Haemoptysis: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Amalia Baroutidou.

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 [12][13]. 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[1314][1415] , raising hopes for relapse prevention [1516]. 

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].
Jcm 11 00633 g001 550
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 [2021]. The high-pressure bronchial circulation is the primary source of bleeding in the majority of massive haemoptysis cases (90%) [2122]. 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 [2223][2324]. 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 [2021][2425]. 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 [2021].
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 [1314][2526][2627]. 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 [1314]. These newly formed collaterals are displayed to high systemic arterial pressures and therefore are sensitive to dilation and rupture, increasing the risk of haemoptysis[1314][2526].
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 [2728][2829]. Finally, in a minority of cases (5%), massive haemoptysis may arise from the aorta (aortobronchial fistula, ruptured aortic aneurysm) or the nonbronchial systemic circulation [2122].
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 [2930]. 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 [3233]. Furthermore, prostanoid use has been associated with the inhibition of platelet function that could trigger haemoptysis [3334]. 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[3435]. 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 [3536].
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 [2728].
 

References

  1. Gérald Simonneau; David Montani; David Celermajer; Christopher P. Denton; Michael A. Gatzoulis; Michael Krowka; Paul G. Williams; Rogerio Souza; Haemodynamic definitions and updated clinical classification of pulmonary hypertension. European Respiratory Journal 2019, 53, 1801913, 10.1183/13993003.01913-2018.
  2. Nazzareno Galiè; Marc Humbert; Jean-Luc Vachiery; Simon D J Gibbs; Irene Lang; Adam Torbicki; Gérald Simonneau; Andrew Peacock; Anton Vonk Noordegraaf; Maurice Beghetti; et al.Ardeschir GhofraniMiguel Angel Gomez SanchezGeorg HansmannWalter KlepetkoPatrizio LancellottiMarco MatucciTheresa McDonaghLuc A. PierardPedro T. TrindadeMaurizio ZompatoriMarius HoeperVictor AboyansAntonio Vaz CarneiroStephan AchenbachStefan AgewallYannick AllanoreRiccardo AsteggianoLuigi BadanoJoan Albert BarberáHélène BouvaistHector BuenoRobert ByrneScipione CarerjGraça CastroCetin ErolVolkmar FalkChristian Funck-BrentanoMatthias GorenfloJohn GrantonBernard IungDavid G KielyPaulus KirchhofBarbro KjellstromUlf LandmesserJohn LekakisChristos LionisGregory Y H LipStylianos E OrfanosMyung H ParkMassimo F PiepoliPiotr PonikowskiMarie-Pierre RevelDavid RigauStephan RosenkranzHeinz VöllerJose Luis ZamoranoLina BadimonGonzalo Barón-EsquiviasHelmut BaumgartnerJeroen J BaxVeronica DeanDonna FitzsimonsOliver GaemperliPhilippe KolhPetros NihoyannopoulosMarco RoffiStephan WindeckerSokol MyftiuDiana BondermanIbrahimov FirdovsiIrina LazarevaMichel De PauwŠekib SokolovicVasil VelchevMaja CikešJosef Antoniou MoutirisPavel JansaJens Erik Nielsen-KudskLy AntonPertti JääskeläinenFabrice BauerArchil ChukhrukidzeChristian OpitzGeorge GiannakoulasKristóf KarlócaiHjörtur OddssonSean GaineDoron MenachemiMichele EmdinTalant SooronbaevTalant Ainars RudzitisLina GumbieneFrederic LebrunJosef MicallefVictor BotnaruLatifa OukerrajArne K AndreassenMarcin KurzynaMaria João Ribeiro Leite BaptistaIoan Mircea ComanOlga MoiseevaBranislav S StefanovicIveta ŠimkováGerhard WikströmMarkus SchwerzmannElizabeta Srbinovska-KostovskaArie P J Van DijkAbdallah MahdhaouiCihangir KaymazGerry CoghlanYuriy Sirenko 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal 2015, 37, 67-119, 10.1093/eurheartj/ehv317.
  3. Alexandra Arvanitaki; George Giannakoulas; Helmut Baumgartner; Astrid Elisabeth Lammers; Eisenmenger syndrome: diagnosis, prognosis and clinical management. Heart 2020, 106, 1638-1645, 10.1136/heartjnl-2020-316665.
  4. Alexandra Arvanitaki; Despoina Ntiloudi; George Giannakoulas; Konstantinos Dimopoulos; Prediction Models and Scores in Adult Congenital Heart Disease. Current Pharmaceutical Design 2021, 27, 1232-1244, 10.2174/1381612827999210111181554.
  5. Mark Schuuring; Annelieke C.M.J. van Riel; Jeroen C. Vis; Marielle G. Duffels; Arie van Dijk; Rianne H.A.C.M. de Bruin-Bon; Aeilko H. Zwinderman; Barbara J.M. Mulder; Berto Bouma; New predictors of mortality in adults with congenital heart disease and pulmonary hypertension: Midterm outcome of a prospective study. International Journal of Cardiology 2014, 181, 270-276, 10.1016/j.ijcard.2014.11.222.
  6. Despoina Ntiloudi; Sotiria Apostolopoulou; Konstantinos Vasiliadis; Alexandra Frogoudaki; Aphrodite Tzifa; Christos Ntellos; Styliani Brili; Athanasios Manginas; Antonios Pitsis; Marios Kolios; et al.Haralambos KarvounisCostas TsioufisJohn GoudevenosSpyridon RammosGeorge Giannakoulas Hospitalisations for heart failure predict mortality in pulmonary hypertension related to congenital heart disease. Heart 2018, 105, 465-469, 10.1136/heartjnl-2018-313613.
  7. Arabinda Saha; K.G. Balakrishnan; Pramod K. Jaiswal; C.G. Venkitachalam; Jaganmohan Tharakan; Thomas Titus; Raman Kutty; Prognosis for patients with Eisenmenger syndrome of various aetiology. International Journal of Cardiology 1994, 45, 199-207, 10.1016/0167-5273(94)90166-x.
  8. L. Daliento; J. Somerville; P. Presbitero; L. Menti; S. Brach-Prever; G. Rizzoli; S. Stone; Eisenmenger syndrome. Factors relating to deterioration and death. European Heart Journal 1998, 19, 1845-1855, 10.1053/euhj.1998.1046.
  9. Warren J Cantor; David A Harrison; Jack S Moussadji; Michael S Connelly; Gary D Webb; Peter Liu; Peter R McLaughlin; Samuel C Siu; Determinants of survival and length of survival in adults with Eisenmenger syndrome. The American Journal of Cardiology 1999, 84, 677-681, 10.1016/s0002-9149(99)00415-4.
  10. Craig S. Broberg; Masuo Ujita; Sanjay Prasad; Wei Li; Michael Rubens; Bridget E. Bax; Simon J. Davidson; Beatriz Bouzas; J. Simon R. Gibbs; John Burman; et al.Michael A. Gatzoulis Pulmonary Arterial Thrombosis in Eisenmenger Syndrome Is Associated With Biventricular Dysfunction and Decreased Pulmonary Flow Velocity. Journal of the American College of Cardiology 2007, 50, 634-642, 10.1016/j.jacc.2007.04.056.
  11. Sebastien Hascoet; Emmanuelle Fournier; Xavier Jais; Lauriane Le Gloan; Claire Dauphin; Ali Houeijeh; Francois Godart; Xavier Iriart; Adelaïde Richard; Jelena Radojevic; et al.Pascal AmedroGilles BosserNathalie SouletieYvette BernardPamela MoceriHélène BouvaistPierre MauranElise BarreAdeline BasquinClement KarsentyDamien BonnetLaurence IserinOlivier SitbonJérôme PetitElie FadelMarc HumbertMagalie Ladouceur Outcome of adults with Eisenmenger syndrome treated with drugs specific to pulmonary arterial hypertension: A French multicentre study. Archives of Cardiovascular Diseases 2017, 110, 303-316, 10.1016/j.acvd.2017.01.006.
  12. Cristel M. Sørensen Hjortshøj; Aleksander Kempny; Annette Jensen; Keld Sørensen; Edit Nagy; Mikael Dellborg; Bengt Johansson; Virginija Rudiene; Gu Hong; Alexander R. Opotowsky; et al.Werner BudtsBarbara J. MulderLidia Tomkiewicz-PająkMichele D'AltoKatja ProkšeljGerhard-Paul DillerKonstantinos DimopoulosMette-Elise EstensenHenrik HolmstrømMaila TuranlahtiUlf ThilénMichael A. GatzoulisLars Søndergaard Past and current cause-specific mortality in Eisenmenger syndrome. European Heart Journal 2017, 38, 2060-2067, 10.1093/eurheartj/ehx201.
  13. Joo-Young Chun; Robert Morgan; Anna-Maria Belli; Radiological Management of Hemoptysis: A Comprehensive Review of Diagnostic Imaging and Bronchial Arterial Embolization. CardioVascular and Interventional Radiology 2010, 33, 240-250, 10.1007/s00270-009-9788-z.Hjortshoj, R.M.S.; Kcempny, A.; Jensen, A.S.; Sorensen, K.; Nagy, E.; Dellborg, M.; Johansson, B.; Rudiene, V.; Hong, G.; Opotowsky, A.R.; et al. Past and Current Cause-Specific Mortality in Eisenmenger Syndrome. Eur. Heart J. 2017, 38, 2060–2067.
  14. Lisa M. Tom; Harold I. Palevsky; Douglas S. Holsclaw; Scott O. Trerotola; Mandeep Dagli; Jeffrey I. Mondschein; S. William Stavropoulos; Michael C. Soulen; Timothy W.I. Clark; Recurrent Bleeding, Survival, and Longitudinal Pulmonary Function following Bronchial Artery Embolization for Hemoptysis in a U.S. Adult Population. JouJoo-Young Chun; Robert Morgan; Anna-Maria Belli; Radiological Management of Hemoptysis: A Comprehensive Review of Diagnostic Imaging and Bronchial Arterial Embolization. Carnal diof Vascular and Interventional Radiology 2015, 26, 1806-1813.e1, 10.1016/j.jvir.2015.08.019.0, 33, 240-250, 10.1007/s00270-009-9788-z.
  15. Bo Ram Lee; Jin Yeong Yu; Hee Jung Ban; In-Jae Oh; Kyu Sik Kim; Yong Soo Kwon; Yu Il Kim; Young Chul Kim; Sung Chul Lim; Analysis of Patients with Hemoptysis in a Tertiary Referral Hospital. TLisa M. Tom; Harold I. Palevsky; Douglas S. Holsclaw; Scott O. Trerotola; Mandeep Dagli; Jeffrey I. Mondschein; S. William Stavropoulos; Michael C. Soulen; Timothy W.I. Clark; Recurrent Bleeding, Survival, and Longitudinal Pulmonary Function following Bronchial Artery Embolization for Hemoptysis in a U.S. Adult Population. Jouberculosis and Respiratory Diseases nal of Vascular and Interventional Radiology 2012, 73, 107-114, 10.4046/trd.2012.73.2.107.5, 26, 1806-1813.e1, 10.1016/j.jvir.2015.08.019.
  16. Marlene Rabinovitch; Pulmonary hypertension: pathophysiology as a basis for clinical decision making. Bo Ram Lee; Jin Yeong Yu; Hee Jung Ban; In-Jae Oh; Kyu Sik Kim; Yong Soo Kwon; Yu Il Kim; Young Chul Kim; Sung Chul Lim; Analysis of Patients with Hemoptysis in a Tertiary Referral Hospital. Thube Journal of Heart and Lung Transplantation rculosis and Respiratory Diseases 201999, 18, 1041-1053, 10.1016/s1053-2498(99)00015-7.2, 73, 107-114, 10.4046/trd.2012.73.2.107.
  17. Gerhard-Paul Diller; Michael A. Gatzoulis; Pulmonary Vascular Disease in Adults With Congenital Heart Disease. CiMarlene Rabinovitch; Pulmonary hypertension: pathophysiology as a basis for clinical decision making. The Journal of Hearct and Lulatng Transplantation 2007, 1999, 115, 1039-1050, 10.1161/circulationaha.105.592386.8, 1041-1053, 10.1016/s1053-2498(99)00015-7.
  18. C. A. Wagenvoort; Vasoconstriction and Medial Hypertrophy in Pulmonary Hypertension. Gerhard-Paul Diller; Michael A. Gatzoulis; Pulmonary Vascular Disease in Adults With Congenital Heart Disease. Circulation 196 200, 22, 535-546, 10.1161/01.cir.22.4.535.7, 115, 1039-1050, 10.1161/circulationaha.105.592386.
  19. Sheila G Haworth; PULMONARY HYPERTENSION IN THE YOUNG. HeC. A. Wagenvoort; Vasoconstriction and Medial Hypertrophy in Pulmonary Hypertension. Circulart 2ion 196002, 88, 658-664, 10.1136/heart.88.6.658., 22, 535-546, 10.1161/01.cir.22.4.535.
  20. Lulu M. Haroutunian; Catherine A. Neill; Pulmonary complications of congenital heart disease: Hemoptysis. American Sheila G Haworth; PULMONARY HYPERTENSION IN THE YOUNG. Heart Journal 197 2002, , 884, 540-559, 10.1016/0002-8703(72)90479-6., 658-664, 10.1136/heart.88.6.658.
  21. Remy, J.; Remy‐Jardin, M.; Voisin, C.; Endovascular management of bronchial bleeding.. LuLulu M. Haroutunian; Catherine A. Neill; Pulmonary complications of congenital heart disease: Hemoptysis. Americang Biol. Health Dis. Heart Journal 19972, 57, 667–723., 84, 540-559, 10.1016/0002-8703(72)90479-6.
  22. J Remy; L Lemaitre; J J Lafitte; M O Vilain; J Saint Michel; F Steenhouwer; Massive hemoptysis of pulmonary arterial origin: diagnosis and treatment. AmericaRemy, J.; Remy‐Jardin, M.; Voisin, C.; Endovascular management of bronchial bleeding.. Lung Journal of Roentgenology Biol. Health Dis. 19984, 143, 963-969, 10.2214/ajr.143.5.963.2, 57, 667–723.
  23. Khalil, A.; Parrot, A.; Nedelcu, C.; Fartoukh, M.; Marsault, C.; Carette, M.F.; Severe hemoptysis of pulmonary arterial origin: Signs and role of multidetector row CT angiography. ChJ Remy; L Lemaitre; J J Lafitte; M O Vilain; J Saint Michel; F Steenhouwer; Massive hemoptysis of pulmonary arterial origin: diagnosis and treatment. American Journal of Roesnt 200genology 198, 4, 1433, 212–219., 963-969, 10.2214/ajr.143.5.963.
  24. Darryl Tio; Edward Leter; Bart Boerrigter; Anco Boonstra; Anton Vonk-Noordegraaf; Harm Jan Bogaard; Risk Factors for Hemoptysis in Idiopathic and Hereditary Pulmonary Arterial Hypertension. PLOS ONE Khalil, A.; Parrot, A.; Nedelcu, C.; Fartoukh, M.; Marsault, C.; Carette, M.F.; Severe hemoptysis of pulmonary arterial origin: Signs and role of multidetector row CT angiography. Chest 2013, 8, e78132, 10.1371/journal.pone.0078132.08, 133, 212–219.
  25. T. J. Marshall; J. E. Jackson; Vascular intervention in the thorax: bronchial artery embolization for haemoptysis. Darryl Tio; Edward Leter; Bart Boerrigter; Anco Boonstra; Anton Vonk-Noordegraaf; Harm Jan Bogaard; Risk Factors for Hemoptysis in Idiopathic and Hereditary Pulmonary Arterial Hypertension. PLOS ONEuropean Radiology 201997, 7, 1221-1227, 10.1007/s003300050279.3, 8, e78132, 10.1371/journal.pone.0078132.
  26. Nald M. McDonald; Angiogenesis and Remodeling of Airway Vasculature in Chronic Inflammation. American JoT. J. Marshall; J. E. Jackson; Vascular intervention in the thorax: bronchial artery embolization for haemoptysis. Eurnal of Respiratory and Critical Care Medicine 200pean Radiology 1, 164, S39-S45, 10.1164/ajrccm.164.supplement_2.2106065.997, 7, 1221-1227, 10.1007/s003300050279.
  27. M E Deffebach; N B Charan; S Lakshminarayan; J Butler; The bronchial circulation. Small, but a vital attribute of the lung.. Nald M. McDonald; Angiogenesis and Remodeling of Airway Vasculature in Chronic Inflammation. American ReviewJournal of Respiratory Diseasand Critical Care Medicine 2001987, , 135, 463–481, 10.1164/arrd.1987.135.2.463.64, S39-S45, 10.1164/ajrccm.164.supplement_2.2106065.
  28. Pump, K.K.; The Bronchial Arteries and their Anastomoses in the Human Lung. JM E Deffebach; N B Charan; S Lakshminarayan; J Butler; The bronchial circulation. Small, but a vital attribute of the lung.. AMA merican Review of Respiratory Disease 1963, 87, 184, 225, 10.1001/jama.1963.03700140159103.35, 463–481, 10.1164/arrd.1987.135.2.463.
  29. P Henriksson; G Varendh; N R Lundstrom; Haemostatic defects in cyanotic congenital heart disease.. Heart Pump, K.K.; The Bronchial Arteries and their Anastomoses in the Human Lung. JAMA 1979, 63, 1841, 23-27, 10.1136/hrt.41.1.23., 225, 10.1001/jama.1963.03700140159103.
  30. Sarah K. Westbury; Kurtis Lee; Christopher Reilly-Stitt; Robert Tulloh; Andrew D. Mumford; High haematocrit in cyanotic congenital heart disease affects how fibrinogen activity is determined by rotational thromboelastometry. Thrombosis RP Henriksson; G Varendh; N R Lundstrom; Haemostatic defects in cyanotic congenital heart disease.. Hesearch 20t 13, 979, 4132, e145-e151, 10.1016/j.thromres.2013.07.006., 23-27, 10.1136/hrt.41.1.23.
  31. A.S. Jensen; P.I. Johansson; L. Bochsen; L. Idorn; K.E. Sørensen; U. Thilén; E. Nagy; E. Furenäs; L. Søndergaard; Fibrinogen function is impaired in whole blood from patients with cyanotic congenital heart disease. InteSarah K. Westbury; Kurtis Lee; Christopher Reilly-Stitt; Robert Tulloh; Andrew D. Mumford; High haematocrit in cyanotic congenital heart disease affects how fibrinogen activity is determined by rotational thromboelastometry. Thrnational Journal of Cardiology mbosis Research 2013, 167, 2210-2214, 10.1016/j.ijcard.2012.06.019.32, e145-e151, 10.1016/j.thromres.2013.07.006.
  32. Michael C. Lill; Joseph K. Perloff; John S. Child; Pathogenesis of Thrombocytopenia in Cyanotic Congenital Heart Disease. ThA.S. Jensen; P.I. Johansson; L. Bochsen; L. Idorn; K.E. Sørensen; U. Thilén; E. Nagy; E. Furenäs; L. Søndergaard; Fibrinogen function is impaired in whole blood from patients with cyanotic congenital heart disease. Inte Americannational Journal of Cardiology 2006, 98, 254-258, 10.1016/j.amjcard.2006.01.083.13, 167, 2210-2214, 10.1016/j.ijcard.2012.06.019.
  33. Barbara LeVarge; Prostanoid therapies in the management of pulmonary arterial hypertension. Michael C. Lill; Joseph K. Perloff; John S. Child; Pathogenesis of Thrombocytopenia in Cyanotic Congenital Heart Disease. The Amerapeutics and Clinical Risk Management ican Journal of Cardiology 20015, 11, 535-547, 10.2147/tcrm.s75122.6, 98, 254-258, 10.1016/j.amjcard.2006.01.083.
  34. 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. RBarbara LeVarge; Prostanoid therapies in the management of pulmonary arterial hypertension. Thespiratory Medicinpeutics and Clinical Risk Manage ment 2020, 15, 1178, 106220, 10.1016/j.rmed.2020.106220., 535-547, 10.2147/tcrm.s75122.
  35. Paul Wood; The eisenmenger syndrome: Or pulmonary hypertension week reversed central shunt. ThHossein-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. Re Amespirican Journal of Cardiology 197atory Medicine 202, 30, 172-174, 10.1016/0002-9149(72)90203-2.0, 178, 106220, 10.1016/j.rmed.2020.106220.
  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.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback