Chronic Thromboembolic Pulmonary Hypertension — Not So Rare after All
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《新英格兰医药杂志》
Chronic thromboembolic pulmonary hypertension (CTPH) is believed to result from single or recurrent pulmonary thromboemboli arising from sites of venous thrombosis. The occurrence of CTPH after a diagnosis of acute pulmonary embolism has been considered to be rare. A recent article in the Journal estimated that CTPH occurs in 0.1 to 0.5 percent of cases of acute, nonfatal pulmonary thromboemboli.1 The natural history of pulmonary thromboemboli includes total resolution or resolution with minimal residua and restoration of normal pulmonary hemodynamics within 30 days in more than 90 percent of patients. Repeated catheterization after acute pulmonary embolism has led to the observation that right heart pressures return to near-normal values in most patients within 10 to 21 days. However, echocardiographic data have indicated that more patients than previously reported have persistent pulmonary hypertension after an acute pulmonary embolism. In this issue of the Journal, Pengo et al. (pages 2257–2264) report that the cumulative incidence of CTPH was 3.8 percent in a careful, prospective, multicenter, cohort study with a median observation period of almost eight years.
The initial thromboembolic event is asymptomatic in most patients with CTPH.1 For example, 90 of 142 consecutive patients (63 percent) who were followed at my institution did not have symptomatic venous thromboembolism (unpublished data). Therefore, the true incidence of CTPH may be even higher than that in the cohort of patients with symptomatic venous thromboembolism who were studied by Pengo et al. In patients with CTPH, thromboemboli do not resolve, but rather form endothelialized, fibrotic obstructions of the pulmonary vascular bed, including the major branches. After a period of months to years, during which the patient has no clinical symptoms, dyspnea on exertion develops. The clinical deterioration parallels the loss of right ventricular functional capacity.
CTPH does not share such important characteristics of venous thromboembolism as the traditional risk factors involving the coagulation system1 or systematic evidence of deep venous thrombosis, which has led to the speculation that CTPH is not a thromboembolic disease. In fact, there is a striking difference in macroscopical appearance between the thromboembolic material removed during pulmonary thromboendarterectomy and the acute pulmonary emboli retrieved during a Trendelenburg's embolectomy (see Figure). CTPH thrombi comprise mostly whitish, organized tissues that are tightly attached to the pulmonary arterial medial layer, replacing the normal intima. In contrast, pulmonary emboli are red, fragile thrombi that adhere loosely to the pulmonary arterial wall. Therefore, a critical question is why thrombi persist in patients with CTPH.
Figure 1. Pulmonary Thromboendarterectomy Specimen and Acute Pulmonary Thromboembolus.
Panel A shows a whitish-yellow, fibrotic, organized thromboembolus with a thin layer of proximal red appositions, which formed a cast of the pulmonary arterial tree in a patient with CTPH. Image courtesy of Dr. Walter Klepetko. By way of contrast, Panel B shows fresh red thrombi that were recovered from a patient with acute pulmonary embolism.
Extensive analyses of plasma proteins in patients with CTPH have shown no abnormalities of fibrinolysis. Lupus anticoagulant may be detected in approximately 10 percent of such patients,1 and 20 percent carry anticardiolipin antibodies, lupus anticoagulant, or both. A recent study2 has demonstrated that the plasma level of factor VIII, a protein that is associated with both primary and recurrent venous thromboembolism, is elevated in 39 percent of patients with CTPH.
Case reports have suggested links between chronic thromboembolism and previous splenectomy, permanent intravenous catheters, and ventriculoatrial shunts for the treatment of hydrocephalus or chronic inflammatory conditions. In addition to these observations, associations with rare combined coagulation defects, sickle cell disease, hereditary stomatocytosis, and the Klippel–Trénaunay syndrome have been described. The majority of the cases of CTPH in the study by Pengo et al. resulted from idiopathic venous thromboembolism. Because neither elevated plasma factor VIII levels nor any of the medical conditions listed above are traditionally considered to be risk factors for CTPH, some patients in the study who were categorized as having idiopathic venous thromboembolism may have had these risk factors.
An analysis of primary endothelial cells cultured from the pulmonary arteries of patients with CTPH revealed no abnormalities in the expression of fibrinolytic proteins or in the response to thrombin stimulation. However, distinct local gene-expression patterns in the thrombi that are associated with this condition differ from those seen in acute pulmonary emboli and suggest that in situ thrombosis within the vascularized fibromuscular obstructions may favor the persistence of thrombi.3 The pathogenesis of CTPH is still unclear, but it is widely accepted that the disease is not caused by thromboembolic obliteration alone. Vascular remodeling due to a variety of factors, such as shear stress, pressure, inflammation, and the release of cytokines and vasculotrophic mediators, is involved in the development of a pulmonary vasculopathy that is indistinguishable from the pulmonary vascular lesions found in conjunction with any other kind of pulmonary hypertension. Evidence is lacking that CTPH occurs in a familial pattern. To date, no mutations of the gene for familial pulmonary hypertension, which encodes bone morphogenetic protein receptor II, have been reported in patients with CTPH.
Making an accurate diagnosis of CTPH requires collaboration among experienced cardiologists, pulmonary physicians, radiologists, cardiothoracic surgeons, and intensive care physicians. There are about 20 CTPH centers worldwide, and the University of San Diego has extensive surgical experience, having treated about 2000 patients surgically. The surgical treatment of CTPH was proposed as early as four decades ago.4 Pulmonary thromboendarterectomy is a classic bilateral endarterectomy in which the thrombus and the adjacent medial layer are carefully dissected with dedicated surgical instruments.5 The procedure is the treatment of choice for CTPH, resulting in an improvement in symptoms that is unprecedented with any other treatment for pulmonary hypertension, including vasodilators, lung transplantation, balloon atrial septostomy, and balloon pulmonary angioplasty. The selection of patients for surgery depends on the extent and location of the thrombus in relation to the degree of pulmonary hypertension.
The data presented by Pengo et al. reinforce the thromboembolic nature of CTPH and show that the disorder is clearly more common than was previously thought. Because CTPH is associated with high morbidity and mortality, the recognition of patients who are at risk has become an important goal.
Source Information
From the Division of Cardiology, Medical University of Vienna, Vienna.
References
Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465-1472.
Bonderman D, Turecek PL, Jakowitsch J, et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2003;90:372-376.
Lang IM, Marsh JJ, Olman MA, Moser KM, Loskutoff DJ, Schleef RR. Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation 1994;89:2715-2721.
Moser KM, Houk VN, Jones RC, Hufnagel CC. Chronic, massive thrombotic obstruction of the pulmonary arteries: analysis of four operated cases. Circulation 1965;32:377-385.
Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457-1464.(Irene M. Lang, M.D.)
The initial thromboembolic event is asymptomatic in most patients with CTPH.1 For example, 90 of 142 consecutive patients (63 percent) who were followed at my institution did not have symptomatic venous thromboembolism (unpublished data). Therefore, the true incidence of CTPH may be even higher than that in the cohort of patients with symptomatic venous thromboembolism who were studied by Pengo et al. In patients with CTPH, thromboemboli do not resolve, but rather form endothelialized, fibrotic obstructions of the pulmonary vascular bed, including the major branches. After a period of months to years, during which the patient has no clinical symptoms, dyspnea on exertion develops. The clinical deterioration parallels the loss of right ventricular functional capacity.
CTPH does not share such important characteristics of venous thromboembolism as the traditional risk factors involving the coagulation system1 or systematic evidence of deep venous thrombosis, which has led to the speculation that CTPH is not a thromboembolic disease. In fact, there is a striking difference in macroscopical appearance between the thromboembolic material removed during pulmonary thromboendarterectomy and the acute pulmonary emboli retrieved during a Trendelenburg's embolectomy (see Figure). CTPH thrombi comprise mostly whitish, organized tissues that are tightly attached to the pulmonary arterial medial layer, replacing the normal intima. In contrast, pulmonary emboli are red, fragile thrombi that adhere loosely to the pulmonary arterial wall. Therefore, a critical question is why thrombi persist in patients with CTPH.
Figure 1. Pulmonary Thromboendarterectomy Specimen and Acute Pulmonary Thromboembolus.
Panel A shows a whitish-yellow, fibrotic, organized thromboembolus with a thin layer of proximal red appositions, which formed a cast of the pulmonary arterial tree in a patient with CTPH. Image courtesy of Dr. Walter Klepetko. By way of contrast, Panel B shows fresh red thrombi that were recovered from a patient with acute pulmonary embolism.
Extensive analyses of plasma proteins in patients with CTPH have shown no abnormalities of fibrinolysis. Lupus anticoagulant may be detected in approximately 10 percent of such patients,1 and 20 percent carry anticardiolipin antibodies, lupus anticoagulant, or both. A recent study2 has demonstrated that the plasma level of factor VIII, a protein that is associated with both primary and recurrent venous thromboembolism, is elevated in 39 percent of patients with CTPH.
Case reports have suggested links between chronic thromboembolism and previous splenectomy, permanent intravenous catheters, and ventriculoatrial shunts for the treatment of hydrocephalus or chronic inflammatory conditions. In addition to these observations, associations with rare combined coagulation defects, sickle cell disease, hereditary stomatocytosis, and the Klippel–Trénaunay syndrome have been described. The majority of the cases of CTPH in the study by Pengo et al. resulted from idiopathic venous thromboembolism. Because neither elevated plasma factor VIII levels nor any of the medical conditions listed above are traditionally considered to be risk factors for CTPH, some patients in the study who were categorized as having idiopathic venous thromboembolism may have had these risk factors.
An analysis of primary endothelial cells cultured from the pulmonary arteries of patients with CTPH revealed no abnormalities in the expression of fibrinolytic proteins or in the response to thrombin stimulation. However, distinct local gene-expression patterns in the thrombi that are associated with this condition differ from those seen in acute pulmonary emboli and suggest that in situ thrombosis within the vascularized fibromuscular obstructions may favor the persistence of thrombi.3 The pathogenesis of CTPH is still unclear, but it is widely accepted that the disease is not caused by thromboembolic obliteration alone. Vascular remodeling due to a variety of factors, such as shear stress, pressure, inflammation, and the release of cytokines and vasculotrophic mediators, is involved in the development of a pulmonary vasculopathy that is indistinguishable from the pulmonary vascular lesions found in conjunction with any other kind of pulmonary hypertension. Evidence is lacking that CTPH occurs in a familial pattern. To date, no mutations of the gene for familial pulmonary hypertension, which encodes bone morphogenetic protein receptor II, have been reported in patients with CTPH.
Making an accurate diagnosis of CTPH requires collaboration among experienced cardiologists, pulmonary physicians, radiologists, cardiothoracic surgeons, and intensive care physicians. There are about 20 CTPH centers worldwide, and the University of San Diego has extensive surgical experience, having treated about 2000 patients surgically. The surgical treatment of CTPH was proposed as early as four decades ago.4 Pulmonary thromboendarterectomy is a classic bilateral endarterectomy in which the thrombus and the adjacent medial layer are carefully dissected with dedicated surgical instruments.5 The procedure is the treatment of choice for CTPH, resulting in an improvement in symptoms that is unprecedented with any other treatment for pulmonary hypertension, including vasodilators, lung transplantation, balloon atrial septostomy, and balloon pulmonary angioplasty. The selection of patients for surgery depends on the extent and location of the thrombus in relation to the degree of pulmonary hypertension.
The data presented by Pengo et al. reinforce the thromboembolic nature of CTPH and show that the disorder is clearly more common than was previously thought. Because CTPH is associated with high morbidity and mortality, the recognition of patients who are at risk has become an important goal.
Source Information
From the Division of Cardiology, Medical University of Vienna, Vienna.
References
Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465-1472.
Bonderman D, Turecek PL, Jakowitsch J, et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2003;90:372-376.
Lang IM, Marsh JJ, Olman MA, Moser KM, Loskutoff DJ, Schleef RR. Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation 1994;89:2715-2721.
Moser KM, Houk VN, Jones RC, Hufnagel CC. Chronic, massive thrombotic obstruction of the pulmonary arteries: analysis of four operated cases. Circulation 1965;32:377-385.
Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457-1464.(Irene M. Lang, M.D.)