The Antiphospholipid Syndrome: The Mount Sinai Hematology Perspective.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2154-2154
Author(s):  
Maria Teresa De Sancho ◽  
Gonzalo Estupinan ◽  
Ilene Schulman ◽  
Mayra Lema ◽  
Jacob Rand
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antithrombotic Therapy ◽  
High Titer ◽  
Clinical Manifestations ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Recurrent Thrombosis ◽  
Clinical Criteria ◽  
Chronic Therapy

Abstract Objective: To evaluate the clinical manifestations, type and persistence of antiphospholipid (aPL) antibodies, and outcomes of patients evaluated in a hematology practice clinic for the diagnosis of antiphospholipid syndrome (APLS). Methods: We systematically reviewed the medical records of all patients referred to our Hemostasis and Thrombosis Practice Clinic for evaluation of APLS from January 1995 to July 2005. APLS was defined by the Sapporo criteria. 180 patients were identified who either had APLS as defined by the Sapporo criteria or had documented aPL antibodies on 2 separate occasions at least 6 weeks apart without any clinical manifestation for APLS. Data collected included demographics, clinical manifestations, type of aPL antibodies, presence or absence of lupus anticoagulant (LAC), persistence or fluctuation of the aPL antibodies, presence of other thrombophilias, antithrombotic therapy, and outcomes. Results: Of the 180 patients, 141 were females and 39 were males. The age range was 21 to 89 yr. 119 patients (66%) fulfilled the clinical criteria for APLS and 61(34%) did not. Among the 119 patients with APLS, the clinical manifestations included arterial thromboembolism (ATE) in 53 (46 idiopathic, 7 secondary), venous thromboembolism (VTE) in 44 (31 idiopathic, 13 secondary), both ATE and VTE in 7 and pregnancy losses (PL) in 30. Among the 30 patients with PL, 19 had recurrent PL before the 10th week of gestation and 11 had PL after the 10th week of gestation. 5 patients with PL also had ATE and/or VTE. 94 patients had anticardiolipin (aCL) antibody (medium titer IgG isotype), 57 had aCL antibody (high titer IgG), 29 had antiphosphatidylserine (aPS) antibody (medium titer IgG), 27 had aPS antibody (high titer IgG), 11 had anti-β2 glycoprotein I (anti-β2GPI) antibody (medium titer), 13 had anti-β2GPI antibody (high titer), 47 had aCL antibody (medium titer IgM), 15 had aCL antibody (high titer IgM), 74 had aPS antibody (medium titer IgM), 43 had aPS antibody (high titer IgM), 20 had anti-β2GPI medium titer IgM, 12 had anti-β2GPI high titer IgM, 10 had anti-β2GPI medium titer IgA isotype, 6 had anti-β2GPI high titer IgA isotype and 36 had LAC. 115 patients had persistent aPLA and 65 had fluctuating aPLA. 33 patients had other thrombophilias: factor V Leiden (n=5), prothrombin gene mutation (G20210A) (n=6), protein S deficiency (n=4), increased homocysteine level (>12 mcmol/L) (n=9), hyperfibrinogenemia (n=3), elevated factor VIII (n=4) and factor XI (n=1) and plasminogen deficiency (n=1). Antithrombotic therapy included warfarin in 71 patients, aspirin in 85, clopidogrel in 3, and LMWH in 36 (2 on chronic therapy and 34 during pregnancy). 21 patients were on no antithrombotic medications. Of the 180 patients, 110 patients had succesful outcomes defined as either absence of recurrent thrombosis or pregnancy losses. 7 patients had recurrent PL while 10 had recurrent thrombosis. 1 patient died. 52 patients were lost to follow-up. Conclusions: The majority of our patients with APLS were women. The most common clinical manifestations were ATE, followed by VTE and PL. The most prevalent aPL antibody was aCL medium titer IgG isotype and the least common was anti-β2GPI high titer IgA. Antithrombotic therapy resulted in successful outcomes in approximately 2/3 of patients.

Hereditary Thrombophilic Risk Factors and Venous Thromboembolism in Istanbul, Turkey: The Role in Different Clinical Manifestations of Venous Thromboembolism

2008 ◽  
Vol 14 (2) ◽  
pp. 168-173 ◽  
Author(s):  
Gulfer Okumus ◽  
Esen Kiyan ◽  
Orhan Arseven ◽  
Levent Tabak ◽  
Reyhan Diz-Kucukkaya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Clinical Manifestations ◽  
Factor V Leiden ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Vein Thrombosis ◽  
Significant Difference ◽  
Deep Vein

The aim of this study was to investigate the hereditary thrombophilic risk factors in patients with venous thromboembolism (VTE) and whether these risk factors play a different role in patients with isolated pulmonary embolism (PE) as compared with patients with deep vein thrombosis (DVT) and patients with PE + DVT. The protein C (PC), protein S, antithrombin activities, homocysteine levels, and factor V Leiden (FVL) G1691A and prothrombin G20210A mutations were evaluated in 191 patients with VTE and 191 controls. The prevalence of FVL and PC deficiency were higher in patients ( P = .003 and P = .02, respectively). There was no significant difference for the other risk factors. The combination of thrombophilic risk factors was significantly higher in patients with DVT + PE as compared with patients with isolated PE or DVT ( P = .04). In conclusion, the most important hereditary risk factors for VTE in this study were the FVL mutation and PC deficiency.

The Prevalence and Clinical Significance of Inherited Thrombophilic Risk Factors in Patients with Antiphospholipid Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4050-4050
Author(s):  
Reyhan Diz-Kucukkaya ◽  
Murat Inanc ◽  
Yuksel Pekcelen
Keyword(s):  
Risk Factors ◽  
Antiphospholipid Syndrome ◽  
Factor V Leiden ◽  
Protein S ◽  
First Trimester ◽  
Prothrombin G20210a ◽  
Antiphospholipid Antibody ◽  
Factor V ◽  
Healthy Controls ◽  
G20210a Mutation

Abstract Antiphospholipid syndrome (APS) is defined as the occurrence of thrombosis and/or recurrent fetal losses in association with the presence of antiphospholipid antibodies (APLA). Although it has been suggested that APLA have a pathogenic role in the thrombotic complications of APS, pathogenicity of APLA has not been conclusively proven. It has been speculated that other inherited or acquired thrombogenic risk factors might influence the development of thrombosis in patients with APS. In the present study, we examined the effect of well known inherited thrombophilic risk factors (inherited protein C (PC), protein S (PS) and antithrombin (AT) deficiencies; factor V Leiden (FVL) G1691A mutation, and prothrombin G20210A mutation) in the development of thrombosis in APS patients. Seventy-three definite APS patients with arterial and venous thrombosis (group 1: APS patients with thrombosis), 29 antiphospholipid antibody-positive patients with first trimester abortus and/or thrombocytopenia and no history of thrombosis (group 2: APLA-positive patients without thrombosis), and 126 healthy controls (group 3) were included into the study. PC, PS, and AT deficiencies were screened with functional assays; the presence of FVL mutation and prothrombin mutation were detected by polymerase chain reaction. PS and AT activities were found to be normal in all groups. Only a single APS patient with thrombosis had been found to have PC deficiency, PC activities were normal in both APLA-positive patients without thrombosis and healthy controls. The frequencies of FVL A allele for APS patients with thrombosis, APLA-positive patients without thrombosis, and healthy controls were 10.4%, 6.8%, and 4.9%, respectively. The frequency of FVL A allele was significantly higher in APS patients with thrombosis compared with healthy controls (10.4% vs 4.9%, p= 0.02 with chi-square test). The frequencies of prothrombin A allele for APS patients with thrombosis, APLA-positive patients without thrombosis and healthy controls were 3.4%, 0%, and 1.3%, respectively. Although the frequency of A allele was higher in APS patients with thrombosis compared with both APLA-positive patients without thrombosis and healthy controls, it was not statistically significant. Our results showed that inherited PC, PS, AT deficiencies, and prothrombin G20210A mutation are not common in patients with APS. FVL G1691A mutation may contribute to the development of thrombosis in a small group of APS patients. This study suggests that the known inherited thrombophilic risk factors are not responsible for the development of thrombosis in the majority of APS patients. Further prospective studies in larger cohorts of patients are needed to delineate the exact role of thrombophilic mutations in the development of thrombosis in APS.

Study on Physician Ordering Behavior on Hypercoaguable Screening Tests

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4745-4745
Author(s):  
Lucas Wong ◽  
Kristen Wortman ◽  
Lisa J Go ◽  
Paul TIpton ◽  
Juhee Song ◽  
...  
Keyword(s):  
Protein C ◽  
Thrombotic Event ◽  
Factor V Leiden ◽  
Protein S ◽  
Screening Tests ◽  
Factor V ◽  
Training Level ◽  
C Protein ◽  
Clinical Criteria ◽  
Hereditary Thrombophilia

Abstract Abstract 4745 Background: We can now identify hereditary and acquired risk factors in patients with a venous thrombotic event. Hereditary factors include factor V Leiden; prothrombin G 20210A mutation; or deficiencies of antithrombin, protein C, or protein S. But considerable uncertainty exists in hypercoagulable testing. Clinical criteria (Bauer, 2002) guidelines are available and laboratory evaluation can confirm the diagnosis. But we know of anecdotal stories where physicians ignored the testing pathways. Even when correctly utilized, testing was inappropriately timed after the thrombotic event. There are many scenarios for thrombosis with no single test to identify these risk factors. We need to re-examine the use of these screening tests for inherited and acquired thrombosis syndromes. Materials and Methods: Retrospectively, 200 patient charts were reviewed on the use of hypercoagulable screening panels, patient characteristics, and physician characteristics. The hypercoaguable screening tests contain prothrombin time, partial thromboplastin time, thrombin time, fibrinogen, antithrombin, plasminogen, activated protein C resistance, protein C, protein S, and lupus anticoagulant. Factor V Leiden and prothrombin G 20210A mutation results were reviewed if available. Data reviewed included age, gender, location of thrombosis (arterial vs. venous), malignancy, connective tissue disorder, diabetes, hypertension, nephrotic syndrome, liver disease, active infections, recent surgery, trauma, anticoagulation medications, obstetric history, family history, hypercoaguable screening test results, physician specialty, training level, and indications for the tests. Results: Patient age range was 18–91; 79 males and 12 females. Among 200 cases, 23 were positive from the hypercoaguable screening tests but only 4 were true positive for hereditary thrombophilia (Factor V Leiden, prothrombin G 20210A, antithrombin deficiency and protein C and S deficiency, respectively). False positive results (low levels of antithrombin, protein C, protein S) were due to coumadin. Ordering physicians were diverse (internal medicine, general medicine, family medicine, hematology/oncology, cardiology, pulmonary, rheumatology, nephrology, neurology, general surgery, vascular surgery, and pediatrics). Reason for ordering tests were varied: family history of thrombosis, recurrent deep vein thrombosis, myocardial infarction, pulmonary embolus, stroke, malignancy, myeloproliferative disorders, connective tissue disorders, inflammatory bowel disease, liver disease, diabetes, nephrotic syndrome, arteriovenous shunt operation, and fetal loss. Few cases fit the clinical criteria. Ordering tests were inconsistent with the indications for hereditary thrombophilia, with no relation to the clinical history, physician training level, or specialty. Discussion and Conclusion: Why these irregularities in behavior exist, we are not sure. From our literature review, there were few papers available on discrepancies in physician reasoning for utilizing laboratory tests. Wertman (1980) identified no single reason for test ordering behavior of physicians. Axt-Adams (1993) suggested that motivators, other than physician education, had a higher correlation of influencing physician ordering behavior when over-utilizing laboratory tests. These motivators included 1) fear of failure to diagnose, 2) fear of criticism, 3) inability to cope with diagnostic uncertainty, 4) eagerness to complete the screening evaluation while in the hospital, 5) desire to be complete in evaluation, 6) hope that additional follow-up testing provides the correct diagnosis, 7) provide reassurance for patient, 8) collective ordering, and 9) ignorance of costs and diagnostic significance of tests and their sensitivity, specificity, and predictability. In many cases, the diagnostic criteria for ordering hypercoagulable screenings were not followed. We did not have the opportunity to interview the ordering physicians about their rationale which may have provided more insight. More education is necessary on hereditary thrombophilia, limitations of coagulation tests, acquired conditions for thrombosis, and the costs of these specialized tests. More studies are necessary to understand physician behaviors in ordering these expensive tests. Disclosures: No relevant conflicts of interest to declare.

Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

1995 ◽  
Vol 74 (05) ◽  
pp. 1255-1258 ◽  
Author(s):  
Arnaldo A Arbini ◽  
Pier Mannuccio Mannucci ◽  
Kenneth A Bauer
Keyword(s):  
Hemophilia A ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor V ◽  
Bleeding Diathesis ◽  
Mutation Site ◽  
Spontaneous Bleeding ◽  
Factor V Leiden Mutation

SummaryPatients with hemophilia A and B and factor levels less than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20–30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in amelio rating the hemorrhagic tendency in these so-called “mild severe” hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme Mnll. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.

The Diagnosis and Clinical Manifestations of Activated Protein C Resistance: A Case Report and Review of the Literature

1996 ◽  
Vol 1 (4) ◽  
pp. 275-280 ◽  
Author(s):  
Howard Daniel Hoerl ◽  
Aldo Tabares ◽  
Kandice Kottke-Marchant
Keyword(s):  
Case Report ◽  
Protein C ◽  
Activated Protein C ◽  
Clinical Manifestations ◽  
Factor V Leiden ◽  
Laboratory Diagnosis ◽  
Factor V ◽  
Review Of The Literature ◽  
Activated Protein C Resistance ◽  
Genetic Anomaly

Activated protein C resistance (APCR) is a recently discovered, medically important cause of venous thrombosis. More than 95% of cases are due to factor V Leiden (FVL), a mutated form of factor V that is resistant to degradation by activated protein C. The prevalence of this disorder, which is inherited in an autosomal dominant fashion, is approximately 5% among asymptomatic people of European heritage. In addition, 20 to 60% of patient cohorts with previous thrombosis demonstrate APCR, making it the most common known genetic cause of abnormal thrombophilia. Current laboratory techniques available for diagnosis include functional assays, such as the APC ratio, as well as DNA-based tests that detect the specific genetic anomaly responsible for FVL. A case report is presented, along with a review of the literature highlighting epidemiology, pathogenesis, clinical features and methods for laboratory diagnosis.

The APC-independent anticoagulant activity of protein S in plasma is decreased by elevated prothrombin levels due to the prothrombin G20210A mutation

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1686-1692 ◽  
Author(s):  
Rory R. Koenen ◽  
Guido Tans ◽  
René van Oerle ◽  
Karly Hamulyák ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Factor V Leiden ◽  
Protein S ◽  
Prothrombin G20210a ◽  
Healthy Population ◽  
Factor V ◽  
Thrombotic Risk ◽  
G20210a Mutation

AbstractProtein S exhibits anticoagulant activity independent of activated protein C (APC). An automated factor Xa–based one-stage clotting assay was developed that enables quantification of the APC-independent activity of protein S in plasma from the ratio of clotting times (protein S ratio [pSR]) determined in the absence and presence of neutralizing antibodies against protein S. The pSR was 1.62 ± 0.16 (mean ± SD) in a healthy population (n = 60), independent of plasma levels of factors V, VIII, IX, and X; protein C; and antithrombin, and not affected by the presence of factor V Leiden. The pSR strongly correlates with the plasma level of protein S and is modulated by the plasma prothrombin concentration. In a group of 16 heterozygous protein S–deficient patients, the observed mean pSR (1.31 ± 0.09) was significantly lower than the mean pSR of the healthy population, as was the pSR of plasma from carriers of the prothrombin G20210A mutation (1.47 ± 0.21; n = 46). We propose that the decreased APC-independent anticoagulant activity of protein S in plasma with elevated prothrombin levels may contribute to the thrombotic risk associated with the prothrombin G20210A mutation.

scholarly journals Thrombophilia And Arterial Ischemic Stroke

2017 ◽  
pp. 45
Author(s):  
A.A. Abrishamizadeh
Keyword(s):  
Ischemic Stroke ◽  
Vitamin K ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Antithrombin Iii ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
C Protein

Ischemic stroke (IS) is a common cause of morbidity and mortality with significant socioeconomic impact especially when it affects young patients. Compared to the older adults, the incidence, risk factors, and etiology are distinctly different in younger IS. Hypercoagulable states are relatively more commonly detected in younger IS patients.Thrombophilic states are disorders of hemostatic mechanisms that result in a predisposition to thrombosis .Thrombophilia is an established cause of venous thrombosis. Therefore, it is tempting to assume that these disorders might have a similar relationship with arterial thrombosis. Despite this fact that 1-4 % of ischemic strokes are attributed to Thrombophillia, this   alone rarely causes arterial occlusions .Even in individuals with a positive thrombophilia screen and arterial thrombosis, the former might not be the primary etiological factor.Thrombophilic   disorders can be broadly divided into inherited or acquired conditions. Inherited thrombophilic states include deficiencies of natural anticoagulants such as protein C, protein S, and antithrombin III (AT III) deficiency, polymorphisms causing resistance to activated protein C(Factor V Leiden mutation), and disturbance in the clotting balance (prothrombin gene 20210G/A variant). Of all the inherited  thrombophilic disorders, Factor V Leiden mutation is perhaps the commonest cause. On the contrary, acquired thrombophilic disorders are more common and include conditions such as the antiphospholipid syndrome, associated with lupus anticoagulant and anticardiolipin antibodies.The more useful and practical approach of ordering various diagnostic tests for the uncommon thrombophilic states tests should be determined by a detailed clinical history, physical examination, imaging studies and evaluating whether an underlying hypercoagulable state appears more likely.The laboratory thrombophilia   screening should be comprehensive and avoid missing the coexisting defect and It is important that a diagnostic search protocol includes tests for both inherited and acquired thrombophilic disorders.Since the therapeutic approach (anticoagulation and thrombolytic therapy) determines the clinical outcomes, early diagnosis of the thrombophilic  disorders plays an important role. Furthermore, the timing of test performance of some of the  thrombophilic  defects (like protein C, protein S, antithrombin III and fibrinogen levels) is often critical since these proteins can behave as acute phase reactants and erroneously elevated levels of these factors may be observed in patients with acute thrombotic events. On the other hand, the plasma levels of vitamin K-dependent proteins (protein C, protein S and APC resistance) may not be reliable in patients taking vitamin K antagonists. Therefore, it is suggested that plasma-based assays for these disorders should be repeated3 to 6 months after the initial thrombotic episode to avoid false-positive results and avoid unnecessary prolonged   anticoagulation therapy. The assays for these disorders are recommended after discontinuation of oral anticoagulant treatment or heparin for at least 2 weeks.    

Sign in / Sign up

Export Citation Format

Share Document