In vivo roles of factor XII Renné, Thomas; Schmaier, Alvin H.; Nickel, Katrin F. ...
Blood,
11/2012, Letnik:
120, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Coagulation factor XII (FXII, Hageman factor, EC = 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by “contact” to ...charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Consistent with their human counterparts, FXII−/− mice have a normal hemostatic capacity. However, thrombus formation in FXII−/− mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology.
Polyphosphate is an inorganic polymer that can potentiate several interactions in the blood coagulation system. Blood platelets contain polyphosphate, and the secretion of platelet-derived ...polyphosphate has been associated with increased thrombus formation and activation of coagulation factor XII. However, the small polymer size of secreted platelet polyphosphate limits its capacity to activate factor XII in vitro. Thus, the mechanism by which platelet polyphosphate contributes to thrombus formation remains unclear. Using live-cell imaging, confocal and electron microscopy, we show that activated platelets retain polyphosphate on their cell surface. The apparent polymer size of membrane-associated polyphosphate largely exceeds that of secreted polyphosphate. Ultracentrifugation fractionation experiments revealed that membrane-associated platelet polyphosphate is condensed into insoluble spherical nanoparticles with divalent metal ions. In contrast to soluble polyphosphate, membrane-associated polyphosphate nanoparticles potently activate factor XII. Our findings identify membrane-associated polyphosphate in a nanoparticle state on the surface of activated platelets. We propose that these polyphosphate nanoparticles mechanistically link the procoagulant activity of platelets with the activation of coagulation factor XII.
•Activated platelets expose insoluble membrane-associated polyphosphate nanoparticles that are complexed with divalent metal ions.•Platelet polyphosphate nanoparticles, but not soluble polyphosphate polymers, activate the contact system.
Coagulation factor XII (FXII, Hageman factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII’s unique ...mechanism of activation that is induced by binding (contact) to negatively charged surfaces. Various substances have the capacity to trigger FXII contact-activation in vivo including mast cell–derived heparin, misfolded protein aggregates, collagen, nucleic acids, and polyphosphate. FXII deficiency is not associated with bleeding, and for decades, the factor was considered to be dispensable for coagulation in vivo. However, despite the fact that humans and animals with deficiency in FXII have a normal hemostatic capacity, animal models revealed a critical role of FXIIa-driven coagulation in thromboembolic diseases. In addition to its role in thrombosis, FXIIa contributes to inflammation through the activation of the inflammatory bradykinin-producing kallikrein-kinin system. Pharmacological inhibition of FXII/FXIIa interferes with thrombosis and inflammation in animal models. Thus, targeting the FXIIa-driven contact system seems to be a promising and safe therapeutic anticoagulation treatment strategy, with additional anti-inflammatory effects. Here, we discuss novel functions of FXIIa in cardiovascular thrombotic and inflammatory disorders.
Cancer is a leading cause of thrombosis. We identify a new procoagulant mechanism that contributes to thromboembolism in prostate cancer and allows for safe anticoagulation therapy development. ...Prostate cancer-mediated procoagulant activity was reduced in plasma in the absence of factor XII or its substrate of the intrinsic coagulation pathway factor XI. Prostate cancer cells and secreted prostasomes expose long chain polyphosphate on their surface that colocalized with active factor XII and initiated coagulation in a factor XII-dependent manner. Polyphosphate content correlated with the procoagulant activity of prostasomes. Inherited deficiency in factor XI or XII or high-molecular-weight kininogen, but not plasma kallikrein, protected mice from prostasome-induced lethal pulmonary embolism. Targeting polyphosphate or factor XII conferred resistance to prostate cancer-driven thrombosis in mice, without increasing bleeding. Inhibition of factor XII with recombinant 3F7 antibody reduced the increased prostasome-mediated procoagulant activity in patient plasma. The data illustrate a critical role for polyphosphate/factor XII-triggered coagulation in prostate cancer-associated thrombosis with implications for anticoagulation without therapy-associated bleeding in malignancies.
•Polyphosphate-activated coagulation factor XII drives prostate cancer-associated venous thrombosis.•Targeting the polyphosphate/factor XII pathway reduces procoagulant activity in prostate cancer patient plasma and may permit safe anticoagulation.
Currently used anticoagulants prevent thrombosis but increase bleeding. We show an anticoagulation therapy without bleeding risk based on a plasma protease factor XII function-neutralizing antibody. ...We screened for antibodies against activated factor XII (FXIIa) using phage display and demonstrated that recombinant fully human antibody 3F7 binds into the FXIIa enzymatic pocket. 3F7 interfered with FXIIa-mediated coagulation, abolished thrombus formation under flow, and blocked experimental thrombosis in mice and rabbits. We adapted an extracorporeal membrane oxygenation (ECMO) cardiopulmonary bypass system used for infant therapy to analyze clinical applicability of 3F7 in rabbits. 3F7 provided thromboprotection as efficiently as heparin, and both drugs prevented fibrin deposition and thrombosis within the extracorporeal circuit. Unlike heparin, 3F7 treatment did not impair the hemostatic capacity and did not increase bleeding from wounds. These data establish that targeting of FXIIa is a safe mode of thromboprotection in bypass systems, and provide a clinically relevant anticoagulation strategy that is not complicated by excess bleeding.
Surgical resection is crucial for curative treatment of rectal cancer. Through multidisciplinary treatment, including radiochemotherapy and total mesorectal excision, survival has improved ...substantially. Consequently, more patients have to deal with side effects of treatment. The most recently introduced surgical technique is robotic-assisted surgery (RAS) which seems equally effective in terms of oncological control compared to laparoscopy. However, RAS enables further advantages which maximize the precision of surgery, thus providing better functional outcomes such as sexual function or contience without compromising oncological results. This review was done according to the PRISMA and AMSTAR-II guidelines and registered with PROSPERO (CRD42018104519). The search was planned with PICO criteria and conducted on Medline, Web of Science and CENTRAL. All screening steps were performed by two independent reviewers. Inclusion criteria were original, comparative studies for laparoscopy vs. RAS for rectal cancer and reporting of functional outcomes. Quality was assessed with the Newcastle–Ottawa scale. The search retrieved 9703 hits, of which 51 studies with 24,319 patients were included. There was a lower rate of urinary retention (non-RCTs: Odds ratio (OR) 95% Confidence Interval (CI) 0.65 0.46, 0.92; RCTs: ORCI 1.290.08, 21.47), ileus (non-RCTs: ORCI 0.860.75, 0.98; RCTs: ORCI 0.800.33, 1.93), less urinary symptoms (non-RCTs mean difference (MD) CI − 0.60 − 1.17, − 0.03; RCTs: − 1.37 − 4.18, 1.44), and higher quality of life for RAS (only non-RCTs: MDCI: 2.99 2.02, 3.95). No significant differences were found for sexual function (non-RCTs: standardized MDCI: 0.46− 0.13, 1.04; RCTs: SMDCI: 0.09− 0.14, 0.31). The current meta-analysis suggests potential benefits for RAS over laparoscopy in terms of functional outcomes after rectal cancer resection. The current evidence is limited due to non-randomized controlled trials and reporting of functional outcomes as secondary endpoints.
Objective
To compare outcomes of endoscopic and surgical treatment for infected necrotizing pancreatitis (INP) based on results of randomized controlled trials (RCT).
Background
Treatment of INP has ...changed in the last two decades with adoption of interventional, endoscopic and minimally invasive surgical procedures for drainage and necrosectomy. However, this relies mostly on observational studies.
Methods
We performed a systematic review following Cochrane and PRISMA guidelines and AMSTAR-2 criteria and searched CENTRAL, Medline and Web of Science. Randomized controlled trails that compared an endoscopic treatment to a surgical treatment for patients with infected walled-off necrosis and included one of the main outcomes were eligible for inclusion. The main outcomes were mortality and new onset multiple organ failure. Prospero registration ID: CRD42019126033
Results
Three RCTs with 190 patients were included. Intention to treat analysis showed no difference in mortality. However, patients in the endoscopic group had statistically significant lower odds of experiencing new onset multiple organ failure (odds ratio (OR) confidence interval CI 0.31 0.10, 0.98) and were statistically less likely to suffer from perforations of visceral organs or enterocutaneous fistulae (OR CI 0.31 0.10, 0.93), and pancreatic fistulae (OR CI 0.09 0.03, 0.28). Patients with endoscopic treatment had a statistically significant lower mean hospital stay (Mean difference CI − 7.86 days − 14.49, − 1.22). No differences in bleeding requiring intervention, incisional hernia, exocrine or endocrine insufficiency or ICU stay were apparent. Overall certainty of evidence was moderate.
Conclusion
There seem to be possible benefits of endoscopic treatment procedure. Given the heterogenous procedures in the surgical group as well as the low amount of randomized evidence, further studies are needed to evaluate the combination of different approaches and appropriate timepoints for interventions.
Polyphosphate is an inorganic procoagulant polymer. Here we develop specific inhibitors of polyphosphate and show that this strategy confers thromboprotection in a factor XII-dependent manner. ...Recombinant Escherichia coli exopolyphosphatase (PPX) specifically degrades polyphosphate, while a PPX variant lacking domains 1 and 2 (PPX_Δ12) binds to the polymer without degrading it. Both PPX and PPX_Δ12 interfere with polyphosphate- but not tissue factor- or nucleic acid-driven thrombin formation. Targeting polyphosphate abolishes procoagulant platelet activity in a factor XII-dependent manner, reduces fibrin accumulation and impedes thrombus formation in blood under flow. PPX and PPX_Δ12 infusions in wild-type mice interfere with arterial thrombosis and protect animals from activated platelet-induced venous thromboembolism without increasing bleeding from injury sites. In contrast, targeting polyphosphate does not provide additional protection from thrombosis in factor XII-deficient animals. Our data provide a proof-of-concept approach for combating thrombotic diseases without increased bleeding risk, indicating that polyphosphate drives thrombosis via factor XII.
Background
Robotic-assisted surgery (RAS) potentially reduces workload and shortens the surgical learning curve compared to conventional laparoscopy (CL). The present study aimed to compare ...robotic-assisted cholecystectomy (RAC) to laparoscopic cholecystectomy (LC) in the initial learning phase for novices.
Methods
In a randomized crossover study, medical students (
n
= 40) in their clinical years performed both LC and RAC on a cadaveric porcine model. After standardized instructions and basic skill training, group 1 started with RAC and then performed LC, while group 2 started with LC and then performed RAC. The primary endpoint was surgical performance measured with Objective Structured Assessment of Technical Skills (OSATS) score, secondary endpoints included operating time, complications (liver damage, gallbladder perforations, vessel damage), force applied to tissue, and subjective workload assessment.
Results
Surgical performance was better for RAC than for LC for total OSATS (RAC = 77.4 ± 7.9 vs. LC = 73.8 ± 9.4;
p
= 0.025, global OSATS (RAC = 27.2 ± 1.0 vs. LC = 26.5 ± 1.6;
p
= 0.012, and task specific OSATS score (RAC = 50.5 ± 7.5 vs. LC = 47.1 ± 8.5;
p
= 0.037). There were less complications with RAC than with LC (10 (25.6%) vs. 26 (65.0%),
p
= 0.006) but no difference in operating times (RAC = 77.0 ± 15.3 vs. LC = 75.5 ± 15.3 min;
p
= 0.517). Force applied to tissue was similar. Students found RAC less physical demanding and less frustrating than LC.
Conclusions
Novices performed their first cholecystectomies with better performance and less complications with RAS than with CL, while operating time showed no differences. Students perceived less subjective workload for RAS than for CL. Unlike our expectations, the lack of haptic feedback on the robotic system did not lead to higher force application during RAC than LC and did not increase tissue damage. These results show potential advantages for RAS over CL for surgical novices while performing their first RAC and LC using an ex vivo cadaveric porcine model.
Registration number
researchregistry6029
Graphic abstract
A potential role for coagulation factors in pulmonary arterial hypertension has been recently described, but the mechanism of action is currently not known. Here, we investigated the interactions ...between thrombin and the nitric oxide-cGMP pathway in pulmonary endothelial cells and experimental pulmonary hypertension.
Chronic treatment with the selective thrombin inhibitor melagatran (0.9 mg/kg daily via implanted minipumps) reduced right ventricular hypertrophy in the rat monocrotaline model of experimental pulmonary hypertension. In vitro, thrombin was found to have biphasic effects on key regulators of the nitric oxide-cGMP pathway in endothelial cells (HUVECs). Acute thrombin stimulation led to increased expression of the cGMP-elevating factors endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) subunits, leading to increased cGMP levels. By contrast, prolonged exposition of pulmonary endothelial cells to thrombin revealed a characteristic pattern of differential expression of the key regulators of the nitric oxide-cGMP pathway, in which specifically the factors contributing to cGMP elevation (eNOS and sGC) were reduced and the cGMP-hydrolyzing PDE5 was elevated (qPCR and Western blot). In line with the differential expression of key regulators of the nitric oxide-cGMP pathway, a reduction of cGMP by prolonged thrombin stimulation was found. The effects of prolonged thrombin exposure were confirmed in endothelial cells of pulmonary origin (HPAECs and HPMECs). Similar effects could be induced by activation of protease-activated receptor-1 (PAR-1).
These findings suggest a link between thrombin generation and cGMP depletion in lung endothelial cells through negative regulation of the nitric oxide-cGMP pathway, possibly mediated via PAR-1, which could be of relevance in pulmonary arterial hypertension.
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