Chronic thromboembolic pulmonary hypertension implies prolonged narrowing or complete obstruction of pulmonary vessels, which is most likely due to a non-resolving thrombi in the setting of a previous pulmonary embolism. It is a rare entity in clinical practice, but more than 50% of patients suffering from this condition are asymptomatic. Imaging studies are required for diagnosis, whereas surgical removal of clots from occluded vessels is the mainstay of therapy.
In general, patients complain of progressive dyspnea, particularly on exertion, together with hemopstysis, fatigue, syncope, palpitations or edema (all signs of right heart failure) [3]. Schistosomiasis can have an acute and chronic course. A severe inflammatory reaction to the parasite that causes nocturnal fever, headaches, dyspnea and myalgia in the setting of acute disease (also known as Katayama syndrome), whereas an asthma-like disease is seen in chronic forms [4]. In both acute and chronic disease, pulmonary vascular disease and cor pulmonale (right heart failure) may develop and lead to CTEPH [4].
A thorough patient history may provide vital clues about the underlying cause, for e.g.recent travel to endemic areas for schistosomiasis and exposure to potentially contaminated waters approximately 2-12 weeks prior to the appearance of symptoms [4]. A meticulous physical examination with an emphasis on cardiopulmonary auscultation is equally important. Namely, distended neck veins, ascites, edema and tricuspid regurgitation may reflect right heart failure, whereas peripheral pulmonary bruits (very rare but highly specific for CTEPH) may be observed in approximately 10% of patients [3]. Imaging studies such as plain chest radiography may show enlarged pulmonary trunk, hypertrophy of the right ventricle and pleural effusions [4], which may be confirmed by echocardiography, a widely recommended procedure for CTEPH evaluation [3]. MRI and CT are also frequently used, but ventilation/perfusion (V/Q) lung scintigraphy may show segmental perfusion defects and for this reason, it is considered as the optimal diagnostic procedure [16]. Pulmonary angiography is equally effective in visualizing the level of obstruction and vessel narrowing [9]. In most patients CTEPH is distinguished from PAH by presence of thrombi in major pulmonary vessels, but virtually any part of the circulation may be affected [12]. Apart from their role in diagnosis, these procedures are important in evaluating the possibility of endarterectomy [9].
Several therapeutic strategies exist for management of CTEPH. Pulmonary endarterectomy is a surgical procedure that provides curative effects in many patients (since it enables complete removal of emboli from the occluded vessels) and is now considered as the mainstay of therapy [5]. But because of its characteristics (profound hypothermia, cardiopulmonary bypass and induced cardiac arrest), a mortality rate of 4.4% during surgery is observed [14]. Moreover, it may not be performed in all patients (presence of additional comorbidities, location of emboli in smaller vessels and poor overall condition). It may also be unsuccessful in patients with significant arteriopathy of smaller vessels, which is why alternative interventions are advocated. Anticoagulant therapy, prostanoids, endothelin receptor antagonists, or phosphodiesterase-5-inhibitors are pharmacological agents most frequently used in these patients, but their efficacy requires further research [17]. As a last resort, lung transplantation may be performed [17].
If CTEPH is left untreated, the estimated survival is about three years [1]. Moreover, the majority of patients are diagnosed in advanced stages of the disease [1], when little can be done in terms of treatment, which is why an early diagnosis is detrimental.
Several conditions have been associated with PAH in literature, including Schistosomiasis (caused by a nematode worm Schistosoma mansoni, S. hematobium or S.japonicum) [7], idiopathic pulmonary arterial hypertension (IPAH), anorexigen exposure and sleep apnea [1] [8]. In all diseases, CTEPH stems from occlusion of pulmonary vessels by thromboemboli that generate increased pressure and resistance. Pulmonary embolism (PE) is, in fact, the condition that predisposes patients to CTEPH, which may develop in any of the mentioned conditions through various pathophysiological mechanisms. However, why do these emboli persist after months or even years remains unclear. Current studies have determined that some patients possess clotting factor aberrations, but in the majority of patients, the exact mechanism is yet to be determined [9].
Studies have determined that CTEPH develops in approximately 4,000 individuals in the United States every year [1], whereas overall incidence rates after pulmonary embolism are up to 3%-4% after 2 years [2] [6]. PE is, by far, the most significant risk factor for CTEPH as approximately 50% of patients report acute pulmonary thromboembolism in their recent history [10]. Schistosomiasis is an infection affecting more than 200 million individuals over the world, but its prevalence is highest in developing countries and certain geographical areas [7]. The Caribbean countries, the eastern part of South America (Brazil), sub-Saharan Africa, China and the Middle east are considered to be endemic regions of this parasite and travel to these areas is considered as an important risk factor [4]. Approximately 8% of individuals suffering from this disease develop PAH [7], but other reports suggest that the prevalence of PAH is as high as 20% [4]. For unknown reasons, CTEPH is more frequently encountered in females [1]. An additional risk factor is the presence of lupus anticoagulant [11], an antibody against phospholipids that promotes coagulation [11], while splenectomy, ventriculoatrial shunts, inflammatory bowel disease and osteomyelitis have also been determined as conditions that increase the susceptibility toward CTEPH [12].
Although the exact model of disease in CTEPH is incompletely understood, current theories implicate various etiologic factors that impair the coagulatory cascade [13]. Numerous diseases have been described as potential triggers of pulmonary arterial hypertension, defined as mean pressure in the pulmonary artery ≥ 25 mmHg at rest or > 30 mmHg during exercise [1]. In virtually all patients, the predisposing condition that leads to CTEPH is pulmonary embolism, in which formation of a thrombus occludes pulmonary vessels and causes increased pressure. Usually, the thrombus dissolves completely, but in some individuals, this process is not carried out in full [14]. The exact mechanism remains unknown, but it is established that up to 10% of patients have some abnormality of the coagulation system, such as protein C or S deficiency and impairment of the fibrin clotting system [14]. Procoagulatory states in the setting of increased factor VIII values were identified as well [15]. Additionally, some patients develop repetitive pulmonary embolism, which further contributes to persistence of clots in the pulmonary vasculature [14]. In the setting of schistosomiasis, the life cycle of the parasite starts by shedding from the initial host (local population) through feces and urine into water, infection of various snail species and subsequent invasion of human hosts through breaks in the skin [4]. Once the parasite spreads through the lymphatic system and into the lungs, it replicates and disseminates throughout the gastrointestinal tract and the liver, eventually forming an embolus in many blood vessels, including pulmonary arteries [4]. Regardless of the pathophysiological mechanism, the end-result in CTEH is remodeling of the emboli that narrows or obstructs the major arteries of the pulmonary system, leading to dysfunction of the right ventricle and increased pulmonary vascular resistance, eventually causing cardiac insufficiency [10].
Although prevention of venous thromboembolism through management of the underlying disease may be a prudent strategy, studies have determined that more than 60% of CTEPH patients do not exhibit any symptoms suggestive of venous disease [6]. For this reason, wide-scale use of echocardiography may be highly effective as a tool for an early diagnosis, especially in the setting of known schistosomiasis infection [7]. Additionally, long-term monitoring and prophylaxis of patients who developed pulmonary embolism and increased awareness of possible CTEPH is detrimental for prevention [2].
Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as persistent pulmonary arterial hypertension (PAH) for three consecutive months after an episode of pulmonary thromboembolism [1]. Although CTEPH is a rarely encountered phenomenon in clinical practice, it is often unrecognized and associated with a substantial risk of mortality [2]. Numerous diseases are known to cause PAH and thus predispose to CTEPH, including schistosomiasis, sleep apnea, exposure to anorexigen (an appetite suppressant) and various collagenoses [1], whereas idiopathic pulmonary arterial hypertension (IPAH) is also an important cause. In the presence of these conditions, intraluminal organization of a thrombus and concomitant stenosis as a result of fibrous tissue accumulation leads to increased resistance in the pulmonary vasculature [3]. In an attempt to overcome this adverse circulatory event, the right ventricle enlarges and increases its contractile force, but because the vessel lumen is persistently narrowed or completely occluded, failure of the right heart eventually ensues [3]. Symptoms of CTEPH are progressive dyspnea, hemoptysis and right-heart failure signs such as fatigue, weakness and edema [3]. Additional complaints depend on the underlying cause. For e.g. schistosomiasis is manifested by nocturnal fever and malaise several weeks after exposure to contaminated waters in endemic areas (the Caribbean island, Brazil, China, the Middle east and sub-Saharan Africa) [4]. To make the diagnosis, a thorough approach consisting of a properly obtained patient history and a detailed physical examination is vital. Initial signs of heart failure (tricuspid regurgitation, distended neck veins, or ascites) are important clinical findings that can guide the physician toward the diagnosis [3], which is confirmed by various imaging studies. Plain radiography, echocardiography, computed tomography (CT), magnetic resonance imaging (MRI), lung scintigraphy and angiography are all indicated when CTEPH is suspected, to solidify the diagnosis and to determine the optimal therapeutic strategy.The procedure of choice (when possible) is pulmonary endarterectomy (PEA), comprising of surgical removal of emboli from pulmonary vessels. Despite a small, but significant risk of death during surgery (4.4%), this procedure has curative effects in the vast majority of patients and can profoundly improve the quality of life [5]. If CTEPH is left untreated, the disease is universally fatal within a few years, which is why an early diagnosis must be made. This may be difficult, however, as more than 60% of patients show no symptoms of previous thromboembolic disease [6], implying the necessity for more detailed regular check-ups and conduction of screening strategies.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition that develops due to narrowing and obstruction of blood vessels in the lungs, most commonly following pulmonary embolism (PE), where a blood clot gets "stuck" in one or more vessels. Because clots block the passage of blood, the heart generates higher pressures to overcome this obstacle, leading to increased pressure inside the blood vessels of the lungs, medically known as pulmonary hypertension (PAH). For yet unknown reasons, CTEPH develops months or even years after the initial episode of PE and factors that promote incomplete resolution of the clot are yet to be discovered. In addition to PE, conditions such as sleep apnea, schistosomiasis (a parasitic infection), exposure to anorexigen (a suppressant of appetite) and idiopathic pulmonary hypertension (IPAH) are known causes of CTEPH. It is estimated that approximately 4,000 cases develop in the United States every year and a strong predilection toward female gender was established. Risk factors that promote coagulatory states (and thus impair resolution of previously formed blood clots) include osteomyelitis, inflammatory bowel disease (IBD), presence of ventriculoatrial shunts and spleen removal. The diagnosis may be attained with great difficulty, as many patients report no obvious signs of thromboembolic disease. Progressive heavy breathing (dyspnea), coughing of blood (hemoptysis) and symptoms that reflect failure of the right side of the heart due to prolonged efforts to combat blood vessel occlusion, such as fatigue, malaise, palpitations and syncope are most frequently encountered. Imaging studies, including plain chest X-ray, computed tomography (CT scan), magnetic resonance imaging (MRI) and echocardiography are all useful in solidifying the diagnosis, but the two most important procedures are CT-guided angiography and lung scintigraphy, which allow direct visualization of blood flow through the lungs and identification of the exact site of occlusion. This is quite important, as the optimal therapeutic strategy is surgical removal of clots from the occluded arteries, known as pulmonary endarterectomy. Because this type of surgery mandates cessation of heart function and marked reduction of body temperature (as low as 20 degrees Celsius), a very small number of patients (around 4%) do not survive this procedure, but its efficacy that may even result in complete cure significantly outweighs the risks. An early diagnosis is essential for patients sufferning from CTEPH, primarily to obtain a much better prognosis, as the condition is fatal within a few years if left untreated.