Hypercoagulability in Pulmonary Hypertension

Hypercoagulability in

Pulmonary Hypertension

Isabel S. Bazan, MD

, Wassim H. Fares,

MD, MSC

INTRODUCTION

Pulmonary hypertension (PH) is defined as

increased pressure in the pulmonary circulation,

defined by convention and consensus as a mean

pulmonary artery pressure of at least 25 mm Hg

at rest.

The World Health Organization (WHO)

has classified PH into 5 major groups: pulmonary

arterial hypertension (PAH), PH caused by left

heart disease, PH caused by lung disease or

chronic hypoxia, PH caused by chronic thrombo-

embolic disease, and a miscellaneous group.

2,3

PAH is a clinical condition that falls under

WHO group 1, and can be idiopathic (IPAH), heri-

table (HPAH), caused by drugs and toxins

(DTPAH), or associated with several other condi-

tions (APAH) including connective tissue disease,

congenital heart disease, HIV infection, or portal

hypertension. PAH is characterized by molecular

and pathologic alterations in the pulmonary circu-

lation that result primarily in progressive vascular

remodeling of the pulmonary arteries, increased

pulmonary vascular resistance, and eventually

right heart failure and death.

4,5

These alterations

are caused by several inflammatory, metabolic,

and cellular changes that ultimately result in occlu-

sive lesions, in situ thromboses, and plexiform

lesions, that are all representative of the patho-

logic findings of PAH.

4,6,7

There is evidence of

pro-thrombotic pathobiology which suggests an

increased hypercoagulable state in PAH patients.

Based on limited evidence, anticoagulation ther-

apy is recommended in certain PH patients; how-

ever, the degree of hypercoagulability and benefit

of anticoagulant therapy are not known.

PATHOPHYSIOLOGY OF PULMONARY

ARTERIAL HYPERTENSION

PAH is characterized by excessive vasoconstric-

tion of the distal pulmonary arteries (although the

vasculopathy is not strictly limited to the pulmo-

nary arterial system

). This is related to endothelial

dysfunction and smooth muscle cell hypertrophy

and proliferation (that at least in part is related

to abnormal function or expression of potassium

channels on smooth muscle cells), which

leads to impaired production of vasodilator and

Disclosure Statement: The authors have no financial or commercial conflicts of interest to disclose. No funding

was used for this article.

Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, 300 Cedar Street, PO

Box 208057, New Haven, CT 06520-8057, USA

* Corresponding author. Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, 300

Cedar Street, TAC-441 South, PO Box 208057, New Haven, CT 06520-8057.

E-mail address: [email protected]

KEYWORDS



Pulmonary arterial hypertension



Hypercoagulability



Thromboembolism



Anticoagulation



Pulmonary hypertension



Pulmonary embolism



Right heart failure



Right ventricle

KEY POINTS

 Patients with pulmonary arterial hypertension are at increased risk of developing thrombi.

 There are known and suspected pathways that contribute to the hypercoagulability in patients with

pulmonary arterial hypertension.

 The benefit of anticoagulation and antiplatelet therapy is not known in this patient population.

 Hypercoagulability is an etiology and a consequence of pulmonary hypertension.

Clin Chest Med 39 (2018) 595–603

https://doi.org/10.1016/j.ccm.2018.04.005

chestmed.theclinics.com

antiproliferative agents such as nitric oxide and

prostacyclin, as well as overexpression of vaso-

constrictor and proliferative substances such as

thromboxane A2 and endothelin-1.

Other path-

ways and molecules, including serotonin,

have

also been implicated in the pathogenesis of PAH.

Activation of the endothelin pathway has been

demonstrated in both plasma and lung tissue of

PAH patients.

Although it is unclear whether

increased endothelin-1 is a cause or consequence

of PAH, it is known that endothelin-1 causes vaso-

constrictive and mitogenic effects by binding to

pulmonary vascular smooth muscle cells.

Endo-

thelin receptor antagonists are efficacious in

improving symptoms, exercise capacity, hemody-

namics, and time to clinical worsening in PAH

patients.

12,13

The nitric oxide and cyclic guanosine mono-

phosphate (cGMP) pathway is also important

in the pathogenesis of PAH. Inhibition of

cGMP destruction by phosphodiesterase type 5

(PDE-5) inhibitors results in pulmonary vasodila-

tion. PDE-5 inhibitors also have antiproliferative ef-

fects.

PDE-5 inhibitors and guanylate cyclase

stimulators are approved for the treatment of

PAH and have shown to varying degrees benefits

in hemodynamics, exercise capacity, and time

to clinical worsening as with endothelin receptor

antagonists.

2,15

The third pathway that has been a major thera-

peutic target for PAH is the prostacyclin pathway.

Prostacyclin is predominantly produced by endo-

thelial cells, and it induces potent vasodilation. It

also inhibits platelet aggregation, and has cytopro-

tective and antiproliferative effects.

PAH patients

have a reduction in prostacyclin synthase expres-

sion in pulmonary arteries and prostacyclin urinary

metabolites.

Synthetic analogs of prostacyclins

have been developed that share similar pharma-

codynamic effects of prostacyclin.

18–20

Efficacy

of prostanoids is also seen in APAH and CTEPH

(although currently not approved for CTEPH).

21–23

A common feature in all forms of PAH is the

vascular remodeling of the distal region of pulmo-

nary arteries. This pathologic remodeling results in

the formation of a layer of myofibroblasts and

extracellular matrix between the endothelium and

the internal elastic lamina, termed the neointima.

The cellular processes underlying the musculariza-

tion of the usually nonmuscular distal arteries is

incompletely understood, but the adventitial fibro-

blast is thought to be the first cell activated to

proliferate and synthesize matrix proteins in

response to a pulmonary hypertensive stimulus.

Upregulation of matrix metalloproteinases occurs,

and these metalloproteinases are involved in the

migration of the adventitial fibroblasts into the

media layer. PAH is also associated with alter-

ations of proliferation and apoptosis, resulting in

thickened and obstructive pulmonary arteries.

Endothelial cells also play a key role in vascular

remodeling. Disorganized endothelial cell prolifer-

ation leads to the formation of plexiform lesions

that are characteristic of PAH. The initiating stim-

ulus that results in abnormal endothelial prolifera-

tion is not known, but may be hypoxia, shear

stress, inflammation, response to drug or toxin,

or a combination of these with a background ge-

netic/genomic susceptibility. Defects in growth-

suppressive genes have been reported in plexi-

form lesions, including growth factors such as

platelet-derived growth factor, fibroblast growth

factor, transforming growth factor beta (TGFb),

and bone morphogenic proteins.

2,25

Inflammation also contributes to the pathogen-

esis of PAH. Pathologic specimens of patients

with PAH show an accumulation of perivascular in-

flammatory cells including macrophages, dendritic

cells, T and B lymphocytes, and mast cells. There

is also an increased level of circulating cytokines

and chemokines.

26–28

The role of inflammation

is particularly noted in certain groups of PAH

including HIV APAH and connective tissue disease

APAH. Interestingly, patients with systemic lupus

erythematosus APAH have improved on immuno-

suppressive therapy, emphasizing the role of

inflammation in this subset of patients.

29–31

The

pathogenesis of PH in patients with sickle cell dis-

ease (WHO group 5 PH) is also linked to inflamma-

tion, as elevated inflammatory markers and levels

of cytokines and chemokines are associated

with worse hemodynamics and poorer clinical out-

comes.

32,33

Mitochondrial dysfunction has also

been shown to be pathologic in PAH.

Pathologically, PAH results in medial hypertro-

phy, intimal proliferative and fibrotic changes,

adventitial thickening, plexiform lesions, and

thrombotic lesions in the distal pulmonary arteries.

Thrombi are present in both the small distal pulmo-

nary arteries and in proximal elastic pulmonary

arteries.

HYPERCOAGULABILITY IN PULMONARY

ARTERIAL HYPERTENSION

There is a high prevalence of vascular thrombotic

lesions found postmortem in patients with IPAH,

as described in several studies.

35–38

These in situ

thromboses may be caused by abnormalities in

the coagulation cascade, endothelial cells, and/or

platelets. Reduced plasma fibrinolysis was first re-

ported in1973.

Since then, studies have shown

that PAH patients have elevated plasma levels of

fibrinopeptide A- and D-dimers,

and 1 study found

Bazan & Fares

596

increased levels of fibrinogen and decreased

fibrinolytic response in patients with IPAH, compa-

rable to that of patients with CTEPH.

Fibrinopep-

tide A is generated when thrombin cleaves

fibrinogen, suggesting an elevated level of plasma

thrombin activity, and indeed studies have shown

increased thrombin activity in treatment-naı

¨ve

PAH patients.

Procoagulant activity and fibrinolytic function of

the pulmonary artery endothelium are also altered.

This dysfunction is reflected by the increased

levels of von Willebrand factor and plasminogen

activator inhibitor type-1 in the plasma of PAH pa-

tients. Plasminogen activator inhibitor was found

in much higher concentrations in arterial blood

than in mixed venous blood, suggesting intrapul-

monary production.

Additionally, shear stress

of blood flow toward vessel walls generates a

thrombogenic surface, resulting in thrombotic le-

sions. The effect of shear stress and vessel injury

can be seen in other types of PH as well, suggest-

ing that the prothrombotic state is not unique to

PAH.

Tissue factor is a transmembrane glycoprotein

that initiates the coagulation cascade, and it is

thought to play a role in angiogenesis and cancer

metastasis.

43–45

Tissue factor binds to factor VII

to catalyze the activation of factor X, leading to

the generation of thrombin and the formation of a

fibrin clot. Tissue factor expression is sensitive to

changes in blood flow, hypoxia, growth factors

such as platelet-derived growth factor, and che-

mokines. One study found that tissue factor

was upregulated in the diseased vessels of PAH

patients.

Another study found tissue factor-

expressing endothelial microparticles in the circu-

lation of PAH patients.

Tissue factor expression

may be a key contributor to the formation of in

situ thromboses.

There is growing evidence that the interaction

between platelets, and the arterial wall may

contribute to functional and structural alterations

in the pulmonary vessels. Apart from their known

role in coagulation, platelets release procoagulant,

vasoactive, and mitogenic mediators in response

to vascular abnormalities, such as thromboxane

A2, platelet-activating factor, serotonin, platelet-

derived growth factor, TGFb, and VEGF.

9,35,40

Thromboxane A2, which stimulates the activation

of new platelets and increases platelet aggrega-

tion, is increased in PAH patients, with a corre-

sponding reduction in prostacyclin metabolites.

Abnormal platelet aggregation has been described

in in vitro, in vivo, and human studies.

49–51

PAH

patients have higher levels of megakaryocyte-

stimulating hormone thrombopoietin, and 1 study

found that the pulmonary vasculature seemed to

be the site of production of thrombopoietin.

Increased platelet production, activation, and ag-

gregation may lead to a vicious cycle that contrib-

utes to thrombosis (Fig. 1). It is unclear whether

thrombosis and platelet dysfunction are causes

or consequences of PAH; however, the over-

arching evidence seems to be pointing toward an

underlying pathology of hypercoagulability as a

contributing etiology to PAH, and it gets worse

as PAH and right heart dysfunction ensue.

In addition to the previously mentioned patho-

physiologic abnormalities, patients with PAH may

also be at increased risk for venous thromboem-

bolism (VTE). PAH can cause significant dyspnea

with exertion, and right heart failure can result in

peripheral edema, both of which can lead a patient

to be immobile.

Additionally, heart failure alone is

an independent risk factor for VTE.

CHRONIC THROMBOEMBOLIC PULMONARY

HYPERTENSION

CTEPH results from the chronic obstruction of pul-

monary arteries due to thromboembolic disease.

Usually, acute pulmonary emboli are resorbed by

local fibrinolysis, with complete restoration of the

pulmonary arterial bed.

CTEPH arises when prior

acute pulmonary emboli for unknown reasons do

not completely resorb. These unresolved clots

then undergo fibrosis into an organized clot, ulti-

mately leading to mechanical obstruction of the

pulmonary arteries.

2,54

This obstruction causes

the release of inflammatory and vasculotropic me-

diators, resulting in vascular remodeling. Micro-

vascular disease is also thought to occur, which

can be related to shear stress in nonobstructed

areas, postcapillary remodeling related to

bronchial-to-pulmonary venous shunting, pres-

sure, and inflammation.

Low blood flow states

are created as a result of obstructed arteries and

can result in the in situ thromboses, related to

those of PAH. Thrombophilic factors such as

antiphospholipid antibodies, lupus anticoagulant,

protein S and C deficiency, activated protein C

resistance including factor V Leiden mutation,

prothrombin gene mutation, antithrombin III defi-

ciency, and elevated factor VIII have been statisti-

cally associated with approximately one-a third of

CTEPH patients.

Obstruction of pulmonary ar-

teries and secondary remodeling of small, periph-

eral pulmonary vessels most likely contribute to

elevated total pulmonary resistance.

8,55–57

Pathologically, organized thrombi are tightly

attached to the medial layer in the elastic pulmo-

nary arteries, and subsequently replace normal in-

tima. The thrombi occlude the lumen or form

different grades of stenosis, webs, and/or bands.

Hypercoagulability in Pulmonary Hypertension

597

Collateral vessels from the systemic circulation

(bronchial, costal, diaphragmatic, and coronary

arteries) can grow to attempt reperfusion of areas

distal to the obstructed territories. The microvas-

cular changes that occur in occluded and nonoc-

cluded areas are similar to those seen in PAH,

although plexiform lesions are uncommon.

2,58

It is estimated that 1% to 4% of acute pulmo-

nary embolism survivors develop CTEPH

within 2 years from their first embolic event.

55,59,60

Anywhere from 25% to 50% of CTEPH patients do

not have a past medical history of pulmonary em-

bolism or deep vein thrombosis.

55,61

It is sus-

pected that thrombotic and/or inflammatory

lesions exist in the pulmonary vasculature, result-

ing in the formation of thromboses and vascular

remodeling without a clinically evident acute

thromboembolic event. Conditions that cause

chronic inflammatory states such as myeloprolifer-

ative disorders and inflammatory bowel disease

Fig. 1. Summary of hypercoagulable pathways in pulmonary arterial hypertension. This figure depicts a schematic

of the pulmonary artery, with the combined known and suspected pathways that contribute to hypercoagulabil-

ity in PAH. This figure is not comprehensive or inclusive of all known hypercoagulability pathways implicated in

PAH. A condensed version of the coagulation cascade is shown, and in PAH, tissue factor (TF) is increased, result-

ing in increased thrombin, fibrin, and formation of clot. Plasminogen activator inhibitor (PAI) is also increased,

decreasing clot inhibitors. Decreased thrombomodulin reduces inhibition of the clot formation. There are also

more activated platelets in patients with PAH, and the effects of activated platelets are shown, including

increased inflammatory mediators, vasoconstriction, platelet aggregation and prothrombotic factors, fibrinogen,

and other adhesion molecules. Activated platelets stimulate growth factors, resulting in proliferation and angio-

genesis. Finally, the prostacyclin, endothelin-1, and nitric oxide pathways are shown, highlighting their differen-

tial effects on vasoconstriction and proliferation, and are the primary targets of the currently available

treatments for PAH. 5HT, serotonin; APC, activated protein C; aPlt, activated platelet; cGMP, cyclic guanosine

monophosphate; eNOS, endothelial nitric oxide synthase; FV, factor V; FVa, activated factor V; FVIIa, activated

factor VII; FX, factor X; FXa, activated factor X; GTP, guanosine triphosphate; NADPH, nicotinamide adenine dinu-

cleotide phosphate hydrogenase; O2, oxygen; PAI, plasminogen activator inhibitor; PC, protein C; PDGF, platelet-

derived growth factor; PGH2, prostaglandin H2; Plt, platelet; PS, protein S; TF, tissue factor; TGFb, transforming

growth factor b; tPA, tissue plasminogen activator; VEGF, vascular endothelial growth factor; vWF, von

Willebrand factor.

Bazan & Fares

598

and postsplenectomy patients have been associ-

ated with the development of CTEPH.

Unlike all

other forms of PH, patients with CTEPH are poten-

tially curable via a pulmonary endarterectomy.

The feasibility and success of this surgery depend

on the surgical accessibility of thromboembolic

residues and the underlying comorbidities of

the patient.

63,64

However, even with successful

removal of chronic clots, some patients continue

to have PH postoperatively. It is speculated that

persistent PH is partly due to the remodeled

microvasculature.

Balloon pulmonary angio-

plasty has also been gaining momentum in CTEPH

management; however, its exact role is yet to be

determined, as its technique, strategy, and cathe-

ters are rapidly evolving.

ANTICOAGULATION AND PULMONARY

HYPERTENSION

Currently, anticoagulation is rec ommended for

patients with IPAH, HPAH, and DTPAH. Accord-

ing to the 2015 European Society of Car diology

and the European Respiratory Society guidelines,

anticoagulation is a class IIb recommendation,

meaning that its usefulness and efficacy are

not we ll established, but it may be considered

(Table 1).

There have been some retrospective

and observational single-center studies that

have shown survival benefit in patients who get

anticoagulation with warfari n.

36,66

These early

studies were done prior to the available PAH-

targeted therapies.

36,66–68

More recent random-

ized control trials and registry data have been

inconclusive . For example, in 2014, the Compar-

ative, Prospective Registry of Newly Initiated

Therapies for Pulmonary Hypertension (COM-

PERA) regis try examined the survival rates of

PAH patient s based on use of anticoagulatio n.

It found that in the subgroup of IPAH patients,

there was a significant improvement in 3-year

survival.

A major caveat to the COMPERA reg-

istry is tha t the median age of this population

receiving anticoagulation was 70 years, and it

does not ref lect the typical demographics of the

PAH popul ation.

In contrast, the Registry to Evaluate Early and

Long-term PAH Disease Management (REVEAL)

compared the survival of IPAH patients on warfarin

with those who have never been anticoagulated,

and found no difference in survival.

These limited

and inconclusive data likely reflect the heteroge-

neity of PAH patients. Clinical use of anticoagula-

tion in IPAH patients is widely variable and

provider dependent. It is generally recommended

that in the absence of contraindications, patients

on long-term intravenous prostanoid analogues

should receive anticoagulation therapy because

of the risk of catheter-associated thrombosis.

The potential benefits of anticoagulation for pa-

tients with APAH is even less clear. A subgroup

analysis of from the REVEAL registry found that

patients with systemic sclerosis APAH had an

increased mortality when treated with warfarin.

The COMPERA registry also found to have other

forms of APAH including those associated with

connective tissue diseases, congenital heart dis-

ease, and portopulmonary hypertension, had no

Table 1

Summary of evidence for anticoagulation by

World Health Organization groups

WHO Group Class of Recommendation

1 PAH IPAH IIb

HPAH IIb

DTPAH IIb

CTD-PAH III

Porto-PH III

HIV-PAH Unknown

CHD-PAH Unknown

2 PH caused by

left heart

disease

Unknown

3 PH caused by

lung disease/

chronic

hypoxia

Unknown

4 CTEPH I

5 Miscellaneous Unknown

Abbreviations: CHD-PAH, congenital heart disease-

pulmonary arterial hypertension; CTD-PAH, connective tis-

sue disease-pulmonary arterial hypertension; CTEPH,

chronic thromboembolic pulmonary hypertension; DTPAH,

drugs/toxins induced pulmonary arterial hypertension;

HIV-PAH, HIV-induced pulmonary arterial hypertension;

HPAH, heritable pulmonary arterial hypertension; IPAH,

idiopathicpulmonaryarterialhypertension;PH, pulmonary

hypertension; porto-PH, portopulmonary hypertension.

Class of recommendation. Class I recommendation: is

recommended/indicated (evidence and/or general agree-

ment that a given treatment of procedure is beneficial,

useful, effective). Class IIa recommendation: should be

considered (conflicting evidence with weight of evi-

dence/opinion in favor of usefulness/efficacy). Class IIb:

may be considered (conflicting evidence with usefulness/

efficacy less well established). Class III: is not recommen-

ded (evidence or general agreement that given treatment

is not useful/effective, and in some cases may be harmful).

Data from Galie

N, Humbert M, Vachiery JL, et al. 2015

ESC/ERS guidelines for the diagnosis and treatment of pul-

monary hypertension. The joint task force for the diag-

nosis and treatment of pulmonary hypertension of the

European Society of Cardiology (ESC) and the European

Respiratory Society (ERS) endorsed by: Association for Eu-

ropean Paediatric and Congenital Cardiology (AEPC), In-

ternational Society for Heart and Lung Transplantation

(ISHLT). Eur Heart J 2015:37(1);67–119.

Hypercoagulability in Pulmonary Hypertension

599

survival benefit with anticoagulation.

Specific to

congenital heart disease APAH, the use of antico-

agulation in patients with Eisenmenger syndrome

is controversial. These patients have a high inci-

dence of pulmonary artery thrombosis and stroke,

but also have an elevated risk of hemorrhage and

hemoptysis.

Although there are no data to guide

this clinical dilemma, the authors’ own practice is

to avoid anticoagulation in congenital heart dis-

ease APAH. Hemoptysis is also a known compli-

cation of patients with IPAH and CTEPH, with

prevalence varying from 1% to 6%,

and it can

limit the use of anticoagulation. Because many pa-

tients with portopulmonary hypertension have

coagulopathy and thrombocytopenia, they have

an elevated bleeding risk; anticoagulation is not

recommended in these patients, although it has

not been studied.

The preferred treatment for patients with

CTEPH, as mentioned previously, is a pulmonary

endarterectomy. Supplemental medical therapy

for CTEPH includes anticoagulation, as well as di-

uretics and supplemental oxygen if needed for

heart failure or hypoxemia, respectively. Although

there are no studies comparing indefinite anticoa-

gulation to no therapy or a shorter duration of anti-

coagulation, data extrapolated from treatment of

acute and recurrent venous thromboembolism

have led to the recommendation of lifelong antico-

agulation for CTEPH patients, even after success-

ful surgical intervention. The placement of routine

inferior vena cava filter placement in this patient

population is not justified by evidence.

The role of direct oral anticoagulants (DOACs)

for any group of PH is unknown. Several studies

have shown that DOACs are at least as effective

as warfarin for the management of venous throm-

boembolism and atrial fibrillation, and some have

shown a reduction in bleeding and mortality.

73,74

DOACs have not yet been studied in people with

PAH, but in a monocrotaline-induced PAH rat

model, rivaroxaban attenuated the increase in

right ventricular systolic pressure and right ventric-

ular hypertrophy caused by monocrotaline.

Although the generalizability of this to people is

limited, it does warrant further investigation into

the role of DOACs in PAH.

Since dysregulated platelets have been identi-

fied in the pathophysiology of PAH, antiplatelet

therapy has been studied. However, although

some studies have shown reduction in throm-

boxane A2 levels and reduction in platelet activa-

tion markers with aspirin, none have shown any

improvement in exercise tolerance.

76,77

These

studies are small, and it is possible that larger

studies or the investigation of newer antiplatelet

agents may identify a role for platelet inhibitors in

the treatment of PAH. It is worth noting, however,

that many of the PAH medications, as mentioned

previously, do have antiplatelet effects.

50,78

SUMMARY

Given how heterogeneous the etiologies and

pathophysiology are for each WHO group o f

PH, it is no surprise that the degree of hyperco-

agulability and benefit of anticoagula tion would

be variable between groups and subtypes.

CTEPH is usually caused by an initial ac ute

venous thromboembolism and has been associ-

ated with thrombophilic disorders; anticoagula-

tion has a clear benefit in these patients. There

is pathophysiological evidence that PAH is a pro-

thrombotic state caused by the dysregulation of

coagulation, fibrinolysis, and endothelial cells.

These abnormalities, combined with in situ

thromboses found in pulmonary arteries, argue

that PAH patients are in a hypercoagulable state

and may benefit from anticoa gulation therapy.

Studies investigating the b enefit of anticoagula-

tion in IPAH patients have yielde d mixed results.

Each individual subtype of APAH will need to be

further investigated to assess the benefit of anti-

coagulation. Given that an increased bleeding

risk limits the use of anticoagulation even in pa -

tients who would derive benefit, further study of

DOACs and antiplatelet agents is also overdue.

ACKNOWLEDGMENTS

The authors have grateful to Ms Isabella Siegel

for her artistic and creative skills in drawing the

figure.

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