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Asthma and coagulation: A clinical and pathophysiological evaluation

Majoor, C.J.

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Citation for published version (APA):Majoor, C. J. (2016). Asthma and coagulation: A clinical and pathophysiological evaluation.

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Download date: 05 Aug 2019

Chapter 1General introduction

11

Asthma

Asthma is a chronic inflammatory disorder of the airways associated with airway

hyperresponsiveness that leads to recurrent episodes of wheezing, chest tightness

and coughing1. Airway inflammation in asthma can be induced by environmental

agents, including inhaled allergens, occupational agents and viruses in genetically

predisposed individuals. The estimated prevalence of asthma is between 1-18%

worldwide depending on the region. In The Netherlands, the total number of

asthmatic patients has been estimated to be 578.000 in the year 2011, a prevalence

of around 34 per 1000 inhabitants2. Although asthma can be well controlled with

inhalational corticosteroid (ICS) treatment in most patients, there is still a subset of

patients with severe asthma requiring chronic oral corticosteroids for control of their

disease. The prevalence of severe refractory asthma, defined as asthma that remains

uncontrolled despite treatment with high doses of inhaled corticosteroids and

longacting β2-agonists, is ≈3.6% of the total asthma population in The Netherlands3.

Pathophysiology of asthma

Inflammation of the airways is a consistent and characteristic feature of asthma that

is strongly associated with airway hyperresponsiveness and asthma symptoms1. It

involves several inflammatory cells and multiple mediators resulting in characteristic

pathophysiological changes4. The characteristic pattern of inflammation in asthma

involves activated mast cells, increased numbers of activated eosinophils and

increased numbers of natural killer and T-helper cells, which release mediators and

contribute to symptoms. Structural cells of the airways, including epithelial cells,

smooth muscle cells, endothelial cells, fibroblasts and myofibroblasts, also produce

inflammatory mediators and contribute to the persistence of inflammation in various

ways1,4. Induced sputum has been a particularly valuable research tool for examining

airway inflammation in asthma5. Normal sputum barely contains eosinophils, but

in untreated patients with symptomatic asthma increased eosinophil counts are

typical. In patients with severe asthma, sputum eosinophils may even persist despite

treatment with high doses of inhaled or oral corticosteroids. These patients with

persistent airway eosinophilia are particularly at risk of frequent severe asthma

exacerbations6 and accelerated decline in lung function7.

12

Inflammation and coagulation

Infl ammation and coagulation are not just interdependent but highly integrated

systems8,9. Infl ammation often leads to activation of coagulation. Infl ammation

has evolved to remove pathogens, harmful cells and materials from the body. But

infl ammation comes at the cost of local tissue injury. Tissue injury results among

others in endothelial damage with plasma leakage in the extracellular tissue as a

consequence. Upon endothelial damage tissue factor (TF) is released and initiates

together with factor VII the extrinsic coagulation cascade (Figure 1). As a result of

activation of hemostasis, blood clots are formed by fi brin and activated platelets.

These blood clots prevent blood loss from the tissue-damaged areas.

Hemostasis has another role beside the prevention of blood loss. It also prevents

spreading of pathogens to other tissues10. In the formation of blood clots neutrophils

and monocytes are entrapped. These neutrophils and monocytes are recruited

to these clot formations by signals depending on the trigger and subsequently

activated. Neutrophils are activated to form neutrophil endothelial traps (NETs).

NETs are comprised of a matrix of DNA and histones catapulted out of neutrophils

upon activation by for example pathogen-associated molecular patterns10. NETs

FIX FIXa

FVIII

FV

FVa

FVIIIa

+

FXIIIProtein Csystem Antithrombin

TFPI

FDPD-dimer

Plasminogen

Plasmin

tPA

uPAPAI-1

α2-antiplasmin

FibrinolysisHemostasis

= inhibiting

= activating

= activating feedback

Figure 1.Extrinsic coagulation cascade and fibrinolytic systemF:factor, FDP: fibrin degradable products, PAI-1: Plasminogen activator inhibitor type 1, TF: Tissue factor, TFPI: Tissue factor pathway inhibitor, tPA: tissue type Plasminogen activator, uPA: urokinase type Plasminogen activator.

13

not only kill the pathogens inside the blood clots, they also activate the intrinsic

pathway by activating factor XII. Furthermore, NETs bind to von Willebrand factor

and thereby activate platelets through the released histones. Finally, NETs inactivate

anticoagulant proteins like tissue factor pathway inhibitor and thrombomodulin by

the release of enzymes like elastase and myeloperoxidase10. This suggests that

coagulation plays an important role in the host defence against invading pathogens.

The close interaction between coagulation and inflammation implies that these

systems need to be well controlled as a disbalance in one of the two systems may

have an effect on the other system.

Therefore the hemostatic balance is maintained by the fibrinolytic system and the

natural anticoagulants, such as antithrombin, tissue factor pathway inhibitor, and

the protein C system. The inflammatory balance is maintained by pro- and anti-

inflammatory cytokines. If these control mechanisms fail, complications may occur.

For example, a failure in coagulation may lead to lethal disseminated infections11 and

autoimmune inflammatory diseases may lead to activation of coagulation resulting in

venous thrombosis12,13. Interference in one of the two systems may have an effect on

the other system. The anticoagulant dabigatran, a direct thrombin inhibitor, reduces

fibrotic changes in mice with an interstitial lung disease 14, whereas corticosteroid

treatment may induce venous thrombosis.

Corticosteroids and coagulation

As early as the 1950s adrenocorticotropic hormone and corticosteroids were

thought to be associated with activation of the hemostatic system15,16. Several studies

suggested that corticosteroids are procoagulant. In patients with Cushing’s disease

or in patients on maintenance corticosteroid therapy, coagulation is activated,

leading to a modest prothrombotic effect17. The effect of glucocorticosteroids on

pro-, anticoagulant and fibrinolytic factors may diverge, depending on the situation

in which they are prescribed (in healthy subjects or patients with active disease)18.

In patients with a renal transplant for instance, long-term oral corticosteroid

treatment leads to a procoagulant state by an increase in PAI-1. After discontinuation

of corticosteroid treatment, PAI-1 levels dropped dramatically19. However, in a

prospective study in healthy individuals, oral dexamethasone 3 mg twice daily for

5 days modestly increased clotting factors VII, VIII and IX, without affecting PAI-1,

D-dimer or soluble CD-40 ligand20. In this study, thrombin-antithrombin complexes

(TATc) and prothrombin fragment 1+2 were not measured.

14

Asthma and coagulation

Hemostasis may also be activated in asthma, probably as a result of inflammation21-24.

In induced sputum, Thrombin, TF and TATc levels are increased in asthmatic mice

and humans23,25,26. Thrombin and TF are correlated with eosinophil count and

with eosinophilic cationic protein in induced sputum23,25. Thrombin and TATc are

also correlated with airway hypersensitivity in patients with asthma25. In a murine

asthma model activated protein C (APC) is reduced and supplementation of APC

is shown to reduce the immunologic and inflammatory Th-2 response26. None of

these studies examined if the activation of coagulation results in clinical symptoms.

The clinical consequence of hemostatic activation may be an increased risk of

pulmonary embolism, especially when exacerbations of asthma occur. Asthma

disease exacerbations are caused among others by allergens, viral infections (like

rhinovirus or RS-virus) or compliance to inhaled and/or oral corticosteroid therapy.

The effect of allergen induced asthma exacerbations on coagulation has previously

been studied, and showed an increased in procoagulant markers in bronchoalveolar

fluid22. Whether more specific disease exacerbations in asthma (like rhinovirus and

compliance to therapy) also induce a procoagulant response is unknown.

Scope of the thesis

Hemostasis is activated in the airways of patients with asthma after an allergic

challenge. It is unknown if local activation of coagulation in the airways due to

respiratory viral infections, such as the common rhinovirus, leads to activation of

coagulation, and whether this activation may induce venous thromboembolism.

Second, corticosteroid therapy may also be procoagulant, but this effect has

not been thoroughly studied, nor has the potential association with the risk of

thrombosis.

If asthma exacerbations or its treatment increase the risk of venous

thromboembolism, thromboprophylactic treatment may be important in these

circumstances. However, anticoagulant treatment increases the risk of bleeding, so

as a first step, a better insight in the clinical and pathophysiological effects of viral

infections and corticosteroid treatment in patients with asthma are mandatory.

15

Aims of the thesis

The aims of this thesis are:

1. To investigate the interaction between asthma and coagulation in general, on

disease severity and clinical implication as specified by the occurrence of venous

thromboembolism.

2. To investigate the interaction between corticosteroid treatment and coagulation

in patients with asthma and healthy controls and the clinical implication specified

by the occurrence of pulmonary embolism in patients using oral corticosteroids.

3. To investigate the effect of rhinovirus infection on coagulation in patients with

asthma and healthy controls.

Outline of the thesis

In Part I of this thesis the interaction between coagulation and asthma is being

presented in three chapters. The current knowledge on the subject of asthma

and coagulation is discussed in a narrative review presented in chapter 2. The

association between asthma and pulmonary embolism and venous thrombosis,

investigated in a cohort of 648 patients collected in three Dutch asthma clinics,

is described in chapter 3. In chapter 4, we investigated the influence of asthma

severity on coagulation in 93 patients with asthma and 33 healthy control subjects in

a cross-sectional analysis.

Oral corticosteroids are the mainstay of treatment of asthma exacerbations and

the maintenance treatment in patients with severe asthma. Therefore, Part II of this

thesis describes the role of oral corticosteroids on coagulation. In chapter 5, the

association between type and duration of corticosteroid therapy, and the incidence

of a first pulmonary embolism is investigated using the PHARMO database cohort. In

chapters 6 and 7, the effect of a 10-day 0.5mg/kg/day oral prednisolone course on

coagulation is investigated in a double blind randomised placebo-controlled study in

patients with asthma of different severity and healthy subjects.

Finally in Part III we investigated the effect of asthma exacerbation on coagulation

in an in vivo human rhinovirus model in patients with mild asthma and healthy control

subjects (chapter 8).

To conclude, in chapter 9 the results of this thesis are summarized, discussed and

implications for future research are suggested.

16

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