A Case of Extensive Portal Venous System Thrombosis and Prehepatic Portal Hypertension Following Transition from Low to High Altitude

Authors: Meijuan Chen, Chunyan Li, Shanhong Tang

Institution: Department of Gastroenterology, General Hospital of Western Theater Command

Editor’s Note: To broaden the horizons and enrich the practical knowledge of clinical hepatologists, and to cultivate clinical thinking abilities, International Liver Disease has invited Professor Shanhong Tang’s team from the Department of Gastroenterology at Western Theater Command General Hospital to create the “Liver Difficult Cases” column. This column compiles “classic cases” encountered by Professor Tang’s team over years of clinical practice and treatment, and will also regularly collect complex or rare clinical cases published in renowned academic journals, emphasizing the diagnostic and therapeutic approaches for various liver diseases, providing valuable clinical references for peers.

Topic Review

This article reports a case of “extensive portal venous system thrombosis” after four months of working in a high-altitude area (4500 meters) from a low-altitude area, with acute abdominal pain as the main symptom. Through various examinations, it was considered that high-altitude polycythemia led to blood viscosity, resulting in extensive portal vein thrombosis. By reviewing the literature, this case explores another cause of thrombophilia – high-altitude polycythemia, aiming to analyze the causes of thrombophilia and discuss anticoagulant therapy.

Case Summary

The patient, a 34-year-old male, began working in a high-altitude area (4500 meters) in July 2020, and after four months, developed abdominal distension and discomfort without obvious inducement. The abdominal pain worsened after eating, localized on both sides of the upper abdomen, was continuous with intermittent relief. The local hospital administered 654-2 intramuscularly for symptomatic support, but the symptoms did not significantly improve. On December 2, 2021, a CT scan at the local hospital indicated extensive portal vein thrombosis involving the main portal vein, left and middle branches, splenic vein, and superior mesenteric vein. After fasting, anti-infection, and low molecular weight heparin anticoagulation treatment, the patient’s pain slightly improved. After remote consultation with a higher-level hospital, he was transferred to the higher-level hospital on December 3, 2021.

Upon admission, an enhanced abdominal CT revealed extensive thrombosis involving the main portal vein, left and right branches, superior and inferior mesenteric veins, and splenic vein. During hospitalization, under local anesthesia, the patient underwent indirect portography, portal vein balloon dilation, and catheter-directed thrombolysis. Postoperatively, he was treated with dalteparin sodium injection and urokinase (800,000 units/day) for anticoagulation. The patient’s abdominal pain gradually alleviated, and a follow-up angiography showed smooth blood flow in the portal vein. The catheter and sheath were removed, and anticoagulation and circulation improvement therapy continued postoperatively. The patient was discharged on long-term rivaroxaban (20 mg once daily) for anticoagulation.

The patient began follow-up visits at our hospital on February 10, 2022. On August 10, 2022, a 320-slice CT portal vein angiography showed poor filling of the right upper branch of the portal vein, with a strip of low-density shadow in the corresponding area, multiple tortuous vascular shadows in the gastric fundus and hepatic hilum, and a slightly enlarged spleen. During follow-up, coagulation and blood routine indicators showed that hemoglobin (ranging from 170-178 g/L) and red blood cells (ranging from 5.61-5.92×10^12/L) were at the upper limit of the normal range, but coagulation parameters (PT, APTT, TT, and D-dimer) were not significantly abnormal. D-dimer: 0.06 mg/L, fibrinogen degradation products: 0.3 mg/L. In September 2022, due to slow healing of a hand injury, the patient consulted a doctor and adjusted the medication to rivaroxaban 10 mg once daily.

In January 2023, the patient was admitted to our department for “extensive portal vein thrombosis detected for 1 year” and underwent polypectomy. Physical examination upon admission: clear consciousness, normal complexion, no jaundice of the skin and sclera, no spider nevi or palmar erythema, soft abdomen, no abdominal varices, no tenderness, rebound tenderness, or muscle rigidity, and no palpable liver or spleen below the ribs. Other physical signs were unremarkable. Complete blood count: WBC: 6.66 x10^9/L, RBC: 5.78 x10^12/L, Hb: 172 g/L, Hct: 52.5%, PLT: 204 x10^9/L; D-dimer: 0.06 mg/L, PT: 13 s, PT activity: 70%, INR: 1.13, fibrinogen: 2.33 g/L, APTT: 30 s, TT: 17.6 s, AT-III: 103.2 g/L, FDP: 0.3 mg/L. Gastroscopy at our hospital revealed 2 varicose veins in the gastric fundus, with one extending to the upper bend of the gastric body, the thickest diameter being 0.4 cm, RC-. A 320-slice abdominal CT showed poor filling of the right upper branch of the portal vein with a strip of low-density shadow in the corresponding area, suggesting a possible thrombus, with no significant change compared to previous findings. The left branch of the portal vein was not clearly visible, with multiple tortuous vascular shadows in the gastric fundus and hepatic hilum, liver calcification, and a slightly enlarged spleen. Non-invasive liver fibrosis assessment showed: FibroScan 9.1 kPa (not reaching the threshold for liver cirrhosis). The patient underwent endoscopic polypectomy without gastrointestinal bleeding or discomfort and was discharged.

From January to June 2023, the patient regularly followed up at our outpatient clinic, taking rivaroxaban 10 mg once daily. On June 21, 2023, a follow-up gastroscopy revealed 3 exposed veins in the lower esophagus, linear in shape, with a diameter of about 0.2 cm. The gastric fundus had 2 varicose veins, one extending to the upper bend of the gastric body, the thickest diameter being 0.4 cm, RC-. Blood test results showed D-dimer: 0.06 mg/L, and fibrinogen degradation products increased from the previous 0.3 mg/L to 0.8 mg/L. Considering the patient’s worsening esophageal and gastric varices and to reduce the risk of portal vein thrombosis and complications, the medication was adjusted to rivaroxaban 10 mg twice daily. During follow-up after the medication adjustment, coagulation and blood routine indicators showed that hemoglobin (ranging from 170-178 g/L) and red blood cells (ranging from 5.61-5.92×10^12/L) remained at the upper limit of the normal range, with no significant abnormalities in coagulation parameters (D-dimer, PT, APTT, TT).

Case Discussion

Thrombophilia is a pathological condition where the body is prone to thrombosis and thromboembolism, caused by various genetic or acquired factors. Genetic thrombophilia primarily includes defects in anticoagulant proteins like antithrombin deficiency, defects in coagulation factors like activated protein C resistance (due to Factor V Leiden mutation), fibrinolytic protein defects like dysfibrinogenemia, metabolic defects like hyperhomocysteinemia (MTHFR mutation), and elevated levels of coagulation factors such as Factor VIII, IX, or XI. Clinically common acquired thrombophilia includes antiphospholipid syndrome, neoplastic diseases, myeloproliferative disorders (MPD), paroxysmal nocturnal hemoglobinuria, and localized inflammatory conditions such as pancreatitis, diverticulitis, and cholecystitis. Other risk factors include high altitudes and liver cirrhosis, with idiopathic portal vein thrombosis accounting for 10-30% of cases. Genetic thrombophilia is mainly due to abnormalities in procoagulant and anticoagulant protein genes, and there is no cure currently; treatment focuses on thrombosis management. Acquired thrombophilia is mainly due to diseases or environmental factors causing hypercoagulability, endothelial damage, or reduced blood flow.

The patient experienced acute abdominal pain three months after starting work in a high-altitude area (4500 meters). The patient had no other systemic symptoms, no history of myeloproliferative tumors, liver cirrhosis, or pancreatitis, temporarily excluding genetic and disease-induced acquired thrombophilia. Reviewing the patient’s high-altitude living history, it was considered that the hypoxic environment caused changes in blood composition. In a high-altitude environment, the oxygen content in the air decreases, putting the body in a hypoxic state. To compensate for the hypoxia, the body increases erythropoietin (EPO) production, leading to an increase in red blood cells and blood viscosity, resulting in thrombosis. The increase in red blood cells and blood viscosity is a trigger for thrombophilia. The causes of increased red blood cells can be divided into primary polycythemia and secondary polycythemia caused by other factors (such as high-altitude polycythemia).

Primary polycythemia is a relatively indolent myeloproliferative disorder caused by genetic abnormalities leading to clonal proliferation of red blood cells, bone marrow, and megakaryocyte lineages. This results in increased blood viscosity and elevated peripheral hematocrit, often accompanied by an increase in white blood cells and platelets, splenomegaly, and complications such as thrombosis and bleeding during the disease course. Thrombosis is the most common complication of primary polycythemia and is the main cause of morbidity and mortality.

Preventing and treating thrombosis is crucial in the management of primary polycythemia. Patients with thrombosis have a higher risk of venous and arterial thrombotic events, with a lifetime incidence of 20-30%. There are also reports of portal vein thrombosis leading to portal hypertension in patients with primary polycythemia without liver cirrhosis. High-altitude polycythemia, on the other hand, is mainly caused by hypoxia leading to a decrease in the oxygen-carrying capacity of red blood cells, resulting in compensatory increases in erythropoietin. This leads to an increase in red blood cells and blood viscosity, causing thrombosis in the brain, lungs, lower extremities, and mesentery. When the hypoxic environment is removed, erythropoietin levels gradually decrease, and red blood cell levels return to normal over time. Although both conditions aim to prevent initial or recurrent thrombosis, their pathological mechanisms and nature differ, leading to different treatment focuses and plans. Therefore, in clinical practice, it is essential to identify the underlying cause of increased red blood cells.

Case Discussion

Thrombophilia is a pathological state where the body is prone to thrombus formation and thromboembolism, caused by various genetic or acquired factors. Genetic thrombophilia primarily includes defects in anticoagulant proteins (e.g., antithrombin deficiency), defects in coagulation factors (e.g., activated protein C resistance due to Factor V Leiden mutation), fibrinolytic protein defects (e.g., dysfibrinogenemia), metabolic defects (e.g., hyperhomocysteinemia due to MTHFR mutation), and elevated levels of coagulation factors (e.g., Factor VIII, IX, or XI). Common acquired thrombophilic conditions include antiphospholipid syndrome, neoplastic diseases, myeloproliferative disorders (MPD), paroxysmal nocturnal hemoglobinuria, and localized inflammatory conditions such as pancreatitis, diverticulitis, and cholecystitis. Other risk factors include high altitudes and liver cirrhosis, with idiopathic portal vein thrombosis accounting for 10-30% of cases. Genetic thrombophilia is mainly due to abnormalities in procoagulant and anticoagulant protein genes, and there is no cure currently; treatment focuses on thrombosis management. Acquired thrombophilia is mainly due to diseases or environmental factors causing hypercoagulability, endothelial damage, or reduced blood flow.

The patient had been living in a plain area and developed acute abdominal pain (an acute phase symptom of mesenteric vein thrombosis) four months after moving to a high-altitude area (4500 meters). The patient’s exposure to the hypoxic environment was relatively short compared to people who permanently reside at high altitudes. Furthermore, the patient had already left the high-altitude environment after becoming ill, which differs from permanent high-altitude residents whose environment and dietary habits increase blood viscosity and thrombotic risk. Research has shown that symptoms of high-altitude polycythemia gradually disappear when patients return to low-altitude areas, but the condition may recur if they return to high altitudes. In this reported case, the patient had left the high-altitude area, reducing the risk of recurrence. Although literature reports that hemoglobin levels can return to normal after returning to low altitudes, with an average recovery time of 11-15 months and the shortest being 1 month, this patient’s hemoglobin levels remained at 170-178 g/L after returning to the plains. Studies have found that for men, hemoglobin levels >160 g/L or <120 g/L are risk factors for thrombosis.

Patients who develop thrombophilia after moving from plains to high altitudes have different physiological changes compared to long-term high-altitude residents. Their dietary habits and the fact that Tibetan residents predominantly consume high-calorie, high-fat foods result in generally higher blood viscosity and more significant endothelial cell damage. The risk of venous thrombosis during hospitalization is significantly higher in Tibetan populations compared to Han populations, leading to slower recovery and higher risks of related complications. Therefore, clinical management should pay attention to the unique characteristics of patients moving from plains to high altitudes.

The patient was diagnosed with acute abdominal pain caused by multiple portal vein thrombosis leading to intestinal ischemia at the local upper-level hospital. The prognosis of chronic non-cirrhotic portal vein thrombosis depends on the underlying cause of the portal vein thrombosis, and the prognosis is generally good. However, studies have found that the most common symptom is bleeding from gastroesophageal varices, which presents a risk of bleeding and the progression of thrombosis, complicating the choice of anticoagulant therapy.

Current EASL guidelines and the Baveno VI consensus statement support indefinite anticoagulation for chronic PVT patients after preventing gastrointestinal bleeding, based on underlying thrombotic risk and history of thrombotic events. For the treatment of acquired thrombophilia, guidelines recommend anticoagulation therapy while actively treating the primary disease and removing or correcting the underlying cause. Decisions on whether to extend or use lifelong anticoagulant therapy require a thorough assessment of the patient’s risk of thrombosis recurrence and potential for bleeding, weighing the risks and benefits.

For the thrombosis in this patient, thrombolytic interventional therapy was performed. Thrombosis leads to roughening of the vascular walls, and blood flowing through these rough surfaces can easily form new thrombi. To prevent recurrent thrombosis, long-term anticoagulant therapy was administered to balance coagulation and anticoagulation. Studies have shown that in 13 clinical cases of mesenteric thrombosis in high-altitude areas, all surviving patients continued to take enteric-coated aspirin and warfarin after discharge. Follow-up CT scans after six months did not detect thrombi. Patients who stopped warfarin and continued to take enteric-coated aspirin long-term had no recurrence signs after two years of follow-up. Additionally, during the patient’s anticoagulant treatment, the wound healing was slow. To balance the risk of recurrent thrombosis and bleeding, rivaroxaban was adjusted from 20 mg/day to 10 mg/day. However, during regular follow-up after dose reduction, the patient’s complications from portal vein thrombosis, such as gastroesophageal varices, worsened, and fibrinogen degradation products increased from 0.3 mg/L to 0.8 mg/L. Therefore, rivaroxaban was adjusted to 10 mg twice daily, and follow-up continued to monitor related indicators.

This patient moved from the plains to a high-altitude area, primarily presenting with “acute abdominal pain.” After the onset of illness, the patient left the high-altitude environment and returned to the plains. The patient underwent portal vein balloon dilation and catheter-directed thrombolysis to treat the thrombosis. After addressing the acute thrombosis symptoms, preventing recurrent thrombosis became a key part of the treatment. The latest thrombophilia guidelines recommend a multidisciplinary evaluation to determine the type, dosage, administration route, and duration of anticoagulant therapy based on the patient’s thrombophilia cause, age, sex, comorbidities, and compliance, exploring individualized prevention and treatment plans.

In conclusion, selecting the duration and dosage of anticoagulant therapy for patients in this special population requires clinicians to have extensive experience in diagnosing and treating thrombophilia. It also requires understanding the patient’s individual characteristics, regularly monitoring relevant indicators, and considering whether the underlying cause has been removed and whether the living environment has changed, to develop a more reasonable individualized medication plan.

Author:.

Meijuan Chen, Master’s candidate, Resident Physician, General Hospital of Western Theater Command

Author:

Chunyan Li, Graduate student, Department of Gastroenterology, General Hospital of Western Theater Command, currently pursuing a Master’s degree at Chengdu University of Traditional Chinese Medicine, mainly engaged in clinical research of liver diseases.

Reviewer:

Shanhong Tang, Director, Department of Gastroenterology, General Hospital of Western Theater Command

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