Increased Risk for Thromboembolism Associated with High Coagulation Factor VIII (F VIII) Levels in Patients with Malignant Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1380-1380
Author(s):  
Martin Mohren ◽  
Ilka Markmann ◽  
Astrid Franke ◽  
Kathleen Jentsch-Ullrich ◽  
Michael Koenigsmann ◽  
...  
Keyword(s):  
Factor Viii ◽  
Malignant Lymphoma ◽  
Solid Tumors ◽  
Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Hematologic Malignancies ◽  
Low Grade ◽  
Factor V Leiden Mutation ◽  
Increased Risk

Abstract An increased annual incidence of thromboembolic events (TE) of up to 11% has been observed in patients with solid tumors, whereas there exists little data on TE in hematologic malignancies. A previous study found a 6,6% incidence of TE in patients with high grade Non Hodgkin’s lymphoma (HG-NHL) mostly occuring during the first three months of therapy. Little is known about pathogenesis and risk factors in this patient group. We retrospectively evaluated the medical records of all patients with malignant lymphoma treated at our institution between 1991 and 2004. In a seperate effort laboratory analysis for detection of acquired and hereditary thrombophilia was performed at diagnosis and during treatment in 44 patients with various hematologic malignancies: HG-NHL (n = 22), Low grade- NHL (LG-NHL) (n = 7), Hodgkin’s disease (HD) (n = 6), CNS-lymphoma (n = 1) and acute myeloid leukemia (AML) (n = 8). A total of 96 TE occurred in 80 of 1048 patients (7,6%) with malignant lymphoma: DVT (n = 51), pulmonary embolism (n = 19), central venous catheter thrombosis (n = 11), upper extremity thrombosis due to tumor compression (n = 9), central nervous system thrombosis (n = 3), arterial thrombosis (n = 2) and portal vein thrombosis (n = 1). 69 TE (72%) occurred during treatment, whereas 27 (28%) were diagnosed prior to (n = 16) (17%) or after completion of therapy (n = 11) (11%). 9 patients (9%) had comorbid solid tumors. In 12 patients (15%) results of thrombophilia screening were available and FVIII levels were high (> 150%) in 7 (58%). In the prospectively analyzed patient cohort 30 (68%) had high FVIII levels, 22 (50%) showing very high levels (> 180%). High FVIII was associated with high von Willebrand factor (vWF) and increased collagen binding activity, but not with elevated IL 6 or TNF-a. 4 patients (9%) had heterozygous factor V Leiden mutation, one had the G20210A mutation of the prothrombin gene. Fibrinolysis was normal in all patients as were protein C, S and AT-III. No anticardiolipin antibodies or lupus anticoagulants were detected. However only 2 patients (4,4%) in this cohort developed TE, one of whom also had heterozygous protein C resistance. Patients with malignant lymphoma are at substantial risk for TE, especially during treatment, thus prophylactic anticoagulation seems warranted. Our study shows sustained strikingly high factor VIII levels in patients with malignant lymphoma even months or years after a TE as well as in a prospectively analyzed, yet mostly asymptomatic cohort with lymphoma and acute leukemia. Infection as a cause of secondary F VIII elevation in these patients was ruled out by absence of fever and normal IL 6 and TNF-a. Increased FVIII activity (> 150%) has been recognized as an independent risk factor for TE, however the pathogenesis is unclear so far and high FVIII and vWF levels have previously also been found in Multiple Myeloma patients. Ongoing investigations will focus on the implication of these findings in the pathophysiology of hematologic disease.

scholarly journals Laboratory Investigation of Thrombophilia / LABORATORIJSKO ISPITIVANJE TROMBOFILIJA

2014 ◽  
Vol 33 (1) ◽  
pp. 28-46 ◽  
Author(s):  
Sandra Margetić
Keyword(s):  
Risk Factors ◽  
Laboratory Investigation ◽  
Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Prothrombin G20210a ◽  
Factor V Leiden Mutation ◽  
G20210a Mutation ◽  
Increased Risk ◽  
Assay Methods

Summary Laboratory investigation of thrombophilia is aimed at detecting the well-established hereditary and acquired causes of venous thromboembolism, including activated protein C resistance/factor V Leiden mutation, prothrombin G20210A mutation, deficiencies of the physio - logical anticoagulants antithrombin, protein C and protein S, the presence of antiphospholipid antibodies and increased plasma levels of homocysteine and coagulation factor VIII. In contrast, investigation of dysfibrinogenemia, a very rare thrombophilic risk factor, should only be considered in a patient with evidence of familial or recurrent thrombosis in the absence of all evaluated risk factors mentioned above. At this time, thrombophilia investigation is not recommended for other potential hereditary or acquired risk factors whose association with increased risk for thrombosis has not been proven sufficiently to date. In order to ensure clinical relevance of testing and to avoid any misinterpretation of results, laboratory investigation of thrombophilia should always be performed in accordance with the recommended guidelines on testing regarding the careful selection of patients, time of testing and assays and assay methods used. The aim of this review is to summarize the most important aspects on thrombophilia testing, including whom and when to test, what assays and assay methods to use and all other variables that should be considered when performing laboratory investigation of thrombophilia.

Coagulation Factor V Leiden Mutation Was Detected in the Patients with Activated Protein C Resistance in Thailand

1998 ◽  
Vol 80 (08) ◽  
pp. 344-345 ◽  
Author(s):  
Pasra Arnutti ◽  
Motofumi Hiyoshi ◽  
Wichai Prayoonwiwat ◽  
Oytip Nathalang ◽  
Chamaiporn Suwanasophon ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Coagulation Factor V

scholarly journals High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Blood ◽  
1995 ◽  
Vol 85 (6) ◽  
pp. 1504-1508 ◽  
Author(s):  
FR Rosendaal ◽  
T Koster ◽  
JP Vandenbroucke ◽  
PH Reitsma
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Absolute Risk ◽  
Thrombotic Event ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Increased Risk ◽  
The Absolute

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.

A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1271-1276 ◽  
Author(s):  
Marieke C.H. de Visser ◽  
Frits R. Rosendaal ◽  
Rogier M. Bertina
Keyword(s):  
Risk Factor ◽  
Confidence Interval ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance ◽  
Increased Risk

Abstract Activated protein C (APC) resistance caused by the factor V Leiden mutation is associated with an increased risk of venous thrombosis. We investigated whether a reduced response to APC, not due to the factor V point mutation, is also a risk factor for venous thrombosis. For this analysis, we used the Leiden Thrombophilia Study (LETS), a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. All carriers of the factor V Leiden mutation were excluded. A dose-response relationship was observed between the sensitivity for APC and the risk of thrombosis: the lower the normalized APC sensitivity ratio, the higher the associated risk. The risk for the lowest quartile of normalized APC-SR (<0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR > 1.05) was greater than fourfold increased (OR = 4.4; 95% confidence interval, 2.9 to 6.6). We adjusted for VIII:C levels, which appeared to affect our APC resistance test. The adjusted (age, sex, FVIII:C) odds ratio for the lowest quartile was 2.5 (95% confidence interval, 1.5 to 4.2). So, after adjustment for factor VIII levels, a reduced response to APC remained a risk factor. Our results show that a reduced sensitivity for APC, not caused by the factor V Leiden mutation, is a risk factor for venous thrombosis.

Oral Contraceptive-Associated Thromboembolism. A Retrospective Analysis of Thrombophilic Work-out and Long Term Follow up in 57 Cases

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5348-5348
Author(s):  
Emmanouil Papadakis ◽  
Smaragda Efremidou ◽  
Haris Kartsios ◽  
Margarita Mpraimi ◽  
Kiriaki Kokoviadou ◽  
...  
Keyword(s):  
Family History ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance ◽  
Increased Risk ◽  
Fv Leiden

Abstract Introduction: The increased risk of venous thrombosis in women taking oral contraceptives (OCs) has been recognized since the early 1960s. Coexistence of hereditary risk factors appears to have an additive effect. Women under OCs that carry the factor V Leiden mutation have a 35-fold increased risk of thromboembolic events compared to women without the mutation who are not on OCs. Evaluation of family and personal history is the mainstay of prophylaxis prior to OC administration, but often family thrombophilia or thromboembolic (TE) events are not reported prior to OCs prescription. Patients-Methods: Fifty-seven women with a median age of 28 (21–48) years, which suffered OC-associated TE, were studied. The median period of OC therapy prior to TE event was 2 months (0.5–60). Fifty-five of them experienced VTE while 2 suffered stroke. Leg thrombosis was the most common clinical finding [37/55 (67,2%) patients] Apart from personal and family history, Thrombophilia investigation included measurement of : serum Homocysteine, Antithrombin, Protein C and S, Lipoprotein (a), Activated Protein C (APC) resistance, antiphospholipid antibodies and lupus anticoagulant. In addition the presence of FV Leiden, FII 20210 GA mutations and MTHFR 677 CT polymorphism were determined. Results: A high prevalence of the factor V Leiden mutation was detected in the study group; 50% had APC-resistance test positive, 26 (45%) patients were found to be heterozygous and 3 (5,2%) homozygous for the FV Leiden mutation. Lp(a) elevation was observed in 19,3% and Homocysteine elevation in 15,8% of patients. In 9 women (15,8%) both family history and thrombophilic profile were negative. Serious VTE events (2 abdominal and 6 CNS thromboses) were observed only in the Leiden subgroup. During the follow up period ranging from months to 18 years, 3 women (6,25%) experienced a miscarriage and 14 suffered additional VTE events (25%) and they are currently on permanent anticoagulation. Conclusions : Universal thrombophilia screening of women prior to prescription of OCs is not advisable as it does not appear to be cost effective. However, screening certain subgroups, such as women with a known personal or family history, may be of great value. If a full thrombophilic profile can’t be performed, a mere activated protein C resistance test, that reflects the presence of the factor V Leiden mutation, may provide an easy and cheap way of identifying and consulting properly women at higher risk for VTE prior to OC use. Women with OC-associated VTE and thrombophilia carry a substantial recurrence risk that persists for years.

scholarly journals Laboratory Investigation of Thrombophilia

2001 ◽  
Vol 47 (9) ◽  
pp. 1597-1606 ◽  
Author(s):  
Armando Tripodi ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Gene Mutation ◽  
Protein C ◽  
Solid Phase ◽  
Factor V Leiden ◽  
Laboratory Diagnosis ◽  
Factor V Leiden Mutation ◽  
Vitamin Deficiencies ◽  
Increased Risk ◽  
Prothrombin Gene Mutation ◽  
Prothrombin Gene

Abstract Until recently, laboratory diagnosis of thrombophilia was based on investigation of the plasmatic anticoagulant pathways to detect antithrombin, protein C, and protein S deficiencies and on the search for dysfibrinogenemia and anti-phospholipid antibodies/lupus anticoagulants. More recently, laboratory investigations have been expanded to include activated protein C (APC) resistance, attributable or not to the presence of the factor V Leiden mutation; hyperprothrombinemia attributable to the presence of the prothrombin gene mutation G20210A; and hyperhomocysteinemia attributable to impairment of the relevant metabolic pathway because of enzymatic and/or vitamin deficiencies. All of the above are established congenital or acquired conditions associated with an increased risk of venous and, more rarely, arterial thrombosis. Testing is recommended for patients who have a history of venous thrombosis and should be extended to their first-degree family members. Because most of the tests are not reliable during anticoagulation, it is preferable to postpone laboratory testing until after discontinuation of treatment. Whenever possible, testing should be performed by means of functional assays. DNA analysis is required for the prothrombin gene mutation G20210A. Laboratory diagnosis for anti-phospholipid antibodies/lupus anticoagulant should be performed by a combination of tests, including phospholipid-dependent clotting assays and solid-phase anti-cardiolipin antibodies. Hyperhomocysteinemia can be diagnosed by HPLC methods or by fluorescence polarization immunoassays.

The G20210A Prothrombin Polymorphism Is not Associated with Increased Thromboembolic Risk in a Large Protein C Deficient Kindred

2000 ◽  
Vol 83 (03) ◽  
pp. 366-370 ◽  
Author(s):  
Sandra Hasstedt ◽  
Peter Callas ◽  
Julia Valliere ◽  
Bruce Scott ◽  
Kenneth Bauer ◽  
...  
Keyword(s):  
Protein C ◽  
Factor V Leiden ◽  
Complex Nature ◽  
Type I ◽  
Factor V ◽  
Protein C Deficiency ◽  
Additional Increase ◽  
Factor V Leiden Mutation ◽  
Increased Risk ◽  
Risk For Thrombosis

SummaryLikelihood analysis was used to test the effect of the G20210A prothrombin mutation and the His107Pro protein C mutation (resulting from a C insertion) on thrombosis status and prothrombin level in a large kindred of French Canadian descent with type I protein C deficiency. Genotypes were available on 279 pedigree members or their spouses. Of this total, 36 pedigree members were heterozygous for the G20210A variant and one pedigree member was homozygous for G20210A, while 64 were heterozygous for the His107Pro protein C mutation. The factor V Leiden mutation (Arg506Gln) was observed in only one of 181 tested family members. Objectively verified thrombosis was present in 26 of the 279 pedigree members. Thrombosis was suspected in an additional 19 pedigree members. The transmission disequilibrium test of Spielman, 1996, as extended to pedigrees, was used to test for excess transmission of G20210A or His107Pro to thrombosis cases, with transmission of 0.5 specifying no effect. Although the His107Pro mutation was over transmitted (0.837 ± 0.075 p <0.001) to thrombosis cases in this pedigree, the G20210A variant was not (0.491 ± 0.130 NS).Measured genotype analysis was used to examine a total of 184 individuals for the relationship between prothrombin level and both the G20210A variant and thrombosis. The G20210A variant increased prothrombin level from 97 ± 2% to 124 ± 4% (p <0.0001), but thrombosis status was not associated with any additional increase in prothrombin level. Thus, in a large thrombophilic, protein C deficient kindred, with the G20210A variant present in a proportion (13%) far higher than the general Caucasian population (∼2%), neither the presence of the variant nor the plasma concentration of prothrombin were associated with increased risk for thrombosis. These findings contrast with those of others who have established the G20210A variant as a thrombophilic risk factor; and emphasize the complex nature of the multigenic pathogenesis of thrombophilia.

An abnormal ProC Global test result is associated with an increased risk of venous thromboembolism independent of test sensitivity for protein C pathway abnormalities

2007 ◽  
Vol 98 (07) ◽  
pp. 228-233 ◽  
Author(s):  
Patricia Perez ◽  
Jocelyn Rapp ◽  
Raphaël Adda ◽  
Pierre Toulon
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Critical Role ◽  
Factor V Leiden ◽  
Global Test ◽  
Factor V Leiden Mutation ◽  
Increased Risk ◽  
Significant Difference ◽  
Assay Result ◽  
Test Result

SummaryThe ProC® Global assay is a clotting assay primarily developed to globally evaluate the functionality of the protein C (PC) pathway. It was shown to lack both sensitivity and specificity for PC pathway abnormalities, i.e. factor V Leiden mutation, PC and PS deficiency. The hypothesis that an abnormal test result could be associated with venous thromboembolism (VTE) was evaluated in a case-control study. The proportion of reduced response was significantly higher in cases than in controls [n=71/139 (51.1%) vs. n=28/147 (19.0%); p<0.0001] and the same applied after exclusion of those subjects with any PC pathway abnormality [n=53/119 (44.5%) vs. n=25/143 (17.5%); p<0.0001]. An abnormal ProC® Global assay result was significantly associated with thrombosis both in the whole population (odds ratio [OR]=4.44, 95% confidence interval [CI]=2.61–7.53) and in those subjects without any PC pathway abnormality (OR=3.70, 95%CI=2.16–6.66). The ProC® Global assay result was significantly lower in cases with idiopathic VTE than in those with secondary VTE (p<0.0001). No significant difference was observed when cases were classified according to the presence or absence of recurrent episodes. Moreover, a reduced response was found to be associated with VTE both in subjects with normal or elevated factor VIII (FVIII) level. In vitro, FVIII was found to play a critical role in the ProC® Global assay result as suggested by the significant trend toward decreasing response with increasing FVIII levels. In conclusion, our results suggest that an abnormal ProC® Global assay result is associated with an increased risk of VTE independently of its sensitivity for PC pathway abnormalities.

The Role of a Thrombofilia Screening in Prospective Liver Donors (LDLT, Live Donor Liver Transplant).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4125-4125
Author(s):  
Rosa M. Ayala ◽  
Angeles M. Martin ◽  
Joaquin Martinez ◽  
Juan Carlos Meneu ◽  
Almudena Moreno ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Factor Viii ◽  
Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Live Donor ◽  
Live Donor Liver Transplant ◽  
Increased Risk ◽  
Thrombotic Complications ◽  
Liver Donors

Abstract Liver transplantation (tx) from live donors brings an opportunity to many patients with terminal stages liver disease, who are at high risk of a fatal event while waiting for a cadaveric liver transplantation. A main issue in this setting is to extreme the safety of the live donor. Tests that could predict the risk of thrombotic complications in the donor of LDLT are under investigation. In addition such tests could be useful in the prevention of vascular hepatic thrombotic complications in the recipient. OBJECTIVES.- In this study we evaluate the value of a thrombophilia screening in the live donor prior to LDLT in order to determine the thrombotic and hemorrhagic risk in both the donor at surgery and in the recipient of LDLT. METHODS.- Genetic study and functional coagulative tests were performed on samples of peripheral blood of 136 candidates liver donors. For genetical tests, genomic DNA was extracted and detection of factor V Leiden, factor II and MTHFR mutations were performed by real-time PCR technology (LightCycler®). Phenotypic tests included prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin clotting time (TT), functional fibrinogen, antithrombin (AT), protein C (PC) and protein S (PS) (coagulative and chromogenic techniques), resistance to activated protein C (RAPC), and factor VIII. In addition the following tests were carried out: anticardiolipin immunoglobulin G and M antibody (ACA IgG and ACA IgM), test for lupus anticoagulant (tissular thromboplastin inhibition, TTI, and diluted TTPA), and quantification of plasmatic homocystein. RESULTS.- Because abnormal thrombophilic studies 32 candidates were excluded for LDLT due to factor V Leiden (2), mutation FII G20210A (4), chromogenic PC deficiency (1), anticoagulant PC deficiency(2), free PS deficiency (Ag) (5), functional PS deficiency (2), factor VIII &lt; 65% (1) or &gt; 150% (4), positive lupic anticoagulant test (5) and high homocystein levels (9). CLINICAL DATA.- Finally there were 34 donors (17M, 17F) selected for LDLT. The 34 recipients of LDLT were 10 children and 24 adults. During the donor operation for an adult recipient, the right lobe of the liver were removed. For infant and pediatric LDLT recipients, smaller pieces of the liver were used. None of donors suffered from thrombotic complications. The average transfusional needs of donors were 1.1 units of packed red cells, (range 0–2), and one donor required fresh plasma transfusion in the early postsurgery. Overalll post-LTLD thrombosis was observed in 4 patients (11,8%). 4 patients were submitted to a second liver tx from a cadaveric donor (2 of them due to hepatic arterial thrombosis). CONCLUSIONS.- Thrombophilia studies in the donor prior to LTDL should be included in the laboratory work, to exclude conditions associates with increased risk of thrombotic and hemorrhagic complications. In addition these studies could minimize the risk of vascular hepatic thrombotic complications in the recipient.

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