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Platelets inthePathogenesis ofVascular Disease andTheir Role asaTherapeutic…
255
Whether the results of platelet function testing for patients taking anti-platelet therapy can assist in the optimal timing of anti-platelet cessation prior to surgery has yet
to be established.
11.11 Conclusion
Given the fundamental role of platelets in cardiovascular medicine combined with
the importance of anti-platelet therapies and the burgeoning eld of novel therapeutics, the eld of platelet biology represents a complex yet exciting eld of
medicine.
Acknowledgments We are grateful for Tobias Ziegler for preparing the schematic drawings
(Figs.11.1, 11.2, 11.3, and 11.4).
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131. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, etal. Thrombin-
receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366:20–33.
132. Armstrong PC, Peter K.GPIIb/IIIa inhibitors: from bench to bedside and back to bench
again. Thromb Haemost. 2012;107:808–14.
133. Bosch X, Marrugat J, Sanchis J.Platelet glycoprotein IIb/IIIa blockers during percutaneous
coronary intervention and as the initial medical treatment of non-ST segment elevation acute
coronary syndromes. Cochrane Database Syst Rev. 2013;11:CD002130.
134. Serebruany VL, Malinin AI, Eisert RM, Sane DC.Risk of bleeding complications with anti-
platelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials.
Am J Hematol. 2004;75:40–7.
135. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A,
etal. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral
haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase
3 trial. Lancet. 2016;387:2605–13.
136. McFadyen JD, Peter K.Novel antithrombotic drugs on the horizon: the ultimate promise to
prevent clotting while avoiding bleeding. Circ Res. 2017;121:1133–5.
261
Further Reading
Armstrong PC, Peter K.GPIIb/IIIa inhibitors: from bench to bedside and back to bench again.
Thromb Haemost. 2012;107:808–14.
Davi G, Patrono C.Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.
Furie B, Furie BC.Mechanisms of thrombus formation. N Engl J Med. 2008;359:938–49.
Gawaz M, Langer H, May AE. Platelets in inammation and atherogenesis. J Clin Invest.
2005;115:3378–84.
Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, etal. 2016 ACC/AHA guide-
line focused update on duration of dual antiplatelet therapy in patients with coronary artery
disease: a report of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68:1082–115.
McFadyen JD, Schaff M, Peter K.Current and future antiplatelet therapies: emphasis on preserv-
ing haemostasis. Nat Rev Cardiol. 2018;15:181–91.
Chapter 12
https://t.me/medicina_free
Abdominal Aortic Aneurysm Pathology
andProgress Towards aMedical Therapy
JosephV.Moxon, SmritiM.Krishna, TejasP.Singh, andJonathanGolledge
Key Learning Points
Important risk factors for AAA include male gender, advanced age, prior or cur-
•
rent smoking and a positive family history. Diabetes appears to be negatively
associated with AAA diagnosis and growth. However, the exact reasons for this
are unclear
• Elective surgery is the only means to treat AAA but is associated with signicant
peri-operative morbidity and mortality, and concerns regarding the durability
of repair;
J. V. Moxon · S. M. Krishna
Queensland Centre for Peripheral Vascular Disease, College of Medicine and Dentistry,
James Cook University, Townsville, QLD, Australia
The Australian Institute of Tropical Health and Medicine, James Cook University,
Townsville, QLD, Australia
e-mail: joseph.moxon@jcu.edu.au; Smriti.krishna@jcu.edu.au
T. P. Singh
Queensland Centre for Peripheral Vascular Disease, College of Medicine and Dentistry,
James Cook University, Townsville, QLD, Australia
The Department of Vascular and Endovascular Surgery, The Townsville Hospital,
Townsville, QLD, Australia
e-mail: Tejas.singh@my.jcu.edu.au
J. Golledge (
Queensland Centre for Peripheral Vascular Disease, College of Medicine and Dentistry,
James Cook University, Townsville, QLD, Australia
The Australian Institute of Tropical Health and Medicine, James Cook University,
Townsville, QLD, Australia
The Department of Vascular and Endovascular Surgery, The Townsville Hospital,
Townsville, QLD, Australia
e-mail: jonathan.golledge@jcu.edu.au
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_12
*)
263© Springer Nature Switzerland AG 2020
264
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• Elective surgery does not improve survival in patients with small (<55 mm)
AAAs. Patients with small AAAs are managed conservatively through repeated
imaging which confers no therapeutic benet and is associated with decreased
health-related quality of life;
• A medical therapy which effectively slows the growth of small AAAs may
improve patient care and a large body of work to identify promising drug leads
has been conducted;
• To date, no randomized controlled trial has delivered an effective medical ther-
apy for small AAAs. This may relate to difculties in translating ndings from
commonly used laboratory models to the patient and to weaknesses in the design
of previous trials.
J. V. Moxon et al.
12.1 Introduction
An aneurysm can be dened as an abnormal, focal dilatation within an artery which
causes vessel diameter to exceed 1.5 times the expected size, and in some cases has
a natural history of progressive enlargement and eventual rupture [1, 2]. The infrarenal aorta is the most common site of aneurysm formation in humans. An infrarenal aortic diameter of ≥30mm is usually used to diagnose an abdominal aortic
aneurysm (AAA), although other denitions have been suggested, for example
those based on normalizing aortic diameter to body surface area [2–5]. AAA is usually asymptomatic, but can be readily diagnosed through the use of imaging such as
ultrasound or computed tomography.
There are, however, no currently available medications which effectively slow
AAA growth and open surgical or endovascular aneurysm repair (EVAR) are the
only treatments for AAA [4]. Four large randomised controlled trials and subsequent meta-analyses have demonstrated that elective repair of asymptomatic AAAs
with diameters smaller than 55mm (regardless of method used) does not improve
patient survival [6–10]. Importantly, most asymptomatic AAAs detected through
population screening, or incidental imaging are smaller than 55mm and current
guidelines recommend that such patients should be treated conservatively with cardiovascular risk management, and regular imaging assessments to monitor AAA
growth [11]. Surgery is only recommended when AAA diameter exceeds 54mm in
men, 50mm in women, or if the AAA becomes symptomatic [11]. Conservative
management of small asymptomatic AAA has been associated with reduced healthrelated quality of life [12, 13]. Moreover the majority of AAAs managed in this
way eventually expand to a size where surgical repair is required [8, 14]. For example, approximately 65% of patients with AAAs measuring 40–55mm within the
conservative arm of the United Kingdom (UK) Small Aneurysm Trial had undergone surgical repair within 5years of recruitment [6]. Due to the absence of an
effective treatment for small asymptomatic AAAs there is signicant interest in
identifying non-surgical therapies capable of slowing the growth of small AAAs,
and this is reected by an increase in the number of drug trials conducted over the
12 Abdominal Aortic Aneurysm Pathology andProgress Towards aMedical Therapy
https://t.me/medicina_free
last decade. The aim of the current chapter is to summarise how results from epidemiological studies and laboratory studies have contributed to current understanding of AAA pathophysiology. In addition this chapter includes a discussion of
current and past clinical trials examining potential medical therapies to limit small
AAA growth.
265
12.2 AAA Epidemiology
Findings from a recent study suggest that the global death rates attributable to AAA
rose by 12% in the 20years between 1990 and 2010 to 2.8/100,000 [15]. The highest rates of death attributable to AAA were observed in higher income countries,
with Australasia, Western Europe and North America having the highest mortality
rates of 8.38/100,000, 7.68/100,000 and 6.11/100,000 respectively [15, 16]. In contrast, reports from screening studies and epidemiological studies in a number of
developed countries suggest that AAA prevalence is declining. The national screening programmes run in the UK and Sweden have reported that the prevalence of
AAA is markedly lower than anticipated (observed prevalence of approximately
2.0% in 65 year old men, compared to 5–7% found in earlier studies) [17–20].
Moreover, reductions in the rates of hospitalisation and death attributable to AAA
have been reported for a range of countries including Australia, New Zealand,
England and Wales [20–22]. Reasons for the falling AAA prevalence remain incompletely understood, although several independent studies have linked this to a
decrease in smoking rates [22, 23]. Whatever the reasons, the potential negative
impact of declining AAA prevalence on the nancial viability of screening programmes has been raised [20]. Some (not all) clinical trials have shown that ultrasound screening programmes in men aged ≥65years reduces AAA-related mortality
by limiting deaths due to AAA rupture [24, 25]. A meta-analysis has suggested that
screening focusing solely on older men with a history of smoking (making up 69%
of the assessed population), would account for 89% of the reduction in AAAmortality expected from a screening programme including all men aged 64–75years
[24]. The US Preventative Services taskforce has suggested that screening be
restricted to individuals considered to be at high risk (persons with a history of
smoking, and/or family history of AAA), in an attempt to improve cost- effectiveness
[26]. In contrast, AAA screening in the UK and Sweden is offered to all males in the
year of their 65th birthday, and it has been suggested that this may not be nancially
viable in the light of falling AAA incidence [
clinical trial demonstrated that a AAA screening program of all men aged >65years
is unlikely to be effective within Australia [28], but there is more support for such a
program in New Zealand [29]. Of note, Māori people are hospitalised for AAA
repair at a signicantly earlier age than those of European ancestry (difference of
8years of age at presentation between these two populations), and Māori women
have increased risk of developing AAA than their European counterparts (relative
risk 1.56 [95% condence intervals 1.37–1.79]) [30]. Thus, any AAA screening
27]. Final ndings from an Australian
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