Background Pulmonary arterial hypertension (PAH) is of great clinical significance as a life-threatening complication of connective tissue diseases (CTD). Pulmonary artery thrombotic microangiopathy (PATM) is an important pathophysiology of PAH. The concept of PATM refers to localized thrombotic microangiopathy to be defined histologically and should be discriminated from systemic thrombotic microangiopathy characterized by microangiopathic haemolysis and thrombocytopenia. The degree of PATM has been suggested to be associated with vasodilator response, severity, and prognosis of PAH, and anticoagulation therapy might be effective in PAH patients with features of PATM [1]. Haptoglobin (Hp) is a plasma protein mainly produced by hepatocytes, which binds free haemoglobin released from erythrocytes and protects the kidneys from damage induced by haemoglobin. The Hp is measured in clinical setting as a sensitive marker to detect intravascular haemolysis including thrombotic microangiopathy [2].

Objectives We hypothesized that serum Hp levels decreased in patients with PAH due to pulmonary microangiopathic haemolysis. The aim of this study was to investigate the association between serum Hp levels and pulmonary artery systolic pressure estimated by echocardiography (ePASP) in patients with CTD.

Methods This study included CTD patients with suspicion of PAH who were attending Rheumatology Department in Hokkaido University Hospital between August 2015 and August 2016 and underwent echocardiography. PAH was diagnosed based on right heart catheter findings. Serum Hp levels were measured by standardised turbidimetric immunoassay in all patients. Demographic data, laboratory results, and echocardiographic findings were extracted from the medical records. Decreased serum Hp levels were defined as below 19 mg/dL based on the 95th-percentile of healthy controls.

Results Twenty-four CTD patients with confirmed PAH (CTD-PAH) and 32 CTD patients without PAH (non-PAH) were enrolled. Decreased serum Hp levels were significantly frequent in patients with CTD-PAH compared with non-PAH patients (29% vs 6%, p=0.03). In patients with CTD-PAH, serum Hp levels had a significant negative correlation (r = -0.692, p<0.0001, Figure 1) with ePASP, and serum lactate dehydrogenase (LDH) levels were significantly elevated in patients with decreased Hp levels (233±47 U/L vs 187±42 U/L, p=0.01). Follow up study showed lowering ePASP led to normalizing serum Hp levels.

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Conclusions Serum Hp levels correlated negatively with ePASP in patients with CTD-PAH, and serum LDH levels were higher in CTD-PAH patients with decreased Hp levels. These findings suggest that decreased Hp levels in CTD-PAH patients may reflect PATM and subsequent subclinical haemolysis. Serum Hp levels are a candidate of additional non-invasive marker of CTD-PAH to assess the degree of PATM.

References

1. Johnson SR, et al. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006.

2. Barcellini W, et al. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers. 2015.

References

Disclosure of Interest None declared