Coagulation factors in citrated plasma predict for benefit from bevacizumab (B) in patients with advanced pancreatic cancer (APC): Results from CALGB 80303 (Alliance).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 306-306
Author(s):  
Jeffrey Melson Clarke ◽  
Herbert Pang ◽  
Mark D. Starr ◽  
Ace Joseph Hatch ◽  
Hedy Lee Kindler ◽  
...  
Keyword(s):  
Cox Model ◽  
Advanced Pancreatic Cancer ◽  
Predictive Biomarkers ◽  
Coagulation Factors ◽  
Matrix Remodeling ◽  
Plasma Samples ◽  
Significant Difference ◽  
Von Willebrand ◽  
Willebrand Factor

306 Background: CALGB 80303 evaluated gemcitabine (G) in combination with either B or placebo (P) in 602 patients (pts) with APC. No significant difference in overall survival (OS) between treatment arms was observed. Previously, plasma EDTA samples from CALGB 80303 were analyzed and potential predictive biomarkers for B were identified. This follow-up analysis evaluated citrated plasma samples for circulating proteins related to matrix remodeling and coagulation. Methods: Multiplex ELISA analysis was employed to assess the following circulating factors: E-selectin, matrix metalloprotease (MMP) 2, MMP9, von Willebrand factor (vWF), D-dimer, thrombospondin 1, and tissue factor (TF). Thrombin-antithrombin complex (TAT) was analyzed using a standard enzyme immunoassay. Prognostic characteristics were determined by associating baseline values with OS using a Cox model. Predictive markers were identified with inclusion of a treatment by marker interaction term. Results: Baseline citrated plasma samples from 109 pts were included in this analysis (59 pts G+P; 50 pts G+B). Negative prognostic factors for OS were identified, including E-selectin (p <0.01) for patients receiving G-based therapy, and E-selectin, TF, and vWF (p <0.05) in pts receiving G+P. Potential biomarkers predicting for OS benefit from B were also identified. Pts with low (< median) levels of TAT (interaction p=0.034) exhibited a median OS of 6.0 months (mo) vs. 8.3 mo (HR=0.49; 95%CI 0.28-0.88) when receiving G+P vs. G+B, respectively. Furthermore, pts with elevated levels of TF (>Q3) were found to benefit from B (interaction p=0.021), with median OS of 4.3 mo vs 4.8 mo (HR=0.44;95%CI 0.18-1.08), respectively. Longitudinal analysis of samples collected at baseline and at cycle 3 indicated that only vWF changed in pts receiving G+P, with an increase in vWF (p<0.05). Conclusions: In patients with APC, baseline levels of TAT and TF were identified as potential predictors of benefit from B. These data emphasize the importance of coagulation factors in modulating tumor angiogenesis. The potential predictive value of these factors warrants further validation.

Analysis of Children with Coagulation Test Abnormality in Pre-Surgical Evaluation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4080-4080
Author(s):  
Seung Yeon Kwon ◽  
Jung Woo Han ◽  
Sung Chul Won ◽  
Jaewoo Song ◽  
Chuhl Joo Lyu
Keyword(s):  
Surgical Procedures ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor Xii ◽  
Surgical Evaluation ◽  
Bleeding History ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Prothrombine time (PT) and activated prothrombine time (aPTT) are common tests used for screening of coagulation function before surgical procedures. We analyzed underlying causes of abnormal coagulation test results which were incidentally found during pre-surgical evaluation in healthy patients without definite bleeding history. Total 58 children referred to pediatric hematoloy service for abnormal PT and aPTT results in pre-surgical evaluation between June 2006 and May 2008 were analyzed retrospectively by review of medical records. 50 patients showed aPTT prolongation, 5 patients PT prolongation, 2 patients PT and aPTT prolongation and another three patients showed normal PT and aPTT. Among 55 patients with abnormal results, 25 patients (43%) were recovered spontaneously during their follow up tests, 17 patients (29%) showed lower level of certain coagulation factor than reference range and the other 13 patients were lost during follow up despite of recommendation for further evaluation. Mean value of international normalized ratio (INR) for PT and aPTT of the patients recovered spontaneously were 1.05±0.11, 44.53±5.01seconds(s), and 1.12±0.11, 47.0±5.36s in patients with lower level of coagulation factor, showing significant increase of PTT in patients with lower factor levels (p&lt;0.05). Median time required for spontaneous recovery was four weeks and 18 patients (72%) were recovered within this time. Among 17 patients with lower level of certain coagulation factor then reference level, there were 11 patients with low factor XII level, three patients with low factor VIII level, three patients with low von Willebrand factor, two patients each for low factor VII and factor XI and one patient with low factor V level. Among them three patients with low level in von Willebrand factor, one patient with low factor VII and two patients with low factor XI showed deficient level of coagulation factors requiring factor replacement for the surgical procedures. From this analysis of patients with incidentally found PT or aPTT prolongation, 43% of patients were spontaneously recovered during follow up period within 4 weeks in median. However, we also found that 29% of patients had relatively lower level of coagulation factor than reference range. Even though most of them were factor XII decrease which is not closely related with bleeding tendency, six patients had significant deficiencies of coagulation factors requiring factor replacement during surgical procedures. These results suggest that we should keep following up and undergo adequate evaluation for underlying coagulation factor deficiencies in patients who have sustaining PT and aPTT prolongation abnormalities despite of absence of any bleeding history.

Standardisation of von Willebrand Factor in Therapeutic Concentrates: Calibration of the 1st International Standard for von Willebrand Factor Concentrate (00/514)

2002 ◽  
Vol 88 (09) ◽  
pp. 380-386 ◽  
Author(s):  
Dawn Sands ◽  
Andrew Chang ◽  
Claudine Mazurier ◽  
Anthony Hubbard
Keyword(s):  
Von Willebrand Factor ◽  
International Study ◽  
Expert Committee ◽  
International Standard ◽  
A Value ◽  
Significant Difference ◽  
Factor Concentrate ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Good Agreement

SummaryAn international study involving 26 laboratories assayed two candidate von Willebrand Factor (VWF) concentrates (B and C) for VWF:Antigen (VWF:Ag), VWF:Ristocetin Cofactor (VWF:RCo) and VWF:Collagen binding (VWF:CB) relative to the 4th International Standard Factor VIII/VWF Plasma (4th IS Plasma) (97/586). Estimates of VWF:Ag showed good agreement between different methods, for both candidates, and the overall combined means were 11.01 IU/ml with inter-laboratory variability (GCV) of 10.9% for candidate B and 14.01 IU/ml (GCV 11.8%) for candidate C. Estimates of VWF:RCo showed no significant difference between methods for both candidates and gave overall means of 9.38 IU/ml (GCV 23.7%) for candidate B and 10.19 IU/ml (GCV 24.4%) for candidate C. Prior to the calibration of the candidates for VWF:CB it was necessary to calibrate the 4th IS Plasma relative to local frozen normal plasma pools; there was good agreement between different collagen reagents and an overall mean of 0.83 IU per ampoule (GCV 11.8%) was assigned. In contrast, estimates of VWF:CB in both candidates showed large differences between collagen reagents with inter-laboratory GCV’s of 40%. Candidate B (00/514) was established as the 1st International Standard von Willebrand Factor Concentrate by the WHO Expert Committee on Biological Standardisation in November 2001 with assigned values for VWF:Ag (11.0 IU/ampoule) and VWF:RCo (9.4 IU/ampoule). Large inter-laboratory variability of estimates precluded the assignment of a value for VWF:CB.

scholarly journals Endothelial Dysfunction, Atherosclerosis, and Increase of von Willebrand Factor and Factor VIII: A Randomized Controlled Trial in Swine

2021 ◽  
Author(s):  
Ferdows Atiq ◽  
Jens van de Wouw ◽  
Oana Sorop ◽  
Ilkka Heinonen ◽  
Moniek P. M. de Maat ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Randomized Controlled Trial ◽  
Endothelial Dysfunction ◽  
Controlled Trial ◽  
Short Term ◽  
Randomized Controlled ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractIt is well known that high von Willebrand factor (VWF) and factor VIII (FVIII) levels are associated with an increased risk of cardiovascular disease. It is still debated whether VWF and FVIII are biomarkers of endothelial dysfunction and atherosclerosis or whether they have a direct causative role. Therefore, we aimed to unravel the pathophysiological pathways of increased VWF and FVIII levels associated with cardiovascular risk factors. First, we performed a randomized controlled trial in 34 Göttingen miniswine. Diabetes mellitus (DM) was induced with streptozotocin and hypercholesterolemia (HC) via a high-fat diet in 18 swine (DM + HC), while 16 healthy swine served as controls. After 5 months of follow-up, FVIII activity (FVIII:C) was significantly higher in DM + HC swine (5.85 IU/mL [5.00–6.81]) compared with controls (4.57 [3.76–5.40], p = 0.010), whereas VWF antigen (VWF:Ag) was similar (respectively 0.34 IU/mL [0.28–0.39] vs. 0.34 [0.31–0.38], p = 0.644). DM + HC swine had no endothelial dysfunction or atherosclerosis during this short-term follow-up. Subsequently, we performed a long-term (15 months) longitudinal cohort study in 10 Landrace–Yorkshire swine, in five of which HC and in five combined DM + HC were induced. VWF:Ag was higher at 15 months compared with 9 months in HC (0.37 [0.32–0.42] vs. 0.27 [0.23–0.40], p = 0.042) and DM + HC (0.33 [0.32–0.37] vs. 0.25 [0.24–0.33], p = 0.042). Both long-term groups had endothelial dysfunction compared with controls and atherosclerosis after 15 months. In conclusion, short-term hyperglycemia and dyslipidemia increase FVIII, independent of VWF. Long-term DM and HC increase VWF via endothelial dysfunction and atherosclerosis. Therefore, VWF seems to be a biomarker for advanced cardiovascular disease.

Plasma von Willebrand factor, thrombosis, and the endothelium: The first 30 years

2006 ◽  
Vol 95 (01) ◽  
pp. 49-55 ◽  
Author(s):  
Andrew Blann
Keyword(s):  
Arterial Disease ◽  
Endothelial Damage ◽  
Contributory Factor ◽  
Long Term Follow Up ◽  
Von Willebrand ◽  
Plasma Marker ◽  
Willebrand Factor ◽  
Late Stages

Summary “It is quite useless to argue the questions concerning the development of intimal scleroses if we study and discuss the late stages of the disease alone. If we wish to gain insight into the complex question of arterio-sclerosis we must attempt to follow the lesion from its earliest beginning” (Klotz and Manning, J Path Bact 1911: 16; 211–20).Over thirty years ago Boneu and colleagues publisheda report of raised levels of plasma vonWillebrand factor (vWf) in patients with arteritis, diabetes and sepsis. They concluded that raised levels of this molecule indicate endothelial damage, and may possibly be a contributory factor in thrombosis in arterial disease. The former aspect of this conclusion is now accepted, and numerous studies on the risk factors for atherosclerosis provide mechanisms for this damage. Other studies have demonstrated raised levels in cancer and in connective tissue disease. Numerous long-term follow-up studies have also demonstrated that increased vWf predicts major cardiovascular end points. However, the link between these studies, and the latter aspect of Boneu’s conclusion, that raised vWf contributes to thrombosis is,although attractive, nevertheless unproven. Despite this, vWf remains the most important plasma marker of endothelial damage/dysfunction and as such attracts clinical attention.

Haemostatic, Endothelial and Lipoprotein Parameters and Blood Pressure Levels in Women with a History of Preeclampsia

1999 ◽  
Vol 81 (04) ◽  
pp. 538-542 ◽  
Author(s):  
Shu He ◽  
Angela Silveira ◽  
Anders Hamsten ◽  
Margareta Blombäck ◽  
Katarina Bremme
Keyword(s):  
Blood Pressure ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Normal Pregnancy ◽  
Index Pregnancy ◽  
History Of ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryTo determine whether perturbations of haemostatic function and lipoprotein metabolism prevail long after preeclampsia and increase the risk of future coronary heart disease (CHD), we conducted a follow-up study in women with (cases, n = 25) or without (controls, n = 24) a history of preeclampsia. Blood samples were taken in the follicular and in the luteal phases of a menstrual cycle. Levels of blood pressure (BP) and proteinuria measured during the index pregnancy were included in the evaluation. Compared to control women who had undergone a normal pregnancy, the formerly preeclamptic patients had higher systolic (p <0.01) and diastolic (p <0.05) BPs and increased plasma levels of von Willebrand factor (vWF), fibrinogen, cholesterol, triglycerides and very low density lipoprotein (VLDL) (all p <0.05). The lipid, vWF, and fibrinogen levels were positively related to the degree of BP elevation but not to the degree of proteinuria during the index pregnancy. Except for the increase in vWF level, all biochemical perturbations were only present in the luteal but not in the follicular phase samples. In conclusion, persistent endothelial dysfunction with ensuing dysregulation of blood pressure, haemostatic perturbation and dyslipoproteinemia after preeclampsia may indicate a proneness to future CHD.

scholarly journals Direct radioimmune detection in human plasma of the association between factor VIII procoagulant protein and von Willebrand factor, and the interaction of von Willebrand factor-bound procoagulant VIII with platelets

Blood ◽  
1983 ◽  
Vol 61 (6) ◽  
pp. 1163-1173 ◽  
Author(s):  
JL Moake ◽  
MJ Weinstein ◽  
JH Troll ◽  
LE Chute ◽  
NM Colannino
Keyword(s):  
Factor Viii ◽  
Human Plasma ◽  
Von Willebrand Factor ◽  
Sodium Dodecylsulfate ◽  
Coagulation Factors ◽  
Cysteine Protease Inhibitors ◽  
Proteolytic Activation ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The predominant procoagulant factor VIII (VIII:C) form in normal human plasma containing various combinations of anticoagulants and serine/cysteine protease inhibitors is a protein with mol wt 2.6 +/- 0.2 X 10(5). This protein can be detected by 125I-anti-VIII:C Fab binding and gel electrophoresis in the presence and absence of sodium dodecylsulfate (SDS) and is distinct from the subunit of factor VIII/von Willebrand factor (VIII:vWF) multimers. No larger VIII:C form is present in plasma from patients with severe congenital deficiencies of each of the coagulation factors, other than VIII:C. The mol wt approximately 2.6 X 10(5) VIII:C form is, therefore, likely to be the in vivo procoagulant form of VIII:C, rather than a partially proteolyzed, partially activated derivative of a larger precursor. About 60% of this procoagulant mol wt approximately 2.6 X 10(5) VIII:C form in plasma is present in noncovalent complexes with larger VIII:vWF multimers, which attach reversibly to platelet surfaces in the presence of ristocetin. This VIII:vWF-bound protein of mol wt approximately 2.6 X 10(5) may be the plasma procoagulant form of VIII:C which, after proteolytic activation, accelerates the IXa-mediated cleavage and activation of X postulated to occur on platelet surfaces.

scholarly journals The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis

Blood ◽  
2018 ◽  
Vol 132 (9) ◽  
pp. 903-910 ◽  
Author(s):  
Camila Masias ◽  
Spero R. Cataland
Keyword(s):  
Thrombotic Microangiopathies ◽  
Acute Setting ◽  
Artery Disease ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Deficient Activity

Abstract ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra-large von Willebrand factor (VWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMAs) and thrombotic disorders, such as ischemic stroke and coronary artery disease. Through its action on VWF, ADAMTS13 can have prothrombotic and proinflammatory properties, not only when its activity is severely deficient, but also when it is only moderately low. Here, we will discuss the biology of ADAMTS13 and the different assays developed to evaluate its function in the context of TTP, in the acute setting and during follow-up. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. This information will be useful for clinicians not only when evaluating patients who present with microangiopathic hemolytic anemia and thrombocytopenia, but also when making clinical decisions regarding the follow-up of patients with TTP.

scholarly journals Increased plasma von Willebrand factor antigen levels but normal von Willebrand factor cleaving protease (ADAMTS13) activity in preeclampsia

2009 ◽  
Vol 101 (02) ◽  
pp. 305-311 ◽  
Author(s):  
János Rigó Jr ◽  
Tamás Bõze ◽  
Zoltán Derzsy ◽  
László Cervenak ◽  
Veronika Makó ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Von Willebrand Factor ◽  
Hellp Syndrome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Adamts13 Activity ◽  
Elevated Liver Enzymes ◽  
Significant Difference ◽  
Low Platelet Count ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease is low in several conditions, including HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome. As HELLP syndrome develops in most cases on the basis of preeclampsia, our aim was to determine whether plasma ADAMTS13 activity is decreased in preeclampsia. Sixty-seven preeclamptic patients, 70 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Plasma ADAMTS13 activity was determined with the FRETS-VWF73 assay, while VWF antigen (VWF:Ag) levels with an enzyme-linked immunosorbent assay. The multimeric pattern of VWF was analyzed by SDS-agarose gel electrophoresis. There was no significant difference in plasma ADAMTS13 activity between the preeclamptic and the healthy pregnant and non-pregnant groups (median [25–75 percentile]: 98.8 [76.5–112.8] %, 96.3 [85.6–116.2] % and 91.6 [78.5–104.4] %, respectively; p>0.05). However, plasma VWF:Ag levels were significantly higher in preeclamptic patients than in healthy pregnant and non-pregnant women (187.1 [145.6–243.1] % versus 129.3 [105.1–182.8] % and 70.0 [60.2–87.3] %, respectively; p<0.001). The multimeric pattern of VWF was normal in each group. Primiparas had lower plasma ADAMTS13 activity than multi-paras (92.6 [75.8–110.6] % versus 104.2 [92.1–120.8] %; p=0.011). No other relationship was found between clinical characteristics, laboratory parameters and plasma ADAMTS13 activity in either study group. In conclusion, plasma ADAMTS13 activity is normal in preeclampsia despite the increased VWF:Ag levels. However, further studies are needed to determine whether a decrease in plasma ADAMTS13 activity could predis-pose preeclamptic patients to develop HELLP syndrome.

BLEEDING TIME IN NORMAL SUBJECTS: ITS RELATIONSHIP WITH SEX, AGE, BLOOD GROUP, HEMATOCRIT, PLATELET COUNT AND PLASMA VON WILLEBRAND FACTOR LEVEL

1987 ◽  
Author(s):  
F Rodeghiero ◽  
G Castaman ◽  
E Di Bona ◽  
M Ruggeri
Keyword(s):  
Platelet Count ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Physiological Parameters ◽  
Factor Level ◽  
Significant Difference ◽  
Von Willebrand ◽  
Willebrand Factor

Bleeding time (BT) is the most important test for in "vivo" Vevaluation of primary hemostasis. Several physiological parameters namely sex, age, blood group, hematocrit, platelet count and von Willebrand factor level could exert a significant influenceIn this study, the relationships between BT (Simplate II,General Diagnostics)and these physiological parameters havebeen examined in 58 subjects aging 17-71 (32 males and 26 females; 26 of 0 and 32 of non-0 group). In all the subjects bleedingdiathesis was excluded by interview. They were not taking anvmedicament for at least 10 days and showed normal platelet aggregation by ADP and ArachidonateMean BT value (seconds) was 318± 65 (range 195-A95)Statistical analysis failed to show any significant difference realated to sex and blood group. There was no significant relationship with hematocrit (0.01), platelet count (−0.2A), age (−0.28) and von Willebrand factor level, mesured as ristocetin cofactor (−0.2A). In particular, our data indicate that higher von Willebrand factor levels found in non-0 group in comparison with O-group (113.3 vs 83.5, P < 0:001) do not exert any apparent influence on bleeding time

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