Platelets and immunity: the interplay of mean platelet volume in health and disease

Abstract

Although it is still unclear whether larger platelets actively participates to the pathogenesis of human diseases or their appearance represents a simple epiphenomenon of an underlying derangement of platelet biology, several lines of evidence seemingly attest that these blood elements may play an active role in certain pathologies, such as myocardial infarction, venous thromboembolism, cancer, and severe infections. The mean platelet volume is a simple measure of platelet size, which is automatically generated by virtually all modern hematologic analyzers. Its measurement should hence be regarded as a valuable perspective of clinical outcome prediction.

Keywords:

• cancer
• prognosis
• mean platelet volume
• platelets
• thrombosis

Platelet biology & mean platelet volume

Platelets are small anucleate discoid cells originating from bone marrow megakaryocytes. Each megakaryocyte can produce up to 1000–5000 platelets and, approximately 1 × 10¹¹ platelets per day are generated under normal conditions. Megakaryopoiesis is regulated by the cytokine thrombopoietin. After circulating for 7–10 days, platelets undergo a process of senescence characterized by the loss of their surface receptors and subsequent removal by phagocytic cells of the reticuloendothelial system [1]. Platelets contain α-granules, δ-granules, lysosomes, peroxisomes, and other organelles, such as mitochondria and the dense tubular system. More than 280 proteins are stored in α-granules, including von Willebrand factor (VWF), platelet-derived growth factor (PDGF), platelet factor 4, and β-thromboglobulin [1]. Fibrinogen, coagulation factors V and XIII are also found in α-granules, but are endocytosed from the blood rather than being synthesized by platelets [1]. ADP, ATP, serotonin, and calcium are conversely contained in δ-granules. When the blood vessel is injured, platelets undergo a series of functional responses, including adhesion, activation and aggregation, which are regulated by specific glycoproteins on the platelet cell surface, and designed to promote rapid formation of hemostatic plugs. Platelets measure approximately 2–4 × 0.5 µm and exhibit a mean volume of 7–11 fl. Several rare inherited platelet disorders are characterized by an increased mean platelet volume (MPV), including the Bernard–Soulier syndrome and the myosin heavy chain 9-related disorders [2].

Challenges in the assessment of mean platelet volume

Despite MPV is an arbitrary measure of platelet size, which is automatically generated by virtually all modern hematologic analyzers, one aspect that remains often unclear is that its routine assessment carries some technical drawbacks. First, the technical approach for platelet analysis differs among different commercial instrumentations, wherein optical or impedance methods can be used. Although a satisfactory imprecision has now been achieved (typically comprised between 1.1 and 3.8%), harmonization across different platforms is still an unresolved issue, with a bias of measured MPV values that can be as high as 30% [3]. From a practical perspective, this precludes the adoption of common reference ranges and unique diagnostic thresholds, but may also impact on patient management when longitudinal patient’s data obtained using different analyzers are directly compared. The potential effect of the anticoagulant used for collecting blood samples is another important aspect. The current anticoagulant of choice for platelet counting and sizing is K₂EDTA (ethylenediaminetetraacetic acid). In a limited number of subjects, usually between 0.1 and 0.5% of the general population, the presence of EDTA-dependent antiplatelet antibodies may cause the so-called EDTA-dependent pseudothrombocytopenia. This condition is typically due to the presence of IgM antibodies, which recognize a calcium-dependent epitope on the cytoadhesive receptor GpIIb–IIIa and results in massive platelet count reduction, usually to values <30,000/µl [4]. This phenomenon is also associated with substantial and time-dependent changes of MPV, and must hence be recognized to prevent inappropriate interpretation of spurious platelet size variations. Importantly, EDTA also generates a time-dependent shape change, swelling and increase of platelet size, so that the MPV measured in citrated blood can differ from that assessed in EDTA blood of the same donor and optimal measuring time should be 120 min after venipuncture [5].

Mean platelet volume in health & disease

A considerable number of papers published in the past few years revealed that MPV may play an important role in the development, progression and complication of several human disorders. A large meta-analysis including 16 cross-sectional studies and 2809 patients concluded that increased MPV was significantly associated with risk of myocardial infarction (MI), as MI cases exhibited a mean increased MPV value of 1.11 fl (95% CI: 0.79–1.42 fl) compared with controls [6]. The further analysis of three prospective trials also revealed that MPV was an independent predictor of both mortality after MI (odds ratio [OR], 1.65; 95% CI: 1.12–2.52), and restenosis following coronary angioplasty (mean difference of MI cases versus control, 0.98 fl; 95% CI: 0.74–1.21 fl) [6]. Another more recent meta-analysis including eight cohort studies found a reinforced association between increased MPV value and coronary artery disease (OR: 2.28; 95% CI: 1.46–3.58) [7]. Even more importantly, a recent study reported that admission MPV independently predicted in-hospital major adverse cardiovascular events (MACEs) in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (OR: 2.81; 95% CI: 1.33–5.95) [8]. A prospective, population-based study including 25,923 subjects followed up for a mean period of 10.8 years also revealed that an increased MPV was independently associated with the risk of both total (hazard ratio [HR]: 1.3; 95% CI: 1.0–1.7) and unprovoked (HR: 1.5; 95% CI: 1.0–2.3) venous thromboembolism [9].

A number of studies have also assessed the potential role of MPV for predicting the outcome of cancer patients. Kumagai et al. [10] showed that an increased preoperative MPV value is an independent predictor of shorter disease-free survival (HR: 1.713; 95% CI: 1.07–2.74) and reduced overall survival (HR: 2.83; 95% CI: 1.30–6.16) in patients with non-small-cell lung cancer. Similar evidence was provided by another retrospective study in patients with metastatic colorectal cancer [11], in that disease progression was found to be significantly reduced in patients with lower MPV values (HR: 0.41; 95% CI: 0.17–0.98). Interestingly, increased platelet size was also found to be a significant predictor of hepatocellular carcinoma in patients with chronic liver disease (area under the curve: 0.676; 95% CI: 0.580–0.773), performing even better than other and most used biomarkers of prognosis, such as alpha-fetoprotein [12].

Beside cardiovascular disease and cancer, emerging evidence attests that an increased MPV may be associated with unfavorable prognosis in other conditions. More specifically, larger platelet size significantly predicted embolic complications and death in patients with infective endocarditis [13], mortality in patients with severe sepsis or septic shock [14,15] as well as overall death in those in critical conditions requiring admission to the intensive care unit [16]. Unfortunately, no study has assessed the longitudinal changes in MPV as risk markers to the best of our knowledge.

Beyond the putative role for predicting an adverse prognosis in a variety of human disorders, recent evidence suggests that an increased MPV may be a significant and independent predictor of endurance performance [17], thus opening an intriguing scenario on the potential interplay between larger platelets and human physiology.

Although it is still unclear whether larger platelets actively participate in the pathogenesis of human diseases or their appearance represents a simple epiphenomenon of an underlying derangement of platelet biology, several lines of evidence seemingly attest that these corpuscular elements may play an active role in certain pathologies. Activated platelets release a large number of bioactive molecules and express several immune receptors on their surface, so that they can be considered immune cells, at large [18]. Experimental data suggests that surface protein activation, thromboxane synthesis as well as release of proteins stored within dense and α-granules are significantly enhanced in large size platelets [19]. Importantly, a number of prothrombotic and bioactive proteins are released from α-granules, including fibrinogen, VWF, clotting factors, and soluble CD40 ligand (sCD40L). This subset of hyperactive platelets may hence be seen as a key determinant for the development of venous and, especially, of arterial and thrombosis [20]. The PDGF is also contained within these granules. After being released by large and hyperactive platelets, PDGF interplays with many cellular processes involved in cancer progression and spread, including cell proliferation, transformation, invasion and angiogenesis [21]. On the other hand, platelet volume usually increases in the presence of enhanced platelet turnover as a result of an increased number of reticulated platelets [22]. This often occurs when blood clotting is permanently activated. In cancer patients, systemic disease is frequently associated with subclinical disseminated intravascular coagulation, whereas enhanced platelet turnover has also been convincingly described in subjects with severe atherosclerosis. According to this perspective, a larger platelet volume (and a perhaps increased number of reticulated platelets) may be regarded as a simple marker of enhanced platelet turnover, and it is hence not surprising that an increased MPV would reflect a poor prognosis in patients with advanced cancer and severe atherosclerosis.

Conclusions

Besides inherited thrombocytopenias, in which platelet size is used in a validated diagnostic algorithm [2], emerging evidence suggests that MPV measurement may be regarded as a promising tool for predicting the risk of developing thrombosis, as well as for help in prognosticating adverse outcomes in patients with cancer and severe infections. Indeed, the statistically significant difference observed between cases and controls in some clinical studies is obviously attributable to the large samples size [6–9], whereas individual MPV values were found to be largely overlapping. Therefore, additional evidence-based studies should be undertaken before the assessment of MPV can be introduced in routine clinical practice for diagnosis and prognostication of patients with myocardial infarction, venous thrombosis, cancer and infection. Due to the putative interplay between large platelets and a number of biological pathways, future investigations should also be planned to establish whether MPV may also be considered a treatment target, especially in patients with cardiovascular disease [23].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.