Relationship between subarachnoid haemorrhage and vasospasm, platelet count, mean platelet volume, platelet distribution width

Introduction

Subarachnoid haemorrhage (SAH) is a life-threatening cause of stroke, 80 % of them are caused by an intracranial aneurysm [1]. Its distinctive difference from other causes of stroke is that it affects younger patients. Subarachnoid haemorrhage (SAH) is more common in women than men [2]. The frequent occurrence of ischaemic processes and the need for care at a young age of patients lead to significant socioeconomic problems even in developed countries. Although leukocytes are the primary inflammatory agent, platelets have been shown to contain inflammatory mediators [3] in delayed cerebral ischemia (DCI) [4]. Studies have also been conducted outside the cerebrovascular field. Increased platelet distribution width (PDW) and mean platelet volume (MPV) have been found to be correlate with ST-elevation myocardial infarction [5]. In a study of 102 patients with vasospastic disorders, MPW and PDW were significantly higher in patients who received cold stimulation for more than 21 min. Studies focusing on this issue have been conducted in different areas. In one study, long-term activation and aggregation were found in platelets obtained from SAH patients [6]. In a study of 197 patients; high MPV, PDW, lymphocyte levels were associated vasospastic disorder [7]. These findings show that platelets play a role in vascular events (haemorrhage and ischaemia). However, the relationship between PDW and ischaemic or haemorrhagic stroke has not been well studied. Therefore, this study investigates the relationship between MPW, PC, PDW and MPW/PC values measured in blood samples collected within 0–12 h after SAH and the development of SAH and subsequent vasospasm in a large series of patients.

Materials and methods

The study was designed as a retrospective and ethics committee approval was obtained before starting the study (Adana City Training and Research Hospital Ethics Committee, 18/11/2021-1639). The study included 698 patients who were hospitalized with diagnosis of SAH and who were found to have a cerebral aneurysm on examination within 0–12 h after the SAH event between December 2017 and September 2021. In addition to demographic data, Glasgow Coma Scale and Fisher and World Federation of Neurosurgical Societies (WFNS) grading scales were recorded for each patient. PC, PDW and MPV values measured in complete blood count (CBC) tests of the patients at the time of admission to the emergency department were recorded. Patients with known blood diseases (sickle cell anaemia, thalassemia, leukemia, lymphoma, etc.), hypertension, diabetes mellitus, rheumatological diseases, and infections were excluded from the study. The control group of the study included 703 patients with comparable demographic characteristics who were hospitalized in our clinic with a diagnosis of lumbar or cervical disc herniation and who did not have any known systemic disease (hypertension, diabetes mellitus, rheumatological diseases), blood disease (sickle cell anaemia, thalassemia, leukaemia, lymphoma, etc.) or infection. A venous peripheral blood sample was taken from each patient in both groups by venipuncture into K2E-EDTA tubes.

Results

A total of 1,401 participants, including 698 patients and 703 controls were included in the study. Vasospasm was observed in 7.7 % of patients (Table 1). There was no significant difference in terms of PC between the patient and control groups (p=0.238). However, the MPV values of the patient group were significantly higher than the control group (p<0.001). Additionally, the PDW values and MPV/PC ratios of the patient group were higher than those of the control group (p<0.05, p<0.001, respectively) (Table 2).

The area under the curve (AUC) of PC values was not found to be significant in the development of SAH (p=0.238). In contrast, the AUC of MPV values was significant (p<0.001), with a cut-off value of >9.25 fL. The AUC of PDW values was also significant (p=0.020), with a cut-off value of >17 %. The AUC of MPV/PC ratios was also significant (p=0.001), with a cut-off value of >3.48 (Table 3).

There was no difference in terms of PC between patients who developed vasospasm and those who did not (p=0.212). There was a difference in terms of MPV value between the patients who developed vasospasm and those who did not (p=0.007). The group of patients developing vasospasm had higher MPV values than those without vasospasm. There was a difference in terms of PDW value between the patients who developed vasospasm and those who did not (p=0.003). The group of patients developing vasospasm had lower PDW values than those without vasospasm. There was no difference in terms of MPV/PC ratio between patients who developed vasospasm and those who did not (p=0.749) (Table 4).

The AUC value of PCs was not significant in the subsequent development of vasospasm (p=0.212). The AUC value of the MPV values was significant in developing subsequent vasospasm (p=0.007). The cut-off value for MPV was found to be 9.6 fL. The AUC value of the PDW values was significant in developing subsequent vasospasm (p=0.003). The cut-off value for PDW was 16.2 %. The AUC value of the MPV/PC ratios was not significant in the development of subsequent vasospasm (p=0.749) (Table 5).

Vasospasm was detected in 5 % of the patients with MPV values <9.6 fL and in 14.7 % of patients with MPW values >9.6 fL. Vasospasm was detected in 5.1 % of the patients with PDW values >16.2 % and in 21.4 % of patients with PDW values <16.2 % (Table 6).

To examine the risk factors associated with the development of vasospasm, a multivariate logistic regression analysis was performed, including the independent variables of MPV and PDW, which were found to be significant in the univariate analysis. The results of the multivariate analysis showed that both MPV and PDW were risk factors for the development of vasospasm (p=0.013 and p<0.001, respectively). It was found that an MPV value of >9.6 fL increased the probability of vasospasm by 2.17 times, and a PDW value of <16.2 fL increased the probability of vasospasm by 3.75 times (Table 7).

Discussion

Platelets are nucleus-less fragments of the megakaryocyte cytoplasm. Platelets contain azurophilic granules that contain substances necessary for inflammation and coagulation [8]. When a vascular injury occurs, a pro-inflammatory process called hemostasis begins, which involves coagulation, vascular repair and wound healing [9]. This process consists of a primary hemostasis, when the platelet plug forms, and secondary hemostasis, when the clot forms. During this process, many mediators are released from the azurophilic granules. Some facilitate hemostasis, while others exhibit microbicidal properties. Some of these trigger inflammations (C3, C4 precursor and IgG). In addition to cathepsin, glucosidase and galactosidase, which can be released from the lysosomal granules in platelets, the dense granules in platelets can also release Ca, Mg, serotonin, histamine, ATP and ADP [10].

MPV measurement can be affected by many different factors, including age, gender, population differences, and genetic component [11]. A comprehensive list of pre-analytical variables includes the method of venipuncture, the accuracy of filling the tube and mixing the sample, the type of anticoagulant, the storage temperature, and analysis time. Factors such as the anticoagulant used in the collection tube and the time from sampling to analysis are also important sources of variation. In particular, ethylenediaminetetraacetic acid (EDTA) – induced platelet swelling by increasing intracellular cAMP and increasing the permeability of the plasma membrane, can increase the MPV measured by impedance by 7.9 % within 30 min after sampling and achieving overall increase of 13.4 % in 24 h [12]. Increased MPV has been reported also in a number of other conditions not clearly related to vascular abnormalities and/or to thrombotic tendency, including pneumoconiosis, nonalcoholic fatty liver disease, primary biliary cirrhosis, psoriasis, varicocele, idiopathic subjective tinnitus, panic disorder, juvenile idiopathic arthritis, and benign prostatic hyperplasia [13].

In the literature, PC, MPV, PDW and MPV/PC values have been used to investigate the involvement of platelets in ischaemic and haemorrhagic events. Ray et al. examined MPV/PC values for three consecutive days after SAH, and found an increase of 0.5 units/day in 38 patients who developed DCI and an increase of 0.2 units/day in patients who did not develop DCI; the researchers have linked this elevation to the post-SAH DCI [14]. Zhao L et al. found that MPV was an early predictor of DCI after SAH [15]. Rzepliński et al. reported that a 1 fL increase in MPV increased the risk of poor prognosis by 3.95 times [16]. In addition, many studies have shown that MPV and MPV/PC values have poor prognostic effects in ischaemic and haemorrhagic stroke cases [17], [18], [19], [20].

Building on these findings, Clarke et al. suggested that factors other than vasospasm may be more effective in developing DCI after SAH. They noted that the timing and incidence of vasospasm and DCI after SAH did not correspond and that some patients developed DCI after SAH despite the absence of vasospasm. By evaluating autopsy studies and experimental studies on SAH, they pointed out that thrombi develop in microvascular areas and are perhaps the main factor responsible for DCI [21].

Collectively, PDW has been underestimated in investigations of cerebrovascular events. Moreover, Vagdatlı et al. reported that PDW is superior to MPV in evaluating platelet functions because it is not affected by platelet elevation [22]. Gao et al. reported that low PDW values were associated with poor prognosis in 3-month follow-up of acute ischaemic stroke (AIS) patients who underwent intravenous thrombolysis [23]. In contrast, Li et al. reported that high PDW rates were associated with poor prognosis in a 3-month follow-up of patients with AIS who underwent mechanical thrombectomy [24].

Our study found a strong connection between SAH and the platelet function indicators, MPV, PDW and MPV/PC values. High MPV and low PDW were significant for the risk of serious complications in patients diagnosed with SAH. Despite previous research indicating that platelets play a role in vasospasm, there are limited studies that demonstrate the correlation between platelet indicators and SAH. Our study is unique in that it is the first study to demonstrate the correlation between SAH and PDW and the tests used are inexpensive and easily available in healthcare institutions.

Conclusions

Our study found a significant correlation between SAH and high MPV, PDW and MPV/PC. High MPV and low PDW were associated with vasospasm after SAH. This is the first investigation to find a correlation between PDW and SAH. At the same time, this study revealed the relationship between PDW and MPV and vasospasm. We believe that this study will contribute to the literature and that a simple and easily accessible test can be used to predict patients who may develop vasospasm.

Limitations and recommendations

A primary limitation of this study is the small sample size in vasospasm. However, the findings obtained from this study can be adapted to future studies with more vasospasm patients. Additionally, further studies with larger series are needed to investigate the fact that low PDW values are a poor prognostic criterion in AIS patients undergoing thrombolysis. On the other hand, high PDW values are a poor prognostic criterion in patients undergoing thrombectomy.