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Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction

Abstract

Veno-occlusive disease is among the most serious complications following hematopoietic stem cell transplantation. While hepatic veno-occlusive disease occurs more commonly, the pulmonary variant remains quite rare and often goes unrecognized antemortem. Endothelial damage may represent the pathophysiologic foundation of these clinical syndromes. Recent advances in the treatment of hepatic veno-occlusive disease may have application to its pulmonary counterpart.

Introduction

In 1959, Thomas et al. first reported the successful application of bone marrow transplantation to treat advanced leukemia in a human subject.1 Since then, the field of hematopoietic stem cell transplantation (HSCT) has been revolutionized by advances in conditioning regimens and novel immunosuppressive therapies such that, today, HSCT is a viable treatment option for a wide array of malignant and nonmalignant conditions. Despite these advances, a number of toxicities associated with HSCT limit its more widespread use.2

Endothelial damage is an increasingly acknowledged feature of the complications associated with HSCT.2, 3, 4 Endothelial damage has been implicated in the pathogenesis of many common and clinically important complications of HSCT, including microangiopathic hemolytic anemia (MAHA), hepatic veno-occlusive disease (HVOD), acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS).3, 4, 5, 6, 7, 8, 9 Rather than specific disease entities, these complications may be viewed as a spectrum of post-HSCT toxicities that share a common pathophysiology of endothelial dysfunction.4

Pulmonary veno-occlusive disease (PVOD), a rare variant of primary pulmonary artery hypertension (PAH), is recognized as an uncommon but devastating complication of HSCT.10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Endothelial damage may play a critical role in the pathogenesis of PVOD, although the etiology and natural history of this condition remain poorly understood. Despite the rare nature of this condition, PVOD may serve as a useful model of vascular injury in the post-HSCT setting as it shares unique pathophysiologic characteristics of vascular thrombosis and fibrosis with some of the more common post-HSCT complications listed above.

In this review we present PVOD as a rare complication of HSCT. We explore the role that vascular endothelial damage may play in PVOD and review currently available treatment options.

Definition and epidemiology of PVOD

PVOD is characterized by postcapillary pulmonary venular obstruction leading to pulmonary vascular congestion, progressive dyspnea and right ventricular heart failure.16, 20, 21, 22 PVOD affects all ages with cases reported as early as 9 days of age to 68 years, although the majority of reported cases are less than 50 years of age.16, 20 Nearly twice as many males are affected in the adult population, while children exhibit a more equal male-to-female distribution.20, 21, 22

To date, fewer than 200 cases of PVOD have been reported since Hora's first clinical description of a case over 70 years ago.22, 23, 24 Due to the rare nature of this condition, the etiology and natural history remain largely unknown.16 Historically, PVOD has been associated with a number of systemic inflammatory conditions, including infections, toxic exposures and antineoplastic chemotherapy, autoimmune disease and malignancy.16, 25, 26, 27, 28, 29 Familial forms of PVOD have also been described30, 31 and recently linked to mutations within the transforming growth factor-β receptor family.32 Given the wide spectrum of incidence and severity of disease, as well as a number of reported risk factors for this condition, the pathogenesis of PVOD is likely multifactorial.16

PVOD occurring after HSCT

Since Troussard's first report of PVOD occurring after HSCT, the description of this transplant-related complication has been primarily limited to case reports (Table 1).10, 11, 12, 13, 14, 15, 17, 18, 19 While the precise mechanism of PVOD pathogenesis following HSCT has yet to be elucidated, review of these reported cases offers insight into the relationship of transplant-associated risk factors and development of this condition. Age and sex of those affected were variable, although the majority of cases were less than 25 years old. The underlying diagnoses preceding transplant and subsequent PVOD were predominantly hematological malignancies. Allogeneic transplants are represented in greater proportion among these cases. Onset of PVOD typically occurred after several weeks to months following transplant, although a minority of cases manifested within days. Although rather nonspecific, dyspnea represented a consistent early symptom in this population.

Table 1 Case reports of pulmonary veno-occlusive disease (PVOD) after hematopoietic stem cell transplant (HSCT)

The inflammatory nature of GVHD associated with allogeneic HSCT may provide an immunologic component to the pathogenesis of PVOD in some patients.14, 16 In addition, post-transplant complications, such as opportunistic infections and sepsis, likely provide an inflammatory substrate for the development of PVOD. However, perhaps the greatest risk factor for developing PVOD is endothelial injury from cytotoxic chemotherapy and irradiation. As seen in Table 1, pre-transplant conditioning regimens including cyclophosphamide (CY) and total body irradiation (TBI)/total lymphoid irradiation (TLI) were utilized in many of the reported cases. CY is associated with a number of pulmonary complications, including interstitial pneumonitis or fibrosis and cryptogenic organizing pneumonia.7, 33 Exposure to cytotoxic conditioning regimens, including CY, has been reported as a risk factor for PVOD in nontransplant patients.28 TBI is associated with hypersensitivity pneumonitis, parenchymal hemorrhage, pleural effusions and pulmonary vascular disease.33 TBI is known to have an activating effect on the vascular endothelium.34 It remains unclear whether treatment for the underlying transplant-associated diagnosis prior to transplantation or the transplant conditioning regimen is responsible for PVOD, although both are likely contributory.

Of the 12 reported cases, 7 underwent histological diagnosis by lung biopsy or at autopsy. The remaining five patients were diagnosed by clinical and radiographic findings compatible with the diagnosis. While the morbidity and mortality of PVOD is historically high, nearly half of reported cases of PVOD after HSCT were alive at the time of the case report. This may suggest a heterogeneous clinical course in this population of patients. In general, post-transplant pulmonary complications are common and broadly represented by a variety of pulmonary diseases.2, 7, 35, 36, 37, 38 As post-transplant lung injury is common, recognition of PVOD as a HSCT-related complication may be obscured by its various risk factors, variable time to presentation and heterogeneous clinical course.

Diagnosis of PVOD

Clinical symptoms and exam findings

PVOD is classically described as a progressively fatal form of PAH with a mortality rate of nearly 100% by 2 years.16, 39 Antemortem diagnosis of PVOD often proves challenging due to vague presenting symptoms, nonspecific findings on radiographic testing and atypical cardiopulmonary hemodynamics.16 Delay in diagnosis of PVOD is not uncommon; in a review of 33 cases of PVOD, Lantuejoul et al.22 reported a mean duration of symptoms prior to diagnosis of 49 months. Milder and nonfatal forms with spontaneous resolution of pulmonary venular obstruction may be an under-recognized course of the disease, thereby underestimating the actual incidence of PVOD.15, 40

Larger case reviews of PVOD have been reported in non-HSCT recipients.16, 22 In these reviews, increasing dyspnea seems to be the most consistent early complaint, with a sensitivity of nearly 100%.16, 22 Symptoms of right heart failure, including exertional dyspnea, lower extremity edema and right upper quadrant pain due to hepatic congestion, may develop as pulmonary hypertension worsens.16 Presenting complaints of PVOD may also include fatigue, orthopnea, paroxysmal nocturnal dyspnea, chest pain, cough, hemoptysis or syncope.16, 20, 22

Physical exam findings are typically nonspecific and consistent with that of pulmonary hypertension. Pulmonary rhales, elevated jugular venous pulse, cyanosis, congestive hepatomegaly are reported exam findings in PVOD.16, 20, 22 Digital clubbing may be a valuable exam finding in PVOD; clubbing is also seen in interstitial lung disease but is not commonly reported in other forms of PAH.20, 39 Pleural effusions are frequently reported in cases of PVOD and represent an exam finding also unusually seen in PAH.16 Electrocardiography may reveal a rightward axis and suggest right ventricular enlargement if compensatory myocardial changes have occurred as a result of PAH. Echocardiography often proves helpful in the diagnosis by confirming elevated pulmonary artery pressures and excluding left ventricular failure or mitral valvular disease as an underlying cause of PAH.41

Radiographic findings

Chest radiographic findings of PVOD include perihilar pulmonary vascular congestion and prominent septal, or Kerley B lines; together these findings are suggestive of postarterial pulmonary capillary congestion and interstitial transudation of fluid.16, 41 Pleural effusions may be confirmed by X-ray. Bilateral infiltrates with scattered airspace opacification may be similar in appearance to acute respiratory distress syndrome.41, 42 Chest computed tomography scans of PVOD may reveal smooth interlobular septal thickening and dilated central pulmonary arteries.41 Poorly defined diffuse ground glass opacification may represent another relatively common and helpful radiographic finding.16, 41 Mediastinal lymphadenopathy has been reported on CT scans of PVOD, although this is a nonspecific finding seen in other forms of PAH.41 Ventilation-perfusion (V/Q) scanning may produce a variety of findings, ranging from normal to diffuse irregularities or segmental V/Q mismatches.41 Pulmonary angiography may reveal enlarged pulmonary arteries and prolonged circulation time through the lungs, although the pulmonary veins may appear relatively normal without an apparent filling defect into the left atrium.41

Cardiac catheterization and hemodynamic assessment

Right heart catheterization is often helpful to confirm elevated pulmonary arterial and right-sided atrial and ventricular pressures. A normal or low pulmonary artery wedge pressure (PAWP) is a classically described feature of PVOD.16, 20, 41, 43, 44 Despite the stenotic pulmonary venules characteristic of PVOD, the larger veins are the primary determinants of resistance to flow beyond the wedged pulmonary artery catheter; these structures are hemodynamically normal in PVOD.44 Consequently, measurement of the PAWP reflects normal pressure in the pulmonary veins, rather than the elevated pulmonary capillary pressures.44 Although an elevated PAWP does not exclude the diagnosis of PVOD, this finding is more commonly seen in pulmonary vein stenosis, severe mitral stenosis or left ventricular failure.20, 41

The triad of severe PAH, radiographic evidence of pulmonary edema and normal PAWP are classically described clinical diagnostic criteria for PVOD.16, 20, 43 However, PAWP measurements can be variable as detailed above, and consequently not all patients with PVOD meet these criteria. Lung biopsy (or post-mortem examination) remains the definitive means of diagnosis of PVOD. Nevertheless, clinical and radiographic findings have been proposed as reliable identifiers of this disease and prove invaluable when surgical lung biopsy is not possible or not warranted due to clinical improvement.16, 20, 22, 40, 45

Pathology of PVOD

On histological section, PVOD is characterized by diffuse, patchy, intimal fibrosis primarily involving the venules and small veins of the pulmonary bed, although larger veins may be affected.16, 22, 39 This hallmark of inter- and intralobular venular fibrosis commonly leads to intraluminal septa and recanalization, eccentric intimal fibrosis, venular hypertrophy and obstruction.22, 39 Capillary congestion often ensues resulting in severe PAH with associated arterial intimal fibrosis and medial hypertrophy. Plexiform lesions characteristic of PAH are not typically seen in PVOD.16, 22 Parenchymal lung findings concomitant with PVOD include interstitial edema, interstitial fibrosis, hemosiderosis and diffuse alveolar damage.16, 22 Interstitial lymphocytic infiltrates, lymphocytic venulitis or leukocytoclastic vasculitis may be associated with interstitial fibrosis.16, 22

Role of vascular injury and endothelial dysfunction

The endothelium plays a dynamic role in maintaining normal microvascular blood flow and preserving vascular integrity.46, 47 The vascular microenvironment determines the balance of an endothelial-dependent equilibrium that exists between anti-inflammatory and anticoagulant effects of these cells with a proinflammatory state promoting fibrinogenesis during times of endothelial activation (Table 2).47

Table 2 Mediators of endothelial function

The surface of quiescent endothelial cells provides an antithrombotic interface that counters a tendency toward thrombosis, primarily by controlling the genesis of thrombin (Figure 1).47 Release of antithrombotic factors by the endothelium, including thrombomodulin and tissue factor pathway inhibitor (TFPI), limit the generation of thrombin. Endothelial-derived tissue plasminogen activator (t-PA) promotes fibrinolysis via the generation of plasmin. These anti-inflammatory effects of the endothelium promote blood flow by limiting platelet and inflammatory cell adhesion, thrombosis and subsequent fibrinogenesis.

Figure 1
figure1

Role of endothelial function in maintaining balance of thrombosis and fibrinolysis. (a) Low levels of thrombin are maintained by antithrombotic effects of endothelium, including tissue plasminogen activator (t-PA) release, nitric oxide production, anti-inflammatory cytokine release and downregulation of leukocyte adhesion molecules. (b) Endothelial injury and activation results in increased levels of tissue factor, leading to formation of thrombin, promoting fibrinogenesis; damaged endothelium releases cytokines and expresses selectins, which promote thrombosis, leukocyte infiltration, inflammation and vascular fibrosis.

The dynamic nature of the endothelium is illustrated by its important prothrombotic role with perturbation by microvascular injury.47 In settings of inflammation, such as that observed with bacterial endotoxins, vascular shear injury and with proinflammatory cytokines, the endothelium provides a substrate for thrombosis and vascular stasis, primarily through the production of tissue factor.47 Coagulation is initiated with exposure of tissue factor at sites of vascular injury and from expression at the endothelial surface, resulting in thrombin generation (Figure 2). Thrombin amplifies its own generation by activating factors V and VIII, which are key cofactors in coagulation. Regulation of thrombin activity is essential to prevent excessive thrombosis.

Figure 2
figure2

Vascular injury and endothelial activation upregulates production of tissue factor, stimulating thrombin formation. Expression of heparan sulfate provides a substrate for antithrombin to limit thrombin generation. Tissue factor pathway inhibitor (TFPI), antithrombin and activated protein C and protein S are important regulators of thrombin generation. Thrombin activable fibrinolysis inhibitor (TAFI), activated by thrombomodulin and thrombin, stabilizes fibrin rendering the fibrin polymer resistant to plasmin-dependent lysis.

Transplant-associated chemotherapeutic regimens and radiation conditioning therapy contribute to vascular inflammation and endothelial activation.48, 49 Markers of endothelial injury, including thrombin activable fibrinolysis inhibitor (TAFI), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), selectins and other cellular adhesion molecules are upregulated and overtly expressed with vascular inflammation.50, 51, 52, 53, 54 Endothelial activation also favors the downregulation of anticoagulant and anti-inflammatory factors, including antithrombin and proteins C and S, which in turn favors thrombosis and fibrinogenesis.

Paracrine signaling by endothelial cells also plays a critical role in the dynamic regulation of vascular tone. Normal microvascular tone is dependent upon a complex set of regulatory factors that balance static vasoconstriction with endothelial-promoted vasodilation, primarily through the constitutive release of nitric oxide.46, 47 Endothelial vasoregulation via production of nitric oxide is regulated by a complex subset of chemical and physical stimuli.46, 47 Transplant-associated endothelial damage results in decreased production of endogenous vasodilators, such as nitric oxide, prostaglandin I2 and other endothelial-derived relaxant factors. Downregulation of these vasorelaxant factors favors unopposed vasoconstriction and, if left unopposed, progression to vascular fibrosis.47

Vascular endothelial growth factor (VEGF), a protein-tyrosine kinase, is the dominant growth factor controlling angiogenesis critical for normal pulmonary endothelial cell function.55 VEGF has several important roles in normal pulmonary vascular blood flow, including promotion of endothelial survival, control of vascular permeability and expression of fibrinolytic mediators.55 Rising VEGF levels have been correlated with development of HVOD and appear to play a role in its pathogenesis.56 VEGF may serve as a therapeutic target in the treatment of endothelial damage given its role in pulmonary vascular remodeling.55 Platelet-derived growth factor (PDGF) is another protein-tyrosine kinase that stabilizes the vascular endothelium and serves as a potent mitogen for pulmonary artery smooth muscle cells.57 Upregulation of PDGF is observed in immunohistochemical stains of pulmonary capillary hemangiosis, a rare form of pulmonary hypertension closely related to PVOD.58 The presence of PDGF suggests that this angiogenic and antiapoptotic kinase is important to the pathogenesis of PCH.58 Gene expression profiling has been utilized to identify upregulation of specific vascular markers associated with PCH.53 Given the rare nature of PCH and PVOD, this technology may offer insights into similar gene expression patterns in the pathogenesis of PVOD.

Modeling the pathogenesis of PVOD: endothelial injury in hepatic veno-occlusive disease

Endothelial injury and associated thrombotic events comprise a common and clinically important set of complications associated with HSCT.48, 49 Perhaps the most representative of these transplant-associated complications is HVOD. Relative to PVOD, HVOD is a much more common and well-described complication of HSCT. While not specific to transplantation, HVOD has been linked with a number of transplant-related variables including cytotoxic conditioning regimens, radiation therapy and allogeneic transplantation.59, 60, 61, 62, 63, 64 The pathogenesis of HVOD is associated with inflammation leading to hepatic endothelial dysfunction, thereby producing intrahepatic venular thrombosis, fibrosis and eventual obstruction of hepatic sinusoids.2, 3, 4, 59, 60, 61 HVOD ranks among the most common acute adverse effects associated with HSCT, with a reported incidence of 10–15% of transplant recipients.2, 59, 60, 61, 62, 63 Recognized as the clinical triad of fluid retention, hyperbilirubinemia and painful hepatomegaly, HVOD causes a variable clinical syndrome ranging from mild disease to death.59, 60, 61 HVOD provides a common and clinically significant example of transplant-associated endothelial injury that is characterized by many of the central pathogenic features that also characterize the vascular injury seen in PVOD.3, 28, 36

In the pathogenesis of HSCT-associated HVOD, PAI-1 is an important marker of endothelial dysfunction.65 Increased production of PAI-1, an antifibrinolytic factor, promotes thrombosis and fibrinogenesis. As PAI-1 is strongly suppressed by nitric oxide, endothelial damage and decreased production of NO favors both vasoconstriction and thrombosis.66 This vasoconstriction and thrombosis leads to eventual vascular fibrosis, which are features that characterize the pathogenesis of HVOD. A similar dysregulation of NO production and increased PAI-1 may characterize the pathogenesis of PVOD, as a similar thrombotic and fibrotic process is observed in the postcapillary venule of this condition.

Pulmonary venular inflammation and increased capillary permeability may play an early role in PVOD, whereas pulmonary venular fibrosis and obstruction may represent later findings that manifest as pulmonary hypertension and right ventricular failure. Whether endothelial dysfunction is simply an initiating event or continuously contributes to disease severity is unclear. Early endothelial recovery and repair after a transplant-related vascular insult may explain why some patients recover from this classically fatal condition. Recurrence of PVOD after lung transplant suggests that extrapulmonary factors, such as genetic variation, environmental exposures and systemic endothelial activation, play a vital role in the pathogenesis of PVOD.67

Treatment of PVOD

The rare nature of PVOD has offered little opportunity for prospective trials of prevention or treatment of this condition. Many of the accepted treatment options for PVOD have been extrapolated from the treatment of PAH and other inflammatory complications associated with transplantation. Overall, current treatment options for PVOD are quite limited and generally not well defined.

Vasodilators

Although PVOD is a rare form of PAH, the use of conventional vasodilator therapy for PAH, such as nitrates, calcium channel blockers, prostacyclins and endothelin receptor antagonists, has yielded limited success when applied to PVOD.16, 20, 26, 68, 69, 70, 71 Use of vasodilators may, in fact, be dangerous in patients with PVOD, precipitating pulmonary edema and even death.72 The fixed venular obstruction of PVOD lends the capillary bed susceptible to increased congestion with dilation of the pulmonary arterial tree, resulting in profound pulmonary edema. Nevertheless, long-term improvement in respiratory symptoms associated with PVOD has been reported with the use of calcium-channel blockers and prostacyclins.73, 74 Adjuvant use of sildenafil, a selective phosphodiesterase type-5 inhibitor, with prostacyclins has reportedly offered clinical and hemodynamic improvements in PVOD.71 Despite these reports, no firm conclusions can be reached or recommendations made regarding the use of vasodilating agents in the setting of PVOD.

Corticosteroids

Corticosteroids have been used in PVOD, presumably to target a concomitant inflammatory disease or component of interstitial pulmonary fibrosis associated with PVOD.16, 20, 25, 26, 27 The role or effectiveness of steroids in the management of PVOD remain poorly defined and unclear, although steroids have been utilized in numerous case reports.12, 13, 14, 15, 16, 20, 25, 26, 27, 29, 75

Anticoagulants and thrombolytics

Thrombotic occlusion of pulmonary veins is a histological hallmark of PVOD. Despite this pathologic feature, the role of anticoagulation in treatment of PVOD is controversial and has not shown durable success. Nevertheless, therapeutic anticoagulation is often used in PVOD based upon observational studies and prospective studies of PAH. Trials of long-term anticoagulation in PAH have been associated with a modest mortality benefit.16, 76 Systemic anticoagulant and thrombolytic therapies have been tested extensively in HVOD. When applied to HVOD, these therapies are generally ineffective and associated with bleeding complications.60, 61

Lung transplantation

Lung transplantation has traditionally been the only durable treatment option for severe PVOD.16 Unfortunately, the wait time to receive a lung transplant is frequently longer than the typical survival time associated with PVOD. Recurrence of PVOD after lung transplantation has recently been reported, which makes this treatment option seemingly less reliable.67

Novel therapies

Defibrotide, a porcine-derived oligonucleotide with antithrombotic, fibrinolytic and endothelial reparative properties has emerged as a novel treatment for HVOD.64 A derivative of defibrotide, oligotide, has been shown to have in vitro endothelial protective properties against fludarabine-induced conditioning regimen toxicity as well as apparent immune protection against allogeneic T-cell mediated damage.77 Antithrombin (AT), a potent inhibitor of the coagulation cascade exhibiting in vitro anti-inflammatory properties, has been studied in pediatric HSCT both as a single prophylactic agent and in conjunction with defibrotide in the treatment of HVOD.78 Although prophylactic use of AT did not alter the incidence of HVOD, it was well tolerated when given with defibrotide in the treatment of HVOD. Defibrotide is currently in a prospective, international, phase III trial validating its effectiveness in severe HVOD.51 At this time it is unclear if defibrotide will have a therapeutic application in PVOD, although the pathophysiologic similarities between these conditions may suggest a benefit in the pulmonary variant.

The use of N-acetylcysteine (NAC) in the treatment of PVOD has not been previously described, although limited use has been reported in HVOD.79, 80 Hepatic sinusoidal inflammation plays a central role in the pathogenesis of HVOD.59, 60, 61 The metabolism of chemotherapeutics provides substantial oxidative stress on metabolically active tissue.28 NAC has antioxidant properties that may relieve oxidative stress in a number of other proinflammatory conditions.81 As with hepatic tissue, the lungs exhibit metabolic activity against xenobiotics.82, 83 Pulmonary metabolism of chemotherapeutics may provide significant oxidative stress, thereby contributing to the pathogenesis of PVOD. Based on this principle, there may be rationale for the use of NAC in the treatment of PVOD.

Conclusion

Due to its rare nature, much is still unknown about the apparent pulmonary vascular and parenchymal damage of PVOD. The pathogenesis of veno-occlusive disease in both HSCT and nontransplant settings is likely multifactorial given the wide spectrum of incidence and severity of disease, as well as the number of reported risk factors. Increasing evidence suggests that PVOD may represent a severe and often lethal form of endothelial damage in the post-HSCT population. As current treatment options for PVOD are limited, a greater understanding of the pathogenesis of this syndrome is paramount. Animal models and in vitro studies of HSCT-related endothelial damage and lung injury will expand on this knowledge and likely suggest future treatment options targeting endothelial repair.

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Correspondence to L J Burns.

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Bunte, M., Patnaik, M., Pritzker, M. et al. Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction. Bone Marrow Transplant 41, 677–686 (2008). https://doi.org/10.1038/sj.bmt.1705990

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Keywords

  • pulmonary veno-occlusive disease
  • endothelial dysfunction
  • hematopoietic stem cell transplant
  • defibrotide

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