Bhavin Patel, Aneesh Pakala, Willard Aronson, Hany Magharyous, And Brent Brown 2014-07-30 04:55:46
Pulmonary arterial hypertension: A clot in question. ABSTRACT Pulmonary arterial hypertension (PAH) is a group of disorders characterized by a progressive increase in pulmonary vascular resistance leading to right heart failure and premature death.We present an unusual case of PAH diagnosed initially as Idiopathic PAH (IPAH) after secondary causes were excluded which was successfully managed for a number of years with vasodilators and anticoagulation. Over the months after stopping anticoagulation (because of recurring small bowel hemorrhaging) patient developed progressive findings of right heart failure, which failed to respond to escalating doses of prostacyclin. The patient died and an autopsy revealed the surprising finding of extensive organized central pulmonary artery thrombi as is seen in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We discuss the question of whether these thrombi are generally embolic or develop in situ and recommend that clinicians have a high index of suspicion for central thrombi in patients with IPAH were anticoagulation is contraindicated. Key Words: Pulmonary hypertension, Idiopathic pulmonary arterial hypertension, Chronic thrombo-embolic pulmonary hypertension, venous thrombo-embolism Conflict of Interest and Support: None Short Title: Pulmonary arterial hypertension INTRODUCTION Pulmonary Arterial Hypertension (PAH) consists of a group of disorders characterized by progressive increase in pulmonary vascular resistance leading to right heart failure and premature death. Idiopathic pulmonary arterial hypertension (IPAH) is a diagnosis of exclusion including sporadic cases as well as familial cases with or without the identifiable gene mutation (BMPR-2, ALK-1).1 IPAH commonly presents with progressive dyspnea on exertion and reduced exercise tolerance. Without treatment the syndrome carries a poor prognosis; however, advances in medical management in the past two decades including vasodilators and anticoagulation have resulted in improved survival.2-5 We present an unusual case of IPAH successfully managed for many years with vasodilators and anticoagulation who deteriorated and died of right heart failure after anticoagulation was discontinued. An autopsy revealed the surprising finding of central pulmonary artery thrombi, but the absence of evidence of deep vein thrombosis. The potential pathophysiologic mechanisms of the formation of central pulmonary thrombi in patients with PAH will be discussed as the difficulty in the clinical distinction between IPA H and chronic thromboembolic pulmonary hypertension (CTEPH). We will additionally discuss diagnostic modalities that might be employed to monitor for the development of central pulmonary artery thrombi in patients with PAH. CASE REPORT A 63-year-old Caucasian male presented with a several year history of progressive shortness of breath, reduced exercise tolerance, and lower leg swelling. There was no history of significant obstructive lung disease, interstitial lung disease, connective tissue disease, liver disease, HIV infection, or left heart failure. On physical examination the patient had a parasternal heave, a loud second heart sound, scant bibasilar crackles, jugular venous distention, and pitting edema of the feet and lower legs. A transthoracic echocardiogram revealed right atrial and ventricular dilation, severe tricuspid regurgitation, an estimated pulmonary arterial systolic pressure of 75 mm Hg, normal LV function and no evidence of aortic or mitral valve disease. Pulmonary function testing showed mild chest restriction, no Airways obstruction, and a reduced DLCO.A high-resolution CT scan of the chest reveals no evidence of significant parenchymal disease. Cardiac catheterization revealed a mean pulmonary pressure of 50 mm Hg, a PA systolic pressure of 77 mm Hg, a left ventricular ejection fraction of 45% in the normal left ventricular end-diastolic pressure. A pulmonary angiogram revealed a dilated pulmonary trunk with significant pruning of the pulmonary vasculature and no evidence of central or peripheral thrombi. A diagnosis of IPAH was made in the patient was started on Epoprostenol via Hickman catheter with escalating doses every six weeks throughout the duration of his life.Warfarin was initiated and an INR of 2-2.5 maintained. The patient was placed on Bosentan with the clinical improvement but the drug was discontinued after the development of abnormal liver function tests. Sildenafil was used for several Months but discontinued due the patient’s belief that it resulted in anorexia. Ambrisentan was initiated but discontinued after several months at the request to the patient due to a lack of clinical improvement. The patient remained clinically stable with NYHA class III symptoms for nine years when he developed recurring bouts of upper gastrointestinal bleeding.Upper and lower GI endoscopy was negative and a small bowel source was suspected. Warfarin was discontinued and over the next 24 months the patient developed progressive symptoms of Right heart failure and worsened exercise tolerance in spite of the continued escalations in his Epoprostenol dosage. At autopsy the expected findings of massive right ventricular and atrial dilation, and hepatic congestion were noted. No gastrointestinal pathology was discovered. There was the surprise finding of large organized intramural central thrombi (figure 1) in the massively dilated pulmonary artery trunk. There was no evidence of acute or previous deep vein thrombosis apparent. Pathology of IPAH: Common pathological findings of IPAH include intimal hyperplasia and fibrosis, fibrinoid necrosis, medial hyperplasia and thickening of the vessel wall.2 Plexiform lesions are characteristic of severe PAH but are not specific for IPAH.3 Prostaglandin I2 and Nitric oxide are endogenous vasodilators and inhibitors of platelet aggregation synthesized and released by the vascular endothelium of the pulmonary artery. Their synthesis is decreased in patients with PAH including IPAH.5,6 Thrombomodulin is an anticoagulant factor produced by the endothelium and its production is decreased in IPAH (thought to be secondary to an increased level of Interleukin (IL) 1 and 6).6 Thrombomodulin has a high affinity receptor for thrombin preventing thrombin from cleaving fibrinogen and from activation of platelets. Thrombomodulin additionally activates protein C, a potent anticoagulant. Reduced production of thrombomodulin in IPAH results in a pro-thrombotic state in patients with pulmonary hypertension.6 Recent studies have shown an increased level of IL-1 and 6 along with a decreased level of thrombomodulin in IPAH.7,8 Activated platelets also play a role in the pathogenesis of IPAH And other forms of PAH. Studies have revealed increased levels of plasminogen activator inhibitor type 1(PAI-1) in IPAH suggesting that fibrinolytic mechanisms are suboptimal in these individuals further predisposing them to thrombosis.5,6,9 Diagnosis of IPAH: Pulmonary angiography is a cornerstone in detecting intravascular occlusion and webbing the in pulmonary artery, which are characteristic features of CTEPH. The advantages of this modality are that it provides a surgical road map for pulmonary endarterectomy in CTEPH and concomitant vasoreactive testing for treatment of IPAH can be performed.10 Ventilationperfusion (V/Q) scanning can reliably exclude clinically significant thrombo-embolic processes and thus differentiate between CTEPH and IPAH by revealing segmental or larger perfusion defect in CTEPH and normal or finding of “mottling” perfusion in IPAH. A further advantage of V/Q scanning is that it does not involve the administration of contrast dye.11,12 Non-invasive studies like multi slice computed tomographic angiography (CTA) and high resolution computed tomography (HRCT) are newer modalities for evaluating PAH. Features suggestive of IPAH on HRCT are uniform involvement of small muscular arteries, mediastinal adenopathy and a nodular ground glass pattern.2,12 In contrast, the characteristic lesion in CTEPH is a patchy occlusion of the larger generation of pulmonary arteries causing a mosaic pattern of lung attenuation.2,12 Thus, an advantage of CTA over conventional angiography is that it is non-invasive, safer, and can provide information about other causes of PAH including venooclusive disease and capillary hemangiomatosis.12 In a patient with IPAH, V/Q scanning may not reveal any segmental or larger defects even when organized thrombi are present in larger generation pulmonary arteries.13 We suggest performing non-invasive studies like CT angiography in patients with suspected IPAH at the time of initial diagnosis and in presence of clinical deterioration. If such thrombi are found on initial work up, then a formal pulmonary angiography and right heart catheterization should be considered to determine the hemodynamic significance of such thrombi to distinguish between IPAH and CTEPH.13 In patients with an established diagnosis of IPAH who experience clinical deterioration, The discovery of central pulmonary artery thrombi on CT angiography might represent venous thrombo-embolism (VTE) or the formation of in-situ thrombi.13 In such situations VTE should be excluded by diagnostic testing. In the absence of large, systemic studies we cannot comment on the how frequently patients with IPAH develop “in-situ” thrombi or VTE or how frequently these thrombi worsen pulmonary artery hemodynamics and right heart failure.13 Management of IPAH: Epoprostenol, a prostacyclin analogue, not only has a vasodilatory effect but also inhibits platelet aggregation and thus prolongs survival in IPAH.5 Long-term anticoagulation also prolongs survival in patients with PAH, including IPAH.3-5 Medical management is preferred in case of IPAH. Whereas, pulmonary end arterectomy (PEA) is first line of treatment for patients with CTEPH. Medical therapy can be used for patients with CTEPH as bridging therapy before surgery, in patients with inoperable and distal smaller pulmonary arterial thrombi, or in cases, which do not respond to pulmonary endarterectomy.5,10 DISCUSSION IPAH is rare disorder and a diagnosis of exclusion. In our case CTEPH was initially excluded by pulmonary angiography which is considered to be definitive in differentiating CTEPH and IPAH.3,12 However, on autopsy we were surprised to find extensive central intramural thrombi generally consistent with a diagnosis of CTEPH.11 Small vessel in-situ thrombosis is a well-known pathologic finding in IPAH [(Kumar Robbins and Cotran Pathologic Basis of Diseases. (8th Ed.) 2009. Saunders, an imprint of Elsevier]. However, there are only a few case reports showing probable in-situ thrombosis involving the central pulmonary arteries in patients with IPAH.2,13 It’s very important to differentiate the phenomenon of extensive small vessel thrombosis from the chronic thrombo-embolic process found in CTEPH, as the management of these two clinical entities is different.2,13 In our patient anticoagulation had to be discontinued about 18 month prior to his death due to gastrointestinal bleeding. We speculate he developed “in-situ” thrombi of his main pulmonary arteries, which resulted in his worsened right heart failure and death. He had no clinical evidence of VTE in life or at autopsy. It is unknown if central thrombi seen in IPAH are in-situ or embolic in origin but previously published case reports have suggested “in-situ” thrombosis and in our case we share this view. 2,10 In a retrospective study involving 120 patients with IPAH which excluded patients with deep vein thrombosis or clinical thrombo-embolic episodes, 56 patients underwent an autopsy, of which 32(59%) patients had some evidence of thrombo-emboli. Of these 32 patients, 22 had thrombi involving pulmonary muscular arteries alone and 10 had thrombi involving both pulmonary muscular and pulmonary elastic arteries.3,4 It’s not possible to determine the origin of these thrombi as histopathology and imaging studies cannot differentiate between in-situ thrombosis and the chronic thrombo-embolic process of CTEPH.3 CONCLUSION There is significant overlap in the diagnostic imaging and clinical features of IPAH and CTEPH, and some patients might suffer from both maladies. Some clinicians are of the opinion that IPAH and CTEPH represent the same disease spectrum with IPAH on one extreme of the spectrum and CTEPH on other.5 Findings also exist that some patients with IPAH may develop in-situ thrombi in large pulmonary arteries which are of no hemodynamic significance, unlike patients who suffer from true CTEPH.10 With advancements in medical therapy, patients with IPAH are surviving longer and are at risk for VTE and/or developing in-situ central pulmonary thrombi over the course of their disease. We emphasize the need for anticoagulation in patients with IPAH and postulate that clinical decline in our patient was likely related to the cessation of warfarin required due to serious GI bleeding. We believe that physicians should consider screening for thrombo-embolic complications in IPAH who are not anticoagulated and experience unexplained declines in clinical status. However, several questions remain unanswered requiring further study: 1) How frequently do patients with IPAH develop central pulmonary artery thrombi? 2) What proportion of these thrombi is in-situ origin versus thrombo-embolic in origin? 3) Is there any difference in the incidence of in-situ thrombi in patients who cannot be anticoagulated? 4) Are such central pulmonary thrombi in patients with IPAH always of hemodynamic significance? We recommend prospective observational studies be conducted where the incidence of central pulmonary thrombi could be established by a routine, annual non-invasive screening method such CT/MR angiogram in patients with IPAH. The incidence of deep vein thrombosis in IPAH also needs to be determined by serial duplex ultrasonography to determine the origin of central thrombi. The incidence of such complications needs to be compared in patients with IPAH who cannot be anticoagulated (due to contraindication) to appropriately matched controls of anticoagulated patients with IPAH. Until further studies have been completed clinician should maintain heightened suspicion for central thrombi leading to deterioration of clinical status in patients with IPAH who cannot be anticoagulated. REFERENCES 1. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology. Jun 30 2009;54(1 Suppl):S43-54. 2. Agarwal PP, Wolfsohn AL, Matzinger FR, Seely JM, Peterson RA, Dennie C. In situ central pulmonary artery thrombosis in primary pulmonary hypertension. Acta Radiol. Nov 2005;46(7):696-700. 3. Weir EK, Archer SL, Edwards JE. Chronic primary and secondary thromboembolic pulmonary hypertension. Chest. Mar 1988;93(3 Suppl):149S-154S. 4. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. Oct 1984;70(4):580-587. 5. Peacock A, Simonneau G, Rubin L. Controversies, uncertainties and future research on the treatment of chronic thromboembolic pulmonary hypertension. Proceedings of the American Thoracic Society. Sep 2006;3(7):608-614. 6. Chaouat A, Weitzenblum E, Higenbottam T. The role of thrombosis in severe pulmonary hypertension. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. Feb 1996;9(2):356-363. 7. Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. American journal of respiratory and critical care medicine. May 1995;151(5):1628-1631. 8. Welsh CH MR, Hassell KL. Coagulation activation, fibrinolysis and severity of pulmonary hypertension. American journal of respiratory and critical care medicine. 1994;149:A746. 9. Eisenberg PR, Lucore C, Kaufman L, Sobel BE, Jaffe AS, Rich S. Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension.Circulation. Sep 1990;82(3):841-847. 10. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines.Chest. Jun 2007;131(6):1917-1928. 11. Auger WR, Kim NH, Kerr KM, Test VJ, Fedullo PF. Chronic thromboembolic pulmonary hypertension. Clin Chest Med.Mar 2007;28(1):255-269, x. 12. Coulden R. State-of-the-art imaging techniques in chronic thromboembolic pulmonary hypertension. Proceedings of the American Thoracic Society. Sep 2006;3(7):577-583. 13. Moser KM, Fedullo PF, Finkbeiner WE, Golden J. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation. Feb 1 1995;91(3):741-745.
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