scholarly journals Contact System Activation and Cancer: New Insights in the Pathophysiology of Cancer-Associated Thrombosis

2018 ◽  
Vol 118 (02) ◽  
pp. 251-265 ◽  
Author(s):  
E. Campello ◽  
M.W. Henderson ◽  
D.F. Noubouossie ◽  
P. Simioni ◽  
N.S. Key
Keyword(s):  
Factor Viia ◽  
Contact System ◽  
Host Cells ◽  
Hypercoagulable State ◽  
Coagulation System ◽  
Contact Activation ◽  
Thrombotic Risk ◽  
Contact Pathway ◽  
Cancer Associated Thrombosis

AbstractCancer induces a systemic hypercoagulable state that elevates the baseline thrombotic risk of affected patients. This hypercoagulable state reflects a complex interplay between cancer cells and host cells and the coagulation system as part of the host response to cancer. Although the tissue factor (TF)/factor VIIa pathway is proposed to be the principal initiator of fibrin formation in cancer patients, clinical studies have not shown a consistent relationship between circulating TF levels (often measured as plasma microvesicle-associated TF) and the risk of thrombosis. A renewed interest in the role of the contact pathway in thrombosis has evolved over the past decade, raising the question of its role in the pathogenesis of thrombotic complications in cancer. Recent observations have documented the presence of activation of the contact system in gastrointestinal, lung, breast and prostate cancers. Although the assays used to measure contact activation differ, and despite the absence of standardization of methodologies, it is clear that both the intrinsic and extrinsic pathways may be activated in cancer. This review will focus on recent findings concerning the role of activation of the contact system in cancer-associated hypercoagulability and thrombosis. An improved understanding of the pathophysiology of these mechanisms may lead to personalized antithrombotic protocols with improved efficacy and safety compared with currently available therapies.

Effects of Plasma Kallikrein Specific Inhibitor and Active-site Blocked Factor VIIa on the Pulmonary Vascular Injury Induced by Endotoxin in Rats

1997 ◽  
Vol 78 (04) ◽  
pp. 1209-1214 ◽  
Author(s):  
Mitsuhiro Uchiba ◽  
Kenji Okajima ◽  
Kazunori Murakami ◽  
Hiroaki Okabe ◽  
Shosuke Okamoto ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Active Site ◽  
Factor Viia ◽  
Specific Inhibitor ◽  
Coagulation System ◽  
Plasma Kallikrein ◽  
Extrinsic Pathway ◽  
E Coli ◽  
Intravascular Coagulation

SummaryThe acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. To evaluate the role of the coagulation system in the pathogenesis of ARDS in sepsis, we examined the effects of the administration of a synthetic plasma kallikrein specific inhibitor (PKSI) and of active-site blocked factor VIIa (DEGR-VIIa) on the pulmonary vascular injury induced by E. coli endotoxin (ET) in rats. Administration of PKSI prevented the pulmonary vascular injury induced by ET as well as pulmonary histological changes in animals administered ET, but it did not affect the intravascular coagulation. The opposite effect was seen with DEGR-VIIa, which prevented the intravascular coagulation but not the pulmonary vascular injury. PKSI did not inhibit the activation of the complement system induced by ET leading to the activation of neutrophils.Findings suggest that PKSI may prevent the pulmonary vascular injury induced by ET by inhibiting kallikrein, which activates the neutrophils. The intrinsic pathway of coagulation may be more important than the extrinsic pathway in the pulmonary vascular injury produced byET.

scholarly journals Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 60-65 ◽  
Author(s):  
Maurits L. van Montfoort ◽  
Joost C.M. Meijers
Keyword(s):  
Molecular Weight ◽  
Small Molecules ◽  
Antisense Oligonucleotides ◽  
Contact System ◽  
Factor Xii ◽  
High Molecular Weight Kininogen ◽  
Vascular Beds ◽  
Contact Pathway

Abstract The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy.

scholarly journals Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 380 ◽  
Author(s):  
Norbaini Abdol Razak ◽  
Gabrielle Jones ◽  
Mayank Bhandari ◽  
Michael Berndt ◽  
Pat Metharom
Keyword(s):  
Risk Factors ◽  
Cancer Patients ◽  
Current Treatment ◽  
Host Cells ◽  
Coagulation Cascade ◽  
Common Complication ◽  
Increased Risk ◽  
Thrombotic Complications ◽  
Cancer Associated Thrombosis

Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed.

scholarly journals Mechanisms of thrombin generation during surgery and cardiopulmonary bypass [see comments]

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3350-3357 ◽  
Author(s):  
MD Boisclair ◽  
DA Lane ◽  
H Philippou ◽  
MP Esnouf ◽  
S Sheikh ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Factor Viia ◽  
Factor Ix ◽  
Contact System ◽  
Coagulation System ◽  
Factor Xiia ◽  
System Factor

Abstract Although in vitro studies have been invaluable in revealing the complex biochemistry of the blood coagulation system, the mechanisms involved during the in vivo response to hypercoagulable stimuli are still unclear. We have used plasma-based enzyme-linked immunosorbent assays (ELISAs) to study the mechanisms by which the coagulation system is activated in vivo during human cardiopulmonary bypass (CPB) surgery (n = 8). A novel immunoassay for factor XIIa was used to detect activation of the contact system, factor IX activation peptide (FIXAP) was used as a marker for activation of factor IX, and prothrombin fragment F1 + 2 (F1 + 2) was used as a marker for thrombin generation. The ELISA for FIXAP is described for the first time herein. F1 + 2 levels increased early in response to surgical intervention: from a baseline of 38.7 +/- 9.7 ng/mL (mean +/-SE), levels increased rapidly during surgery and bypass to a maximum of 448.5 +/- 92.0 ng/mL. A modest yet significant increase in factor XIIa levels from 3.47 +/- 0.54 ng/mL to 4.33 +/- 0.85 ng/mL was evident during surgery before bypass, but no further significant increase was detected on establishing extracorporeal circulation. FIXAP levels demonstrated a small and late increase during surgery from 4.98 +/- 0.55 ng/mL to a maximum of 10.20 +/- 1.23 ng/mL, the increase beginning at the time of near maximal F1 + 2 levels. There was no association between activation of the contact system (factor XIIa levels) and the generation of thrombin (F1 + 2 levels). However, a strong association (r = .705) was apparent between the generation of thrombin (F1 + 2 levels) and activation of factor IX (FIXAP levels), despite the delay between the activation of prothrombin and factor IX. The data do not support the established view that contact activation resulting from exposure of blood to foreign surfaces is the major procoagulant stimulus in CPB. Instead, the results suggest that the main trigger to coagulation during CPB surgery was provided via the tissue factor-factor VIIa mechanism in response to the cutting of blood vessels, which directly activated factor X and then prothrombin. The late activation of factor IX, which presumably also contributed to maximal prothrombin activation, could have arisen due to direct tissue factor-factor VIIa action, or by secondary feedback action of thrombin on the intrinsic system.

scholarly journals Mechanisms of thrombin generation during surgery and cardiopulmonary bypass [see comments]

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3350-3357
Author(s):  
MD Boisclair ◽  
DA Lane ◽  
H Philippou ◽  
MP Esnouf ◽  
S Sheikh ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Factor Viia ◽  
Factor Ix ◽  
Contact System ◽  
Coagulation System ◽  
Factor Xiia ◽  
System Factor

Although in vitro studies have been invaluable in revealing the complex biochemistry of the blood coagulation system, the mechanisms involved during the in vivo response to hypercoagulable stimuli are still unclear. We have used plasma-based enzyme-linked immunosorbent assays (ELISAs) to study the mechanisms by which the coagulation system is activated in vivo during human cardiopulmonary bypass (CPB) surgery (n = 8). A novel immunoassay for factor XIIa was used to detect activation of the contact system, factor IX activation peptide (FIXAP) was used as a marker for activation of factor IX, and prothrombin fragment F1 + 2 (F1 + 2) was used as a marker for thrombin generation. The ELISA for FIXAP is described for the first time herein. F1 + 2 levels increased early in response to surgical intervention: from a baseline of 38.7 +/- 9.7 ng/mL (mean +/-SE), levels increased rapidly during surgery and bypass to a maximum of 448.5 +/- 92.0 ng/mL. A modest yet significant increase in factor XIIa levels from 3.47 +/- 0.54 ng/mL to 4.33 +/- 0.85 ng/mL was evident during surgery before bypass, but no further significant increase was detected on establishing extracorporeal circulation. FIXAP levels demonstrated a small and late increase during surgery from 4.98 +/- 0.55 ng/mL to a maximum of 10.20 +/- 1.23 ng/mL, the increase beginning at the time of near maximal F1 + 2 levels. There was no association between activation of the contact system (factor XIIa levels) and the generation of thrombin (F1 + 2 levels). However, a strong association (r = .705) was apparent between the generation of thrombin (F1 + 2 levels) and activation of factor IX (FIXAP levels), despite the delay between the activation of prothrombin and factor IX. The data do not support the established view that contact activation resulting from exposure of blood to foreign surfaces is the major procoagulant stimulus in CPB. Instead, the results suggest that the main trigger to coagulation during CPB surgery was provided via the tissue factor-factor VIIa mechanism in response to the cutting of blood vessels, which directly activated factor X and then prothrombin. The late activation of factor IX, which presumably also contributed to maximal prothrombin activation, could have arisen due to direct tissue factor-factor VIIa action, or by secondary feedback action of thrombin on the intrinsic system.

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 60-65 ◽  
Author(s):  
Maurits L. van Montfoort ◽  
Joost C.M. Meijers
Keyword(s):  
Molecular Weight ◽  
Small Molecules ◽  
Antisense Oligonucleotides ◽  
Contact System ◽  
Factor Xii ◽  
High Molecular Weight Kininogen ◽  
Vascular Beds ◽  
Contact Pathway

The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy.

Role of acquired and hereditary thrombotic risk factors in patients with ischemic colitis

2001 ◽  
Vol 120 (5) ◽  
pp. A282-A282
Author(s):  
I KOUTROUBAKIS ◽  
A SFIRIDAKI ◽  
A THEODOROPOULOU ◽  
A LIVADIOTAKI ◽  
P DIMOULIOS ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ischemic Colitis ◽  
Thrombotic Risk

A Re-Appraisal of the Role of Blood Coagulation and Platelets in the Generalized Shwartzman Phenomenon

1966 ◽  
Vol 15 (03/04) ◽  
pp. 519-538 ◽  
Author(s):  
J Levin ◽  
E Beck
Keyword(s):  
Blood Coagulation ◽  
The State ◽  
Coagulation System ◽  
Renal Lesions ◽  
Intravascular Coagulation ◽  
Renal Glomeruli ◽  
Coagulation Mechanism ◽  
Shwartzman Phenomenon ◽  
Do So

SummaryThe role of intravascular coagulation in the production of the generalized Shwartzman phenomenon has been evaluated. The administration of endotoxin to animals prepared with Thorotrast results in activation of the coagulation mechanism with the resultant deposition of fibrinoid material in the renal glomeruli. Anticoagulation prevents alterations in the state of the coagulation system and inhibits development of the renal lesions. Platelets are not primarily involved. Platelet antiserum produces similar lesions in animals prepared with Thorotrast, but appears to do so in a manner which does not significantly involve intravascular coagulation.The production of adrenal cortical hemorrhage, comparable to that seen in the Waterhouse-Friderichsen syndrome, following the administration of endotoxin to animals that had previously received ACTH does not require intravascular coagulation and may not be a manifestation of the generalized Shwartzman phenomenon.

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