Left Carotid Artery Thrombosis Due to Thromboangiitis Obliterans.

ABSTRACT: Thromboangiitis obliterans (TAO, Buerger disease) is a segmental, non-atherosclerotic vasculitis that causes occlusion of the small and medium sized vessels of the distal extremities. In rare cases, it can affect vessels in the gastrointestinal, cerebrovascular, coronary, and renal systems. The etiology of thromboangiitis obliterans is unknown, but there is a strong association with smoking in the development and the progression of the disease. We present the case of a 42-year-old homeless female smoker, who was found dead outdoors. Although originally suspected to be a possible trauma-related death, autopsy revealed a thrombus in her left carotid artery, which caused an acute cerebral infarction. It was concluded that thromboangiitis obliterans, likely precipitated by smoking, was the cause of the thrombosis and subsequent death.

Red and White Thrombus Characteristics in Patients Undergoing Carotid Endarterectomy.

OBJECTIVE: The study aimed to compare the characteristics of red and white thrombi in patients undergoing carotid endarterectomy. MATERIAL AND METHODS: The study was conducted in 81 patients with ischemic stroke who underwent carotid endarterectomy for carotid artery stenosis. Carotid plaques were graded by two pathologists. Thrombus materials were divided into two groups: white and red. The parameters of assessment were plaque rupture, lipid core, fibrous cap thickness, inflammation, intraplaque hemorrhage, calcification, necrotic core, and neovascularization. Normally distributed data were evaluated using Mann-Whitney U and Chi-squared tests. RESULTS: The ratio of white and red thrombus was 19.8% and 80.2%, respectively. Lipid core, plaque rupture, necrotic core, neovascularization, intraplaque hemorrhage, obstruction, and inflammation were observed more in red thrombus, which were statistically significant. Calcification and fibrous cap thickness were not statistically significant in the two groups. Moreover, intimal smooth muscle cells were present in all thrombus types. CONCLUSION: In our study, we found that red thrombi had more unstable characteristics than white thrombi. Thus, the risk for ischemic cerebrovascular events is more in red thrombi. However, this finding cannot be generalized due to the small number of patients in this study. Therefore, studies involving more patients are needed.

Intraluminal Thrombi in the Cervico-Cephalic Arteries.

Background and Purpose- Intraluminal thrombus (ILT) is an uncommon finding among patients with ischemic stroke. We report clinical-imaging manifestations, treatment offered, and outcome among patients with ischemic stroke/transient ischemic attack and ILT in their cervico-cephalic arteries. Methods- Sixty-one of 3750 consecutive patients with acute ischemic stroke/transient ischemic attack (within 24 hours of onset) and ILT on initial arch-to-vertex computed tomography angiography from April 2015 through September 2017 constituted the prospective study cohort. Functional outcome was assessed using the modified Rankin Scale score with functional independence at discharge defined as modified Rankin Scale score ≤2. Results- Prevalence of ILT on computed tomography angiography was 1.6% (95% CI, 1.2%-2.1%). Median age was 67 years (interquartile range, 56-73), and 40 subjects (65%) were male. The initial clinical presentation included transient ischemic attack in 12 (20%) and stroke in 49 patients (80%); most strokes (76%) were mild (National Institutes of Health Stroke Scale ≤5). The most common ILT location was cervical carotid or vertebral artery (n=48 [79%]) followed by intracranial (n=11 [18%]) and tandem lesions (n=2 [3%]). The most common initial treatment strategy was combination antithrombotics (heparin with single antiplatelet agent) among 57 patients (93%). Follow-up computed tomography angiography (n=59), after a median 6 days (interquartile range 4-10 days), revealed thrombus resolution in 44 patients (75% [completely in 27%]). Twenty four of 30 patients (80%) with >50% residual carotid stenosis underwent carotid revascularization (endarterectomy in 15 and stenting in 9 patients) without peri-procedural complications a median of 9 days after symptom onset. In-hospital stroke recurrence occurred in 4 patients (6.6%). Functional independence was achieved in 46 patients (75%) at discharge. Conclusions- Patients presenting with acute stroke/transient ischemic attack with ILT on baseline imaging have a favorable clinical course in hospital with low stroke recurrence, high rate of thrombus resolution, and good functional outcome when treated with combination antithrombotic therapy.

Adamts18 deficiency increases arterial thrombus formation associated with vascular defects in mice.

ADAMTS18 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) that are known for their crucial role in development, angiogenesis, inflammation and coagulation. It was previously reported that ADAMTS18 cleaved by thrombin induced platelet fragmentation, through which thrombus were dissolved. However, it remains unclear whether this represents a dominant physiologic mechanism controlling thrombus growth in vivo. Here, we used an established Adamts18 knockout (KO) mouse model to determine its function in thrombus formation. ADAMTS18 deficiency accelerated FeCl3-induced carotid artery thrombosis and aggravated postischemic cerebral infarction in mice. However, this accelerated thrombus phenotype in Adamts18 KO mice was not due to the lack of ADAMTS18-mediated-platelet fragmentation. Moreover, Adamts18 deficiency exerted little effects on mouse platelet functions. The underlying molecular mechanisms could be attributed in part to the abnormal vascular remodeling, including deficiency of carotid body (glomus) and aberrant carotid basal lamina. These results indicate a novel function of ADAMTS18 in vascular remodeling and associated thrombus formation.

Reduced thrombosis in Klkb1-/- mice is mediated by increased Mas receptor, prostacyclin, Sirt1, and KLF4 and decreased tissue factor.

The precise mechanism for reduced thrombosis in prekallikrein null mice (Klkb1(-/-)) is unknown. Klkb1(-/-) mice have delayed carotid artery occlusion times on the rose bengal and ferric chloride thrombosis models. Klkb1(-/-) plasmas have long-activated partial thromboplastin times and defective contact activation-induced thrombin generation that partially corrects upon prolonged incubation. However, in contact activation-induced pulmonary thromboembolism by collagen/epinephrine or long-chain polyphosphate, Klkb1(-/-) mice, unlike F12(-/-) mice, do not have survival advantage. Klkb1(-/-) mice have reduced plasma BK levels and renal B2R mRNA. They also have increased expression of the renal receptor Mas and plasma prostacyclin. Increased prostacyclin is associated with elevated aortic vasculoprotective transcription factors Sirt1 and KLF4. Treatment of Klkb1(-/-) mice with the Mas antagonist A-779, COX-2 inhibitor nimesulide, or Sirt1 inhibitor splitomicin lowers plasma prostacyclin and normalizes arterial thrombosis times. Treatment of normal mice with the Mas agonist AVE0991 reduces thrombosis. Klkb1(-/-) mice have reduced aortic tissue factor (TF) mRNA, antigen, and activity. In sum, Klkb1(-/-) mice have a novel mechanism for thrombosis protection in addition to reduced contact activation. This pathway arises when bradykinin delivery to vasculature is compromised and mediated by increased receptor Mas, prostacyclin, Sirt1, and KLF4, leading to reduced vascular TF.

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.

Cerebral microembolic signal (MES) is an independent predictor of stroke risk and prognosis. The objective of this study is to assess the effects of apixaban, as a representative of the novel oral anticoagulant class, on a rabbit model of cerebral MES. A clinical transcranial Doppler ultrasound instrument was used to assess MESs in the middle cerebral artery in a 30% FeCl3-induced carotid arterial thrombosis model in male New Zealand White rabbits. Ascending doses of apixaban were evaluated as monotherapy and in combination with aspirin on both arterial thrombosis and MES. Pharmacokinetic and pharmacodynamic responses were also evaluated. The effective dose for 50% inhibition (ED50) of thrombus formation for monotherapy was 0.04 mg/kg per hour apixaban, i.v. (0.03 µM plasma exposure) for the integrated blood flow, 0.13 mg/kg per hour apixaban (0.10 µM plasma exposure) for thrombus weight, and 0.03 mg/kg per hour apixaban (0.02 µM plasma exposure) for MES. Dual treatment with aspirin (5 mg/kg, PO) and apixaban (0.015 mg/kg per hour, i.v.) resulted in a significant reduction in cerebral MES (P < 0.05) compared with monotherapy with either agent. Pharmacokinetic analysis of apixaban and pharmacodynamic assays using activated partial thromboplastin time (aPTT) and prothrombin time (PT) for apixaban- and arachidonic acid-induced platelet aggregation for aspirin were used to confirm the exposure-response relationships. In summary, our study demonstrates that apixaban in a concentration-dependent manner inhibits both arterial thrombosis and MES, suggesting a potential association between factor Xa (FXa) blockade and the reduction in MES in patients at risk of ischemic stroke.

The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2).

Multiple myeloma confers a high risk for vascular thrombosis, a risk that is increased by treatment with immunomodulatory agents. Strikingly, inclusion of the proteasome inhibitor bortezomib reduces thrombotic risk, yet the molecular basis for this observation remains unknown. Here, we show that bortezomib prolongs thrombosis times in the carotid artery photochemical injury assay in normal mice. Cell-based studies show that bortezomib increases expression of the transcription factor Kruppel-like factor 2 (KLF2) in multiple cell types. Global postnatal overexpression of KLF2 (GL-K2-TG) increased time to thrombosis, and global postnatal deletion of KLF2 (GL-K2-KO) conferred an antiparallel effect. Finally, studies in GL-K2-KO mice showed that the thromboprotective effect of bortezomib is KLF2 dependent. These findings identify a transcriptional basis for the antithrombotic effects of bortezomib.

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.

Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus formation by increased accumulation and activity of von Willebrand factor (vWF) at poststenotic sites. Resonant-scanning multiphoton microscopy revealed that in vivo arterial stenosis of a damaged carotid artery markedly increased platelet aggregate formation in the stenotic outlet region. Complementary in vitro studies using microfluidic stenotic chambers, designed to mimic the flow conditions in a stenotic artery, showed enhanced platelet aggregation in the stenotic outlet region at 60-80% channel occlusion over a range of input wall shear rates. The poststenotic thrombus formation was critically dependent on bloodborne vWF and autocrine platelet stimulation. In stenotic chambers containing endothelial cells, flow provoked increased endothelial vWF secretion in the stenotic outlet region, contributing to exacerbated platelet aggregation. Taken together, this study identifies a role for the shear-sensitive protein vWF in transducing hemodynamic forces that are present around a stenosis to a prothrombogenic microenvironment resulting in spatially confined and exacerbated platelet aggregation in the stenosis outlet region. The developed stenotic microfluidic chamber offers a realistic platform for in vitro evaluation of shear-dependent thrombus formation in the setting of atherosclerosis.

Intraluminal thrombus, intraplaque hemorrhage, plaque thickness, and current smoking optimally predict carotid stroke.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH) is associated with acute and future stroke. IPH is also associated with lumen markers of stroke risk including stenosis, plaque thickness, and ulceration. Whether IPH adds further predictive value to these other variables is unknown. The purpose of this study was to determine whether IPH improves carotid-source stroke prediction. METHODS: In this retrospective cross-sectional study, patients undergoing stroke workup were imaged with MRI and IPH detection. Seven hundred twenty-six carotid-brain image pairs were analyzed after excluding vessels with noncarotid plaque stroke sources (420) and occlusions (7) or near-occlusions (3). Carotid imaging characteristics were recorded, including percent diameter and mm stenosis, plaque thickness, ulceration, intraluminal thrombus, and IPH. Clinical confounders were recorded, and a multivariable logistic regression model was fitted. Backward elimination was used to determine essential carotid-source stroke predictors with a threshold 2-sided P<0.10. Receiver operating characteristic analysis was performed to determine discriminatory value. RESULTS: Significant predictors of carotid-source stroke included intraluminal thrombus (odds ratio=103.6; P<0.001), IPH (odds ratio=25.2; P<0.001), current smoking (odds ratio=2.78; P=0.004), and thickness (odds ratio=1.24; P=0.020). The final model discriminatory value was excellent (area under the curve=0.862). This was significantly higher than the final model without IPH (area under the curve=0.814), or models using only stenosis as a continuous variable (area under the curve=0.770) or cutoffs of 50% and 70% (area under the curve=0.669), P<0.001. CONCLUSIONS: After excluding patients with noncarotid plaque stroke sources, optimal discrimination of carotid-source stroke was obtained with intraluminal thrombus, IPH, plaque thickness, and smoking history but not ulceration and stenosis.

Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway.

AIMS: Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway. METHODS AND RESULTS: Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbß3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl3. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbß3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor. CONCLUSION: This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.

Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice.

Modulation of purinergic signaling, which is critical for vascular homeostasis and the response to vascular injury, is regulated by hydrolysis of proinflammatory ATP and/or ADP by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) to AMP, which then is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. We report here that compared with littermate controls (wild type), transgenic mice expressing human ENTPDase-1 were resistant to the formation of an occlusive thrombus after FeCl(3)-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S], negated the protection from thrombosis, consistent with a role for ADP in platelet recruitment and thrombus formation. ENTPD-1 expression decreased whole-blood aggregation after stimulation by ADP, an effect negated by adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein α(IIb)/ß(3), in a fully activated state, which is critical for thrombus formation. In vivo treatment with a CD73 antagonist, a nonselective adenosine-receptor antagonist, or a selective A(2A) or A(2B) adenosine-receptor antagonist, negated the resistance to thrombosis in transgenic mice expressing human ENTPD-1, suggesting a role for adenosine generation and engagement of adenosine receptors in conferring in vivo resistance to occlusive thrombosis in this model. In summary, our findings identify ENTPDase-1 modulation of purinergic signaling as a key determinant of the formation of an occlusive thrombus after vascular injury.

Endovascular therapy in 201 patients with acute symptomatic occlusion of the internal carotid artery.

BACKGROUND AND PURPOSE: Endovascular therapy is used increasingly for treatment of acute symptomatic internal carotid artery (ICA) occlusion, although randomized trials are lacking. Predictors of outcome are therefore of special interest. METHODS: From 1992 to 2010 we treated 201 patients with acute ICA occlusion with intra-arterial pharmacological thrombolysis (32), endovascular mechanical therapy (78) or a combination of both (91). All data were assessed prospectively. RESULTS: There were 76/38% patients with tandem occlusions [ICA plus middle (MCA) or anterior cerebral arteries (ACA)], 18/9% without concomitant occlusions of major intracranial arteries (ICA plus branch occlusion) and 107/53% with functional ICA-T occlusions (ICA plus MCA and ACA). Median baseline National Institute of Health Stroke Scale (NIHSS) score was 17. Good recanalization (Thrombolysis in Myocardial Infarction 2-3) was achieved in (157/201) 78% patients and good reperfusion (Thrombolysis in Cerebral Infarction 2-3) in (151/182) 83%. Better recanalization rates were obtained with mechanical approaches, with/without thrombolytics (78/91 = 86% and 64/78 = 82%) compared with pharmacological thrombolysis only (15/32 = 47%; P < 0.001). Twelve patients (6%) suffered symptomatic intracranial haemorrhages. The 3-month outcome was favourable [modified Rankin score (mRS) 0-2] in 54/28% patients and moderate (mRS 0-3) in 90/46%; 60/31% patients died. Only 17/16% patients with functional ICA-T occlusions had favourable outcomes compared with 32/44% with tandem occlusions and 5/31% with ICA plus cerebral branch occlusions (P = 0.001). In multivariate analysis age [odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.93-0.98], NIHSS on admission (OR = 0.9, 95% CI = 0.83-0.98) and functional ICA-T occlusion (OR = 0.35, 95% CI = 0.16-0.77) were non-modifiable predictors, and vessel recanalization was the only modifiable predictor of outcome (OR = 9.30, 95% CI = 2.03-42.63). CONCLUSIONS: The outcome of acute symptomatic ICA occlusion is poor. However, recanalization is associated with better outcome, and recanalization rates with mechanical techniques were superior to merely pharmacological recanalization attempts.

A comparative ultrastructural study of a new type of autoschizis versus a survival cellular mechanism that involves cell membranes of cerebral arteries in humans.

The authors analyzed by transmission electron microscopy the modifications of plasmalemma and nuclear envelope in the cerebral arterial wall in humans. Their ultrastructural observations are performed on the tunica media and endothelium. During autoschizis, some smooth muscle cells showed deep invaginations of the nuclear envelope with multiple craters that disintegrate the nucleus, whereas in the endothelium repetitive invaginations of plasmalemma lead to cell demise by cytoplasmic self-excisions. During survival mechanism, a perinuclear constriction of plasmalemma occurs, which conserves nucleus and cytoskeleton, and only a segregated cytoplasmic area, without organelles, is removed in lumen.

Traumatic thrombosis of internal carotid artery sustained by transfer of kinetic energy.

A 31-year-old male patient with a fatal thrombosis of the internal carotid artery caused by gun shot injury was presented in this case report. The patient was referred to the hospital with a diffuse edema on his left cheek. On otolaryngologic examination, there was a bullet entrance hole at the left mandibular corpus. No exit hole could be found. The finding from his axial computed tomography of neck and paranasal sinuses was normal. On neurological examination, a dense right hemiparesis was observed. In his cerebral angiogram, left common carotid artery was totally obliterated. Diffuse ischemia was observed in the left cerebral hemisphere. Despite intensive interventions, the patient died 4 days after the accident. In the autopsy, a large thrombosis was obtained in the left common carotid artery. This case emphasizes a fatal kinetic energy effect in vascular structures. It is stressed that a gun shot injury could be fatal with its indirect kinetic energy effects at subacute phase.

A malignant case of acute promyelocytic leukemia with occlusion of carotid artery by tumor thrombus.

We report an unusual and malignant presentation of acute promyelocytic leukemia (APL) resulting in thrombosis of a cervicocephalic artery by tumor in a healthy 37-year-old woman. The patient's rapid decline and multiorgan involvement proved to be a diagnostic and therapeutic challenge, and despite the efforts of a coordinated multidisciplinary health care team, she suffered a cardiac arrest and died within 48 hours of presentation to the emergency department. Autopsy revealed an APL-related tumor thrombus obstructing the left internal carotid artery, which to the best of our knowledge has not yet been described as a cause of fatal stroke.

[Free floating thrombus on carotid megabulb or suspended bulb: what kind of dysplasia?]. / Thrombus flottant sur un mégabulbe carotidien ou sur un bulbe suspendu, quel type de dysplasie ?

Floating carotid thrombi are a rare cause of stroke mostly associated with atheromatous plaques, cardiogenic emboli, arterial dissections and systemic diseases related to coagulopathic states or iron deficiency anaemia. We report the cases of two patients with stroke and carotid megabulb or suspended bulb associated with floating thrombus. These findings are rarely described probably related to a form of arterial dysplasia and seem to be responsible of local haemodynamic modifications.

[Study of dahuangzhechong pills on anti-arterial thrombosis with the orthogonal design].

OBJECTIVE: To screen the main component of Dahuangzhechong pill's anti-arterial thrombosis with the orthogonal design and refine Dahuangzhechong pills. METHODS: In accordance with the orthogonal design table (L(16)2(15)), divided herbs into 16 groups and made the appropriate liquid. The liquid was gave to SD rats by intragastric administration,the model group, normal control group received the same volume of physiological saline. Isolated rats' carotid artery after intragastric administration a week,modeled according to ferric chloride inducement the carotid artery thrombosis method, then collected blood, detected content of platelet, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), sheared and measured dry weight of the modeling artery, then placed arteries in 10% formalin fixation, observed morphological changes in vascular tissue by HE staining. RESULTS: Pathological examination revealed: each experimental group had thrombosis, softening, dissolution, absorption, and intimal injury, but the severity of thrombosis were diferent. Orthogonal analysis showed: 1, influence on dry weight of thrombus: rhubarb, ground beetle, leeches, peach seed, dry paint, except dry paint P<0.05, the others P<0.01.2, influence on plasma 6- keto-PGF1alpha level: peach seed, dry paint, ground beetle, gadfly, grubs, leeches, rhubarb, except rhubarb P<0.05, the others P<0.01.3, influence on plasma TXB2: ground beetle, peach seed, dried paint, rhubarb, leeches, except leech P<0.05, the others P<0.01.4, influence on platelet count: peach seed, dry paint, rhubarb, ground beetle, gadfly, leeches, except gadfly, leeches P<0.05, the others P<0.01. CONCLUSION: Anti-artery thrombosis of Dahuangzhechong Pill is most closely related with rhubarb, ground beetle, leeches, peach seed, dry paint and gadfly.