Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms

BackgroundHaptoglobin (Hp) polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases and atherosclerosis. Circulating neutrophils and neutrophil-associated proteases are an important initial component of experimental abdominal aortic aneurysm (AAA) formation. Elastase and C-reactive protein (CRP) levels are elevated in patients with AAAs. This study assessed the relationship between AAA expansion and Hp phenotypes, neutrophil count, elastase, and CRP levels.MethodsEighty-three consecutive AAA patients underwent annual ultrasound scans. Three major Hp phenotypes (1-1, 2-1, and 2-2) were determined, and the neutrophil count, serum elastase, and high-sensitivity (hs) CRP levels were measured at the initial examination. After initial screening, patients were rescanned at 6- to 12-month intervals up to a period of 2 to 7 years. The mean yearly growth of the AAA largest transverse diameter was estimated for each group of Hp patients. The results are presented as median (interquartile range).ResultsHp 2-1 patients had a significantly higher growth rate (3.69 [2.40] mm/y) of AAA compared with patients with Hp 2-2 (1.24 [0.79], P < .00001) and Hp 1-1 (1.45 [0.68], P = .00004). This association remained significant in the multivariate analysis. Elevated elastase serum activity was also evident in AAA patients with Hp 2-1 (0.119 [0.084] arbitrary units) in contrast to Hp 2-2 (0.064 [0.041], P < .00001) and Hp 1-1 (0.071 [0.040], P = .0006) patients. CRP serum levels (mg/L) were significantly higher in patients with Hp 2-1 (7.2 [7.1]) than in Hp 2-2 (3.4 [3.1], P = .0058) and Hp 1-1 (2.8 [4.1], P = .044). The neutrophil count was not significantly different among Hp groups.ConclusionsThe Hp 2-1 phenotype showed a strong association with increased rates of the expansion of AAAs and may be a useful independent predictor of growth rate. Further large follow-up studies will be needed to investigate the pathomechanisms of association and the role of elastase and inflammation in the progression of AAA.Clinical RelevanceElective surgical or endovascular repair is recommended for large aneurysms, whereas small aneurysms are managed by watchful waiting. The diameter and rate of growth of the AAA are the most important determinants of the risk of rupture and in deciding when elective repair is justified. In the present study, the Hp 2-1 phenotype predicted rapid aneurysm expansion. This may have implications for the frequency of follow-up and timing of repair of AAA in patients with the Hp 2-1 phenotype

Coagulation and fibrinolysis in the abluminal layer of the thrombus within abdominal aortic aneurysm

Background. The development of intraluminal thrombus in the abdominal aortic aneurysm (ILT) is a natural reaction to lesion of the arterial wall. Local haemostatic processes and secondary thrombolysis in the intraluminal thrombus, through the stimulation of proteolysis in extracellular matrix, may constitute one of the factors that lead to aneurysm rupture. In our study, we evaluated the coagulation and fibrinolytic parameters in the abluminal layer of the thrombus within the aneurysmal sack in order to find the differences between the thin (&#8804; 10 mm) and the thick parts. Material and methods. The sections sampled for the study were harvested from the thick (> 25 mm) and thin (&#8804; 10 mm) slices of the ILT obtained from the same 32 abdominal aortic aneurysms, namely from the layer directly adjacent to the aneurysmal wall. The tissue factor activity, antiheparin and antithrombin activity, plasminogen content, plasminogen activator levels and concentration of D-dimers in the samples were measured. Results. The activities of the tissue factor and antiheparin activity in the abluminal layer of the ILT were statistically significantly higher in the thin thrombi than in the thick ones (p < 0.001). Thin thrombi revealed significantly higher plasminogen (p < 0.001) and D-dimer (p < 0.01) concentrations when compared to thick thrombi, while the activity of plasminogen activators was higher in the thick thrombi (p < 0.05). Conclusions. The abluminal layer of the thin thrombus (up to 10 mm) of the abdominal aortic aneurysm shows higher activities of coagulative processes when compared to thicker thrombi (> 25 mm); moreover, this site reveals strong secondary activation of the fibrinolytic system. Further investigation of the association between coagulation/fibrinolytic activity and proteolysis occurring within the AAA wall requires evaluation of such processes with regard to differences in the thickness of the thrombus.Wstęp. Tworzenie się zakrzepu wewnątrz tętniaka jest naturalną reakcją na uszkodzenie ściany naczynia. Miejscowe procesy hemostatyczne i wtórna tromboliza w zakrzepie przyściennym poprzez stymulowanie proteolizy matrix pozakomórkowego mogą być też jednym z czynników prowadzących do pęknięcia tętniaka. W pracy oceniono wybrane parametry krzepnięcia i fibrynolityczne w zakrzepie, w warstwie przylegającej bezpośrednio do ściany tętniaka, poszukując różnic pomiędzy cienką, do 10 mm, a grubszą częścią zakrzepu. Materiał i metody. Do badania pobierano skrawki z grubej (ponad 25 mm) i cienkiej (do 10 mm) części zakrzepu, uzyskanego z 32 tętniaków aorty brzusznej (AAA), z warstwy przylegającej bezpośrednio do ściany tętniaka. W materiale oznaczono aktywność czynnika tkankowego (TF), aktywność antyheparynową (AH) i antytrombiny (AT), zawartość plazminogenu (Plg), stężenie aktywatorów plazminogenu (PA) i stężenie D-dimerów (DD). Wyniki. Aktywność TF i AH w przyściennej warstwie zakrzepu tętniaka były znamiennie wyższe w zakrzepach cieńszych niż grubszych (p < 0,001). W zakrzepach cieńszych stężenie Plg (p < 0,001) i D-D (p < 0,01) było znacznie wyższe niż w zakrzepach grubszych, natomiast aktywność PA była wyższa w zakrzepach grubszych (p < 0,05). Wnioski. Warstwa przyścienna cienkiego zakrzepu (do 10 mm) AAA cechuje się aktywniejszymi procesami krzepnięcia w porównaniu z grubszym (ponad 25 mm), w tym silnie wyrażoną wtórną aktywacją układu fibrynolizy. W badaniach zależności pomiędzy aktywnością procesów krzepnięcia/fibrynolizy a proteolizą ściany tętniaka powinno się uwzględniać różnice grubości zakrzepu przyściennego (ILT)

Efficacy of Liver Chemoembolization after Prior Cetuximab Monotherapy in Patients with Metastatic Colorectal Cancer

Purpose: Chemoembolization of liver lesions, metastatic from colorectal cancer (CRC), with irinotecan-loaded microspheres shows less efficacy if applied after previous systemic chemotherapy. This is because cancer cells acquire resistance to previously used chemotherapeutic agents, e.g., irinotecan or perhaps via, e.g., modulations of EGFR receptors after use of anti-EGFR antibodies. Objective: To evaluate the effects of prior treatment with anti-EGFR (cetuximab) antibodies on the efficacy of chemoembolization, with irinotecan-loaded microspheres, of liver lesions metastatic from CRC. Patients and methods: The study included 50 patients (27 female, 23 male) with inoperable liver metastases in the course of CRC who underwent a total of 192 chemoembolization procedures with microspheres loaded with 100 mg of irinotecan. Chemoembolization of the right or left liver lobes was performed alternately at three-week intervals. Patients were divided into two groups: group A (n = 26): patients who had previously received anti-EGFR (cetuximab) antibodies; and group B (n = 24): patients who had never received anti-EGFR antibodies. Response to treatment was assessed according to mRECIST criteria. Overall survival time (OS) was calculated using the Kaplan–Meier method. Evaluation of adverse effects was performed according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (Version 5.0). Results: Analysis did not show a statistically significant difference in radiological response between the two groups: partial response: 36.2% in group A and 32.9% in group B (p = 0.139); and stable disease: 19.2% in group A and 21.7% in group B (p = 0.224). Post-treatment progression was comparable at 46.2% in group A and 41.6% in group B (p = 0.343). There was a significant difference in OS (p = 0.043 log-rank test), however, prior treatment with cetuximab showed no significant effect on OS in a Cox proportional hazards regression model HR 1.906 (0.977–3.716), p = 0.058. Mean OS was 15.2 months (95% confidence interval (Cl): 6 to 23 months) in group A and 13.1 months (95% Cl: 7 to 22 months) in group B. In both groups, there was a negative correlation between carcinoembryonic antigen (CEA) levels below 10 mg/mL before surgery and OS (hazard ratio (HR) 0.83 (0.47–8.43), p = 0.005 in group A and HR 1.02 (0.56–7.39), p = 0.003 in group B). There was no significant difference in the number of prominent complications between group A (7 complications) and group B (6 complications), p = 0.663. Conclusions: Previous therapy with anti-EGFR antibodies before treatment with irinotecan chemoembolization of liver metastatic lesions did not have a significant effect on radiological response to treatment or post-treatment progression. However, higher baseline levels of CEA (>10 ng/mL) were correlated with worse OS (p = 0.039)

MMP-9, homocysteine and CRP circulating levels are associated with intraluminal thrombus thickness of abdominal aortic aneurysms: New implication of the old biomarkers, Dis Markers 31

Abstract. Background: Abdominal aortic aneurysms (AAAs) are characterized by presence of high proteolytic activity, atherosclerotic lesions, extensive transmural inflammation and the presence of variably sized and shaped intraluminal thrombus (ILT). Therefore, we evaluated a possible association between plasma matrix metalloproteinase-9 (MMP-9), homocysteine (Hcy), high-sensitivity C-reactive protein (hsCRP) levels and ILT thickness in patients with AAA. Methods: Plasma concentrations of MMP-9, Hcy and hsCRP were determined and ILT thickness was measured in 71 patients with AAA. They were divided into 2 groups according to ILT thickness: 34 patients with ILT mean thickness 9 mm and 37 patients with ILT &lt; 9 mm. Results: Plasma MMP-9 and CRP concentrations in patients with thin ILT were significantly higher than in group with thick ILT (medians 610 vs. 485 ng/mL, p = 0.00003, and 7.7 vs. 3.3 mg/L, p &lt; 0.00001, respectively). In contrast, plasma Hcy concentrations in patients with thin ILT were significantly lower than in the group with thick ILT (medians 14.3 vs. 19.2 µmol/L, p &lt; 0.00001). Multiple regression models adjusted for age and AAA diameter showed that thin ILT is an independent predictor of high MMP-9 and CRP concentrations, while thick ILT predicts high Hcy concentrations. Conclusions: Association of higher plasma levels of MMP-9 and CRP with thin ILT may be related to two phenomena: thin thrombi convey more elastolysis-stimulating factors from blood to the AAA wall and thin thrombi convey more factors involved in proteolysis and inflammation from AAA wall to blood. The association of thin ILT with lower plasma Hcy concentrations may be related to the role of Hcy as a prothrombotic marker and needs further research

Research update for articles published in EJCI in 2008

Eur J Clin Invest 2010; 40 (9): 770-78