Pulmonary Embolism at Extreme High Altitude: A Study of Seven Cases

Abstract

Wu, Jialin, Xiaobo Han, Haiwen Ke, Li Wang, Kun Wang, Jianli Zhang, Jun Tang, Wei Yan, Guangjun Wang, and Peng Jiang. Pulmonary embolism at extreme high altitude: A study of seven cases. High Alt Med Biol. 23:209–214, 2022.

Background:

The incidence of venous thromboembolism (VTE) is high in high-altitude (HA) areas. We analyzed cases of pulmonary embolism (PE) in extreme HA areas to explore the epidemiological characteristics and risk factors of PE in these regions.

Methods:

Seven cases of PE occurring in an extreme HA region were prospectively collected at an HA (3,800 m) hospital from May to November 2020. All patients resided 5,000 m above sea level and were diagnosed with PE using computed tomography pulmonary angiography.

Results:

Seven patients (24 ± 3.6 years old) had symptom onset at a mean altitude of 5,200 ± 200 m, and the duration spent at HA ranged from 8 to 210 days (99.29 ± 77.31 days). Cough, expectoration, chest tightness, fever, shortness of breath, and chest pain were the most common symptoms. Six of the seven patients were initially diagnosed with pulmonary inflammation, and four were diagnosed with high-altitude pulmonary edema using computed tomography or X-ray. Most patients presented with an increased concentration of inflammatory cells and high initial D-dimer levels.

Conclusions:

In this study, a retrospective analysis of PE case data in extreme HA areas suggested that PE was underdiagnosed owing to misdiagnosis or masking by HA-associated disease.

Background

Pulmonary embolism (PE) is a disease characterized by circulation and respiratory dysfunction caused by a thrombus from the venous system or the right heart blocking the pulmonary artery or its branches. Progressive dyspnea, tachycardia, pleuritic chest pain, and hemoptysis are the cardinal symptoms of PE (Tapson, 2008). PE and deep venous thrombosis (DVT) represent distinct phases of venous thromboembolism (VTE) (Heit, 2015). Because of its poor prognosis and high mortality rate, much attention has been paid to PE in recent decades.

Certain acquired factors (including major surgery, cancer, advanced age, and pregnancy) and hereditary factors (including protein C/S deficiency, factor V Leiden, and plasminogen deficiency) increase the risk of DVT and PE (Heit and Anderson, 2005; Tapson, 2008). Moreover, several case reports and small studies have indicated that prolonged stay and travel to a high altitude (HA) are risk factors for PE (Kumar, 2006; Jha et al., 2018; Trunk et al., 2019).

Many diseases that have emerged at HA areas are distinct from those at low-altitude (LA) areas, given the presence of hypobaric hypoxia and cold conditions. At HA, VTE is associated with high morbidity and mortality rates. Kumar compared the data of 28 Indian soldiers with DVT, who were located at 11,800 feet, to the data of patients who were in a hospital at LA, and the results showed a significantly higher incidence of DVT in patients at HA. Soldiers at HA had a 24.5-fold greater relative risk for DVT than those at LA area (Kumar, 2006). Another prospective study showed an odds ratio of 30.5 for vascular thrombosis in HA Indian soldiers when compared to non-HA soldiers (<3,000 m) (Anand et al., 2001).

In addition, Dutta et al. (2018) reported 53 Indian soldiers who had a prolonged stay at HA area (>4 months) and were diagnosed with PE; 17% of them had hereditary risk factors for thrombophilia. Khalil and Saeed (2010) reported that HA was the only risk factor for 50% of 50 PE cases in Pakistani soldiers at HA. Currently, only a limited number of studies have indicated that HA is a potential risk factor for PE and DVT, and further studies are needed to support these findings.

In this study, we describe seven patients at HA area, who were diagnosed with PE, to explore the epidemiological characteristics of PE in these regions, and provide some reference for diagnosis and treatment.

Methods

All clinical data for this prospective study were collected at a medical station that provides medical services to fewer than 10,000 residents in the surrounding area, located in Pishan County, Xinjiang, an autonomous region of China (3,800 m above sea level), from May to November 2020. Patients were further treated at the People's Liberation Army 950th Hospital and the General Hospital of Xinjiang Military Command located in Kashgar and Urumqi, Xinjiang, respectively. HA was defined as an altitude >2,500 m, whereas extreme HA was defined as an altitude >5,000 m above sea level (Anand et al., 2001).

All patients were diagnosed with PE using computed tomography pulmonary angiography. Thromboembolism of the lower extremity vein, iliac vein, inferior vena cava, and heart chamber was confirmed using color Doppler ultrasonography. High-altitude pulmonary edema (HAPE), HA cerebral edema, and pneumonia were determined using radiography or computerized tomography. Intracranial venous sinus thrombosis was diagnosed using magnetic resonance venography. Data, including routine blood and coagulation function tests, were obtained from the patients' initial hematologic test since the start of the illness.

In addition to the clinical examination data, the patients' own and family history of embolic disease were included. Special notes were made relating to, among others, alcohol consumption, smoking history, previous HA exposure, total duration of stay at HA, symptoms, and weight loss. All these items were included in the risk factor assessment.

Results

Patient characteristics

Seven male patients with PE, who were hospitalized at a medical station between May to December 2020, were enrolled in this study. All of them fell ill at an altitude above 5,000 m and were sent down to the medical station for further treatment. The basic diagnostic information and clinical characteristics of patients are shown in Tables 1 and 2, respectively. The patients' age ranged from 20 to 31 years, with an average age of 24 ± 3.6 years. All patients had previously lived at LA areas, and resided at an altitude above 5,000 m after entering the HA areas.

Table 1.

Basic Diagnostic Information of Pulmonary Embolism Patients

No.	Age (years)	Sex	Max altitude (m)	Time at HA (days)	Initial diagnosis	Final diagnosis
1	26	Male	5,300	210	DVT	PE, DVT
2	21	Male	5,000	30	HAPE, pneumonia	PE, HAPE, pneumonia, DVT, cerebral venous sinus thrombosis, right ventricular thrombosis
3	31	Male	5,500	183	HAPE, pneumonia	PE, HAPE, HA pulmonary hypertension, pneumonia, acute respiratory failure, acute heart failure, DVT, subarachnoid hemorrhage
4	20	Male	5,000	8	Pneumonia	PE, HAPE, pneumonia
5	26	Male	5,300	61	HAPE, Pneumonia	PE, HAPE, pneumonia
6	25	Male	5,300	60	Pneumonia	PE, pneumonia, DVT
7	23	Male	5,000	122	Pneumonia	PE, pneumonia, thrombosis of the right renal vein, acute kidney injury

DVT, deep venous thrombosis; HA, high altitude; HAPE, high-altitude pulmonary edema; PE, pulmonary embolism.

Table 2.

Basic Characteristics of Patients

Variable	Mean or proportion
Age (years)	24 ± 3.6
Time at HA (days)	99.29 ± 77.31
Altitude (m)	5,200 ± 200
Combined with HAPE	4/7
Combined with pneumonia	6/7
Prodromal upper respiratory tract infection history	6/7
Smoking	2/7
Alcohol consumption	3/7
Weight lose	5/7
HA exposure history	3/7
Family history of thrombotic disease	1/7
Immobility	0/7
Estrogen	0/7
Varicose vein of lower limb	1/7
Recent surgery	0/7
Symptoms
Cough and expectoration	5/7
Fever	4/7
Chest tightness	5/7
Short of breath	5/7
Chest pain	4/7
Nausea and vomiting	2/7
Extremity pain	2/7
Pink frothy sputum	2/7
Headache	2/7
Waist pain	1/7
Dyspnea	1/7
Signs
Tachycardia	3/7
Cyanosis	3/7
Tachypnea	4/7
Engorgement of the neck veins	2/7
Abnormal respiratory sounds	5/7
Percussion tenderness over kidney region	1/7

Basic diagnostic information

The timing of patients' migration varied, with symptoms appearing in as few as 8 days and as many as 210 days. Six of the seven patients were initially diagnosed with pulmonary infection, and four of seven patients were diagnosed with HAPE using computed tomography or X-ray.

It is worth noting that patients 2, 3, and 5 had not just recently ascended to the plateau, but had descended to an LA area before ascending to the HA area again, before the onset of their symptoms. Finally, PE was diagnosed by computed tomography pulmonary angiography. Only one patient sought medical attention because of lower extremity pain and was diagnosed with DVT of the lower extremity on color Doppler ultrasonography. The presence of PE was confirmed by further examination. Notably, in addition to PE in patient 2, cerebral venous sinus thrombosis and right ventricular thrombosis were diagnosed.

A clear history of having a cold before the onset of symptoms and the development of pneumonia was observed in six patients, four of whom developed HAPE (Table 2). Smoking and alcohol consumption were present in a minority of patients, whereas a majority of patients experienced weight loss, which was positively correlated with the duration spent at HA.

Clinical features and examination profiles

Abnormal manifestations in the respiratory tract were the main symptoms, particularly respiratory infection-related symptoms (Table 2). The most common symptoms were cough, expectoration, chest tightness, and shortness of breath. Two of the three patients with a definite diagnosis of DVT presented with lower extremity pain, and only one had DVT-related symptoms as the first manifestation.

As mentioned previously, the majority of patients had a preinfection history. The first routine blood examination suggested that five patients had increased white blood cell and neutrophil counts (Table 3). Hemoglobin and hematocrit levels showed an upward trend with an increase in the duration spent at HA. Abnormalities in coagulation function were observed in all patients, with a definite increase in D-dimer levels and changes in fibrinogen and thrombin time. Imaging results showed that all patients had pulmonary artery branch thrombosis and three had pulmonary trunk thrombosis. Renal vein, right ventricle, and superior sagittal sinus thrombosis were reported in one case each (Table 4).

Table 3.

Biochemical and Coagulation Profile of Patients

No.	D-dimer (0–0.5 mg/l)	FIB (2–4 g/l)	TT (14–21 seconds)	WBC (3.97–9.15 × 10⁹/l)	Neut. count (2–7 × 10⁹/l)	Neut. % (50%–70%)	Platelet count (85–303 × 10⁹/l)	HGB (131–160 g/l)	HCT (38%–50.8%)
1	0.77	2.31	20.7	6.47	3.25	50.2	151	222	66.5
2	1.52	4.19	21	15.09	12.97	85.8	159	169	53.6
3	12.82	4.16	25	18.1	16.1	89.3	243	192	61
4	0.75	3.16	19.1	14.44	12.78	88.5	192	164	51.1
5	4.9	4.2	22.3	12.57	8.47	67.3	213	155	52
6	7.92	5.12	21.6	8.66	5.76	66.5	302	161	51.8
7	5.2	4.41	23	11.2	8.2	73	346	154	49

FIB, fibrinogen; HGB, hemoglobin; HCT, hematocrit; Neut., neutrophil; TT, thrombin time; WBC, white blood cell.

Table 4.

Anatomical Site of Thrombosis, Abnormal Results of Electrocardiogram, and Ultrasonography Examination in Patients with Pulmonary Embolism

Variable	No.
Location of thrombus (total no. = 7)
Pulmonary trunk	3
Pulmonary artery branches	7
Lower extremity	3
Inferior vena cava	1
Renal vein	1
Iliac vein	1
Superior sagittal sinus	1
Right ventricle	1
Cerebral hemorrhage	1
Electrocardiogram (total no. = 7)
Starboard electrical axis	3
T wave inversion	1
Cardiac color Doppler ultrasonography (total no. = 7)
Pericardial effusion	2
Right heart enlargement	2
Pulmonary hypertension	1

Treatments and outcomes

Each patient goes through the process from the local medical station to the center hospital. Anticoagulant therapy, including oral and subcutaneous injection, was administered to every patient after diagnosis (Table 5). Two patients underwent inferior vena cava filter implantation after consultation with multidisciplinary doctors. In compliance with the surgical guidelines, patient 3 underwent thrombectomy and pulmonary artery catheter-directed thrombolysis therapy under general anesthesia. However, the patient experienced progressive deterioration of his respiratory and circulatory systems, and required extracorporeal membrane oxygenation for life support, which failed and he eventually died. With the exception of this patient, the other patients improved gradually after comprehensive treatment and were followed up regularly.

Table 5.

Treatment and Outcome of Pulmonary Embolism Patients

No.	Treatment	Outcome
1	Anticoagulant (Warfarin + LMWH) + symptomatic support therapy	Improvement
2	Anticoagulant (Warfarin + LMWH) + Antibiotic (Vancomycin + CAZ) + Glucocorticoid pulse therapy + Mannitol + symptomatic support therapy	Improvement
3	Inferior vena cava filter implantation + Pulmonary artery catheter directed thrombolysis therapy + Antibiotic (Imipenem) + Thrombectomy + Anticoagulant (LMWH) + Glucocorticoid pulse therapy + Antifungal therapy (Fluconazole) + ECMO + Aminophylline + symptomatic support therapy	Death
4	Anticoagulant (Warfarin + LMWH) + Antibiotic (AZM) + HBOT + Aminophylline + symptomatic support therapy	Improvement
5	Anticoagulant (Warfarin) + Antibiotic (CRO) + Aminophylline + symptomatic support therapy	Improvement
6	Anticoagulant (LMWH) + Antibiotic (Levofloxacin) + Inferior vena cava filter implantation + Aminophylline + symptomatic support therapy	Improvement
7	Anticoagulant (LMWH + Rivaroxaban) + Antibiotic + symptomatic support therapy	Improvement

Symptomatic support therapy, including oxygen therapy, gastric mucosa protection, antiasthmatic, cough suppressant and expectorant, maintaining water, electrolyte acid-base balance and other conventional treatment.

AZM, azithromycin; CAZ, ceftazidime; CRO, ceftriaxone; ECMO, extracorporeal membrane oxygenation; HBOT, hyperbaric oxygen therapy; LMWH, low molecular weight heparin.

Discussion

Previous studies have reported that HA may be a risk factor for PE (Anand et al., 2001; Wheatley et al., 2011). When individuals stay at HA areas, plasma fibrin activity increases, leading to a persistent hypercoagulable state (Jiang et al., 2014). Furthermore, adaptive changes generated by long-term migration to HA can result in a gradual increase in red blood cells, and high-altitude polycythemia (HAPC) has been shown to be induced under an uncontrolled compensatory mechanism (Li et al., 2011). People with HAPC have a 1.5–2.4-fold greater risk of VTE than the general population (Braekkan et al., 2010).

The study enrolled seven PE patients in an observation group of nearly 10,000 people over a 6-month period (from May to November 2021). They migrated from lower to higher altitudes and were admitted to the hospital with a diagnosis of PE. This provides a rough estimate of an annual hospitalization rate of PE of 140 per 100,000 people per year in HA areas. There was no control group; therefore, we could not obtain a risk ratio for HA and LA areas.

However, an epidemiological study in China showed that the average annual hospitalization rate for PE in the population was ∼7.1 per 100,000 people (Zhang et al., 2019). The hospitalization rate of people 20–40 years of age is much lower than the average rate, and the risk of PE increases dramatically after the age of 40 years. It has been recognized that advanced age is an acquired factor for PE. In brief, the prevalence of PE in HA areas was significantly increased in this study when compared with LA areas. Notably, such a high hospitalization rate in HA areas appears in the younger age group.

Patients with intracranial venous sinus, right ventricular, and renal venous thrombosis were also included in this study. Although it is not uncommon for such patients to develop thrombosis in other parts of the body, it is worth noting that systemic venous thrombosis may occur at HA. Whether endogenous or other factors contribute to thrombus formation in multiple sites is not clear at present. Owing to medical limitations, an effective early diagnosis of PE may not be possible at HA. Meanwhile, since PE has no specific clinical manifestations, it can be easily diagnosed as other respiratory diseases (such as pneumonia or HAPE) at the initial stage, and a combination of these diseases cannot be ruled out. These results make it difficult to diagnose PE. Therefore, more attention should be paid to the high-risk PE groups in HA areas.

D-dimer is an important indicator for diagnosing of patients with VTE, and its increase is important significance for the differential diagnosis of patients with symptomatic PE. Le Roux et al. (1992) demonstrated that the levels of D-dimer levels increased significantly at 6,542 m after 1 week and at 3 weeks compared to those observed at sea level in seven climbers. Analogously, Pichler Hefti et al. (2010) found that D-dimer levels increased with increasing altitude in Muztagh Ata, China. Our data showed that serum D-dimer levels in patients with PE at HA were higher than normal (referring to the cutoff in the LA areas). This suggests that D-dimer, as an important differential index for PE diagnosis, still has diagnostic efficacy at HA areas.

A transcriptomic and proteomic analysis of platelets demonstrated that HA was associated with the upregulation of proteins with thrombosis and platelet activation without thrombosis in HA-residing patients compared to subjects residing at LA (Shang et al., 2020). Moreover, a novel genome-wide expression analysis performed by Jha et al. (2018) showed that genes associated with the coagulation cascade and platelet activation were significantly upregulated in patients with DVT at HA. These studies indicate that platelet activation may induce thrombosis, but the platelet counts in our study were within the normal range. Additional parameters associated with platelet activation should be analyzed in future studies to verify these findings.

The activation of inflammatory signaling pathways is involved in the formation of venous thrombosis by promoting the activation and aggregation of platelets and endothelial cells and increasing the expression of tissue factors (Tyagi et al., 2014). Gupta et al. demonstrated that inflammasome activation under hypoxic conditions promotes venous thrombosis by ligating the inferior veins in rats (Gupta et al., 2017). They revealed that hypoxia inducible factor-1α increased nucleotide binding oligomerization domain-like receptor 3 (NLRP3) expression and promoted the transformation of pro-interleukin-1β (IL-1β) to IL-1β, ultimately mediating thrombus formation. Notably, NLRP3 promoted thrombosis under the noninflammatory state of hypoxia in this study.

Whether the preinflammatory state mediates the expression of NLPR3 and promotes thrombosis is unclear. Of interest, six of seven patients had a history of prodromal infection and were initially diagnosed with pulmonary inflammation. Therefore, we speculate that the preinflammatory state may promote venous thrombosis under hypoxic conditions. By identifying the key targets of the inflammatory pathway-mediated thrombosis under hypoxic conditions, it is possible to search for targeted prevention and treatment drugs.

This study had some limitations. First, the number of cases was small, and additional cases are needed to confirm this perspective in the future. Second, there was a lack of detection of patients with genetic predisposing factors for PE, such as protein S/C, plasminogen deficiency, and variations in related genes (Rosendaal et al., 1995; Rosendaal, 2005), and, as a result, we could not rule out the interference of endogenous factors. Indeed, this was a retrospective analysis of case data, and a major limitation was the lack of a control group.

Conclusions

In this study, a retrospective analysis of PE case data in extreme HA areas suggested that inflammation or HAPE might be related to the occurrence of PE. Meanwhile, PE was underdiagnosed owing to misdiagnosis or masking by HA-associated diseases such as HAPE.

Footnotes

Authors' Contributions

J.W. and G.W. conceived the project; J.W., X.H., H.K., L.W., K.W., J.Z., J.T., and W.Y. collected the data; J.W. and X.H. wrote the article; P.J., J.W., and X.H. analyzed the data.

Ethics Approval and Consent to Participate

The protocol of this study was approved by the Committee for Ethical Affairs of the General Hospital of Xinjiang Military Command, Urumqi, China.

Availability of Data and Materials

The datasets used during this study are available from the corresponding author upon reasonable request.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by grants from the Natural Science Foundation of Xinjiang Uygur Autonomous Region (No. 2020D01A139).

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