Factors Contributing to Individual Propensity for Arterial Thrombosis

Karnicki, Krzysztof; Owen, Whyte G.; Miller, Randall S.; McBane, Robert D.

doi:10.1161/01.atv.0000029968.34056.94

Cited by 37 publications

(24 citation statements)

References 36 publications

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“…Previous studies utilizing the carotid injury model have specifically considered thrombolysis at sites of arterial injury (4) and found a specific contribution to fibrinolysis. This observation is confirmed by a study (14) that demonstrates that arterial thrombosis is more influenced by blood components than elements within the arterial wall. Thus in this setting of carotid injury, the secondary effect of NO deficiency, namely, the enhanced release of t-PA from endothelial Weibel-Palade bodies, is of greater relevance than the release of NO from the endothelium.…”

Section: Discussionsupporting

confidence: 59%

Compensatory mechanisms influence hemostasis in setting of eNOS deficiency

Iafrati

Vitseva²,

Tanrıverdi³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Compensatory mechanisms influence hemostasis in setting of eNOS deficiency. Am J Physiol Heart Circ Physiol 288: H1627-H1632, 2005. First published November 24, 2004 doi: 10.1152/ajpheart.00819.2004The balance between thrombosis and hemorrhage is carefully regulated. Nitric oxide (NO) is an important mediator of these processes, as it prevents platelet adhesion to the endothelium and inhibits platelet recruitment. Although endothelial NO synthase (eNOS)-deficient mice have decreased vascular reactivity and mild hypertension, enhanced thrombosis in vivo has not been demonstrated. To determine the role of endogenous NO in hemostasis, a model of carotid arterial injury and thrombosis was performed using eNOS-deficient and wild-type mice. Paradoxically, the eNOS-deficient animals had a prolongation of time to occlusion compared with the wild-type mice (P Ͻ 0.001). Consistent with this finding, plasma markers suggesting enhanced fibrinolysis [tissue plasminogen activator (t-PA) activity and antigen and D-dimer levels] were significantly elevated in eNOS-deficient animals. Vascular tissue expression of t-PA and platelet activity levels were not altered. In endothelial cells, t-PA is stored in Weibel-Palade bodies, and exocytosis of these storage granules is inhibited by NO. Thus in the absence of NO, release of Weibel-Palade body contents (and t-PA) could be enhanced; this observation is also supported by increased von Willebrand factor levels observed in eNOS-deficient animals. In summary, although eNOS deficiency attenuates vascular reactivity and increases platelet recruitment, it is also associated with enhanced fibrinolysis due to lack of NO-dependent inhibition of Weibel-Palade body release. These processes highlight the complexity of NO-dependent regulation of vascular homeostasis. Such compensatory mechanisms may partially explain the lack of spontaneous thrombosis, minimally elevated baseline blood pressure, and normal life span that are seen in animals deficient in a pivotal regulator of vascular patency. platelets; thrombosis; endothelial nitric oxide synthase; transgenic mice NORMAL HEMOSTATIC BALANCE is maintained by tight regulation of coagulation, fibrinolysis, and platelet activation. Adhesion of platelets to the endothelium is prevented by several mechanisms including endothelial cell production of nitric oxide (NO) and prostacyclin (3,22). NO inhibits platelet adhesion and aggregation (2, 26) and prevents thrombosis (25). Exogenous NO inhibits the normal activation-dependent increase in the expression of platelet-surface glycoproteins including Pselectin and the integrin glycoprotein IIb-IIIa complex. Platelet-derived NO appears to inhibit the primary aggregation response only modestly, but NO release from activated human platelets markedly inhibits platelet recruitment (7) and thus may attenuate the progression of intraarterial thrombosis. The vascular endothelium, which mediates vasomotor tone in part through NO release, has been extensively characterized. Endothelium-dependent dilation is impai...

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Section: Discussionsupporting

confidence: 59%

Compensatory mechanisms influence hemostasis in setting of eNOS deficiency

Iafrati

Vitseva²,

Tanrıverdi³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Using porcine models of thrombus deposition onto excised vessel segments, Karnicki et al found that thrombus deposition varied strongly with individual blood donors and relatively little with the source of the aortic segment. 97 Together, these studies suggest that in contrast to thrombus initiation, the primary regulators of thrombus growth may come from the blood and not the vessel wall, and that these regulators may vary significantly among individuals.…”

Section: Temporal and Spatial Considerations In Thrombus Growthmentioning

confidence: 95%

Flow Effects on Coagulation and Thrombosis

Hathcock¹

2006

ATVB

348

281

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Abstract-Thrombosis occurs in a dynamic rheological field that constantly changes as the thrombus grows to occlusive dimensions. In the initiation of thrombosis, flow conditions near the vessel wall regulate how quickly reactive components are delivered to the injured site and how rapidly the reaction products are disseminated. Whereas the delivery and removal of soluble coagulation factors to the vessel is thought to occur via classic convection-diffusion phenomena, the movement of cells and platelets to the injured wall is strongly augmented by flow-dependent cell-cell collisions that enhance their ability to interact with the wall. In addition, increased shear conditions have been shown to activate platelets, alter the cellular localization of proteins such as tissue factor (TF) and TF pathway inhibitor, and regulate gene production. In the absence of high shearing forces, red cells, leukocytes, and platelets can form stable aggregates with each other or cells lining the vessel wall, which, in addition to altering the biochemical makeup of the aggregate or vessel wall, effectively increases the local blood viscosity. Thus, hemodynamic forces not only regulate the predilection of specific anatomic sites to thrombosis, but they strongly influence the biochemical makeup of thrombi and the reaction pathways involved in thrombus formation. T hrombosis is thought to begin with an event such as plaque rupture, vessel damage, or dysfunctioning endothelium, resulting in the exposure of active tissue factor (TF) on the vessel wall. 1 The exposed TF binds circulating factor VII/VIIa (fVII/fVIIa) with high-affinity (Kd Ͻ10 pM), forming a reactive vessel surface that proteolytically cleaves fIX and fX. The rate of this surface-bound reaction depends not only on biochemical factors (number and surface density of TF:VIIa complexes, intrinsic kinetic activity, and local phospholipid composition 2 ) but on the rate at which the substrates fIX and fX are transported by the flowing medium to the reactive surface 3 and the rate at which product is removed. 4 Moreover, the local accumulation of reaction product may be critical in overpowering endogenous inhibitors and successfully initiating coagulation.Although convective flow forces dominate the axial movement of blood components (coagulation factors, platelets, red cells, leukocytes, and inhibitors) throughout most of the body, in the few microns approaching the vessel wall where thrombosis is thought to initiate, the frictional drag of the vessel wall causes the axial flow velocity to slow to 0, and the convective and diffusive motion of blood components becomes comparable. 5 In this initial coagulation reaction, blood flowing parallel to the wall convectively transports coagulation factors (fIX and fX) from upstream to a region close to the reactive site, and Brownian motion mediates the radial movement toward the reactive wall. In the case of platelets adhering to the wall, a similarly defined adhesion rate is often inferred. 6 The bound proteins fIX and fX become proteolyt...

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“…Vulnerable blood (prone to thrombosis)plays an important roleinthe outcome of CAD (7).The importanceofthe coagulation system underlying plaque complications hasbeen experimentallyaddressed by Karnicki et al whodemonstrated in a porcine modelt hat blood factorsm ust have am ajor role in thrombus propagation (12). Moreover, it hasa lso been establishedt hat after an episode of unstable angina or AMI, ah igh proportion of patients showbiochemical signs of coagulation activation in their blood (13)(14)(15)(16),which mayhaveagreat impact in termsofrecurrence and long-termmortality (17).…”

Section: Introductionmentioning

confidence: 99%

Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test

Orbe¹,

Zudaire²,

Serrano³

et al. 2008

Thromb Haemost

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SummaryAtherosclerosisi st he most commonp athophysiologics ubstrateofcoronaryarterydisease (CAD).Whereasplaque progression anda rterial remodeling arec ritical components in chronic CAD, intracoronarythrombosis over plaque disruption is causally related to acute CAD. It wast he objectiveo ft his study to investigate thed ifferencesb etween priora cute CAD and chronic CADbyasimple global coagulation assaymeasuring thrombin generation.A cross-sectional study involving 15 healthyc ontrols,35p atientsw ith chronic stable CAD, and 60 patientsa fter an episodeo fa cute myocardial infarction (AMI) was performed. Thrombin generation wasm easuredb etween three and 11 monthsafter the initialdiagnosis (mean6months) by acommerciallya vailable fluorogenic assay(Te chnothrombin TGA). In each patient the lag phase,v elocityi ndex and peak thrombin were obtained from the thrombogram profile.TradiKeywords Thrombin,acute myocardial infarction, coronarysyndrome tional cardiovascular risk factors were recorded, andthe inflammatorymarkers, fibrinogen and hs-C-reactive proteinweredetermined. Compared with stable CADpatients, showing normal thrombograms, those with previous AMIs howede arlierl ag phase (p<0.05) and significant increase of botht he velocity index (p<0.001) and peak thrombin (p<0.05),indicating faster and higherthrombin generation in theAMI group.Differencesin thrombin generation between stable and acute CADp atients remaineds ignificant (p<0.001) after adjusting forc onventional CADriskfactors (age,gender, diabetes,hypertension,smoking, andh ypercholesterolemia). In conclusion, patients with ap revious historyo fa cute CADs howede arlier, faster and higher thrombin generation than stable chronic CADp atients. The thrombin generation test maybeofclinical value to monitor hypercoagulable/vulnerable blood and/or guide therapyinCAD.

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Factors Contributing to Individual Propensity for Arterial Thrombosis

Cited by 37 publications

References 36 publications

Compensatory mechanisms influence hemostasis in setting of eNOS deficiency

Compensatory mechanisms influence hemostasis in setting of eNOS deficiency

Flow Effects on Coagulation and Thrombosis

Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test

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