scholarly journals Ponatinib and Cardiovascular Complications

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3055-3055 ◽  
Author(s):  
Alvin H. Schmaier ◽  
Alona A. Merkulova ◽  
Steven Mitchell ◽  
Evi X Stavrou
Keyword(s):  
Carotid Artery ◽  
Arterial Thrombosis ◽  
Vessel Wall ◽  
Ex Vivo ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Ppar Γ ◽  
Thrombosis Risk ◽  
Prothrombotic Effect

Abstract Patients with T315I positive CML are resistant to most tyrosine kinase inhibitors (TKIs). Ponatinib (Iclusig) is approved for CML patients with the T315I ABL kinase polymorphism. However, ponatinib treatment is associated with vascular events (myocardial infarction, stroke, coronary artery stenosis, limb ischemia and occlusion, and venous thrombosis) in~29% of patients. The mechanism(s) for these events has not been characterized. We developed a murine model to examine TKIs influence on arterial thrombosis risk. C57BL/6 mice, 18-22 weeks of age and treated with ponatinib by gavage for 14 days at 15 mg/kg PO BID, had significantly shorter carotid artery occlusion times induced by photochemical activation of Rose-Bengal compared to vehicle-treated mice (10.4 ± 2.9 min versus 32.3 ± 4.8 min, p < 0.0001). Mice were treated with ponatinib for 14 days at the 3 mg/kg PO BID, a dose that yields plasma concentrations similar to patients at 45 mg po daily, also had significantly shorter vessel occlusion times compared to control (18.7 ± 3.7 min versus 32.3 ± 4.8 min, p<0.0001). No difference in time to carotid artery occlusion was observed between imatinib at 180 mg/kg PO BID treatment compared to control (32.7 ± 5.6 min versus 32.3 ± 4.8 min, p = 0.85) or nilotinib at 29 mg/kg PO BID treatment compared to vehicle-treated mice (32.8 ± 5.5 min versus 33.8 ± 5.1 min, p = 0.71). These studies show that uniquely ponatinib treatment is prothrombotic. Plasma of ponatinib-treated animals had normal PT, aPTT, and complete blood counts (WBC, RBC, Hgb, Hct, MCV, MCH, MCHC and platelet counts) assays. Also contact activation- and tissue factor-initiated thrombin generation times (TGT) showed no difference between treated and untreated mouse plasma. We next examined the mechanism(s) of ponatinib-induced thrombosis. Ponatinib at 3 mg/kg PO BID daily inhibited p-LynY396 in murine platelets. Lyn is a negative regulator of platelet GPVI. Collagen-related peptide (CRP)-induced expression on murine platelets of the activated heterodimeric complex of α2bβ3 integrins (the JON/A epitope) and the alpha granule constituent P-selectin (CD62) when examined by flow cytometry ex vivo were significantly higher at 3 μg/ml in ponatinib-treated versus untreated mice (p< 0.03). The CRP concentration needed to induce platelet activation in ponatinib-treated mice was significantly lower than untreated mice (p<0.0001, 2-way ANOVA). These data suggested that platelets from ponatinib-treated mice are more GPVI actable. Additional studies with α-thrombin also show ponatinib-treatment makes more active platelets. The threshold for α-thrombin-induced expression of the JON/A epitope also was significantly lower (p<0.0125) at 0.075 and 0.1 nM in ponatinib-treated platelets versus untreated platelets. Likewise, α-thrombin-induced platelet membrane expression of P-selectin also was significantly lower (p<0.025) at 0.075 and 0.1 nM in ex vivo studies of ponatinib-treated platelets. Next, we examined vessel wall for changes in ponatinib-treated mice. Aortic sections showed increased caspase 3 staining in vessel adventitia and surrounding adipose tissue in treated mice, a sign of apoptosis. Also genes involved in vessel anti-thrombosis were altered in 3 mg/kg PO BID ponatinib-treated mice. Expression of mRNA of both COX2 and eNOS and their vasculo-protective transcriptional regulators, Sirt1 and KLF4, respectively, were significantly decreased (p<0.05) in the vessel wall of ponatinib-treated mice. We then sought agents to blunt the prothrombotic changes with ponatinib treatment. Since PPAR-γ agonism elevates Sirt1, and vessel wall Sirt1 is reduced in treated mice, we determined if pioglitazone treatment, a PPAR-γ agonist thiazolidinedione, corrects thrombosis risk after ponatinib in vivo. When ponatinib-treated mice were given oral pioglitazone (10 mg/kg/day po), their short times to thrombosis significantly lengthened (49±6.9 min, p<0.0251) to values like untreated mice. Additionally, neither lisinopril nor atorvastatin ameliorated the ponatinib's prothrombotic effect in vivo. In sum, ponatinib uniquely induces a prothrombotic state due increased platelet activation and reduced vessel wall anti-thrombosis. The effect of ponatinib on platelets may arise in part from its inhibition of p-Lyn. In a murine model of arterial thrombosis, ponatinib's prothrombotic effect is ameliorated by PPAR-γ agonism with pioglitazone. Disclosures No relevant conflicts of interest to declare.

Prolylcarboxypeptidase Deficiency Is a Risk Factor for Arterial Thrombosis and Hypertension

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 651-651
Author(s):  
Gregory Adams ◽  
Gretchen LaRusch ◽  
Evi Stavrou ◽  
Yihua Zhou ◽  
Marvin T. Nieman ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Arterial Thrombosis ◽  
Renal Tissue ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Plasma Kallikrein ◽  
Wild Type ◽  
Carotid Artery Thrombosis ◽  
Artery Thrombosis ◽  
Thrombosis Risk

Abstract Abstract 651 Background. Prolylcarboxypeptidase (PRCP), an S28 serine protease, degrades bradykinin, angiotensin II, and alpha melanocyte stimulating hormone and activates prekallikrein to plasma kallikrein (Blood 103:4554, 2004). In GWAS, it has been recognized as a risk factor for metabolic syndrome, hypertension, and pre-eclampsia. We postulated that PRCP murine hypomorphs (PRCPgt/gt) have a cardiovascular phenotype. Methods and Results. PRCP is mostly found in kidney in proximal tubules. In arteries, it is found both on endothelium and in media. A gene-trap murine hypomorph was created with 7% mRNA and 23% PRCP antigen in renal tissue. Using the Rose Bengal carotid artery thrombosis models, PRCPgt/gt mice had shorter carotid artery occlusion times (24±3 min [mean±SD]) compared to wild type (52±8 min). On a 4% ferric chloride carotid artery thrombosis assay PRCPgt/gt occluded in 21±8 min whereas wild type do not occlude at 60 min. Pharmacologic inhibition of PRCP with Z-pro-prolinal or plasma kallikrein with soybean trypsin inhibitor, Pro-Phe-Arg-Chloromethylketone or PKSI-572 in 3 mouse strains also shortened the time to carotid artery occlusion. PRCPgt/gt were constitutively hypertensive during the late night cycle (122±5 mm Hg mean arterial pressure vs 114±6 mm Hg for wildtype) as measured by carotid artery telemetry. Treatment of these animals with the mitochondria specific antioxidant mitoTEMPO significantly reduced (113±7 mm Hg) the elevated BP. Plasma angiotensin II and bradykinin levels were unaltered in PRCPgt/gt. PRCPgt/gt plasma had a significant increase in contact activation-induced thrombin generation. Aortic and renal reactive oxygen species (ROS) were increased (3.2-fold and 2.8-fold, respectively) in PRCPgt/gt mice as determined by dihydroethidium (DHE) fluorescence. PRCPgt/gt aortic and renal superoxide measured by lucigenin luminescence also was increased (1.6-fold and 1.7-fold, respectively). In PRCPgt/gt kidneys Amplex Red fluorescence, a measure of hydrogen peroxide, was increased 2.4-fold. Renal tissue had 1.6-fold increased uncoupled eNOS on SDS-PAGE. Arterial occlusion times in PRCPgt/gt were corrected by treatment with antioxidant apocynin or tempol. PRCP siRNA knockdowns in HUVEC or mesenchymal embryonic fibroblasts prepared from PRCPgt/gt embryos had increased constitutive DHE fluorescent ROS (2.1-fold and 1.4-fold, respectively). PRCPgt/gt aorta had decreased expression of Kruppel-like factors 2 and 4, thrombomodulin and eNOS. Moreover, PRCP knockdowns in HUVEC had 36% reduced eNOS mRNA expression. Conclusion. These investigations indicate that PRCP is a specific gene/protein target for arterial thrombosis risk and hypertension. Its presence modulates constitutive cell and tissue ROS. Arterial thrombosis risk is related to effect of ROS on endothelial cell anticoagulant mechanisms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Vascular Diameters as Predictive Factors of Recanalization Surgery Outcomes in Internal Carotid Artery Occlusion

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengrui Yan ◽  
Jiaru Wang ◽  
Ruohan Guo ◽  
Weitao Jin ◽  
Yang Zhao ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Predictive Factors ◽  
Vessel Wall ◽  
Internal Carotid ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Internal Carotid Artery Occlusion ◽  
Success Rates ◽  
Revascularization Surgery

Background: Revascularization surgery sometimes can achieve recanalization in patients with internal carotid artery occlusion (ICAO). High-resolution vessel wall magnetic resonance imaging (HRVWI) is a feasible technique to give detailed characteristics of the vessel wall, which may help to identify patients that carry higher success rates and more suitable for revascularization surgery.Objective: To examine the association between HRVWI characteristics of ICAO and the success rate of revascularization surgery in ICAO patients.Methods: We conducted a retrospective analysis of 31 ICAO recanalization patients enrolled from October 2017 to May 2019. The clinical data of patients and lesions were collected and analyzed.Results: A total of 31 ICAO patients were enrolled in this study. No significant differences were found between recanalization success and recanalization failure groups with regard to occlusion length, distal end of the occluded segment, and the treatment applied. The ipsilateral-to-contralateral diameter ratios (I/C ratios) of C1 or C2 and the diameter of C7 were positively related to recanalization success. A two-factor predictive model was constructed, and the I/C ratio of C2 &lt; 0.86 and the diameter of C7 &lt; 1.75mm were separately assigned 1 point. The ICAO patients who scored 0, 1, or 2 points had a risk of 5.6% (1/18), 55.6% (5/9), or 100% (4/4) to fail in the recanalization.Conclusions: The I/C ratios of C1 or C2 and the diameter of C7 are predictive factors of a revascularization surgery success in ICAO patients. A risk stratification model involving C2 and C7 was constructed for future clinical applications.

Contribution of Intrinsic and Extrinsic Coagulation Pathways to Thrombus Formation in the Mouse Carotid Artery.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1900-1900
Author(s):  
Antonella Zampolli ◽  
Patrizia Marchese ◽  
Wolfram Ruf ◽  
Nigel Mackman ◽  
Zaverio M. Ruggeri
Keyword(s):  
Carotid Artery ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Flow Index ◽  
Fibrin Deposition ◽  
Fibrin Formation ◽  
Coagulation Pathway

Abstract We studied how the intrinsic and extrinsic coagulation pathways contribute to thrombus formation. Ex vivo experiments were performed with citrated blood re-calcified before perfusion over different thrombogenic substrates. This allowed evaluation of fibrin deposition along with platelet adhesion/aggregation in real time and under relevant shear rates. Under these conditions, human melanoma cells expressing human tissue factor (TF) supported platelet adhesion/aggregation and fibrin formation, but only under relatively low shear rate (200–800 s-1). Anti-TF antibodies markedly inhibited both platelet and fibrin deposition, and no reactivity was observed using the parental cell line not transfected with TF. Blood perfusion over fibrillar collagen type I resulted in platelet adhesion/aggregation and subsequent fibrin deposition even under relatively high shear rate (1500 s-1). Corn trypsin inhibitor (CTI), a specific inhibitor of coagulation factor XIIa, had no effect on platelet adhesion/aggregation but inhibited fibrin deposition, while anti-TF antibodies had no significant effect. Preincubation of blood with prostaglandin E1 or a monoclonal antibody against integrin αIIbβ3 blocked not only thrombus growth on the surface but also fibrin formation. Such a finding indicates that thrombin generation leading to fibrin deposition occurs after platelet activation. Blood perfusion over dermal fibroblast extracellular matrix (F-ECM) from mice expressing human but lacking murine TF resulted in the rapid formation of platelet- and fibrin-rich thrombi at all shear rates tested (up to 1500 s-1). Using this thrombogenic substrate containing both collagen and TF, we found that blockade of the intrinsic coagulation pathway with CTI had a minimal effect on platelet adhesion/aggregation and fibrin formation, while inhibition of the extrinsic coagulation pathway with anti-human TF antibodies reduced thrombus growth and stabilization and abolished fibrin formation. The results of these ex vivo studies demonstrate that the relative contribution of the intrinsic and extrinsic coagulation pathways to fibrin and platelets deposition depends on the composition of the thrombogenic surface exposed to blood flow, and indicate also that CTI and anti-TF antibodies can be used as specific inhibitors of thrombin generation through the intrinsic and extrinsic coagulation pathways, respectively. We then established a model of carotid artery injury induced by ferric chloride to evaluate whether the information obtained under controlled experimental conditions ex vivo can help interpret the mechanisms underlying arterial thrombus formation in vivo. In this model, all control C57BL6 mice exhibited a stable carotid artery occlusion within a predictable time frame. To obtain a quantitative parameter of the progression of thrombosis we calculated a flow index. This represents the ratio between the volume of blood that flew through the injured artery from the induction of the lesion to occlusion (or to the end of the predetermined 30 min observation period) and the volume of blood that during the same period of time should have flown through the artery if the initial (pre-injury) flow rate had been maintained. We found that blocking the intrinsic coagulation pathway with CTI injected through the jugular vein significantly delayed, and in most cases prevented, the formation of a stable occlusion, resulting in a significantly altered flow index. The injection of antibodies against human TF, on the other hand, resulted in a trend towards thrombus destabilization, but in most cases the artery still occluded and the flow index was less significantly altered that with CTI. Of note, CTI at a dose that inhibited carotid artery occlusion had no effect on the tail bleeding time. Co-administration of CTI and anti-TF antibodies showed a cooperative effect across the tested concentration range. In conclusion, extrinsic and intrinsic coagulation pathways have complementary roles in thrombus formation and stabilization, and the specific contribution of each depends upon the nature of the thrombogenic surface, i.e. of the causative lesion. The marked effect of factor XIIa inhibition in preventing carotid artery occlusion suggests that a functional link between contact phase activation and tissue factor pathway leading to thrombin generation may be operative under defined conditions in vivo.

scholarly journals C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates, and protects against carotid artery occlusion and cerebral stroke

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6051-6060 ◽  
Author(s):  
Zongdong Li ◽  
Michael A. Nardi ◽  
Yong-Sheng Li ◽  
Wei Zhang ◽  
Ruimin Pan ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Ex Vivo ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Cerebral Stroke ◽  
Thrombin Cleavage ◽  
Acid Fragment ◽  
Platelet Thrombus ◽  
Platelet Aggregates ◽  
Nadph Oxidase Activation

Abstract Anti-platelet integrin GPIIIa49-66 antibody (Ab) induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385–amino acid fragment of ADAMTS-18 (a disintegrin metalloproteinase with thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti–GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP or collagen and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti–ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCI3-induced carotid artery thrombosis as well as cerebral infarction in a postischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18.

scholarly journals Nitrophorin 2, a factor IX(a)-directed anticoagulant, inhibits arterial thrombosis without impairing haemostasis

2010 ◽  
Vol 104 (12) ◽  
pp. 1116-1123 ◽  
Author(s):  
Daniella M. Mizurini ◽  
Ivo M. B. Francischetti ◽  
John F. Andersen ◽  
Robson Q. Monteiro
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Factor Ix ◽  
Occlusion Time ◽  
Venous Shunt ◽  
Blood Sucking ◽  
Antithrombotic Effects

SummaryNitrophorin 2 (NP2) is a 20 kDa lipocalin identified in the salivary gland of the blood sucking insect, Rhodnius prolixus. It functions as a potent inhibitor of the intrinsic pathway of coagulation upon binding to factor IX (FIX) or FIXa. Herein we have investigated the in vivo antithrombotic properties of NP2. Surface plasmon resonance assays demonstrated that NP2 binds to rat FIX and FIXa with high affinities (KD = 43 and 47 nM, respectively), and prolongs the aPTT without affecting the PT. In order to evaluate NP2 antithrombotic effects in vivo two distinct models of thrombosis in rats were carried out. In the rose Bengal/laser induced injury model of arterial thrombosis, NP2 increased the carotid artery occlusion time by ≈35 and ≈155%, at doses of 8 and 80 μg/kg, respectively. NP2 also inhibited thrombus formation in an arterio-venous shunt model, showing ≈60% reduction at 400 μg/kg (i.v. administration). The antithrombotic effect lasted for up to 48 hours after a single i.v. dose. Notably, effective doses of NP2 did not increase the blood loss as evaluated by tail-transection model. In conclusion, NP2 is a potent and long-lasting inhibitor of arterial thrombosis with minor effects on haemostasis. It might be regarded as a potential agent for the treatment of human cardiovascular diseases.

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