Download

Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic 

Francesco Rodeghiero1, Silvia Cantoni2, Giuseppe Carli3, Monica Carpenedo4, Valentina Carrai5, Federico Chiurazzi6, Valerio De Stefano7, Cristina Santoro8, Sergio Siragusa9, Francesco Zaja10 and Nicola Vianelli11.

1 Fondazione Progetto Ematologia, Vicenza.
2 Dipartimento di Ematologia e Oncologia, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano, Ospedale Niguarda, Milano.
3 Divisione Ematologia, Ospedale S. Bortolo Vicenza, Vicenza.
4 UO Ematologia e Trapianto, Azienda Ospedaliera "S. Gerardo", Monza.
5 A.O.U. Careggi - Ematologia, Firenze.
6 Dipartimento di Ematologia e Trapianto di Midollo, Ospedale Universitario Federico II, Napoli.
7 Dipartimento di Scienze Radiologiche ed Ematologiche, Sezione di Ematologia, Università Cattolica del Sacro Cuore – Fondazione Policlinico A. Gemelli IRCCS, Roma.
8 Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, Roma.
9 Dipartimento Promise, Università degli Studi di Palermo, Palermo.
10 Dipartimento Clinico di Scienze Mediche, Chirurgiche e della Salute, Università degli Studi di Trieste, Trieste.
11 Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Correspondence to: Francesco Rodeghiero. Hematology Project Foundation, Contrà San Francesco 41, 36100 Vicenza - Italy. Tel. +39 0444 751731 - +39 0444 926190. E-mail rodeghiero@hemato.ven.it  

Published: May 1, 2021
Received: March 25, 2020
Accepted: April 10, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021032 DOI 10.4084/MJHID.2021.032

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(
https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The current COVID-19 pandemic requires revisiting our current approach to major blood disorders, including ITP (Immune Thrombocytopenia), stirring  up the production of several disease-specific practical guidelines. This report describes an updated version of consensus-based practical guidelines on the management of ITP, adapted to the Italian health system and social context.  It highlights the role of the hematologist in offering guidance for choosing differentiated approaches in relation to specific circumstances and is intended to provide them with a useful tool for sharing the decision-making process with their patients.

Probably, the greatest risk to avoid for a patient with suspected, ongoing or relapsed ITP - that is not severe enough to place him or her at risk for major bleeding - is to be infected in non-hospital and hospital healthcare settings. This risk must be carefully considered when adapting the diagnostic and therapeutic approach.

More in detail, the document first addresses the appropriate management for COVID-19 negative patients with newly diagnosed ITP or who experience a relapse of previous ITP, according to first and second-line of treatment and then the management of COVID-19 positive patients according to their severity, from paucisymptomatic to those requiring admission to Intensive Cure Units (ICU). The pros and cons of the different treatments required to correct platelet count are discussed, as are some specific situations, including chronic ITP, splenectomy, thromboembolic complication and anti COVID-19 vaccination.



Introduction

The current COVID-19 emergency, which is still in full development, suggests keeping ITP management guidelines updated - giving them wide dissemination. For Italy, this has been done thanks to the collaboration of many interested stakeholders (HPF, GIMEMA, SISET, Ematologia in Progress, AIPIT). A first version, available on request, released in June 2020 by the Hematology Project Foundation (HPF), was made available to several ITP centers as well as to individual patients.
This update was coordinated by Nicola Vianelli in collaboration with HPF to adapt some of the previous practical recommendations to the new knowledge and the suggestions collected in some recent discussion forums organized by HFP. Moreover, the panel of experts was enlarged, and preliminary results from a recent survey on the management of patients with ITP during this pandemic, jointly conducted by HPF and GIMEMA with the involvement of all major Italian referral centers for ITP, have been taken into consideration in this update. We reiterate the strictly indicative value of the recommendations due to their limited scientific evidence and the consequent low level of recommendation compared to the so-called "trustworthy guidelines". [1,2] Within these limitations, we intend to offer guidance to physicians who treat ITP patients while providing them with a useful tool for sharing the decision-making process with the patients.
Furthermore, after the release of the first version of the document, additional discussion forums, promoted by HPF, were held among experts from the major Italian ITP centers, and the recommendations of British colleagues[3] and an updated version of the FAQs by ASH[4] were taken in due account.
The term COVID-19 defines the disease caused by the novel coronavirus, named SARS-CoV-2. For convenience, we will use the term COVID-19 extensively to refer to the disease and infected patients, using the term SARS-CoV-2 where required by the context.

Thrombocytopenia and COVID-19

Generalities. Thrombocytopenia - defined as a platelet count < 150,000/μL - is quite frequent in patients with COVID-19, reaching up to 36% of cases,[5] whereas cases with moderate or severe thrombocytopenia are quite rare. However, within an analysis of 183 patients who were hospitalized for COVID-19, thrombocytopenia < 100,000/μL (7 cases) and < 50,000/μL (5 cases) was observed in the 21 patients who died,[6] confirming an association between the level of thrombocytopenia and the severity of the clinical picture of SARS-CoV-2 infection.[6,7] According to a recent revision, patients with severe thrombocytopenia hospitalized for COVID-19 (values < 50,000/μL) have a mortality relative risk 13.7 times higher compared to patients with a normal platelet count.[8] COVID-19 thrombocytopenia is generally concurrent with a complex coagulopathy characterized by APTT/PT prolongation and also by a marked increase of D-dimer while fibrinogen is either within normal ranges or notably increased. This coagulopathy (DIC-like) first represents a local pulmonary vascular reaction and then a systemic reaction to the hyperinflammation and cytokine storm triggered by the viral infection. The virus interferes directly with the coagulation system or acts indirectly through the immune response.[9-11] This results in a prothrombotic state with probable activation of endothelium and platelets.[12] Similar phenomena are observed in other serious infections (septicemia, SARS, MERS) that require treatment in the Intensive Care Unit (ICU). Among the many factors responsible for thrombocytopenia, exposure to numerous drugs, hemodialysis, and ECMO (Extra Corporeal Membrane Oxygenation) should also be noted. No cases of heparin-induced thrombocytopenia (HIT) have been reported so far, which only exceptionally occurs with the low molecular weight heparin (LMWH) commonly used in Italy, but less infrequently with the use of standard heparin. However, this eventuality should be considered in differential diagnoses.
Role of the hematologist. Based on the experience of the authors of these recommendations, Italian internists and anesthesiologists treating COVID-19 patients require hematologic consultation almost exclusively in patients in whom the suspicion of ITP appears likely, such as in case of a rapid (1-3 days) onset of severe thrombocytopenia with levels < 30-50,000/
μL. In these cases, the consultation of a hematologist, preferably an expert in hemostasis and thrombosis, can be crucial in excluding other causes of thrombocytopenia, such as HIT (which is very rare with the use of LMWH), drug-induced thrombocytopenia, bone marrow aplasia/megakaryocytic aplasia, thrombotic thrombocytopenic purpura. The hematologist may also be consulted in the interpretation of coagulopathy and in the choice of a prophylactic or therapeutic approach to thromboembolic phenomena (see paragraph “Management of second or further line”).
At the moment, there is no evidence of an increased incidence of ITP in patients with COVID-19 infection. However, at least 30 cases of severe thrombocytopenia classifiable as COVID-19-associated with reduced response to corticosteroids and immunoglobulins have been reported (individual publication references are available upon request). This apparent low incidence of ITP in patients with COVID-19 will, however, need to be confirmed by literature data, as it is well known that some viral infections may be a factor favoring the onset of ITP.

Management of COVID-19 Negative Patients WITH Newly Diagnosed ITP or Who Experience A Relapse of Previous ITP

Preface. This section refers to patients who are COVID-19 negative on the basis of molecular swab testing or antigen test or to asymptomatic patients with an unavailable result at the time of initiation of therapy.
Probably the greatest risk for a patient with suspected ITP or relapse of previous ITP, not at risk for major bleeding, is to be infected in non-hospital and hospital healthcare settings, through contact with contaminated objects, or directly by health care personnel, especially if personnel and patients are not adequately equipped with prescribed personal protective equipment. This risk must be carefully considered when adapting the diagnostic and therapeutic approach proposed to the patient.
However, in the suspicion of a new diagnosis or a relapse of ITP, we suggest performing appropriate tests to ascertain the absence of previous or ongoing SARS-CoV-2 infection, if these are available, and if they can be performed without any predictable risk of infection. Molecular testing by nasopharyngeal or oropharyngeal swab using the rt-Real Time PCR technique remains the standard test. If not possible or in case a quick response is required, a rapid antigenic test can be considered, remembering, however, that the sensitivity of this type of test can be just above or equal to 70% of positive cases (up to 30% of positive cases not identified). Serologic testing has a minimal role and might be reserved for asymptomatic patients to rule out prior or early COVID-19 disease. In addition, serologic testing has limitations, for example, in patients treated in recent months with rituximab because of insufficient antibody response; generally, positivity appears about 12 days after the infection, making these tests of little use for the diagnosis of recent infection. Moreover, it has not been established whether the presence of the so-called neutralizing or protective antibodies prevents the patient from being re-infected by SARS-CoV-2. See also the ISS website.[13]
Asymptomatic patients with an unavailable result at the time of initiating therapy are considered from a practical standpoint to be COVID-19 negative.
Moreover, always in the light of the risks of contagion, we should consider that - except for particular situations (advanced age, previous history of major bleeding) - most patients do not present relevant bleeding symptoms in the presence of platelet counts ≥ 10-20,000/
μL. Therefore, in stable patients, even if with low platelet counts, as long as they have no bleeding symptoms, it is recommended to reduce the frequency of ambulatory visits and platelet count checks to reduce the risk of contagion associated with patients' access to health care facilities.
First-line treatment. First-line treatment of ITP in COVID-19-negative patients does not require substantial changes from recent international guidelines.[14,15] There is no evidence that corticosteroid use increases the risk of developing COVID-19 infection or of worsening its course.[16]
Therefore, the initial treatment remains based on corticosteroids, such as prednisone 1 mg/kg/day (maximum initial dose 80 mg) for 3-4 weeks, including the tapering phase. The current practice in some centers to use dexamethasone (40 mg/day for 4 days with several cycles repeated at intervals of 10 days up to a maximum of 4 cycles) is not supported by the indications on ITP and COVID-19 produced by British colleagues[3] and by the updated version of the FAQs by ASH[4] and therefore could be reserved for cases with a very low platelet count (< 10,000/
μL), especially if with hemorrhagic symptoms, in which a very rapid increase in platelet count is considered clinically relevant. However, in such cases - if applicable - the administration of intravenous immunoglobulins (IVIg), 400 mg/day for 5 days or 1 g/kg/day for 1-2 days, is preferred. In case of major life-threatening bleeding or associated with severe organ damage, such as cerebral hemorrhage,[17] the use of platelet transfusion remains recommended. There are no reported cases of SARS-CoV-2 transmission through platelet transfusions.
However, it is reasonable to avoid or limit steroid use in a severe pandemic situation (see paragraph "Patients admitted into ICU" for the use of corticosteroids in symptomatic COVID-19 patients). Therefore, in the absence of need for a rapid increase of platelet count, the early (off label) use of a TPO-RA (possibly combined with IVIg) is suggested, aware that its possible efficacy will require 1-2 weeks to become apparent. The dose adjustments could be made on the basis of telephone or electronic (email) contacts, being the platelet counts performed in laboratories located close to the patients. This is the only approach feasible in patients with significant contraindications to steroids. The use of tranexamic acid (about 15 mg/kg/day every 8 hours), considered helpful in controlling mucosal bleeding such as epistaxis, menorrhagia, gingival bleeding, is not supported by clear evidence. In clinical practice, 2 vials of 500 mg every 8 hours are administered orally (or intravenously) in adults. Antifibrinolytics should be avoided in case of hematuria.
Management of second or further line. In the absence of direct comparison studies in terms of risk/benefit, the current guidelines do not allow to establish any superiority among the three main therapeutic approaches: TPO-RA, rituximab, and splenectomy. However, from a careful reading of the parts of the documents where the advantages and disadvantages of individual treatments are discussed in the context of good clinical practice, we can note a general preference of the authors for the use of TPO-RA compared to rituximab and even to splenectomy. When it can be safely performed even from a hospital organizational point of view, splenectomy remains a viable option even in the current pandemic situation. No evidence indicates an increased risk of contracting SARS-CoV-2 infection.
Among the two TPO-RA available in Italy (romiplostim and eltrombopag), there is no preference between the two products in patients starting the treatment in the COVID-19 period. However, for both, remote monitoring is recommended, and self-treatment is suggested for patients treated with romiplostim. Moreover, in some local healthcare centers, the delivery of both TPO-RAs to the patient's home has been activated, a valuable practice to be encouraged extensively. If patients are already in treatment at the time of the COVID-19 pandemic, there is no reason to switch from one TPO-RA to the other unless in case of loss of response to the agent in use. However, we should consider that the use of TPO-RA is associated with an increased thromboembolic risk,[18,19] which in case of development of COVID-19 infection could further increase. In case of inefficacy or intolerance to TPO-RA (around 70%), it seems reasonable to suggest as third-line treatment the use of minimal doses of corticosteroids (
10 mg/day) for the time strictly necessary, or immunosuppressants at the minimum effective dose, or possibly dapsone for centers that have experience with its use. In some patients, the combination of TPO-RA with low doses of steroids or immunosuppressants can restore a clinically effective platelet count, reducing the use of high doses of the individual active drug.
The administration of rituximab, even in reduced doses, is not recommended, also in compliance with what is suggested by the authors of the UK and ASH guidelines. The latter - if in the individual case rituximab should be used in the absence of alternative therapies - recommend the possibility of administering plasma from donors recovering from COVID-19. Indeed, patients recently treated with rituximab (up to 6 months earlier) may not have adequate antibody response to the infection[20] and - more importantly - may not respond to COVID-19 vaccines. There are no data regarding the use of fostamatinib in patients with ITP and COVID-19. However, its use in the treatment of severe COVID-19 in non-ITP patients is being considered of potential value[21,22] and, if prospective controlled trials prove its favorable effect, this agent could be an option in some refractory ITP patients at risk of bleeding.

Management of COVID-19 Positive Patients with Newly Diagnosed ITP or Who Experience a Relapse of Previous ITP 

Paucisymptomatic patients not admitted into ICU. In paucisymptomatic COVID-19 patients who are not admitted to the ICU, we suggest the same approaches recommended by the first-line treatment guidelines and reported above. However, without evidence on the effect of steroids on the course of COVID-19 infection, in patients without hemorrhagic manifestations the general consensus, as a precaution, is to reduce the dosage and duration of administration (e.g., initial prednisone dose 20-25 mg/day regardless of body weight, with dose increase if necessary after 3-5 days, up to a maximum of 80 mg/day). In any case, prolonged administrations should be avoided, and tapering should be initiated within 2 weeks after the start of therapy. The use of IVIg is generally encouraged and could positively affect the infection's evolution.[23] There is no contraindication to the infusion of plasma obtained from patients recovering from COVID-19. However, hematologic consultation is required.
Patients admitted into ICU. Patients with ITP hospitalized for COVID-19, in internist wards and even more in the ICU, have numerous thromboembolic risk factors in addition to the infectious state (immobilization, respiratory failure, mechanical ventilation, use of central venous catheters). Moreover, COVID-19 infection with the associated cytokine and coagulation disorder is of particular concern in the absence of evidence on its treatment. For patients hospitalized in the ICU, each therapeutic intervention should be discussed, case by case, by the consultant hematologist and the intensivist. While the above suggestions for corticosteroids, IVIg, and TPO-RA treatments remain generally valid, it should be noted that it could be advantageous to use a TPO-RA administered subcutaneously in patients receiving parenteral nutrition.
It should also be noted that on the basis of the results of the so-called Recovery Trial,[24] the administration of 6 mg per day of dexamethasone (equivalent to about 60 mg of prednisone) for a maximum of 10 days, allowed to significantly reduce mortality at 28 days from randomization only in those patients who required invasive mechanical ventilation or simple assistance with oxygen, but not in those without the need for respiratory support. Particular attention should be paid to prophylaxis and possible antithrombotic treatment with LMWH or sodium heparin under continuous infusion in the ICU setting and the possible use of antifibrinolytic agents.
Thromboembolic risk and diffuse arterial microthrombosis. It is now well established that COVID-19 patients, even if only hospitalized, without the need to be treated in the ICU, have a thromboembolic risk 3-4 times higher than internist patients in general, who have a risk estimated around 10%. Unexpectedly, even in initially asymptomatic cases, a severe infectious picture can worse very rapidly, often complicating with a complex coagulopathy. This latter is clinically expressed with a further marked increase in thromboembolic risk, as well as with altered coagulation tests, and may be associated with the presence of microthrombi disseminated in the arterioles of various organs (heart, brain, kidneys), in a framework of diffuse endothelitis starting from the capillaries of the pulmonary alveoli.[9-11,25]
A systematic literature review with a meta-analysis of 66 clinical trials, including 28,173 COVID-19-positive patients with a mean age of 62.6 years (60% males) showed an overall VTE prevalence of 14.1%.[11] A subanalysis showed a prevalence of venous thromboembolism (VTE) of 22.7% in patients admitted to ICU and 7.9% in non-ICU patients. The prevalence of pulmonary embolism (PE) in ICU and non-ICU patients was 13.7 and 3.5%, respectively. A higher plasma level of D-dimers emerged as the only significant predictor for VTE.
In a series of 182 ICU patients with COVID-19 pneumonia, venous and arterial thromboembolic complications were identified in 31% of cases, 81% represented by PE.[26]
In a single-center series of 198 patients treated in various medical departments (n=123) or in ICU (n=75) at the University of Amsterdam, thromboembolic events were studied, using objective methods, even in asymptomatic patients. VTE in patients with permanence in the ICU was much higher (47% equal to 35/75 up to 60-70% in cases of prolonged permanence in the ICU) than in patients hospitalized in internal medicine departments (3.2% equal to 4/124). In patients admitted to the ICU, the high incidence of thromboembolism was reduced by about half when only symptomatic patients were considered. This alarming frequency of thromboembolic complications occurred even though all patients were administered nadroparin at prophylactic doses and then had their doses doubled (ICU patients 2850 IU anti-Xa twice a day if bodyweight <100 kg or 5700 IU anti-Xa twice a day if bodyweight ≥100 kg; in non-ICU patients half of the standard dose for surgical prophylaxis).[27]
In another study conducted in China on 449 patients with severe COVID-19 with mortality around 30%, the use of LMWH in the 99 treated patients (22%) was shown to reduce mortality only in those with the most severe coagulopathy (60 to 40%), despite using prophylactic doses of enoxaparin (40-60 mg/day).[6] In both these studies, almost prophylactic doses were administered (apart from the ICU patients in the Dutch study), and therefore it remains to be determined whether an increase in heparin dosage was not preferable. 
In any case, LMWH is not recommended even at prophylactic doses if the platelet count is < 30,000/
μL; higher doses require a count > 50,000/μL. However, the use of LMWH in these cases should be shared with the physician/anesthesiologist treating the patient for COVID-19. Close monitoring is recommended with regard to both the hemorrhagic risk, which is still increased even in severe patients with COVID-19 without thrombocytopenia, and the thrombotic risk.
The venous and arterial thrombotic risk could be further enhanced in patients with previous splenectomy,[28] even more when treated with TPO-RA. On the other hand, the need for generalized antithrombotic prophylaxis with LMWH and especially the need to use therapeutic doses justifies implementing an appropriate therapy with TPO-RA to obtain a platelet count that allows antithrombotic treatments. 
As mentioned above, we cannot exclude that in addition to classical thromboembolism, hemostatic abnormalities and hyperinflammation may result in the in situ formation of microthrombi at the level of the pulmonary vascular system, with subsequent extension of the phenomenon to the local pulmonary level and other districts (heart, brain, kidneys).[9-11,29,30]
Given that COVID-19 coagulopathy could be associated with intense fibrinolysis (as indicated by an exceedingly high D-dimers level) that may be protective,[31] the use of tranexamic acid should be reserved for patients with active bleeding and only after careful evaluation of the risk-benefit ratio in the individual patient, due to the possible protective mechanism of fibrinolysis, where plasmin formation can be either deleterious or beneficial.[32]
Accordingly, antifibrinolytics should be avoided in cases of evident DIC. The duration of treatment should be as short as possible. However, the relationship between COVID-19 infection and the coagulation and fibrinolytic system is an area of clinical research. The use of bedside diagnostic methods such as thromboelastography could potentially guide the approach towards severe coagulopathy in patients admitted to the ICU,[33] but further confirmatory data are needed.

Management of Patients with Chronic ITP

In COVID-19 negative patients. In stable patients with a satisfactory response to current treatments, there is no need to make any particular changes from the second-line treatments proposed in paragraph "Management of second or further line". Any change in therapy could result in increased risks related to the need for more frequent monitoring and the possibility of a loss of response.
In COVID-19 positive patients. The same recommendations proposed in paragraph “Management of second or further line” apply, recalling as a precaution the need to avoid high doses of corticosteroids or immunosuppressive drugs unless strictly indicated by the treatment protocols adopted, even in the absence of direct evidence. The use of rituximab is definitively discouraged for the reasons stated above, but if absolutely necessary, the availability of plasma from donors recovering from COVID-19 should be preliminarily ascertained.
If a COVID-19 infection develops in a patient with ITP and platelet count falls to unsafe levels (< 10-20,000/
μL), the recommended approach is the use of IVIg, possibly repeated as needed, reserving platelet transfusion for major bleeding. If the patient was already on TPO-RA, the dose could be increased to the maximum allowed. Short-term use of steroids (e.g., prednisone 1 mg/kg/day for 5 days) or possibly a dexamethasone cycle (40 mg/day for 4 days) could also be considered.
To date, no data are demonstrating an increased incidence of COVID-19 infection in patients with current or prior ITP, nor more severe manifestations of infection.

Splenectomized Patients

It is reasonable to assume that splenectomized patients do not have an increased risk of COVID-19 infection. However, they are more likely to be exposed to some bacterial infections. It is crucial to ascertain their vaccination status and, if necessary, revaccinate them for Pneumococcal, Meningococcal, and type b Hemophilus influenzae, as well as for seasonal flu. Moreover, should they not be on permanent prophylactic antibiotic therapy, as routinely prescribed in some countries (e.g., UK), it is recommended from the first onset of fever over 37.5°C, to start antibiotic therapy without delay, if possible preferably intravenous (e.g., amoxicillin combined with clavulanic acid).
If the situation does not show a rapid improvement, hospitalization is recommended because of the need for close surveillance and clinical and laboratory examinations, which must necessarily include blood culture tests. This recommendation derives from the possible occurrence (albeit very rare) of septicemia with acute or fulminant course and from the possibility of bacterial superinfections resistant to common antibiotics.

 

Pregnancy

The risk of adverse outcome during pregnancy in women with COVID-19 is estimated to be around 2.4% and 1.8% for the newborn.[34,35]
Published epidemiological data indicate that, although the mortality due to COVID-19 in Italy was initially higher than in China, the prognosis of pregnant women in our country is comparable with that in China. An Italian study including 42 pregnancies in women positive for SARS-CoV-2 documented, out of 7000 deliveries observed between February and April 2020 in Lombardy, two preterm deliveries, seven accesses of pregnant women in the ICU with excellent resolution, and no fetal or neonatal deaths.[36] However, vertical transmission cases from mother to fetus have been described in the literature.[37]
Therefore, even for pregnant women with ITP positive for SARS-CoV-2, the recommendations derived from the non-pregnant ITP population can be maintained, with the specific precautions adopted in pregnancy, particularly contraindications to the use of TPO-RA and immunosuppressive drugs. A constant multidisciplinary approach is recommended for the pregnant woman with ITP, including the involvement of different specialists (hematologist, gynecologist, intensivist and infectious disease specialist).
There are no specific contraindications to pregnancy in COVID-19 negative ITP patients, for whom the commonly accepted indications in this setting are applicable. There is no contraindication to the COVID-19 vaccine in pregnant women. Should de-novo ITP develop in a COVID-19 positive pregnant woman, steroids at lower than standard doses and immunoglobulins can be used in current clinical practice.

Measures to Prevent Contagion

Scrupulous application of the indications on interpersonal distancing and the use of masks and gloves are required. There are no specific contraindications about returning to work if adequate protection measures against contagion are ensured. However, it is advisable to check with the referring hematologist.

Anti-COVID-19 Vaccination

Since January 2021, an anti-SARS-CoV-2 vaccination campaign has been launched in Europe and in particular in Italy, initially targeting healthcare workers and subsequently the most fragile categories of the population (elderly over 80 years, etc.), with priorities yet to be precisely established. The presence of current or previous ITP should not be a criterion for priority in vaccination.
Data on the two vaccines available at the writing date (Pfizer and Moderna) are presented by two phase 3 papers published in the New England Journal of Medicine.[38,39] Although conducted in a relatively small number of individuals observed for a short period of time, these studies did not show specific side effects.
Immune thrombocytopenia, especially if in a stable phase, should not represent a contraindication to vaccination. In patients with risk of bleeding after intramuscular administration (e.g., platelet count < 20,000/
μL), adequate patient disclosure and possible prolonged observation are recommended.
Vaccination is strongly suggested for patients in whom treatment with rituximab or immunosuppressive agents is expected to be needed soon (to be administered, if possible, at least one month before starting these therapies).
Data on the use of the vaccine during pregnancy are currently very limited. Laboratory studies conducted on animals have not shown harmful effects during pregnancy. Although there are no specific recommendations based on clinical trials, vaccination is not contraindicated in an absolute way in pregnancy and, once the risk/benefit ratio has been positively assessed during the patient's consultation with the hematologist, the infectious disease specialist, and the gynecologist, it can be considered feasible. The same considerations apply to breastfeeding women.[40,41] In this regard, see also the links to AIFA FAQ (in Italian) and CDC recommendations.[42,43]

Additional Note

The Authors of these guidelines recommend that, despite the COVID-19 pandemic, all involved centers continue to actively participate without interruption to all company or investigator-driven clinical trials exploring the safety and efficacy of new drugs for ITP, possibly also using direct contact with patients, by means of electronic communications or by phone. In particular, the following drugs in phase III studies are of primary interest: FcRn inhibitors like efgartigimod (Argenx) or rozanolixizumab (UCB); rilzabrutinib (Principia) and a reversible inhibitor of Bruton Tyrosine Kinase (TAK-079/ mezagitamab (Takeda) an inhibitor of CD 38 cells, still in phase II).
Similarly, there is a need to continue to enroll patients into the national registries and to participate in “real word studies” exploring traditional approaches, such as those based on the various TPO-RA and on the recently introduced Syc inhibitor (Fostamatinib).
Updated information on new and old drugs is even more relevant since this pandemic reveals that precision medicine should be adopted and that all current treatments have some limitations.

Caveat

This document, updated to 27 April 2021, is limited to offer general suggestions and it remains the responsibility of the individual hematologist to adapt them to the individual patient.
Regarding potential SARS-CoV-2 vaccine–risk, last release updates from EMA should be considered (https://www.ema.europa.eu/en). Unfortunately, recently rare cases of massive disseminated thrombosis often accompanied by severe to moderate thrombocytopenia or DIC have been reported. This new syndrome manifests with venous sinus thrombosis (CVST) and/or splanchnic venous thrombosis and in some cases also with venous or arterial thromboembolism. So far, the occurrence of this severe complication, not rarely resulting in death, has been described only with DNA recombinant vaccines using adenoviral vector encoding the spike protein of SARS-CoV-2.
Initially described in association with the first dose of AstraZeneca vaccine (Vaxzevria), mostly in women younger than 55 years, more recently, similar events were also reported after Janssen (Johnson&Johnson) vaccine, apparently at a lower rate. While Vaxzevria uses a chimpanzee adenovirus as vector (ChAdOx1 nCoV-19), Janssen (Johnson&Johnson) uses a human one (Ad26.COV2.S). Occasionally, atypical thrombosis has been reported also with RNA-based vaccines.
Given the rarity of the events, the strength of any association is not yet definitely proven and the benefits of vaccination still outweigh the risks. For more information on Vaxzevria visit the EMA safety committee (PRAC) press release of 7 April 2021 at https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood and of 13 April 2021 at https://www.ema.europa.eu/en/medicines/dhpc/vaxzevria-previously-covid-19-vaccine-astrazeneca-link-between-vaccine-occurrence-thrombosis.
For Johnson & Johnson vaccine, visit https://www.ema.europa.eu/en/documents/product-information/covid-19-vaccine-janssen-epar-product-information_en.pdf, updated at 22 April 2021. A Eudra Vigilance report as of 4 April 2021 includes a total of 169 cases of CVST and 53 cases of splanchnic vein thrombosis with Vaxzevria vaccine. Around 34 million people have been vaccinated in the EEA (Economic European Area) and UK by this date. The more recent data do not change the EHA PRAC recommendations. Recently, three articles and an Editorial paper were published in a leading medical journal describing 39 cases associated with the newly described syndrome, characterized by thrombosis and thrombocytopenia, that developed 5 to 24 days after initial vaccination with Vaxzevria.[44-47] The pathogenic mechanism of this new entity called Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) seems related to the induction of autoantibodies against platelet factor 4 (PF-4)-polyanion complexes. This is similar to heparin induced thrombocytopenia (HIT), in which PF-4-heparin complexes are the target of the autoantibodies that inappropriately activate platelets inducing thrombocytopenia and thrombosis. It is recommended to avoid heparin and to prefer other anticoagulants, like fondaparinux. High doses of corticosteroids and IVIG are suggested as the most effective treatment for the correction of the accompanying severe thrombocytopenia in order to control or prevent cerebral hemorrhages, often the leading cause of death in CVST.
Currently, different European Countries are following specific policies of vaccination that may deviate from EMA precise indications and the treating physician is required to access the most updated information from the competent national regulatory agencies.
At this moment in Italy both the DNA recombinant vaccines are preferably administered to people aging 60 or more (https://www.aifa.gov.it/domande-e-risposte-su-vaccini-vettore-virale). Fortunately, so far no cases of VITT have been reported in patients with past or ongoing ITP.
In addition to VITT, some cases of “typical” ITP with or without bleeding, but without thrombosis, have been reported as induced by or revealed after exposure to the messenger RNA (mRNA)–based vaccines as those produced by Moderna (mRNA-1273) and Pfizer–BioNTech (BNT162b2).[44,48] This is not of major surprise, considering that similar rare cases have been observed after “traditional” vaccine administration against other infectious agents and could thus be expected. In this regard, a study is ongoing in Italy to better evaluate the frequency and severity of isolated thrombocytopenia with or without bleeding occurring after COVID-19 vaccination.


Acknowledgments

We thank the GIMEMA Foundation (Italian Group for Hematological Malignancies in Adults), HPF (Hematology Project Foundation), SISET (Italian Society for the Study of Hemostasis and Thrombosis), AIPIT (Italian Association on Idiopathic Thrombocytopenic Purpura), and Ematologia in Progress (Mattioli Health Ed.) for accepting to publish the Italian version of these recommendations on their websites, and any other institutions that may wish to publicize them.
We thank Lisanna Ghiotto (Hematology Project Foundation, Vicenza, Italy) for her collaboration and Daniela Bartoletti (IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy) for editing the English version of this document.

References   

  1. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, DeBeer H, Jaeschke R, Rind D, Meerpohl J, Dahm P, Schünemann HJ. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011 ;64(4):383-94. https://doi.org/10.1016/j.jclinepi.2010.04.026 PMid:21195583
  2. Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines; Graham R, Mancher M, Miller Wolman D, et al., editors. Clinical Practice Guidelines We Can Trust. Washington (DC): National Academies Press (US). 2011.
  3. Pavord S, Thachil J, Hunt BJ, Murphy M, Lowe G, Laffan M, Makris M, Newland AC, Provan D, Grainger JD, Hill QA. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic. Br J Haematol. 2020 ;189(6):1038-1043. https://doi.org/10.1111/bjh.16775 PMid:32374026 PMCid:PMC7267627
  4. Bussel J, Cines D, Cooper N, Dunbar C, Michel M, Rodeghiero F. COVID-19 and ITP: Frequently Asked Questions. https://www.hematology.org/covid-19/covid-19-and-itp. American Society of Hematology. (last updated April 21, 2021)
  5. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 ;382(18):1708-1720. https://doi.org/10.1056/NEJMoa2002032 PMid:32109013 PMCid:PMC7092819
  6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 ;18(5):1094-1099. https://doi.org/10.1111/jth.14817 PMid:32220112
  7. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 ;395(10223):497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
  8. Yang X, Yang Q, Wang Y, Wu Y, Xu J, Yu Y, Shang Y. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost. 2020 ;18(6):1469-1472. https://doi.org/10.1111/jth.14848 PMid:32302435
  9. Jiménez D, García-Sanchez A, Rali P, Muriel A, Bikdeli B, Ruiz-Artacho P, Le Mao R, Rodríguez C, Hunt BJ, Monreal M. Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis. Chest. 2021;159(3):1182-1196. https://doi.org/10.1016/j.chest.2020.11.005 PMid:33217420 PMCid:PMC7670889
  10. Marchandot B, Trimaille A, Curtiaud A, Matsushita K, Jesel L, Morel O. Thromboprophylaxis: balancing evidence and experience during the COVID-19 pandemic. J Thromb Thrombolysis. 2020 ;50(4):799-808. https://doi.org/10.1007/s11239-020-02231-3 PMid:32696172 PMCid:PMC7372740
  11. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis. Res Pract Thromb Haemost. 2020 ;4(7):1178-91. https://doi.org/10.1002/rth2.12439 PMid:33043231 PMCid:PMC7537137
  12. Violi F, Pastori D, Cangemi R, Pignatelli P, Loffredo L. Hypercoagulation and Antithrombotic Treatment in Coronavirus 2019: A New Challenge. Thromb Haemost. 2020 ;120(6):949-956. https://doi.org/10.1055/s-0040-1710317 PMid:32349133 PMCid:PMC7295290
  13. Ministero della Salute, Istituto Superiore di Sanità. Nota tecnica ad interim. Test di laboratorio per SARS-CoV-2 e loro uso in sanità pubblica. https://www.iss.it/documents/20126/0/COVID+19_+test+v4k_last.pdf/9ab1f211-7d88-bcb1-d454-cfed04aa8b05?t=1604483686312 (updated 23 October 2020).
  14. Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 ;3(22):3780-3817. https://doi.org/10.1182/bloodadvances.2019000812 PMid:31770441 PMCid:PMC6880896
  15. Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, George JN, Grace RF, Kühne T, Kuter DJ, Lim W, McCrae KR, Pruitt B, Shimanek H, Vesely SK. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 ;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum in: Blood Adv. 2020 ;4(2):252. https://doi.org/10.1182/bloodadvances.2019000966 PMid:31794604 PMCid:PMC6963252
  16. Mahévas M, Moulis G, Andres E, Riviere E, Garzaro M, Crickx E, Guillotin V, Malphettes M, Galicier L, Noel N, Darnige L, Terriou L, Guerveno C, Sanchis-Borja M, Moulinet T, Meunier B, Ebbo M, Michel M, Godeau B. Clinical characteristics, management and outcome of COVID-19-associated immune thrombocytopenia: a French multicentre series. Br J Haematol. 2020 ;190(4):e224-e229. https://doi.org/10.1111/bjh.17024 PMid:32678953 PMCid:PMC7404899
  17. Magdi M, Rahil A. Severe Immune Thrombocytopenia Complicated by Intracerebral Haemorrhage Associated with Coronavirus Infection: A Case Report and Literature Review. Eur J Case Rep Intern Med. 2019 ;6(7):001155.
  18. Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019 ;104(6):1112-1123. https://doi.org/10.3324/haematol.2018.212845 PMid:31073079 PMCid:PMC6545830
  19. Rodeghiero F. Is ITP a thrombophilic disorder? Am J Hematol. 2016 ;91(1):39-45. https://doi.org/10.1002/ajh.24234 PMid:26547507
  20. Nazi I, Kelton JG, Larché M, Snider DP, Heddle NM, Crowther MA, Cook RJ, Tinmouth AT, Mangel J, Arnold DM. The effect of Rituximab on vaccine responses in patients with immune thrombocytopenia. Blood. 2013;122(11):1946-53. https://doi.org/10.1182/blood-2013-04-494096 PMid:23851398 PMCid:PMC3773242
  21. Alimova M, Sidhom EH, Satyam A, Dvela-Levitt M, Melanson M, Chamberlain BT, Alper SL, Santos J, Gutierrez J, Subramanian A, Grinkevich E, Bricio ER, Kim C, Clark A, Watts A, Thompson R, Marshall J, Pablo JL, Coraor J, Roignot J, Vernon KA, Keller K, Campbell A, Emani M, Racette M, Bazua-Valenti S, Padovano V, Weins A, McAdoo SP, Tam FWK, Ronco L, Wagner F, Tsokos GC, Shaw JL, Greka A. A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic. bioRxiv [Preprint]. 2020 :2020.06.30.180380. doi: 10.1101/2020.06.30.180380. Update in: Cell Rep Med. 2020 Oct 29;1(8):100137. https://doi.org/10.1101/2020.06.30.180380
  22. Strich JR, Ramos-Benitez MJ, Randazzo D, Stein SR, Babyak A, Davey RT, Suffredini AF, Childs RW, Chertow DS. Fostamatinib Inhibits Neutrophils Extracellular Traps Induced by COVID-19 Patient Plasma: A Potential Therapeutic. J Infect Dis. 2021 ;223(6):981-984. https://doi.org/10.1093/infdis/jiaa789 PMid:33367731 PMCid:PMC7799006
  23. Xie Y, Cao S, Dong H, Li Q, Chen E, Zhang W, Yang L, Fu S, Wang R. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect. 2020 ;81(2):318-356. https://doi.org/10.1016/j.jinf.2020.03.044 PMid:32283154 PMCid:PMC7151471
  24. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 ;384(8):693-704. https://doi.org/10.1056/NEJMoa2021436 PMid:32678530 PMCid:PMC7383595
  25. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 ;383(2):120-128. https://doi.org/10.1056/NEJMoa2015432 PMid:32437596 PMCid:PMC7412750
  26. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 ;191:145-147. https://doi.org/10.1016/j.thromres.2020.04.013 PMid:32291094 PMCid:PMC7146714
  27. Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, Bouman CCS, Beenen LFM, Kootte RS, Heijmans J, Smits LP, Bonta PI, van Es N. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 ;18(8):1995-2002. https://doi.org/10.1111/jth.14888 PMid:32369666 PMCid:PMC7497052
  28. Rodeghiero F. A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol. 2018 ;181(2):183-195. https://doi.org/10.1111/bjh.15090 PMid:29479668
  29. Corbett V, Hassouna H, Girgis R. In Situ Thrombosis of the Pulmonary Arteries: An Emerging Perspective on Pulmonary Embolism. Medical Student Research Journal. 2015;4(Winter):54-8.
  30. Marongiu F, Grandone E, Barcellona D. Pulmonary thrombosis in 2019-nCoV pneumonia? J Thromb Haemost. 2020 ;18(6):1511-1513. https://doi.org/10.1111/jth.14818 PMid:32293083 PMCid:PMC7262115
  31. Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med. 2020 ;8(7):681-686. https://doi.org/10.1016/S2213-2600(20)30243-5
  32. Medcalf RL, Keragala CB, Myles PS. Fibrinolysis and COVID-19: A plasmin paradox. J Thromb Haemost. 2020 ;18(9):2118-2122. https://doi.org/10.1111/jth.14960 PMid:32543119 PMCid:PMC7323332
  33. Tsantes AE, Tsantes AG, Kokoris SI, Bonovas S, Frantzeskaki F, Tsangaris I, Kopterides P. COVID-19 Infection-Related Coagulopathy and Viscoelastic Methods: A Paradigm for Their Clinical Utility in Critical Illness. Diagnostics (Basel). 2020 ;10(10):817. https://doi.org/10.3390/diagnostics10100817 PMid:33066390 PMCid:PMC7602239
  34. Mazur-Bialy AI, Kołomańska-Bogucka D, Tim S, Opławski M. Pregnancy and Childbirth in the COVID-19 Era-The Course of Disease and Maternal-Fetal Transmission. J Clin Med. 2020 ;9(11):3749. https://doi.org/10.3390/jcm9113749 PMid:33233369 PMCid:PMC7700491
  35. Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies. Acta Obstet Gynecol Scand. 2020 ;99(7):823-829. https://doi.org/10.1111/aogs.13867 PMid:32259279 PMCid:PMC7262097
  36. Ferrazzi EM, Frigerio L, Cetin I, Vergani P, Spinillo A, Prefumo F, Pellegrini E, Gargantini G. COVID-19 Obstetrics Task Force, Lombardy, Italy: Executive management summary and short report of outcome. Int J Gynaecol Obstet. 2020 ;149(3):377-378. https://doi.org/10.1002/ijgo.13162 PMid:32267531
  37. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during Pregnancy and Possible Vertical Transmission. Am J Perinatol. 2020 ;37(8):861-865. https://doi.org/10.1055/s-0040-1710050 PMid:32305046 PMCid:PMC7356080
  38. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021 ;384(5):403-416. https://doi.org/10.1056/NEJMoa2035389 PMid:33378609 PMCid:PMC7787219
  39. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 ;383(27):2603-2615. https://doi.org/10.1056/NEJMoa2034577 PMid:33301246 PMCid:PMC7745181
  40. Dashraath P, Nielsen-Saines K, Madhi SA, Baud D. COVID-19 vaccines and neglected pregnancy. Lancet. 2020 ;396(10252):e22. https://doi.org/10.1016/S0140-6736(20)31822-5
  41. Rasmussen SA, Kelley CF, Horton JP, Jamieson DJ. Coronavirus Disease 2019 (COVID-19) Vaccines and Pregnancy: What Obstetricians Need to Know. Obstet Gynecol. 2021 ;137(3):408-414. https://doi.org/10.1097/AOG.0000000000004290 PMid:33370015 PMCid:PMC7884084
  42. Agenzia Italiana del Farmaco (AIFA). Domande e risposte sui vaccini COVID-19. https://www.aifa.gov.it/documents/20142/1297852/domande_risposte_vaccini_COVID.pdf. (updated April 26, 2021)
  43. Centers for Disease Control and Prevention (CDC). Information about COVID-19 Vaccines for People who Are Pregnant or Breastfeeding. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html. (updated 18 March 2021)
  44. Cines DB, Bussel JB. SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia. N Engl J Med. 2021 Apr 16. doi: 10.1056/NEJMe2106315. Online ahead of print https://doi.org/10.1056/NEJMe2106315 PMid:33861524
  45. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840. Online ahead of print. https://doi.org/10.1056/NEJMoa2104840 PMid:33835769
  46. Schultz NH, Sorvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. DOI: 10.1056/NEJMoa2104882. https://doi.org/10.1056/NEJMoa2104882 PMid:33835768
  47. Scully M, Singh D, Lown R, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med. DOI: 10.1056/NEJMoa2105385. https://doi.org/10.1056/NEJMoa2105385 PMid:33861525
  48. Lee EJ, Cines DB, Gernsheimer T, et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol 2021; 96: 534-7. https://doi.org/10.1002/ajh.26132 PMid:33606296 PMCid:PMC8014568

[TOP]