key: cord-0696601-ic6rsiar authors: Hermans, Cedric; Lambert, Catherine; Sogorb, Amaury; Wittebole, Xavier; Belkhir, Leila; Yombi, Jean Cyr title: In‐hospital management of persons with haemophilia and COVID‐19: practical guidance date: 2020-05-08 journal: Haemophilia DOI: 10.1111/hae.14045 sha: 21ab6cbbb205120ba83e627de342fd1475a82cad doc_id: 696601 cord_uid: ic6rsiar A new disease (COVID‐19) caused by a coronavirus (SARS‐CoV‐2) that appeared in China at the end of 2019 is currently spreading globally. This emerging virus is mainly responsible for respiratory tract infections and potentially fatal pneumonia, mainly in more frail patients. Persons with haemophilia of variable severity and from all parts of the world will likely be infected and develop COVID‐19. We here propose practical guidance for the in‐hospital specific management of haemophilia persons with COVID‐19 including their possible transfer to intensive care unit. Rapid identification of the haemophilia status, undelayed and regular liaison with the haemophilia team, proper therapy with factor concentrates or alternative treatments appear instrumental to prevent haemophilia‐related complications in this setting. Information of patients and their families about COVID‐19, psychological support and good appreciation of the impact of haemophilia on therapeutic decisions including end of life directives are also addressed. Although published epidemiological data are not currently available, it is likely that despite containment measures, haemophilia patients will be exposed to SARS-CoV-2 and develop COVID-19 [1] . Here we offer some practical guidance for persons with haemophilia (PWH) diagnosed with COVID-19, admitted in hospital and possibly transferred to intensive care unit (ICU). These recommendations are empirical and not validated. They are inspired by common sense and the experience gained by a group of haemophilia physicians, specialists in intensive care, internal medicine and infectious diseases from the recent management of patients with COVID-19, including patients with severe haemophilia admitted in our centre. Several national or international haemophilia organizations (World Federation of Haemophilia, European Haemophilia Consortium, ..) have recently issued practical recommendations for PWH or other inherited haemorrhagic diseases affected by COVID-19 [2;3] . It is currently impossible to evaluate the impact of these widely echoed statements on the haemophilia community and on individual PWHs. With the exception of 2 recently published case reports [4;5] , no data have so far been collected about the impact, knowledge, understanding and perception of COVID-19 among PWHs. Proactively, many haemophilia treatment centres have taken the initiative to contact their patients directly to gather information on their current health status and remind them key preventive measures. The recent history of haemophilia is intrinsically linked to viruses, particularly hepatitis viruses B (HBV) and C (HCV) as well as human immunodeficiency virus (HIV) [6] . PWHs and their families are familiar with viruses and their potential dramatic consequences on health, at least those who This article is protected by copyright. All rights reserved have been exposed as a result of the contamination of intravenously administered blood products. Compared to HIV and HCV, SARS-CoV-2 presents major differences due to its mode of transmission and the damage it causes on the lungs. Like HCV and HIV, it is a lipid enveloped virus, that would be destroyed by solvents and detergents used during the production process of plasma-derived clotting factors, a concept familiar to the haemophilia community [7] . Although the presence of SARS-CoV-2 RNA has been detected in blood of patients admitted in hospital with COVID-19 [8] , there is currently no evidence of transfusion transmission of SARS-CoV-2. In a recent study, no recipients of platelets or red blood cell transfusions from donors diagnosed with SARS-CoV-2 infection following donation developed COVID-19-related symptoms or tested positive for SARS-CoV-2 RNA [9] . It seems important to explain to PWHs the fundamental differences between these viruses with respect to their mode of transmission and effects on health. PWHs should also clearly understand that they should follow the same preventive measures against SARS-CoV-2 as the rest of the population. There is no reason to suspect that the clinical presentation of COVID-19, its severity and complications are influenced by haemophilia. It has been hypothesized that PWHs would be at greater risk of developing haemorrhagic complications of the upper or lower respiratory tract directly related to the infection or intracranial haemorrhage following coughing efforts. At present, these data are not confirmed and not supported by evidence. In the absence of published data, these patients are however in theory and in the absence of replacement therapy This article is protected by copyright. All rights reserved with clotting factor concentrates, more likely to develop bleeding complications following invasive procedures such as endotracheal aspiration, intubation and mechanical ventilation. Most PWHs with a suspicion or proven diagnosis of COVID-19 without criteria for hospital admission will be managed at home. Reasons for hospitalization should be the same as in patients without inherited bleeding diseases. Ideally, the following measures should be followed at home: 2. Regular contacts with the HTC. 3. Avoidance of paracetamol over use (not more than 3 g/day). and self-care. 5 . Continuation of regular replacement therapy with not delayed treatment in case of bleeding episode. 6 . Avoidance of shortage of concentrates at home. 7. Maintenance of physical activities to avoid deterioration of joint stiffness and prevent muscle loss. Self-physiotherapy should be recommended. As soon as a PWH is admitted to the hospital, it is essential that the staff be informed about his bleeding disease, regardless of its severity. The use of electronic alerts is strongly encouraged. Patients must be educated to show their haemophilia identification card on admission. Ideally and if logistically possible, PWHs should be referred to the hospital where their HTC is located. This article is protected by copyright. All rights reserved This would contribute to optimizing efficient communication between the different specialists involved, including the haemophilia physicians. Confirmation of diagnosis is based on a Real-Time Polymerase Chain Reaction search for SARS-COV-2 on a deep nasal swab. No special haemostatic precautions appear to be warranted during this procedure for PWHs. The Chest X-Ray is the initial imaging tool of choice. The chest CT-Scan can be used to better assess the extent of disease, identify complications and monitor treatment response [10] . Admission and hospitalization criteria are no different for PWHs compared to non-haemophilia patients. On top of the routine clinical examination, which should include a measurement of the respiratory rate and the non-invasive measurement of oxygen saturation by pulse oximetry, the following work-up is recommended: 1. General biological assessment: CRP, full blood count, renal function, electrolytes, aPTT (activated partial thromboplastin time), prothrombin time, fibrinogen, D-Dimers, FVIII or FIX assay, inhibitor screening, ferritin and troponin levels. 2. Imaging work-up: chest X-ray and chest CT-Scan if indicated. 3. ECG to rule out any underlying cardiac disease and to measure the QTc interval if treatment with hydroxychloroquine is considered. 4 . PWHs should not have arterial blood gases without correction of the FVIII or FIX deficiency (> 50 %). It is important to collect accurate information on the current drug treatment, the recent use of paracatemol, NSAIDs or other drugs, and establish whether the patient is on immunosuppressive (IS) (steroids/other) or on any antithrombotic treatment (aspirin,..). A list of co-morbidities for each patient must be rigorously established: hypertension, diabetes, obesity, cardiovascular disease, renal failure, untreated HCV infection, HIV infection, IS treatment, past history of venous or arterial thrombo-embolic disease. Patients with one or more comorbidities are at risk of developing more complications and adverse outcomes [11] . Information on haemophilia treatment should be collected: replacement therapy (type of FVIII or FIX concentrate, treatment regimen, timing of last administration, presence of inhibitor, past history of inhibitor development, pharmacokinetic data when available, venous access) -Emicizumab (treatment modalities, timing of last administration) -treatment with gene therapy (date of vectors' infusion -study protocol). It is essential to know if the patient is participating in a clinical trial and contact the local study coordinator for further information. PWHs' management is not fundamentally different from that of non-haemophilia patients. It is based primarily on symptomatic fever and pain control, compensation for insufficient oxygenation, and careful monitoring of any deterioration in oxygenation. This management is ideally supervised by internists interacting closely with infectious diseases and intensive care specialists. This article is protected by copyright. All rights reserved The following measures are recommended: 1. Oxygen supply: modalities not different from non-haemophiliac patients. Emicizumab who require activated prothrombin complex concentrate (aPCC) due to the known drug-drug interaction between Emicizumab and aPCC. [2] 7. Rule out associated condition increasing the risk of bleeding (thrombocytopenia). 8. Blood Pressure: careful monitoring of blood pressure and control of hypertension to minimize the risk of intracranial haemorrhage. This article is protected by copyright. All rights reserved 9. Biological monitoring: regular and ideally daily blood tests (CRP, full blood count, liver function tests, aPTT and FVIII or FIX assays, D-dimers) are required. 10 . Thromboprophylaxis: it is not systematically contraindicated in PWHs and should be discussed with the haemophilia team, balancing the bleeding risks and the antithrombotic benefits. COVID-19 appears indeed to increase significantly the risk of arterial and venous thrombosis, especially in patients with severe inflammation, as suggested by markedly elevated D-dimers levels [12] [13] [14] . Thromboprophylaxis with low molecular weight heparin For PWHs admitted to the ICU, the following specific measures are recommended: 3. Daily biological monitoring of haemophilia replacement therapy (aPTT -FVIII or FIX levels need to be monitored using a one-stage or chromogenic based assay). 4 . Presence of severe arthropathy should be taken into account when positioning the patient. Adult PWHs could be more susceptible to nerve compression because of their arthropathy. This is of particular importance in intubated patients when they are set in prone position. 5. Consider thromboprophylaxis unless contra-indicated, even at higher doses (see above), ideally with regular monitoring (anti-Xa assay). 6 . No contraindication to inclusion in any clinical study evaluating a new therapeutic approach, including immunomodulatory agents. Risk and benefits should be evaluated. long as a close monitoring of coagulation parameters is performed and correction of coagulation factors deficiency is achieved. There is very limited published experience of ECMO in PWHs [18] . However, with appropriate replacement and regular monitoring of clotting factor levels, ECMO is feasible in PWHs. 8 . Monitoring of von Willebrand factor (VWF) concentrations is recommended to exclude an acquired VWF deficiency that could be induced by ECMO [19] . Acquired deficiency of VWF could increase the risk of bleeding and alter the efficacy of replacement therapy with FVIII concentrates. It is likely that as for other patients, decisions will have to be made regarding resuscitation in critically ill PWHs. Haemophilia itself, irrespectively of its severity, should not influence the endof-life directives and the "Do Not Resuscitate" order. However, the latter must integrate possible associated co-morbidities and the clinical frailty score. The guidelines developed locally to manage these situations and approved by the local ethics committee should also be considered. Members of the haemophilia team should ideally be consulted. This article is protected by copyright. All rights reserved PWHs and their families usually have a close and long-standing relationship with the multidisciplinary team at their HTC. Every effort should be encouraged to provide PWHs and their families with the necessary support, information and emotional relief throughout this difficult period. As detailed above, the haemophilia specialists will play an important consulting role during the pandemic for PWHs admitted with COVID-19. In our view, they should also proactively value their medical expertise as internists or haematologists by joining the medical workforce required for the daily care of hospitalized patients with COVID-19. Even if challenging, this would give them a unique opportunity to get major insights into the suspected or not yet known implications of the COVID-19 pandemic on PWHs and their management. The same is true for haemophilia nurses and other members of the haemophilia multidisciplinary teams. This article provides practical guidance for the management of PWHs admitted with COVID-19. These recommendations are not based on evidence which is currently lacking. The coming months will be valued to collect data in many HTCs globally, including less developed countries, promote interactions between all stakeholders managing this crisis, update these recommendations and learn useful lessons for the future. 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