Addressing the impact of SARS‐CoV‐2 infection in persons with congenital bleeding disorders: The Italian MECCOVID‐19 study

Abstract

Since January 2020, the severe acute respiratory syndrome coronavirus 2 (SARSCoV2) pandemic is challenging healthcare systems worldwide with the impact of the associated disease (COVID19), often characterized by severe interstitial pneumonia and respiratory insufficiency, up to need for intensive care (IC) and fatal outcome, particularly in elderly individuals and those with multimorbidities. On the other hand, the scientific community is deeply involved to fill the numerous pathophysiological and clinical knowledge gaps. The large allocation of human and economic resources to face the pandemic and the lockdown mobility restrictions led to develop strategies to minimize risks of inadequate access to the standard medical care for patients with chronic diseases and/or requiring regular clinical monitoring, like those with congenital bleeding disorders (CBD).1 A Spanish experience recently showed that the use of remote telematic communication by physicians and nurses of the Haemophilia Centre (HC) and the logistics for the home transport of the lifesaving treatment products ensured the continuity of diagnostic and therapeutic services and followup of patients, including those enrolled in the clinical studies.2 Further challenges are related to the specific risks and the management of symptomatic disease in patients with CBD.1,3 Indeed, COVID19 is associated with an acquired coagulopathy (COVID19Associated Coagulopathy, CAC), triggered by a powerful storm of inflammatory cytokines, resulting in a hypercoagulable state and risk of venous and arterial thromboembolic events.4 Different protocols of thromboprophylaxis with lowmolecularweight heparin (LMWH) are therefore currently used and studied in clinical trials to reduce thrombotic complications and mortality.5 Specific guidance about the management of hospitalized persons with CBD and COVID19 has been proposed, highlighting the need for rapid identification of the CBD status, undelayed and close contacts with the specialists of the HCs, continuing/intensifying prophylaxis regimens (both replacement and nonreplacement therapy) according to the actual bleeding risk and the association of LMWH thromboprophylaxis.3 At present, limited literature data are available about the prevalence and clinical implications of COVID19 in patients with haemophilia and CBDs. A registry of patients with CBDs and COVID19 was set up in Madrid, Spain by a telephone survey.6 Suggestive symptoms were reported in 42 patients, but SARSCoV2 infection was confirmed by RTPCR only in 6, accounting for a cumulative incidence of 1.73%. All patients showed a mild course of the disease, not requiring hospitalization.6 Restrictions due to the lockdown and limited access to diagnostic tests in the first phase of pandemic clearly affect these data. Furthermore, larger collections of data are needed to address the intriguing issue of the impact of CAC and the related hypercoagulability in infected persons suffering from a congenital condition of hypocoagulability. Indeed, a letter by Iranian authors questioned whether CBD patients could somehow be spared from thrombotic complications. In a series of 9 CBD patients, a single thrombotic event was reported, occurring in a young type 1 von Willebrand disease patient needing IC admission due to severe COVID19.7 The authors concluded that patients with moderate to severe CBD with COVID19 appear to be less likely to have a hypercoagulable state.7 Few data are available also concerning the bleeding risk in patients with CBDs and COVID19. In the Iranian series, two patients experienced bleeding.7 A severe abdominal hematoma in a woman with inherited FXIII deficiency and severe cough due to COVID19 has been reported. She was able to receive LMWH thromboprophylaxis after treatment of acute bleeding and prolonged prophylaxis with FXIII concentrate.8 LMWH was used in a patient with severe haemophilia A on emicizumab prophylaxis and COVID19,9 as well in a patient with mild haemophilia A hospitalized because of acute respiratory failure, in whom, consistent with the hyperinflammatory state, high FVIII levels were found.10 Both these patients did not experience thrombotic or haemorrhagic complications. However, the safety of LMWH in CBD patients with COVID19 and indications about concomitant haemostatic prophylaxis are still uncertain, poorly supported by clinical data. In light of these considerations, the urgent need to perform ad hoc clinical studies in patients with haemophilia and other CBDs infected by SARSCoV2 emerged. These patients are carefully monitored by HCs for their bleeding disorder and the related or unrelated comorbidities, therefore accurate information can be retrieved and prospective followup can be planned. Moreover, national/regional registries of CBD patients are available for epidemiological assessments. An observational retrospectiveprospective multicentre cohort study evaluating the impact of COVID19 in the Italian population of patients with haemophilia and other CBDs was recently designed on behalf of the Italian Association of Haemophilia Centers (AICE). The study (named MECCOVID19, acronym from the Italian Malattie Emorragiche Congenite and COVID19) is aimed to collect epidemiological data about prevalence and incidence of COVID19 in