Haemoptysis: Comparison
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Pulmonary arterial hypertension (PAH) is a rare, heterogeneous disease of the pulmonary vasculature, haemodynamically defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg, a normal pulmonary artery wedge pressure ≤15 mmHg and elevated pulmonary vascular resistance ≥3 Wood units. Congenital heart disease (CHD) is frequently complicated by PAH, including four individual groups with shared features; Eisenmenger syndrome (ES), congenital systemic to pulmonary shunts, PAH associated with coincidental or small defects, and PAH encountered in patients with repaired congenital defects.  

Spontaneous bleeding events are common in PAH-CHD and usually minor and self-limiting (e.g., dental bleeding, epistaxis, easy bruising, menorrhagia). Haemoptysis is one of the most perilous major bleeding manifestations in the clinical course of PAH-CHD and can be life-threatening. 

  • haemoptysis
  • congenital heart disease

1. Introduction

Pulmonary arterial hypertension (PAH) is a rare, heterogeneous disease of the pulmonary vasculature, haemodynamically defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg, a normal pulmonary artery wedge pressure ≤15 mmHg and elevated pulmonary vascular resistance ≥3 Wood units [1]. Congenital heart disease (CHD) is frequently complicated by PAH, including four individual groups with shared features; Eisenmenger syndrome (ES), congenital systemic to pulmonary shunts, PAH associated with coincidental or small defects, and PAH encountered in patients with repaired congenital defects [2]. Although the use of PAH targeted pharmacotherapy has substantially improved functional capacity and survival in these patients over the last years, the morbidity burden remains high, affecting their quality of life and posing an impact on healthcare systems globally[3][4].
Spontaneous bleeding events are common in PAH-CHD and usually minor and self-limiting (e.g., dental bleeding, epistaxis, easy bruising, menorrhagia). Haemoptysis is one of the most perilous major bleeding manifestations in the clinical course of PAH-CHD and can be life-threatening. Its incidence is estimated as 3.1% to 5.5% [5][6] in PAH-CHD patients, whereas it is markedly elevated in patients with ES, accounting for 6% to 49% of cases[7][8][9][10][11][12]. Although it is an alarming symptom for patients and physicians, haemoptysis seems to be a relatively infrequent cause of death, accounting only for 3% of deaths in a recent international, multi-centre, retrospective study of patients with ES [13][12]. Haemoptysis requires instant management and constitutes a major clinical diagnostic and therapeutic challenge. Technological advances of modern medicine led to the application of bronchial artery embolization (BAE), a minimally invasive technique for managing massive and recurrent haemoptysis[13][14][15] , raising hopes for relapse prevention [1615]. 

2. Pathophysiology of Haemoptysis

The underlying pathophysiology of haemoptysis in PAH-CHD remains intricate and involves various, complex mechanisms (Figure 1). Obliterative remodeling of the pulmonary vascular bed, pulmonary microvascular changes, endothelial damage, vasoconstriction and thrombosis have been correlated with the progression of PAH [16][17][18][19][20].
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Figure 1. Pathophysiology of haemoptysis in patients with PAH-CHD. CHD: Congenital heart disease, PAH: Pulmonary arterial hypertension, PA: Pulmonary artery.
All these processes lead to a vulnerable pulmonary vascular substrate in PAH-CHD, in which episodes of haemoptysis may occur, especially after shunt reversal and the establishment of fixed pulmonary vascular disease. Robust data about the exact mechanisms of haemoptysis are lacking. The erosion of hypertrophied bronchial arteries into a bronchus has been described as a possible explanation, but the reason for this bronchial arterial hypertrophy remains unidentified [2120]. The high-pressure bronchial circulation is the primary source of bleeding in the majority of massive haemoptysis cases (90%) [2221]. Nonetheless, not all cases of haemoptysis can be attributed to eroded bronchial arteries. In approximately 5% of the cases, bleeding originates from the pulmonary vessels [22][23][24]. Existing pulmonary artery (PA) dissection or aneurysm are vulnerable to rupture, in the setting of increased PAP in PAH, and, in several cases, they have been associated with haemoptysis [2120][2524]. Furthermore, dilation or angiomatoid lesions of the pulmonary arteriolar wall are frequently encountered in patients with PAH-CHD (mainly with large post-tricuspid shunts) due to the presence of pulmonary vascular obstructive disease, and have been related to haemoptysis [2120].
Furthermore, the release of angiogenic growth factors, triggered by the inflammatory response in PAH-CHD, induces neoangiogenesis and the development of bronchial and non-bronchial systemic collateral circulation [1413][25][26][27]. Systemic aortopulmonary collateral vessels may emerge from the subclavian, intercostal, thoracic branches of the axillary artery, internal mammary arteries and infradiaphragmatic branches from the inferior phrenic, left gastric, and celiac axis [1413]. These newly formed collaterals are displayed to high systemic arterial pressures and therefore are sensitive to dilation and rupture, increasing the risk of haemoptysis[1413][2625].
The pulmonary arteries account for 99% of the arterial blood supply to the lungs and take part in gas exchange, while the bronchial arteries provide nourishment to the supporting structures of the airways. The bronchial vasculature is in close proximity to the pulmonary arteries at the level of the vasa vasorum where the two systems are connected by thin-walled anastomoses between the systemic and pulmonary capillaries. These anastomoses may open up in regions of the lung that are deprived of pulmonary arterial blood flow due to pulmonary vascular obstructive disorders in the setting of PAH-CHD. Consequently, these fragile vessels are subjected to increased systemic arterial pressure and can lead to haemoptysis by rupturing into the alveoli or bronchial airways [27][28][29]. Finally, in a minority of cases (5%), massive haemoptysis may arise from the aorta (aortobronchial fistula, ruptured aortic aneurysm) or the nonbronchial systemic circulation [2221].
Abnormalities of the hemostatic mechanisms in patients with ES could also explain the hemorrhagic diathesis in these patients. Hemostatic abnormalities are attributed both to platelet disorders (thrombocytopenia and thrombasthenia) and abnormalities in coagulation pathways (overactivation), while increased hematocrit has been correlated with impaired fibrinogen function [29][30][31][32]. Vitamin K-dependent clotting factors (prothrombin, factors VII and IX) and factor V are reduced due to hypoxic induced impaired liver synthesis, fibrinolytic activity is increased, and the largest von Willebrand multimers are depleted [3029]. Additionally, right-to-left shunting in ES delivers megakaryocytes into the systematic circulation, bypassing the lungs where megakaryocytic cytoplasm is normally fragmented into platelets, and thus is associated with thrombocytopenia [3332]. Furthermore, prostanoid use has been associated with the inhibition of platelet function that could trigger haemoptysis [3433]. Recently, another prospective open-label study of riociguat in patients with PAH reported haemoptysis in 2.5% of patients (n = 8). Of the six patients with serious hemoptysis, three were receiving concomitant anticoagulants, two were receiving a concomitant prostanoid, and one was receiving concomitant antiplatelet therapy[3534]. Therefore, the role of PAH targeted therapies in triggering haemoptysis and the underlying mechanisms have yet to be proved.
On the other hand, patients with PAH-CHD are at increased risk for thromboembolic events that could equally contribute to the occurrence of haemoptysis. Thrombosis is associated with blood stasis in dilated heart chambers and pulmonary arteries, atherosclerosis and/or endothelial dysfunction, atrial arrhythmias and the presence of thrombogenic material (e.g., conduits). Laminated thrombi in large, partially calcified and aneurysmal pulmonary arteries are common, may occur in up to 30% of patients with ES [10], and have been associated with pulmonary infarction that could be related with massive haemoptysis as pointed out in the Paul Wood series [3635].
Acute lower respiratory tract infections could be an additional aggravating factor in patients with PAH-CHD. Inflammation of the tracheobronchial tree renders airways congested, friable, and therefore susceptible to bleeding. Chronic respiratory tract infections lead to an increase in systemic arterial flow via formation of new vessels, which in turn are prone to rupture and cause haemoptysis [2827].
 

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  35. Hossein-Ardeschir Ghofrani; Miguel-Angel Gomez Sanchez; Marc Humbert; David Pittrow; Gérald Simonneau; Henning Gall; Ekkehard Grünig; Hans Klose; Michael Halank; David Langleben; et al.Repke J. SnijderPilar Escribano SubiasLisa M. MielniczukTobias J. LangeJean-Luc VachiéryHubert WirtzDouglas S. HelmersenIraklis TsangarisJoan A. BarberáJoanna Pepke-ZabaAnco BoonstraStephan RosenkranzSilvia UlrichRegina Steringer-MascherbauerMarion DelcroixPavel JansaIveta ŠimkováGeorge GiannakoulasJens KlotscheEvgenia WilliamsChristian MeierMarius M. HoeperJorge CanevaGraciela TuhayMirta DiezMaria Lujan TalaveraAdriana AcostaNorberto VulcanoMartin BosioLorena MaldonadoSabino DeleoLuciano MelatiniAnne KeoghEugene KotlyarJohn FeenstraNathan DwyerHeath AdamsWendy StevensPeter SteeleSusanna ProudmanRobert MinsonGlenn ReevesMelanie LavenderBenjamin NgMichele MackenzieLisa BarryMargarethe GruenbergerCharlotte HuberIrene LangIoana TileaRoela Sadushi-KoliciJudith Löffler-RaggLisa-Theresa FeistmantlPatrick EvrardRenaud LouisJulien GuiotMarco NaldiMichel De PauwSanjay MehtaRafael Conde CamachoPatricia Parada TovarAlejandro LondoñoFelipe CampoPaula GarciaCamila LemaMauricio Orozco-LeviWilliam MartinezJuan Esteban GomezJens Erik Nielsen-KudskSoren MellemkjaerLy AntonAlan AltrajaTapani VihinenTuija VasankariOlivier SitbonVincent CottinLaurent TêtuElise Noël-SavinaNicole ShearmanSusanne TaylerIlona OlzikChristine KulkaJan GrimmingerMarcel SimonAnna NoldeTim OquekaLars HarbaumBenjamin EgenlaufRalf EwertChristian SchulzSabine RegottaTilmann KramerSusanne Knoop-BuschFelix GerhardtStavros KonstantinidesGeorgia PitsiouIoannis StanopoulosEvdokia SourlaSofia MouratoglouHaralambos KarvounisAthanasios PappasDimitrios GeorgopoulosMichail FanaridisIoanna MitrouskaLampros MichalisKonstantinos PappasAnna KotsiaSean GaineCarmine Dario VizzaGiovanna ManziRoberto PosciaRoberto BadagliaccaPiergiuseppe AgostoniNoemi BrunoStefania FarinaMichele D'AltoPaola ArgientoAnna CorreraGiovanni Maria Di MarcoChiara CresciVieri VannucchiElena TorricelliAlessio GarceaAlberto PesciLuca SardellaGiuseppe PacioccoFederico PaneAndrea Maria D'ArminiMaurizio PinValentina GrazioliGiulia MassolaAntonio SciortinoRenato PredilettoCarolina BauleoEdoardo AiròRudina NdreuIvana PavlickovaClaudio LunardiMassimiliano MulèSilvia FarruggioSerena CostaGiuseppe GalganoMario PetruzziAnna De LucaFrancesco LombardiLoris RonconLuca ConteClaudio PicarielloGil WirtzMyriam AlexandreA. Vonk-NoordegraafH. BoogaardJ. MagerH. ReesinkLeon M. Van Den ToornKarin BoomarsArne K. AndreassenGraça CastroGonçalves TaniaRui BaptistaAntónio MarinhoTeresa ShiangAna OliveiraDaniel CoutinhoJoana SousaMaria José LoureiroDébora RepolhoSusana Maria Martins JesusMarta CapinhaJoão AgostinhoTania CardosoAndreia RochaMafalda EspinhaKyundyul Ivanovich IvanovDalyana Eduardovna AlexeevaMarina Vadimovna BatalinaDaria Viktorovna HegyaTatyana Nikolaevna ZverevaSergey Nikolaevich AvdeevNatalia Anatolievna TsarevaAlbert Sarvatovich GalyavichBykov Aleksander NikolaevichEvgeny Vladimirovich FilippovOlga Eduardovna YakovlevaOlga Borisovna PavlovaElena Sergeevna SkripkinaTamila Vitalievna MartynyukIrina Fedorovna BukatovaAnna Viktorovna TregubovaDmitry Yurievich PlatonovTatyana Mikhaylovna KolomeytsevaAbdullah Al DalaanAbeer Abeer AbdelsayedIhab WehebaSarferaz SaleemiHussam SakkijhaMarcela BohacekovaTatiana ValkovicovaIveta FarkasovaCarlos Andres QuezadaLucilla PiccariIsabel BlancoLaura SebastianAntonio RomanManuel LopezRemedios OteroTeresa EliasLuis JaraIsabel AsencioJosefa Jiménez ArjonaRaúl Menor AlmagroSalvador López CárdenasSalvador Alcaraz GarcíaPatricia Villanueva RodríguezRaquel LopezAlberto GarciaFrancisco Fernandez AvilésSebastian De La PavaRaquel YottiGregorio Pérez PeñateFernando León MarreroJosé Manuel Cifrián MartínezAmaya Martinez-MeñacaLecue Pilar AlonsoSonia Fernandez RozasDavid Iturbe FernandezVictor Mora CuestaStefan SöderbergSven-Erik BartfayBengt RundqvistMonthir AlfetlawiPeter WodlinEsther Irene SchwarzRudolf SpeichFrédéric LadorThierry RochatPaola Gasche-SoccalChih-Hsin HsuTsung-Hsien LinHo-Ming SuWen-Ter LaiChun Yuan ChuPo-Chao HsuWen-Chol VoonHsueh-Wei YenJacob Yih-Jer WuShu-Hao WuWen-Pin HuangMan-Cai FongChien-Lung HuangPing-Hung KuoYen-Hung LinJiunn-Lee LinChi-Sheng HungCho-Kai WuShih-Hsien SungWei-Chun HuangChin-Chang ChengShu-Hung KuoWen-Hwa WangWan-Jing HoTsu-Shiu HsuBülent MutluHalil AtasGul OngenZeynep UnGulfer OkumusIsmail HantaPaul CorrisAndrew PeacockColin ChurchMark ToshnerMichael Newnham Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry. RPaul Wood; The eisenmenger syndrome: Or pulmonary hypertension week reversed central shunt. The Amespriratory Medicine can Journal of Cardiology 1972020, 178, 106220, 10.1016/j.rmed.2020.106220., 30, 172-174, 10.1016/0002-9149(72)90203-2.
  36. Paul Wood; The eisenmenger syndrome: Or pulmonary hypertension week reversed central shunt. The American Journal of Cardiology 1972, 30, 172-174, 10.1016/0002-9149(72)90203-2.
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