LA) activity or positive anticardiolipin immunoabsorbent assay (ACA) are associated with a predisposition to thromboses, recurrent fetal loss or thrombocytopenia. The mechanisms for these predispositions remain undefined. We have enriched immunoglobulin fractions from two patient plasmas to obtain antibodies with LA activity but no ACA, or conversely, with ACA positivity but no LA, in order to investigate in vitro characteristics which might explain a thrombotic propensity. β2-glycoprotein I (β2-GPI), the plasma cofactor required for ACA binding to negatively charged phospholipid, has previously been shown to inhibit prothrombinase generation in the presence of activated platelets (8). We now report that β2-GPI, at physiological concentrations, inhibits the generation of factor Xa in the presence of activated gel-filtered platelets. Further, ACA interferes with this inhibition, resulting in protracted, unopposed factor Xa generation. This interference with β2-GPI, a natural anticoagulant component of plasma, is potentially prothrombotic. LA immunoglobulins behave differently and inhibit factor Xa generation in a manner similar to β2-GPI. These findings provide the basis for a previously unsuspected mechanism for thrombosis in patients with aPL.

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The Association Between Antiphospholipid Antibodies and Adverse Pregnancy Outcomes: A Metaanalysis.

Blood ◽

10.1182/blood.v112.11.1819.1819 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1819-1819

Author(s):

Karim Abou-Nassar ◽

Marc Carrier ◽

Marc Rodger

Keyword(s):

Pregnancy Outcomes ◽

Pregnancy Complications ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Placental Abruption ◽

Fetal Loss ◽

Anticardiolipin Antibodies ◽

Adverse Pregnancy Outcomes ◽

Clinical Criteria ◽

Adverse Pregnancy

Abstract BACKGROUND: The Sapporo criteria for the diagnosis of the antiphospholipid syndrome (APS) are based on the presence of antiphospholipid antibodies (APLA) and clinical criteria. Although pre-eclampsia, intra-uterine growth restriction (IUGR), late fetal loss and placental abruption, collectively termed “placenta mediated complications”, are recognized as clinical criteria for the APS, their association with APLA remains controversial. OBJECTIVE: This review was conducted to evaluate the association between APLA (anticardiolipin antibodies, lupus anticoagulant, anti B2 glycoprotein 1 antibodies) and placenta mediated complications in untreated women without autoimmune diseases. METHODS: We performed a systematic review of published case-control, cohort and cross sectional studies using MEDLINE (1975 to October week 2 2007), EMBASE 16 (1980 to 2007 week 42) and all EBM Reviews (3rd quarter of 2007). For eligible studies, the rates of adverse pregnancy outcomes were compared between patients with and without specific APLA. Pooled odds ratios with 95% CI were generated using random-effects models. RESULTS: Our search strategy identified 1204 potentially relevant studies. Twenty five were included in the final analysis. Results are outlined in table 1. CONCLUSION: The association between various APLA and pregnancy complications is for the most part weak and inconsistent. There is currently insufficient data to support a significant link between anti-B2 glycoprotein 1 antibodies and pregnancy morbidity. Caution should be used when establishing a diagnosis of APS based on the presence of any APLA, particularly anti-B2 glycoprotein 1 antibodies, in the setting of late pregnancy complications. Table 1 Association Between APLA and Adverse Pregnancy Outcomes Pre-eclampsia OR (95%CI) # studies / participants IUGR OR (95%CI) # studies / participants Placental abruption OR (95%CI) # studies / participants Late fetal loss OR (95%CI) # studies / participants LA: Lupus anticoagulant; aCL: Anticardiolipin antibodies; Anti-B2 GP1 antibodies: Anti-B2 glycoprotein 1 antibodies italic characters indicate statistically significant associations LA 2.88 (1.42, 5.87)  11 / 6085 3.51 (1.38, 8.93)  4 / 3232 0.78 (0.13, 4.80)  2 / 226 3.56 (0.12, 106.05)  3 / 3870 aCL (IgG/IgM) 1.71 (1.09, 2.70)  21 / 9722 2.31 (0.74, 7.17)  6 / 5753 1.35 (0.45, 4.02)  4 / 1274 3.86 (1.14, 13.07)  7 / 5963 aCL IgG 1.65 (0.84, 3.22)  15 / 3627 6.16 (2.50, 15.18)  2 / 1006 1.87 (0.21, 16.83)  2 / 500 10.06 (0.88, 114.96)  2 / 1006 aCL IgM 1.36 (0.93, 1.97)  13 / 5397 0.75 (0.19, 2.93)  2 / 3002 0.96 (0.24, 3.85)  2 / 500 1.37 (0.42, 4.46)  3 / 3212 anti- B2GP1 (IgG/IgM) 2.97 (0.47, 18.69)  4 / 2225 20.03 (4.59, 87.43)  1 / 1108 2.64 (0.14, 50.63)  1 / 510 6.74 (0.24, 191.23)  3 / 1828 anti- B2GP1 IgG 0.87 (0.38, 2.01)  2 / 607 N/A  0 / 0 N/A  0 / 0 0.52 (0.02, 11.02)  1 / 212 anti- B2GP1 IgM 0.37 (0.16, 0.85)  1 / 400 N/A  0 / 0 N/A  0 / 0 1.32 (0.24, 7.42)  1 / 210

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Detection of Lupus Anticoagulant In Women with Obstetric complications

Blood ◽

10.1182/blood.v116.21.3185.3185 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3185-3185

Author(s):

Andrea Laura Avigliano ◽

Juan Carlos Galli ◽

Beatriz Grand

Keyword(s):

Lupus Anticoagulant ◽

Conflicts Of Interest ◽

Fetal Loss ◽

Negative Control ◽

Screening Tests ◽

Initial Cohort ◽

Uterine Growth ◽

Confirmatory Tests ◽

History Of ◽

Low Performance

Abstract Abstract 3185 Introduction: Lupus anticoagulant (LA) is one of the laboratory criteria for the diagnosis of antiphospholipid syndrome. To detect the presence of LA, ISTH recommends performing two assays based on different principles. Our LA profile includes dilute Russell viper venom time (dRVVT) and two different activated partial thromboplastin time (aPTT) reagents. The aim of the study was to evaluate sensitivity and specificity of aPTT and dRVVT in women with a history of pre-eclampsia, intra-uterine growth restriction, early recurrent abortion, late fetal loss and placental abruption collectively termed “placenta mediated complications”. Materials and Methods: We studied a total of 247 patients and 287 samples in a 10 months period. Based on consensus criteria, samples were retested within a period of three months. 62/247 plasmas samples were collected during pregnancy. Laboratory studies: Screening tests: aPTT was performed using PTT-LA (Stago) and an aPTT home made reagent with diluted cephalin. dRVVT was performed using Russel viper venom RVV (Stago) and diluted cephalin. Negative control plasma was prepared according to ISTH LA recommendations for the mixing tests. Confirmatory tests: We performed a home made reagent for platelet neutralization procedure (PNP)-aPTT and dRVVT; Rosner Index and % of Correction as criteria for mixing and confirmatory tests interpretation. Statistical evaluation was performed by ROC method using EP Evaluator 9.9 software. Results: 172/287 samples (59.9%) were negative, while 115/287 samples (40.1%) were positive for LA. 44/115 samples (38.26%) were positive for both tests (aPTT and dRVVT), 60/115 samples (52.17 %) were positive only for dRVVT and 11/115 samples (9.57%) were positive only for aPTT. LA was confirmed in 9/62 pregnant women samples (14.5 %). 7 (11.3%) had abnormal dRVVT, the remaining 2 samples were positive for both tests. Conclusions: Our results demonstrated: 1- High prevalence of dRVVT positive plasmas 104/115 (90.43%); 2- Despite showing a low performance regarding sensitivity when compared to dRVVT, both aPTT tests were able to detect LA in 47.83% of the positive studies. 3- According to our experience, considering this initial cohort of selected patients, the use of dRVVT as the first and aPTT as the second screening test may help improve the performance for the diagnosis of LA. Disclosures: No relevant conflicts of interest to declare.

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IgA Anticardiolipin Antibodies – Relation with other Antiphospholipid Antibodies and Clinical Significance

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614978 ◽

1998 ◽

Vol 79 (02) ◽

pp. 282-285 ◽

Cited By ~ 49

Author(s):

Josep Ordi-Ros ◽

Francesc Monegal-Ferran ◽

Nuria Martinez ◽

Fina Cortes-Hernandez ◽

Miquel Vilardell-Tarres ◽

...

Keyword(s):

Lupus Erythematosus ◽

Antiphospholipid Antibodies ◽

Fetal Loss ◽

Cross Sectional Study ◽

Anticardiolipin Antibodies ◽

Antiphospholipid Antibody ◽

Antiphospholipid Antibody Syndrome ◽

Serum Samples ◽

Cross Sectional ◽

Vein Thrombosis

SummaryObjective: To evaluate the usefulness of IgA antiphospholipid antibodies as markers of thrombosis and/or antiphospholipid antibody syndrome. Patients and Methods: A cross-sectional study design in a tertiary, university-based, autoimmune reference hospital. Seven-hundred ninety-five patients classified into five different groups – autoimmune diseases (255), deep vein thrombosis (153), transitory ischemic attacks (108), obstetric complications (196), infectious diseases (83) and controls (81) – were tested for IgA, IgG and IgM aPL, and lupus anticoagulant. Plasma and serum samples were drawn for detection of aPL using an internationally standardized ELISA method and LA was carried out using coagulometric assays. Results: True IgA aPL were found only in two patients with systemic lupus erythematosus; these patients were also positive to IgG aPL. Conclusion: The incidence of true positivity to IgA anticardiolipin antibodies is extremely low. Their determination was not helpful in diagnosing the antiphospholipid syndrome or in explaining thrombotic events or aPL related manifestations – fetal loss – in the groups studied.

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Hemostasis system and immunomorphologic state of placenta under presence of antiphospholipid antibodies in plasma with consideration of their class and pregnancy outcome

Journal of obstetrics and women s diseases ◽

10.17816/jowd86971 ◽

2004 ◽

Vol 53 (1) ◽

pp. 22-26

Author(s):

N. G. Kosheleva ◽

L. В. Zubzhitskaia ◽

О. N. Arzhanova ◽

О. V. Tyshkevich ◽

Y. Gromyko ◽

...

Keyword(s):

Pregnancy Outcome ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Recurrent Miscarriage ◽

Anticardiolipin Antibodies ◽

Research Groups ◽

Hemostasis System ◽

Autoimmune Antibodies ◽

Glycoprotein I ◽

Tissue Damages

The present study was undertaken to investigate hemostasis system of 197 women with recurrent miscarriage: Analysis placentas by immunomorphology are studied of 41 women and of 52 women with autoimmune antibodies to 2-glycoprotein-I (2-GPI) in placenta. There was exposed hyperactivation platelets blood of all women with antiphospholipid antibodies irrespective of groups with significantly was increased at the beginning of pregnancy and progressed with growing gestation. As result of investigation it is determined certain connection between outcome of pregnancy and activation degree platelets blood in vasculars. Was found absence influence anticardiolipin antibodies (aCL) on plasmocoagulative link hemostasis. The circulation of lupus anticoagulant (LA) was accompanied indication of hypercoagulation. In all research groups was determined significant oppression of fibrinolisis. Analysis placentas by immunomorphology was determined significantly tissue damages with LA and 2-GPI-dependent aCL.

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Detection of antitrophoblast antibodies in the sera of patients with anticardiolipin antibodies and fetal loss

Blood ◽

10.1182/blood.v82.9.2730.2730 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2730-2741 ◽

Cited By ~ 35

Author(s):

KR McCrae ◽

AM DeMichele ◽

P Pandhi ◽

MJ Balsai ◽

P Samuels ◽

...

Keyword(s):

Fetal Loss ◽

Thromboxane A2 ◽

First Trimester ◽

Anticardiolipin Antibodies ◽

Trophoblast Cells ◽

Fetal Demise ◽

Blood Fluidity ◽

Increased Risk ◽

History Of ◽

Placental Blood

Abstract Women with anticardiolipin antibodies (ACLA) are at increased risk for fetal loss. One potential explanation for this outcome is that sera from these individuals contain antibodies reactive with trophoblast cells, which are involved in the establishment of the uteroplacental vasculature and maintenance of placental blood fluidity. To examine this hypothesis, we compared the incidence of trophoblast-reactive antibodies in 27 patients with ACLA and a history of fetal loss with that in 29 normal pregnant women. Sera from 20 patients, but only one control, contained trophoblast-reactive antibodies (P < .001). These antibodies were not directed against major histocompatibility class I antigens, and reacted with both term and first-trimester trophoblast cells. In most cases, sera from which ACLA were adsorbed by cardiolipin- containing liposomes maintained reactivity against cells. In addition, patient Ig fractions immunoprecipitated an approximately 62-kD protein from the trophoblast cell surface, stimulated the release of arachidonic acid and thromboxane A2 by trophoblasts, and inhibited the binding of prourokinase to trophoblast urokinase receptors. These observations show that sera from women with ACLA and a history of fetal loss contain antitrophoblast antibodies. These antibodies may be serologically distinct from ACLA, and may contribute to the pathogenesis of fetal demise.

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Patients with the Antiphospholipid Syndrome (APLS) Show Hypercoagulability Due to Hypofibrinolysis and Increased Fibrin Generation, but Thrombin Generation Is Variable

Blood ◽

10.1182/blood.v112.11.3833.3833 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3833-3833

Author(s):

Jennifer L Curnow ◽

Marie-Christine Morel-Kopp ◽

Ninfa Rojas ◽

Margaret Aboud ◽

Christopher Ward

Keyword(s):

Lupus Anticoagulant ◽

Thrombin Generation ◽

Thrombotic Event ◽

Anticardiolipin Antibodies ◽

Hypercoagulable State ◽

Control Group ◽

Royal North Shore Hospital ◽

Thrombin Generation Assay ◽

Healthy Donors ◽

History Of

Abstract We have previously demonstrated hypercoagulability utilizing a global haemostatic assay, the Overall Haemostatic Potential (OHP) in a heterogenous population of patients with a demonstrable lupus anticoagulant. Our aim in this study was to determine whether the OHP assay demonstrated a persistent hypercoagulable state in a well-defined prospective population with APLS and whether global assays were able to predict the occurrence of thrombotic complications. Informed consent was obtained and blood was collected on three occasions, three months apart from 54 patients with APLS, recruited from Haematology clinics at Royal North Shore Hospital, Sydney, Australia between May 2005 and November 2007. Clinical data was collected including history of prior and subsequent thrombotic events. Two control groups consisted of 200 healthy blood donors and 20 patients with autoimmune disorders, but no history of thrombosis. Assays performed were PT, INR, APTT, FVIIIc, lupus anticoagulant assay (LAC), anticardiolipin antibodies (ACLA), b2-glycoprotein1 antibodies (B2GP1), a thrombin generation assay (Calibrated Automated Thrombogram, CAT) and the OHP assay which utilizes thrombin (0.03 IU/ml) and rt-PA (350 ng/ml) to trigger fibrin generation and fibrinolysis, respectively, in platelet poor plasma. Change in optical density in microtitre wells is measured over 60 minutes. Statistical analysis involved calculation of means, SD, T-tests and paired T-tests utilizing SPSS v16.0. Fifty percent of APLS patients were male, compared with 10% of the autoimmune control group. APLS had been diagnosed on the basis of persistent antiphospholipid antibodies and at least one thrombotic event: VTE (n=46), ATE (n=6) or recurrent late miscarriage (n=2). Number of thrombotic events prior to study entry ranged form 1 to 6 per patient, with 49/66 events unprovoked. Samples from APLS patients on anticoagulation (OAC, n=35) were analysed separately from those not anticoagulated (n=19). Global assay results for samples collected at different time points were stable, with no significant differences on paired T-test. APLS patients had significantly shorter PT, higher fibrinogen, increased fibrin generation and reduced fibrinolysis parameters (p<0.001), compared with healthy donors. The autoimmune control group also showed hypercoagulable OHP parameters compared with healthy donors (p<0.001), with assay results comparable to those in APLS patients, not on OAC. The only thrombin generation assay parameter significantly increased in APLS patients, not on OAC, compared with controls was peak thrombin (266 vs 298 nM, p=0.016). However thrombin generation was significantly suppressed in those on OAC (p<0.001). Only one patient had recurrent DVT during the study. The OHP assay identifies a hypercoagulable state in APLS patients with reduced fibrinolysis and increased fibrin generation, even when anticoagulated. The calibrated automated thrombogram (CAT) showed increased peak thrombin generation in APLS patients not on OAC but endogenous thrombin potential (ETP) was not significantly elevated. Thrombin generation was suppressed by OAC therapy. These global assays show differential results in patients with APLS. More prolonged follow up will be necessary to determine whether the assays predict recurrent thrombotic events and are useful in risk stratification of APLS patients.

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Clinical and Economic Impact of Pre-Operative Coagulation Screening in Children

Blood ◽

10.1182/blood.v120.21.3379.3379 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3379-3379

Author(s):

Trishala Agrawal ◽

Louisa Mazza-Hilway ◽

Alice J. Cohen ◽

Sari H Jacoby

Keyword(s):

Family History ◽

Major Bleeding ◽

Conflicts Of Interest ◽

Personal History ◽

Screening Tests ◽

Factor Vii ◽

Factor Xii ◽

Coagulation Tests ◽

History Of ◽

The Mean

Abstract Abstract 3379 Background: The literature in the past has recommended pre-operative (PRE-O) coagulation screening only when indicated by history or physical exam. Despite these recommendations, surgeons continue to order PT and PTT prior to surgery, especially in children, because they have often not been hemostatically challenged. We evaluated the usefulness of screening tests in identifying significant bleeding risk and associated cost. Methods: We performed a retrospective audit on children referred to the hemophilia center sent for further evaluation of abnormal PT and PTT on PRE-O screening. We reviewed 62 patients who had 80 procedures, out of which 70 procedures were evaluable with complete data. Age, personal and family history of bleeding, coagulation tests, PRE-O and post-operative (PO) treatment, and immediate PO bleeding were assessed. Results: The most common procedure that led to PRE-O screening was tonsillectomy/adenoidectomy at 61% (49/80). Other procedures included orthopedic, GI, oral, dental extractions, and myringotomies. Only 2.5% (2/80) were cardiac procedures. The mean patient age was 6 years (range 1–16). 55% (34/62) had no personal or family history of bleeding. 22.5% (14/62) had a family history of mild bleeding such as epistaxis or menorrhagia. 8% (5/62) had a family history of major bleeding disorders such as Von Willebrand disease (VWD) or hemophilia. 14.5% (9/62) had a personal history of bleeding, mild or major. The most common abnormal screening test was the PT at 40% (25/62). 27% (17/62) had an abnormal PTT (3.2% \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $262$ \end{document} with a significantly abnormal PTT above 50). 22.5% (14/62) were referred for abnormal PT/PTT. 8% (5/62) with an abnormal PT and/or PTT corrected on repeat studies. The remaining 9.6% (6/62) were referred for other reasons such as positive family or personal history and a high risk procedure. Additional coagulation tests ordered because of prolonged PT or PTT varied and included additional factor assays (Table 1). The mean cost of additional testing was >$1000. Factor VII was the most common factor deficiency identified with a mean activity of 47% (27–54%) (normal 55–163%) followed by factor XII deficiency with a mean activity of 39% ( 19–49%) (normal 46–168%). PRE-O, 5 patients received support with either Humate P, Stimate, Amicar, or DDAVP, 4 with a diagnosis of VWD and 1 with Jacobsen Syndrome; 3 of these patients received PO Amicar. PO, 69/70 procedures were completed with minimal (2–45 mL) bleeding. Only 1/70 procedures had significant PO bleeding, despite normal tests. This patient did not have any significant immediate PO bleeding, but had delayed bleeding reported at day 7 requiring cauterization. No other cases of delayed PO bleeding were reported to our clinic. Conclusion: In patients who undergo routine screening by laboratory testing only, the most common abnormality found was a prolonged PT. Subsequent workup of patients with abnormal screening tests identified factor VII or factor XII deficiencies most frequently. Only one patient with abnormal PT/PTT was diagnosed with a significant bleeding disorder, VWD. Major bleeding occurred rarely. This study demonstrates that the cost of extensive PRE-O coagulation testing is high with minimal clinical impact. Disclosures: No relevant conflicts of interest to declare.

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Application of Thrombomodulin-Thrombin Generation to Diverse Abnormalities of the Protein C System

Blood ◽

10.1182/blood-2020-140385 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Marilyn J Manco-Johnson ◽

Linda Jacobson ◽

Dianne Thornhill ◽

Christine Baird ◽

Beth Boulden Warren

Keyword(s):

Family History ◽

Lupus Anticoagulant ◽

Protein C ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Positive Family History ◽

Factor V Leiden ◽

Healthy Controls ◽

Blood Draw ◽

History Of

Background: Increased thrombin generation is an interesting candidate as a potential indicator of hypercoagulability and thrombosis risk. Increased thrombin generation using the calibrated automated thrombogram (CAT) has been reported in antithrombin deficiency but the CAT does not reflect protein C deficiency without the addition of thrombomodulin (TM). TM activates protein C (PC) in the CAT and reduces thrombin generation. Objective: The objective of this study was to determine the capacity of the TM-augmented CAT to detect defects in various protein C system components; the lupus anticoagulant was also investigated as a cause of decreased protein C activation. Methods: The CAT-TM was performed with reagents and methods per the manufacturer's instructions using 5 pM tissue factor and TM (Stago). Other assays included: PC (chromogenic), free protein S (PS, LIA), activated protein C resistance (aPTT-based clotting assay), factor V Leiden (FVL PCR) and lupus anticoagulant (LA, dRVVT and Staclot LA, Stago). Platelet poor plasma samples were obtained from the biobank of a consented prospective inceptional cohort study of thrombosis and thrombophilia or a positive family history of either (ThromboPICS #05-0339); samples from healthy controls with no personal or family history of thrombosis or thrombophilia were collected on a consented protocol (#09-0816). Samples from participants on therapeutic inhibitors of factor Xa or thrombin were treated with appropriate neutralizers; no sample was tested on warfarin. Clinical data included gender, age (< 18 versus ≥ 18 years), history of thrombosis, timing of sample from most recent thrombosis (acute < 14 days; subacute 14-90 days; or chronic > 90 days) and use of anticoagulants at the time of the blood draw. Tests for violations of normality were negative. Therefore, results of cohorts versus controls were compared with independent sample t-test and subgroup analyses relative to control used One-Way ANOVA. Post-hoc comparisons of each subgroup to the controls were collected for multiple comparisons using the Bonferroni correction. Results: Ninety-nine cases and 45 normal controls were studied. Overall half of the cases had a history of thrombosis and 66% of those with thrombosis were on no anticoagulation at the time of testing. Table 1 displays results of the CAT-TM in the 2 control and 6 study groups. Control adults and children showed a mean 50% thrombin reduction in thrombin generation with CAT-TM; overall, persons with protein C system defects showed approximately 25% reduction, with the least reduction of thrombin generation in the cohort of PC deficiency at 19%. Sensitivity of the CAT-TM was 100% for PC deficiency, 81% for LA positivity, 80% for PS deficiency and 72% for FVL positivity with no difference in degree of thrombin reduction between hetero- and homozygous FVL. In addition, we identified 14 individuals with CAT-TM results similar to protein C system defects but with confirmed normal PC, PS, FVL and LA tests. Although 9 of these unknowns had a personal (7) or family (2) history of thrombosis, five came from the healthy controls. The false positive results in 3 adult and 2 pediatric controls conferred a CAT-TM test specificity of 89%. Furthermore, analyses showed no differences in CAT-TM results related to gender, age group, history of thrombosis, age of clot at blood draw (acute, subacute or chronic) or use of anticoagulation at the time of blood draw. Conclusions: The CAT-TM is a useful screening test for defects in the protein C system, including LA, although this test could not discriminate between heterozygous and homozygous FVL. The etiology of positive CAT-TM in normal individuals or individuals with a personal or family history of thrombosis without identified PC system defects is currently unknown and under ongoing investigation. Disclosures No relevant conflicts of interest to declare.

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