Abstract
▪INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder of the hematopoietic stem cells characterized by chronic, uncontrolled complement-mediated intravascular hemolysis resulting in thrombophilia with thromboembolic events (TEs) and cytopenia due to bone marrow failure. PNH is the most vicious acquired thrombophilic state and TEs represent the leading cause of morbidity and mortality in PNH. PNH clone size correlates with the possibility to acquire a thrombosis but thromboses are also present in patients (pts) with small clones. Early detection of TEs is critically to improve the outcome in PNH with the availability of the terminal complement inhibitor eculizumab.METHODS: Between Dec 2013 and Jan 2016 whole-body magnetic resonance imaging (WB-MRI) scans at 1.5 Tesla (T) (Siemens MAGNETOM® Avanto) were performed in 37 pts (51% (19/37) females; median age 44 years (range 24-73 years), median D-dimer 0.23 mg/l (range 0.2-5.1 mg/l) with either PNH (n=23) or AA/PNH-syndrome (n=14). The protocol included a cranial time-of-flight magnetic resonance angiography (TOF-MRA), an arterial and venous contrast-enhanced MRA (CE-MRA), and a T1-weighted contrast-enhanced fat-suppressed gradient-echo sequence (radial volumetric interpolated breath-hold examination (VIBE)). Median clone size of GPI-deficient granulocytes (FLAER) was 88% (range 2.6-100%) and all pts were treated according to the German PNH guidelines, including the use of the terminal complement inhibitor eculizumab (70% (26/37)), with eculizumab being initiated in 23 pts prior to MRI. In the remaining pts eculizumab was initiated post MRI for reasons other than TEs. In 64% (24/37) of the pts no TEs were documented prior to the MRI scans. Two pts had a possible clinical history of TEs, including pulmonary embolism (PE) or deep venous thrombosis (DVT). The remaining pts (29% (11/37)) had a history of venous thromboses (e.g. DVT (5/11), portal venous thromboses (4/11), or vena caval thromboses (2/11)). One pt even had a myocardial infarction and two had a cerebral venous sinus thrombosis or a thalamic infarction. Six pts (16%) had more than just one documented TE in their medical history.RESULTS: In pts with the history of TEs we did not observe a progression of the existing TEs. There was no evidence of PE throughout observation time. In pts under chronic eculizumab therapy and prior TEs, additional bone infarcts involving the lower extremities were seen in one pt. In a second pt the diagnosis of a bilateral renal infarction was made. In two pts with no history of TEs bone infarcts of the lower extremities were seen (clone size >50%). In another pt a previously undiagnosed left renal infarction was observed. Moreover, a clinical non-critical occlusion of the right posterior tibial artery was identified in one pt.CONCLUSIONS: In contrast to previous studies there was no evidence for silent major TEs (e.g. PE) at the time of analysis. We were able to identify previously undiagnosed renal and bone infarctions (overall unknown prevalence) in our cohort of PNH pts. This is the first description of bone infarctions as possible thromboembolic complications in PNH. WB-MRI scans seem to be a novel and feasible method for the assessment of the whole vascular status of a PNH pt and allow the detection of previously unidentified vascular complications. This might directly affect treatment as eculizumab is indicated in PNH pts with TEs. Furthermore, in pts with existing TEs WB-MRI scans might be implicated to document their impact prior to treatment, especially in pts with major TEs or in pts with high disease acitivity and suspicion for TEs (e.g. recurrent abdominal pain or persisting dyspnea). DisclosuresDührsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.
Highlights
In Paroxysmal noctural hemoglobinuria (PNH) thromboembolic events (TEs) represent the leading cause of morbidity and mortality
The diagnostic examination is dependent on the clinical symptoms of the patient, e.g. a patient presenting with unexplained abdominal pain and known PNH would be examined with an abdominal CT or MRI scan only
In PNH patients with a medical (10/37) or even possible medical history (2/37) of TEs, we could not confirm a progression of the existing thrombotic events at the time of MRI examination
Summary
In PNH thromboembolic events (TEs) represent the leading cause of morbidity and mortality. The defective GPI-anchored protein synthesis results in a reduced expression or even absence of GPI-anchored proteins such as CD55 (DAF - decay accelerating factor) and CD59 (MIRL - membrane inhibitor of reactive hemolysis), which play an essential role in complement regulation, especially affecting the alternative complement pathway, explaining the increased sensitivity of PNH cells to complement-mediated intravascular hemolysis, vascular inflammation, and systemic hemoglobin release All of these factors account in part for the increased thrombophilic tendency in PNH patients, in addition to platelet activation, impaired nitric oxide (NO) bioavailability, impairment of the fibrinolytic system, etc.[3,4,5]. Silent TEs in other areas, would not be detected by the abdominal examination even though silent TEs could result in a change of the therapeutic regimen
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