Clinical features of patients with cerebral venous sinus thrombosis at plateau areas

Abstract Objective Cerebral venous sinus thrombosis (CVST) is believed to be associated with high‐altitude exposure and has worse clinical prognosis in plateau areas than in plain areas, although this needs to be further verified. This retrospective study aims to compare the clinical differences of patients with CVST in plateau and plain areas and further ascertain the role of high‐altitude exposure in the etiology of aggravating predisposition toward CVST. Methods Twenty‐four symptomatic CVST patients occurring at plateau areas (altitude ≥ 4000 m), in corresponding with 24 CVST patients occurring at plain areas (altitude ≤ 1000 m), were recruited according to the inclusion and exclusion criteria from June 2020 to December 2021. The collected data and compared parameters include clinical features, neuroimaging findings, hematology profile, lipid profile, and coagulation profile within 24 h of hospital admission, as well as the treatment method and final outcome. Results There were no obvious differences of demographic characteristics, including gender, age, height, and weight between patients with CVST in plateau and plain areas, as well as medical history, neuroimaging findings, treatment protocols, and clinical outcome (all p > .05). Compared to patients with CVST at plain areas, time before hospital admission was longer and heartbeat was slower in patients with CVST at plateau areas (all p < .05). More importantly, elevated red blood cells counts, hemoglobin level, and altered coagulation function were found in patients with CVST at plateau areas (all p < .05). Conclusion CVST patients in plateau areas presented with altered clinical characteristics, altered coagulation function, and aggravated predisposition toward venous thromboembolism compared with CVST patients in plain areas. Future prospective studies will be needed to further elucidate the influences of a high altitude on the pathogenesis of CVST.


INTRODUCTION
Cerebral venous sinus thrombosis (CVST) is a rare form of neurovascular disorder, accounting for 0.5%-1% of all stroke patients and often affects the young population (Liang et al., 2017). The major pathological mechanism of CVST is the thrombosis of cerebral veins and/or dural sinus, which further leads to the reduction of CSF resorption and the elevation of intracranial pressure (Silvis et al., 2017). CVST has a variety of predisposing factors, age of onset, clinical manifestations, and radiological presentations. The most common risk factors of CVST include genetic/acquired prothrombotic conditions, infections, malignancy, pregnancy, oral contraceptives, and so on (Bano et al., 2021). In recent years, a relationship between high-altitude exposure and CVST has been established, as a result of the documentation of CVST at high altitude has raised obviously owing to the availability of better neuroimaging facilities, such as MRI and MRV (Devasagayam et al., 2016;Khattar et al., 2019). The diagnosis of CVST occurring at high altitude is often delayed, as CVST is a rare disease, and its clinical symptoms and radiologic findings are usually similar with other neurological conditions occurring at high altitude such as altitudinal sickness (Hassan et al., 2019). As the timely diagnosis and treatment of CVST occurring at high altitude needs a more thorough understanding of the clinical presentation, it is essential to conduct research to clarify the clinical features of patients with CVST at plateau areas by comparing them with CVST patients at plain areas.
The clinical symptoms of CVST are variably ranging from isolated headache to focal neurological symptoms and signs, seizures, and coma (Gazioglu et al., 2017). As for the neuroimaging presentation, the thrombosis of cerebral sinus can be founded in the majority of patients with CVST (Anadure et al., 2018). Newly studies indicate that the regional variation of CVST can also influence the clinical presentation (Kalita et al., 2016;Wasay et al., 2019). For example, CVST patients in Asian countries have different clinical presentations, compared with in USA and other Western countries . Therefore, it can be speculated that CVST patients at plateau and plain areas may have a variety of clinical differences as well. The alteration of hemostasis secondary to high-altitude hypoxia-induced polycythemia coupled with volume depletion and immobility can not only increase the risk of developing CVST but also can bring about characteristic clinical presentations (Zavanone et al., 2017). However, the existing literature on CVST at high altitude is very scant, and the accurate diagnosis is relatively difficult due to the wide spectrum of presenting symptoms (Zavanone et al., 2017). Correspondingly, it is imperative to clarify the clinical features and identify the presumed risk factors of CVST occurring at high altitude, which can contribute to the early diagnosis and treatment.
The purpose of this study is to compare the clinical differences of patients with CVST in plateau and plain areas and further ascertain the role of high-altitude exposure in the etiology of aggravating predisposition toward CVST. Concretely, the clinical features, neuroimaging findings, medical history, hematological status, coagulation function, treatment methods, and final outcomes of CVST patients at high altitude and plain areas were documented in detail and comprehensively compared.

Setting
This retrospective cross-sectional study was conducted in China at The  (Bousser, 2000). The and mRS score. According to mRS score, the outcome was classified into: complete recovery (mRS 0-1), partial recovery (independent mRS 2), dependent (mRS 3-5), and death (mRS 6).

Data Analysis
Measurement data was expressed as mean value ± standard deviations (M ± SD). Differences between two groups were analyzed by unpaired t test with Welch's correction. Relationships between two variables were evaluated using the Spearman rank correlation test. Enumeration data was analyzed by Chi-squared test. SPSS version 18.0 software (SPSS Inc., USA) was used to perform the analysis, and two-tailed p < .05 was considered statistically significant. Photoshop software (Adobe Software, Inc., USA) was used to draw the figure.

Patients selection
All CVST patients were chosen from the inpatient service of a tertiary hospital in plateau area and The General Hospital of Western Theater Command in Chengdu from June 2020 to December 2021 by using ICD-9 procedural code terminology. Patients were qualified for recruitment if the diagnosis was isolated CVST, and they were further

Clinical features of CVST patients at plateau and plain areas
CVST patients at plateau and plain areas were parallel in the demographic baseline including gender, age, height, and weight, as well as the medical history of drinking and smoking. The mean altitude and time duration of CVST patients at plateau areas were 5200 ± 276.6 meters and 90.3 ± 107.6 days. CVST patients at plateau and plain areas were similar in the time before hospital admission, mean GCS score, onset type, and major symptoms. Moreover, the most common onset type of CVST occurring at plateau and plain areas was subacute (91.7% and 83.3% respectively), and the most frequent symptom was headache (37.5% and 33.3% respectively). As for the vital signs at hospital admission, CVST patients at plateau areas were analogical in body temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP), and breathing frequency, but the heartbeat was slower in CVST patients at plateau areas (p < .001). Detailed data is showed in Table 1.

CVST patients at plateau and plain areas had similar neuroimaging findings
CVST patients at plateau and plain areas were diagnosed with similar neuroimaging techniques, including cranial CT, MRI, and MRV, of which the most frequent one was cranial MRI + MRV (54.2% and 45.8%, respectively). Neuroimaging findings showed that the most common sinus affected was sigmoid sinus (16 and 14, respectively), followed by superior sagittal sinus and right transverse sinus, and the distribution of sinus involvement had no significant difference between CVST patients at two areas. In addition, the most common number of sinus involvement was "more than two" (66.7% and 58.3%, respectively), the number of sinus involvement and the MRI presentation (hemorrhage/infarcts) had no significant difference between two groups.

F I G U R E 1 The selection flowchart of cerebral venous sinus thrombosis (CVST) patients in plateau and plain areas.
These results indicated that CVST patients at two areas had similar neuroimaging findings. Detailed data is showed in Table 2.

CVST patients at plateau areas presented with altered coagulative state
As shown in Table 3, the HGB level, RBCs count, and HCT were obviously higher (both p < .001) in CVST patients at plateau areas than at plain areas, as well as the total leukocyte count (p = .016). In addition, the lipid profile analysis indicated that CVST patients at plateau areas had lower level of HDL (p < .001) but had similar level of TC, TG, and LDC with CVST patients at plain areas. In the analysis of coagulation function, CVST patients at plateau areas had considerably longer PT, APTT, TT, and INR (p = .017, .010, .015, and .001, respectively), and obviously higher level of D-D (p < .001) than CVST patients at plain areas. These results indicated that CVST patients at plateau areas presented with altered coagulative state.

Correlation between basic coagulation parameters and RBCs indexes in CVST patients
In order to explore the coagulative state of CVST patients furthermore, the correlations between basic coagulation parameters (APTT, PT, TT, FIB, and PLT) and RBCs indexes (HGB and HCT) were analyzed.
As demonstrated in Table 4 Table 5, FIB was positively correlated with D-D in CVST patients at plain areas (r = .428, p = .037), but they had no correlation at plateau areas. In addition, no correlation was found between APTT, PT, and TT and PLT in CVST patients at plateau and plain areas.

CVST patients at plateau areas and plain areas had similar treatment and outcome
At last, the differences of treatment and outcome in CVST patients at two areas were analyzed. As shown in Table 6, the anticoagulation drug LMWH was used in most of CVST patients at plateau and plain areas (83.3% vs. 87.5%, p = .683). However, the endovascular therapy was performed in only a small part of CVST patients at plateau and plain Prothrombotic states 0 0 Note: p < .05 represents statistically significant (marked with "*" and bold). Abbreviations: DBP, diastolic blood pressure; GCS, Glasgow coma scale; IIH, isolated intracranial hypertension; SBP, systolic blood pressure.
areas (20.8% vs. 37.5%, p = .434). In addition, the rate of endovascular therapy application was higher in CVST patients at plain areas than at plateau areas, but without significant difference. In addition, CVST patients at plateau areas gained similar recovery outcome with CVST patients at plain areas.

DISCUSSION
To our knowledge, this is the first study that investigated the clinical differences of patients with CVST in plateau and plain areas. Main findings were as follows: (1)  CVST is a rare but significant cause of stroke, which is associated with various risk factors, including inherited thrombophilia, acquired prothrombotic state, oral contraceptives, and so on (Appenzeller et al., 2005). Latest studies indicate that high-altitude exposure might be a
risk factor for CVST as well, as the risk of venous thrombotic events is reported to increase by 30 times at high altitude (Anand et al., 2001;Devasagayam et al., 2016;Hassan et al., 2019;Khattar et al., 2019). Nevertheless, the exact prevalence and mechanism of CVST at high altitudes are still unknown, probably because the literature of CVST at high altitude is scarce and contains only a few case reports or case series. According to the existed literature, there might be several factors contributing to the occurrence of CVST at high altitude. First, the slowing of cerebral blood flow may play an important pathogenetic role, as high-altitude exposure leads to the increase of blood viscosity that further causes the decrease of cerebral blood flow and oxygen transport (Song et al., 1986). Second, preexisting prothrombotic states, such as hereditary thrombophilia, may be the most likely predisposing factors for CVST occurring at high altitude (Zavanone et al., 2017).
Moreover, other factors, including secondary polycythemia, hypoxiainduced hemostatic alterations such as increased platelet activity, inflammatory changes secondary to endothelial injury, and coagulation pathway activation triggered by hypothermia might play essential roles in the occurrence of CVST at high altitude as well (Zavanone et al., 2017). These issues would be explored if much more studies with a large sample could be conducted in the future.
CVST is more frequent in female than in male at plain areas, as previous studies indicated that the incidence of CVST in women was threefold higher due to the use of oral contraceptives and puerperium (Coutinho et al., 2009;Ferro et al., 2004). However, the majority of CVST patients at plateau areas were males, and females developing CVST at plateau areas are limited (Cheng et al., 2009). Similarly, all the CVST patients at plateau areas in this study were males. The reason for men are more susceptible to CVST at high altitude is unclear; one probable explanation is that most of the research subjects are men who usually work at plateau areas (Song et al., 1986;Torgovicky et al., 2005). CVST patients usually present with a wide range of clinical symptoms, including headache, seizures, vomiting, altered consciousness, and papilledema, of which the most common one is headache (Coutinho, 2015;Coutinho et al., 2015). This conclusion is consistent with our study, as 37.5% and 33.3% CVST patients at plateau and plain areas present as headache. Headache usually reflects the increase of intracranial pressure, which is also a common symptom of other neurological conditions occurring at high altitude such as acute mountain sickness or high-altitude cerebral edema. Herein, the diagnosis of CVST at plateau areas might face some challenges, as the symptom is varying and misleading. In order to improve the accuracy, neuroimaging techniques, such as CT, CTV, MRI, and MRV, have been generally applied in the accurate diagnosis of CVST. Noninvasive imaging significantly increases the sensitivity of diagnosis, as MRV is the most sensitive diagnostic modality and CTV is a reasonable alternative to MRV for the diagnosis of CVST, both of which have equivalent sensitivity and specificity Lafitte et al., 1997;Silvis et al., 2017). In our study, the most frequently used neuroimaging techniques were cranial MRI+MRV in CVST patients at plateau and plain areas. In addition, neuroimaging findings indicated that the most common sinus affected was sigmoid sinus, the most common number of sinus involvement was "more than two", without difference between two groups. Our results might be inconsistent with other studies, because the proportion of sinus involvement was quite variable due to the type and timing of neuroimaging (Devasagayam et al., 2016;Kalita et al., 2016;Wang et al., 2019;Zhou et al., 2017). which promotes the oxygen-carrying capacity of RBCs but aggravates the risk of thrombosis (Li et al., 2018;Liu et al., 2017). High altitude brings about hypercoagulability manifested as increased D-D levels, which are usually applicated in the diagnosis of venous thrombotic diseases, but cannot be reliably used to exclude CVST due to their high negative predictive value (Dentali et al., 2012;Hiltunen et al., 2013). As the D-D level was obviously higher in CVST patients at plateau areas than at plain areas, D-D testing might be useful to make a diagnosis for patients with the suspicion of CVST at plateau areas. Second, PT, APTT, TT, and INR were found to be obviously higher in CVST patients at high altitude, which was consistent with the result of other studies (Damodar et al., 2018;Vij, 2009;Zhang et al., 2019) but was contradictory to the conclusion that high-altitude activated the coagulation cascade and caused the increased risk of thrombosis (Damodar et al., 2018). These results can be explained by the influence of high-altitude exposure, which induced the compensatory hyperplasia of RBCs and the elevation of HCT and further led to the prolongation of PT, APTT, and TT, as our and other studies both demonstrated that HCT was positively correlated with PT, APTT (Marlar et al., 2006;Zhang et al., 2019).
Third, CVST patients at plateau areas had positive correlation between PT and HGB/HCT, APTT and HGB/HCT, FIB and HGB/HCT, and PLT and HCT. In addition, CVST patients at plain areas had positive correlation between PT and HCT, APTT and HCT but had negative correlation between PLT and HGB/HCT. In addition, FIB was positively correlated with D-D in CVST patients at plain areas, but they had no correlation at plateau areas. It is worth noting that the correlations between these variables were weak, which might have little clinical significance. Moreover, no studies have studied the coagulation function of CVST patients at plateau areas so far. Herein, it might be difficult to make precise conclusions based on these results, and further studies will be needed to analyze the influence of high altitude on the coagulation function in CVST patients.
The alternative treatments for CVST include anticoagulation drugs such as unfractionated heparin and LMWH, and endovascular operations such as local thrombolysis with the thrombolytic drug infusion and mechanical thrombectomy with special devices (Saposnik et al., 2011;Stam et al., 2008). At present, no convincing studies have evaluated the efficacy and safety of endovascular treatment for CVST, except several case reports mentioned the therapeutic effect of local thrombolysis in CVST (Guo et al., 2012;Li et al., 2013;Stam et al., 2008).
Our study showed that the anticoagulation drug LMWH was used in most of CVST patients at plateau and plain areas (83.3% vs. 87.5%), but the endovascular therapy was performed in only a small part of CVST patients at plateau and plain areas (20.8% vs. 37.5%). As for the final outcome, CVST patients at plateau areas gained similar recovery outcome with CVST patients at plain areas. These results indicated that CVST patients in plateau areas had received similar treatment protocols and gained similar recovery outcome with CVST patients in plain areas.
There are several limitations in this study. First, this study is an observational and retrospective one without intervention and followup visits. Second, the number of subjects is relatively small. Third, the gender of recruited patients is only male because of the particular geographical environment in plateau areas restricted the population recruitment. At last, the outcome of this study is relatively underpowered, and much more studies with large sample will be needed in the future.
In conclusion, this retrospective cross-sectional study demonstrated that CVST patients in plateau areas presented with longer time before hospital admission, altered coagulation function, and aggravated predisposition toward venous thromboembolism compared with CVST patients in plain areas. The most common symptom was headache, the most common sinus affected was sigmoid sinus, and the most common number of sinus involvement was "more than two," without differences between CVST patients in plateau and plain areas. In addition, CVST patients in plateau areas and plain areas received similar treatment protocols and gained similar recovery outcome. These findings are of great significance to clarify the clinical features of CVST patients in plateau areas.

AUTHOR CONTRIBUTIONS
Yuan Ma and Yongjian Yang designed the study and guided the writing of this article. Yongxiang Yang, Jingmin Cheng, and Yuping Peng were responsible for conducting the study and writing the manuscript.
Yan Luo and Dongbo Zou contributed to acquire and analyze the data.
Authors included in this article agreed with the final manuscript.