Pulmonary Hypertension in Thalassemia: Association with Platelet Activation and Hypercoagulable State.
Authors: Singer Sylvia Titi , Rosenfeld Howard , Vichinsky Elliott 
Published: October 2019

Abstract
Pulmonary hypertension (PHT) is a serious, under diagnosed, potentially fatal complication, reported mostly in non-transfused adult thalassemia intermedia (TI) and fewer thalassemia major (TM) patients. Even a mild PHT can further impair cardiac function in these patients with a frequent left heart disease. Yet, understanding of the pathogenesis, early detection and treatment of established PHT are inadequate. Previous reports and autopsies in patients with PHT, suggest thrombotic obstruction of pulmonary arteries, more so in splenectomized non-transfused TI patients.
25 patients, 7 TI and 18 transfused TM patients ages 10 to 47 years (mean 26±10 years) were screened for PHT by Doppler echocardiogram. A right ventricular (RV) pressure of 25mmHg or higher, corresponding to 2.5meter/second (m/sec) tricuspid jet velocity (TJV) was used as the threshold for presence of increased pulmonary artery pressure indicating PHT. In order to determine that hypercoagulability has an important role in the pathogenesis and progression of PHT, we evaluated specific markers of platelet activation and hypercoagulability and their association with PHT. We measured P-selectin levels, a marker for platelet activation; thrombin-anti thrombin III (TAT), indicating increased thrombin generation; abnormal fibrinolysis as indicated by plasminogen activator inhibitor-1 (PAI-1) and by elevated d-dimers, and vWF:Ag a marker for endothelial cell activation/platelet adhesion. PHT was found in seventeen out of twenty five patients (68%). Mean pulmonary artery pressure was 39.8±5.4mmHg (range 33–53mmHg), corresponding to a TJV of 2.5 to 3.6 m/sec. The remaining 8 patients had only trace or no tricuspid regurgitation.
PHT was strongly associated with prior splenectomy, noted in 16 of the 17 patients, and was more severe in older patients: 7/17 (41%) with a pressure of ≥40mmHg, were over 30 years old. Surprisingly, a high proportion of patients 10/17 (58%), was on regular transfusions. Elevated P-selectin levels were significantly associated with PHT (p<0.0001) and higher in non-transfused TI patients (67.8±13 ng/ml) compare to transfused ones (47±19 ng/ml). Elevated P slectin and PHT were associated with absence of spleen. TAT Levels were higher in patients with PHT at 16±33μg/L, compare to those with normal pulmonary artery pressure 13±6μg/L (nl <4μg/L). Increased fibrinolysis was not associated with PHT as indicated by normal PAI-1 activity (mean 13.2±3.9) and non elevated d-dimers values. There was a trend of elevated vWF:Ag levels among patients with PHT; 128±35% Vs 100±12% (nl 50-150%).
Our data shows a high prevalence of mild to moderate PHT in adult thalassemia patients, even in the ones on regular transfusions, implying that regular transfusions do not prevent but rather attenuate the progression of increased pulmonary pressure. The impact of even modest PHT is crucial in these patients who have a limited ability to tolerate cardiac dysfunction due to other cardiac and systemic manifestations of their disease. This preliminary data confirms the presence of platelet activation and a procoagulant state in patients with PHT, correlating with prior splenectomy, and suggests that endothelial disruption is involved in the pathogenesis. Moreover, P-selectin, a marker of platelet activation and a direct inducer of procoagulant activity, proved to be a sensitive marker for the presence of PHT. Future interventional studies with direct P-selectin inhibitors may be an effective treatment modality.