Eleni Vrigkou, Argyrios Tsantes, Athanasios Pappas Iraklis Tsangaris

1 Second Department of Critical Care Medicine, Attiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

2 Laboratory of Hematology & Blood Bank Unit, Attiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

INTRODUCTION

Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by pathologic alterations to the anatomical and molecular structure of the pulmonary vasculature, resulting in increased pulmonary vascular resistance and right-sided heart failure.1Since the early 2000s, treatment options for PAH patients are based on agents targeting the prostaglandin, endothelin and nitric oxide pathways.2Even though the advanced PAH therapies have dramatically improved survival, morbidity and mortality rates remain high.3For several decades, oral anticoagulants have been used as supportive treatment in PAH.2The rationale behind this recommendation is quite solid,even though it is acknowledged that it is based mainly on non-controlled, single-centered observational studies, while current literature is controversial. The lack of suf ficient data on the subject is re flected in the current European Society of Cardiology and European Respiratory Society (ESC/ERS)pulmonary hypertension guidelines. The con flicting current research, the potential side effects of the anticoagulation treatment and the ambiguity of the ESC/ERS guidelines have raised concerns regarding the implementation of this intervention and heterogeneity in its application in every day clinical practice.

CURRENT PRACTICE

PAH is a complex disease, whose multifactorial etiopathology is the basis for its classi fication in 4 groups: idiopathic(IPAH) and heritable PAH (HPAH), PAH associated to drugs and toxins and associated forms of PAH that localize to small pulmonary muscular arterioles (like connective tissue disease (CTD), human immunode ficiency virus infection, portal hypertension, congenital heart disease and schistosomiasis).1Advanced PAH medical therapy includes three major categories: endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclin analogues. Oral anticoagulants are a part of the background medical therapy,along with oxygen, diuretics and calcium channel blockers.

The ESC/ERS pulmonary hypertension guidelines2state that “oral anticoagulant treatment may be considered in patients with IPAH, HPAH and PAH due to use of anorexigens” (recommendation class IIb/level C). Oral anticoagulants may also be considered in cases of CTD-PAH and PAH associated with congenital heart disease in cases of thrombophilic predisposition, signs of thrombosis or heart failure in the absence of contradictions (recommendation class IIb/level C). Regarding the other forms of PAH, there are insuf ficient data for a recommendation to be made, apart from porto-pulmonary hypertension where anticoagulation is not recommended due to the increased bleeding risk. The oral anticoagulant of choice is warfarin.

PAH PATHOPHYSIOLOGY AND ORAL ANTICOAGULANTS

Even though the etiology behind PAH is variable and its pathophysiology is complex and still elusive, the hallmarks of the disease justify the introduction of oral anticoagulants in the PAH treatment scheme. PAH is a proliferative vasculopathy, where endothelial dysfunction, pathologic remodeling, vasoconstriction and an imbalance in vasoactive mediators (favoring vasoconstrictors and pro-proliferative mediators and decreasing vasodilators) play a central role in its pathophysiology.1The addition of oral anticoagulants as supportive treatment in PAH was brought by the results of several observational studies demonstrating evidence of vascular thrombotic lesions and in situ thrombosis in the small caliber peripheral pulmonary vessels in post-mortem evaluations.4The value of those classic studies is immense regarding the understanding of the pathophysiological background of the disease. Nevertheless, it should be acknowledged that they were conducted in the 80s and 90s,they involved mainly IPAH and CTD-PAH patients and they did not demonstrate a causative role between those findings and the disease. Moreover, they stated that fresh platelet- fibrin thrombi and organized arterial thrombi were infrequent in the tested specimens.5

Recent studies regarding the coagulation status of PAH patients are con flicting. Current data of dysregulation of the coagulation process and impaired fibrinolysis have suggested a possible prothrombotic state and supported the use of oral anticoagulation in PAH.6Interestingly,a number of studies assessing the levels of circulating markers of thrombogenesis and fibrinolysis (namely plasminogen activator inhibitor-1, thrombin-antithrombin,prothrombin fragments 1+2) have rendered inconsistent results,6leaving unanswered questions about the role of the observed coagulation abnormalities in the disease’s natural history.

As the coagulation cascade is a complex and fast-changing dynamic equilibrium and PAH is a progressive, chronic disease, the nature of the coagulation de ficits observed in the PAH setting could be associated to variable factors,such as the etiology of PAH or the severity, trajectory and duration of the disease, rendering dif ficult for conclusions to be made about the coagulation pro file of the patients(especially in cases were a thrombophilic predisposition is lacking). Moreover, the frequently detected and still of unknown etiology thrombocytopenia observed in the PAH population7could play a signi ficant part in the disease’s hemostatic state, even more so since it has been correlated with the disease’s prognosis.

THE PAH PATIENT AND ORAL ANTICOAGULANTS

Since immobility, venous congestion, sluggish pulmonary blood flow and right-sided heart failure are parts of PAH’s clinical presentation,8anticoagulation treatment is a logical option. Furthermore, PAH patients often present with prothrombotic conditions and increased risk of catheterassociated thrombosis (in cases receiving intravenous prostanoids).8A thrombus formation or an embolism could result in the hemodynamical destabilization of the patients with serious consequences, strengthening the importance of anticoagulation therapy.

With the change of the PAH population’s demographics,4more and more patients with advanced age and serious concomitant conditions (like liver or kidney failure) are being diagnosed with the disease. PAH patient’s bleeding risk can also be augmented by conditions like hemoptysis,gastrointestinal disease, esophageal varices and liver dysfunction frequently presented in that population.5

Studies conducted to make a risk-bene fit analyses on the use of anticoagulants in PAH patients are scarcer than those conducted to determine the effect of anticoagulation treatment on survival.9Although the latter are controversial, the former show an increased risk of bleeding in the CTD-PAH and IPAH population, but are still uncon firmed by larger, controlled studies. An additional concern is that in cases PAH patients are prescribed oral anticoagulants,there are no guidelines on their anticoagulation management or even a consensus for the target international normalized ratio (INR) range.9

The ‘advanced’ PAH therapies have greatly improved survival and they are used as monotherapy or (more often in our days) combination therapy according to the risk strati fication.2Some of those medications have a direct effect on the coagulation process (like prostacyclin analogues that inhibit platelet aggregation and are as-sociated with thrombocytopenia), while others have an indirect effect (through, for example, the NO pathway).6Moreover, endothelin-receptor antagonists and sildena fil interfere with the metabolism of vitamin K antagonists and bosentan decreases warfarin’s anticoagulant effects.6To date, there are no reliable data evaluating the risks and bene fits of concomitant prescription of oral anticoagulants and advanced PAH therapies.

The most frequent anticoagulant used in the PAH setting is warfarin. Warfarin presents with several problems regarding its use, like the non- fixed dose regime, the continuous need for monitoring, the non-reliable anticoagulant effect, the interactions with diet and the increased bleeding complications. Limited data are available regarding the use of alternative coagulation treatment to warfarin, like the new oral anticoagulants (NOACs) or antiplatelet agents.10NOACs could have some advantages over warfarin, mainly due to their easier management and fewer bleeding complications.Even though preliminary data from experimental models are encouraging, larger studies are warranted in order to fully assess their role in the PAH treatment scheme.11

DISCUSSION

There is considerable uncertainty regarding the use of anticoagulation in PAH patients. The con flicting data from observational studies and the lack of randomized controlled trials have raised concerns about the prescription of oral anticoagulants in every day clinical practice. Two of the most important studies in the field, the Comparative,Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)12and the Registry to Evaluate Early And Long-term PAH Disease Management(REVEAL)13have rendered respective results concerning CTD-PAH, but not IPAH patients: they did not demonstrate a positive effect of the anticoagulation therapy on survival in CTD-PAH, but while COMPERA showed a bene ficial impact in IPAH, the REVEAL registry did not.

The most important question that needs to be answered for a de finite decision to be made regarding anticoagulants in PAH is whether in situ thrombosis or thromboemboli may have an important impact in the disease’s natural history and if so, which of the patients present with increased risk of thrombosis. It is well known that the pathophysiological background of the disease is, for a great part, still elusive.It has not been yet established if thrombosis is a cause, a consequence or merely a finding with no particular signi ficance to the diseases progression.14

Nonetheless blood coagulation abnormalities have been observed in PAH along with evidence of in situ thrombosis(especially in the IPAH population). Those findings suggest that at least a subgroup of PAH patients may bene fit from oral anticoagulants, since their disease could be complicated by thrombosis or thromboembolism. In order to detect those hidden patients, periodically conducted ventilation/perfusion lung scans or CT angiograms could be of use.6

In patients at a greater risk of thromboemboli due to lower cardiac output, higher pulmonary vascular resistance, progressive right ventricle failure, immobility or thrombophilia,anticoagulation is a vital option. Even though there are no de finite guidelines regarding anticoagulation management in those cases, a close monitoring of the anticoagulation treatment (by regular blood works, INR tests and clinical examinations) could be of importance.

Anticoagulation therapy could be considered based on case-by-case evaluation. The etiology of the disease should be an important factor towards making that decision: CTDPAH patients have an increased bleeding risk, patients with congenital heart disease often present with hemoptysis and in porto-pulmonary hypertension anticoagulants are contradicted due to hemorrhage complications. Individual patient characteristics should also be taken under consideration, such as the severity and trajectory of the disease, prior bleeding history,concomitant clinical conditions and medications.

PAH is a severe, complex disease, whose treatment can be in fluenced by various factors. Anticoagulation treatment is a part of the PAH treatment scheme for some patient subgroups, but is recently subjected to scrutiny due to the con flicting data regarding its bene ficial impact on survival and its potential side effects. A careful consideration of individual patient characteristics and a close monitoring of the anticoagulation treatment could be of importance in order to minimize any potential side effects.

Author contributions

All authors contributed to the design and writing of this manuscript and approved the final version of this manuscript for publication.

Conflicts of interest

None declared.

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Peer review

Externally peer reviewed.

Open access statement

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