**Knowledge, Attitudes and Perceptions of Immigrant Parents Towards Human Papillomavirus (HPV) Vaccination: A Systematic Review**

**Faeza Netfa 1,2,\*, Mohamed Tashani 1,3, Robert Booy 1,4, Catherine King 1,4, Harunor Rashid 1,4 and Susan R. Skinner 1,2**


Received: 26 December 2019; Accepted: 7 April 2020; Published: 9 April 2020

**Abstract:** Background: Our understanding about knowledge, attitudes and perceptions (KAP) of immigrants regarding human papillomavirus (HPV) vaccine is poor. We present the first systematic review on KAP of immigrant parents towards HPV vaccine offered to their children. Methods: Major bio-medical databases (Medline, Embase, Scopus and PsycINFO) were searched using a combination of keyword and database-specific terms. Following identification of studies, data were extracted, checked for accuracy, and synthesised. Quality of the studies was assessed using the Newcastle Ottawa Scale and the Joanna Briggs Institute Qualitative Assessment tool. Results: A total of 311 titles were screened against eligibility criteria; after excluding 292 titles/full texts, 19 studies were included. The included studies contained data on 2206 adults. Participants' knowledge was explored in 16 studies and ranged from none to limited knowledge. Attitudes about HPV vaccination were assessed in 13 studies and were mixed: four reported negative attitudes fearing it would encourage sexual activity; however, this attitude often changed once parents were given vaccine information. Perceptions were reported in 10 studies; most had misconceptions and concerns regarding HPV vaccination mostly influenced by cultural values. Conclusion: The knowledge of HPV-related diseases and its vaccine among immigrant parents in this study was generally low and often had negative attitude or perception. A well-designed HPV vaccine health educational program on safety and efficacy of HPV vaccination targeting immigrant parents is recommended.

**Keywords:** cervical cancer; human papillomavirus; HPV vaccine; knowledge; attitudes and perceptions

#### **1. Introduction**

Human papillomavirus (HPV) infection is a sexually transmitted disease and both women and men are rapidly exposed to it after the onset of sexual intercourse [1,2]. Oncogenic HPV can cause cervical, anogenital, head and neck cancers [3,4].

Cervical cancer is the fourth most common cancer found in women and the third most frequent cause of death with approximately 570,000 cases and 311,000 deaths in 2018 worldwide [5,6]. In developed countries nearly half of the cervical cancer cases are diagnosed in women aged less than 50 years old [6,7]. Rates of HPV infection vary greatly between geographic regions and population

groups. In developed countries, cervical cancer has been declining for many years largely due to the cervical cytology screening programme which is now being replaced by HPV screening. However, cervical cancer is increasing in developing countries where nationwide cervical cancer screening is currently unavailable. It is the second most common cancer in countries with a lower human development index ranking and is the most common cancer in about 28 countries [6,8]. The high-risk types, HPV 16 and HPV 18, cause 70% of all invasive cervical cancers and HPV types: 6, 11, 16, 18, 31, 33, 45, 52 and 58 together can cause 95% of cervical cancers.

HPV vaccination is the most effective method of preventing HPV infection [9]. The immunity gained via HPV vaccination is mainly responsible for the reduction in HPV infection and related cancers [10]. The main goal of this vaccination is to avoid persistent infections that may progress to an invasive carcinoma [10,11]. HPV vaccine is safe, well tolerated and has the potential to significantly reduce the incidence of HPV-associated precancerous lesions [12,13]. It can also effectively protect against certain HPV types that can lead to genital warts. This vaccine is most beneficial if delivered prior to the commencement of sexual activity [13,14]. During the last 12 years, over 80 countries have introduced national HPV vaccination programs [15]. The United States of America (USA), Australia, Canada and the United Kingdom (UK) were among the first countries to introduce HPV vaccine into their national immunization programs (Table 1). All countries programs target young adolescent girls, with some countries also having programs for adolescent males [16]. Specific target age groups differ as do catch-up vaccination recommendations. The majority of countries are delivering vaccine through school-based programs, health centres or primary care providers [15]. National HPV vaccination programs of two or three dose schedules have demonstrated a dramatic impact on population level HPV prevalence, persistent HPV infection, genital warts, and cervical intraepithelial neoplasia [17]. The coverage of HPV vaccine achieved by the national programs has been highly variable within the countries [13]. During the past ten years, since HPV vaccine was licensed, there has been an increase in immigrants from different cultures and languages travelling to the Western countries. Most of the immigrants originate from socio-economically underprivileged countries [17,18], and do not have a nationally funded HPV vaccination program (Table 1); therefore, it is reasonable to believe that most immigrants do not have a background knowledge about HPV vaccination.


**Table 1.** Human papillomavirus (HPV) vaccination programs in several countries that receive high numbers of immigrants from developing countries.


```
Table 1. Cont.
```
\* If not specified this coverage data is for adolescent girls.

Knowledge and understanding of HPV infection and HPV vaccine are important factors in decision-making about disseminating the vaccine [13]. Since the licensure of HPV vaccine in 2006, research regarding the uptake of HPV vaccine among ethnic minorities, immigrants and refugees, has been limited [18,19]. This is attributed to factors such as language barrier and cultural differences, legal issues, religion, education, lack of specialized migrant health services and lack of awareness among migrants of their rights [20]. To our knowledge, there is no systematic study on immigrant parents' knowledge, attitudes and perceptions (KAP) towards HPV vaccination. This study aims to address this research gap by systematically synthesising published data on immigrant parents' KAP towards HPV disease and vaccination offered to their children to inform future efforts to increase HPV vaccine coverage.

#### **2. Materials and Methods**

Literature searches were performed using OVID Medline (1946–April 2019), OVID Embase Classic (1947–April 2019), PsycINFO (1806–May 2019) and SCOPUS (1945–May 2019). The searches used a combination of data base-controlled vocabulary terms and text word terms. These included "Papillomavirus vaccines", "Human Papillomavirus vaccine", "knowledge, attitudes, perceptions", "emigrants", "immigrants", "population groups", "ethnic groups", "refugees", "mothers", "fathers" and "parents". Searches were conducted from 2007 to 2019. The final search was conducted on 1 May 2019. No language or date restrictions were applied. The OVID Medline search strategy used is available upon application to authors. We additionally searched the reference lists of review articles to identify original research articles describing knowledge, attitudes and perceptions of HPV vaccine among immigrant parents.

For inclusion in this review, papers needed to discuss knowledge or attitudes or perceptions of immigrant parents (defined as parents who have been permanently living in a foreign country along with their children) and/or primary immigrant caregivers towards HPV vaccine. Papers were excluded if they did not include the views of parents or only discussed other childhood vaccines. Perception was defined as how parents interpreted/perceived HPV vaccine in light of their life experiences, and attitude was defined as their reactions to those perceptions. After screening the titles, full texts were retrieved and reviewed, and data were extracted in an Excel sheet by the first author. The data collection form included the author, year, country of study, method, population, result of the study. Another author (HR) checked data abstraction and any discrepancy was resolved through discussion then data were synthesised. The quality of included studies was assessed by Newcastle Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses http: //www.ohri.ca/programs/clinical\_epidemiology/oxford.asp and by Joanna Briggs Institute (JBI) Critical Appraisal tools for use in JBI Systematic Reviews Checklist for Qualitative Research https://joannabriggs. org/sites/default/files/2019-05/JBI\_Critical\_Appraisal-Checklist\_for\_Qualitative\_Research2017\_0.pdf.

#### **3. Results**

In this systematic review, 311 titles from four databases were retrieved in total. There were 134 duplicates leaving 177 records to be screened. Of 177 titles, 121 were excluded for not meeting inclusion criteria. The full texts of the remaining 56 titles were assessed. Of these 36 studies were determined to be out of scope of this systematic review and excluded with reasons, the remaining 19 articles met the eligibility criteria of the systematic review as shown in the PRISMA flowchart (Figure 1). There were 12 qualitative studies and five quantitative studies and two mixed method studies.

*Trop. Med. Infect. Dis.* **2020**, *5*, x FOR PEER REVIEW 5 of 22

**Figure 1.** PRISMA flow diagram of the systematic review. **Figure 1.** PRISMA flow diagram of the systematic review.

were conducted in the USA, three in the UK, one in the Netherlands, one in Denmark, one in Sweden, and one in Puerto Rico. Six studies were conducted in community organizations including faithbased centres like churches and mosques [21–26], eight in health and social service agencies [27–34], two in schools and/or community groups [35,36], another two in social clubs [37,38], and one in a

household [39].

Total number of participants in all included studies was 2206 (M = 74, F = 1976 in addition to

Of the 19 studies, 16 reported on knowledge of the immigrant parents about HPV vaccine (Table 2), 13 reported their attitudes (Table 3) and 10 recorded perceptions (as defined by study author) towards HPV vaccine (Table 4). Four studies reported knowledge and attitudes [21,27,30,37] and one reported knowledge and perceptions [26], seven studies reported on all three outcomes

All included studies discussed the KAP of immigrant populations. If the study author(s) used the term "ethnic minority" to represent, we have similarly reported this term in the result tables.

(knowledge, attitude and perceptions) [22,23,29,35,36,38,39].

Total number of participants in all included studies was 2206 (M = 74, F = 1976 in addition to 156 parents with gender unclassified) with a male to female ratio of 1:27, where data were provided. Where age of interviewees was mentioned, the range varied from 18 to 66 years. Twelve studies were conducted in the USA, three in the UK, one in the Netherlands, one in Denmark, one in Sweden, and one in Puerto Rico. Six studies were conducted in community organizations including faith-based centres like churches and mosques [21–26], eight in health and social service agencies [27–34], two in schools and/or community groups [35,36], another two in social clubs [37,38], and one in a household [39].

Of the 19 studies, 16 reported on knowledge of the immigrant parents about HPV vaccine (Table 2), 13 reported their attitudes (Table 3) and 10 recorded perceptions (as defined by study author) towards HPV vaccine (Table 4). Four studies reported knowledge and attitudes [21,27,30,37] and one reported knowledge and perceptions [26], seven studies reported on all three outcomes (knowledge, attitude and perceptions) [22,23,29,35,36,38,39].

All included studies discussed the KAP of immigrant populations. If the study author(s) used the term "ethnic minority" to represent, we have similarly reported this term in the result tables.

For knowledge, the level of parents' knowledge about HPV disease and HPV vaccine ranged from no knowledge in 11 studies [21–24,26,27,29,33,35,37,39] to limited knowledge regarding HPV and HPV vaccine, as they heard about the vaccine but they did not know HPV vaccine's purpose, the eligibility requirements for the vaccine, and the vaccine's dosing/schedule requirements in three studies. Five studies revealed that some participants had not heard of HPV disease or HPV vaccine [27,33,35,39]. There were four studies that reported participants had no prior knowledge of HPV as a sexually transmitted disease or as a cause of cancer [25,30,32]. In four studies, participants described a lack of information and knowledge about the purpose of HPV vaccination, and HPV transmission [21,29,37]. Two studies found participants had limited knowledge regarding the relation between sexual transmission of HPV and cervical cancer [22,36] (Table 2).

In regards to attitudes towards HPV disease and HPV vaccine (Table 3), a number of non-vaccinating ethnic minority parents had negative attitudes to HPV vaccination thinking it would encourage unsafe sexual practices and promiscuity [22,30,35]. However, three studies showed that once parents were informed about the vaccine during the focus groups, they became keen to vaccinate their children [34,36,37]. Non-vaccinating and partially vaccinating parents from various ethnic backgrounds expressed concerns about potential side effects [35]; religious values and cultural norms also influenced vaccine decision-making [28,29], and a majority of participants (regardless of vaccination status) had a more positive attitude towards vaccination when they received information about HPV vaccine (Table 3).

Participants had misperceptions about HPV vaccine. The main reasons for declining HPV vaccine were their religious belief and culture; in particular, their belief that abstinence from sex before marriage would provide protection from disease [22,31,36]. Awareness of a health intervention is recognised as necessary but not sufficient condition for performing a health behaviour. As women become aware of HPV vaccine, they may have additional questions or concerns that may function as barriers to getting their daughters vaccinated [31] (Table 4).

Most studies were of generally good quality. When scored against the checklist used, ten qualitative studies received eight out of a possible 10 points, and one 10 of 10 [37]. Four of the eight quantitative observational studies scored eight of nine points, and the other scored seven of nine points (Table 5).



**Table 2.**

Studies reporting

 knowledge

 of

immigrants

 about HPV vaccine (16 articles).









Stephens et al., 2014 [22] Haiti, USA October

2010–May 2011

31

immigrants (18–22) 31

Immigrant mothers who had little knowledge about HPV or the vaccine, felt unsure about vaccination; their concern centered on conflict with cultural values and perceptions of risks associated with HPV vaccine.



*TMID* **2020**, *5*, 58


**Table 5.** Quality assessment of the included studies.

#### **4. Discussion**

This systematic review identifies gaps in knowledge, attitudes, and perceptions about HPV infection and its vaccine among immigrant parents in western countries. Our analyses indicate that although HPV vaccine has been in use for over a decade, information about this vaccine, and HPV infection in general, and its relation to cancer in particular, does not appear to have been well disseminated to immigrant parents. Most participants in 12 included studies had no knowledge about HPV vaccine (Table 2), one third of participants in two studies reported receiving no information about HPV vaccine, [27,35]. All participants in one study have not even heard of the vaccine [29]. This systematic review showed participants had both negative and positive attitudes towards HPV vaccination, and most participants had misconceptions about HPV vaccination.

In concordance with our systematic review findings, semi-structured interviews conducted with non-parent immigrant participants also showed limited knowledge about HPV infection its vaccine. For example, a study conducted in a Western Canadian province, found participants had limited knowledge about HPV. Most women perceived their risk of HPV to be low but reported willingness to receive the vaccine when recommended by their doctors [19]. Similarly [35], in Italy, knowledge and attitude toward HPV infection and vaccination among non-parent immigrants and refugees was low [40]. In Sweden, adolescent school students were interviewed in relation to their beliefs and knowledge about HPV prevention: HPV vaccination was found to be associated with ethnicity and the mothers' education level; i.e., girls with a non-European background, including those of Arabic background, and with a less educated mother were less likely to have received the vaccine. Vaccinated girls perceived HPV infection as more severe, had more insight into women's susceptibility to the infection, perceived more benefits of the vaccine as protection against cervical cancer and had a higher intention to engage in HPV-preventive behaviour [41].

Furthermore, another systematic review that explored knowledge and attitudes of Iranian people towards HPV vaccination found that the overall knowledge and awareness about HPV vaccination was low; however, their attitude toward HPV vaccination was positive and strong [42]. This corroborates the findings from three studies included in our systematic review that showed positive attitude towards HPV vaccines once parents were informed about it during focus groups. [34,36]. This could possibly explain why the negative attitude to HPV vaccination found in most of the studies included in our systematic review was stemmed from poor knowledge/misconceptions and may change after providing the right information.

Unlike the immigrants, mainstream populations of USA had better knowledge and more positive attitudes toward HPV vaccine. A quantitative study conducted in Southern California compared knowledge and acceptability between US-born African Americans and African immigrants, and between US-born Latinas and Latina immigrants. African and South American immigrants were less likely to know where they can get/refer for HPV vaccine and less likely to have heard about HPV vaccine than South Americans and US-born Africans [43]. Similarly, a study in Denmark found that refugee girls, mainly from Muslim countries, had significantly lower HPV immunization uptake compared to Danish born girls, indicating that refugee girls may face challenges to access and use of immunization services [44].

A study in 2018 indicated that the increase in refusal and hesitancy of Muslim parents to accept childhood vaccination was identified as one of the contributing factors in the increase of vaccine-preventable diseases cases in several countries such as Afghanistan, Malaysia and Pakistan. News disseminated via some social media outlets claiming that the vaccine has been designed to weaken Muslims, reinforced the suspicion and mistrust of vaccines by parents [45]. A qualitative study of the views of young non-parent Somali men and women in the USA demonstrated that the participants had limited knowledge about the vaccination and had suspicions concerning the effectiveness or value of immunization, with most participants stating that the Somali community was mostly Muslim and did not engage in sexual activity before marriage [46]. A cross-sectional study included in our systematic review conducted to evaluate awareness of women from major UK ethnic minority groups (Indian, Pakistani, Bangladeshi, Caribbean, African and Chinese women) toward HPV vaccination identified that those from non-Christian religions were less accepting of the vaccine (17–34%). The study concluded that some cultural barriers could be addressed by tailored information provided to ethnic minority groups [47].

Attitudes toward HPV vaccine are important in HPV vaccine uptake. Our systematic review revealed certain attitude-related barriers to vaccine acceptability for adolescents, particularly vaccine hesitancy among some mothers. A qualitative study reported that Latin American immigrant mothers of adolescent daughters expressed more hesitancy regarding adolescent vaccines compared to childhood vaccines expressed an increased sense of belief in their ability to determine what is best for their children [48]. In contrast to the negative attitudes of immigrant parents as found in most of the included studies in our systematic review, most mainstream non-immigrant women had positive attitudes about receiving an HPV vaccine and high intention to receive the vaccine both for themselves and their daughters [49]. Variables associated with intention to vaccinate included knowledge, personal beliefs, confidence that others would approve of vaccination, and having a higher number of sexual partners [49]. However, negative or variable attitudes of parents to vaccinate their children have been reported in a systematic review involving Turkish population [50]. The systematic review showed that between 14.4% and 68.0% of Turkish parents were willing to have their daughters vaccinated with HPV vaccine and between 11.0% and 62.0% parents were willing to have their sons vaccinated [50], suggesting a negative attitude may not be just a phenomenon of immigrants, many non-immigrants in their own countries too may have negative attitudes towards HPV vaccination. However, since this attitude appeared amenable to change in our systematic review, innovative simple interventions may improve attitudes to HPV vaccination. For instance, a higher vaccination rate was achieved at three clinics in Texas, USA among children and adolescents through the involvement of patient navigators. The patient navigators met the parents of unvaccinated or incompletely vaccinated children while they waited for their children's health providers in private clinic rooms to confirm the need for additional HPV vaccine doses. Parents of children who needed ≥1 dose were offered personal counselling and given handouts in English or Spanish on HPV vaccine. Following such counselling about 67% parents

got their children vaccinated either immediately or at a follow-up visit soon thereafter, indicating that providing counselling in a clinic setting can improve vaccination acceptance [51].

To our knowledge this is the first systematically conducted review of HPV vaccination knowledge, attitudes and perceptions among immigrants. Most included studies were of acceptable quality. We failed to identify research regarding knowledge, attitudes and perceptions of immigrant parents towards HPV vaccine in developing countries. Some papers did not clearly distinguish between attitudes and perceptions as outcomes. However, these studies suggest that tailored educational programs to improve KAP on HPV vaccine among immigrant parents may be a valuable intervention for HPV vaccination uptake.

#### **5. Conclusions**

Parental knowledge and attitudes towards HPV vaccine have been examined in many recent studies and lower uptake of HPV vaccine among immigrants, refugees and ethnic minorities has been documented. Our results support the pressing need to develop an intervention aimed to improve HPV vaccination uptake in these populations. More research is needed in the design and evaluation of tailored educational resources for ethnic minority groups, particularly in the framework of the vaccination programme.

**Author Contributions:** Conceptualization, F.N., H.R. and S.R.S.; methodology, F.N., C.K. and H.R.; software, F.N.; validation, F.N., M.T., C.K., H.R., R.B. and S.R.S.; formal analysis, F.N., H.R. and C.K.; investigation, F.N., H.R. and C.K.; resources, F.N., H.R., C.K. and S.R.S.; data curation, F.N., H.R., and S.R.S.; writing—original draft preparation, F.N., H.R. and C.K.; writing—review and editing, F.N., H.R., C.K., M.T., R.B. and S.R.S.; visualization, F.N., H.R. and C.K.; supervision, F.N., M.T., C.K., H.R., R.B. and S.R.S.; project administration, S.R.S.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors wish to thank Trish Bennett, Manager the Children's Hospital at Westmead Library for assistance with the literature searches.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

## *Review* **The COVID-19 Pandemic: Disproportionate Thrombotic Tendency and Management Recommendations**

**Sabina Karim 1,\*, Amin Islam 2,3,4, Shafquat Rafiq <sup>5</sup> and Ismail Laher <sup>6</sup>**


**Abstract:** COVID-19 is an infectious disease caused by the SARS COV-2 virus. Patients with COVID-19 are susceptible to thrombosis due to excessive inflammation, platelet activation, endothelial dysfunction, and circulatory stasis, resulting in an increased risk of death due to associated coagulopathies. In addition, many patients receiving antithrombotic therapy for pre-existing thrombotic diseases can develop COVID-19, which can further complicate dose adjustment, choice and laboratory monitoring of antithrombotic treatment. This review summarizes the laboratory findings, the prohemostatic state, incidence of thromboembolic events and some potential therapeutic interventions of COVID-19 associated coagulopathy. We explore the roles of biomarkers of thrombosis and inflammation according to the severity of COVID-19. While therapeutic anticoagulation has been used empirically in some patients with severe COVID-19 but without thrombosis, it may be preferable to provide supportive care based on evidence-based randomized clinical trials. The likely lifting of travel restrictions will accelerate the spread of COVID-19, increasing morbidity and mortality across nations. Many individuals will continue to receive anticoagulation therapy regardless of their location, requiring on-going treatment with low-molecular weight heparin, vitamin K antagonist or direct-acting anticoagulants.

**Keywords:** anticoagulant; antiplatelet; antithrombotic therapy; COVID-19; SARS-CoV-2; thrombosis; disseminated intravascular coagulation

#### **1. Background**

Travel has greatly accelerated the global spread of COVID-19 and has so far affected over 107 million people with more than 2.3 million deaths (as of 10 February 2021) [1]. SARS-CoV-2, the cause of the COVID-19 pandemic, replicates in the upper respiratory tract to enable active viral shedding with minimal symptoms [2]. Survival of the virus for 24 to 72 h on different types of surfaces further facilitates fomite transmission [3], allowing the virus to be readily transmissible in travel settings. The early symptoms of COVID-19, such as fever, fatigue, headache, cough, shortness of breath, diarrhea and myalgia, are similar to those in other viral infections [4]. The virus binds to the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed at higher levels in males compared to females, and also in Asians compared to white Caucasians or Africans [5]. The clinical course of the disease can be divided into three phases: the viremic phase, the acute or pneumonic phase and the severe or recovery phase [6]. Much like other virulent zoonotic coronavirus infections such

**Citation:** Karim, S.; Islam, A.; Rafiq, S.; Laher, I. The COVID-19 Pandemic: Disproportionate Thrombotic Tendency and Management Recommendations. *TMID* **2021**, *6*, 26. https://doi.org/ 10.3390/tropicalmed6010026

Academic Editor: Ameneh Khatami Received: 15 October 2020 Accepted: 8 January 2021 Published: 18 February 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome corona virus (MERS-CoV), COVID-19 can potentially lead to systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), multi-organ dysfunction and shock [7]. Though severe COVID-19 and its complications are common in the elderly and individuals with comorbidities such as diabetes and cardiovascular diseases, younger and healthy persons are not always spared and can also develop severe and complicated disease [8]. Increases in lactate dehydrogenase, C-reactive protein (CRP), D-dimer, ferritin and interleukin-6 (IL-6) are common laboratory findings in patients with COVID-19 [4,9]. Plasma IL-6 levels can correlate with disease severity and pro-coagulant states [9].

#### **2. Possible Pathophysiology of Coagulopathy**

There is a complex interplay between pro-inflammatory cytokine/chemokine release, increased endothelial dysfunction/damage and potential sepsis-induced coagulopathy during the acute phase of the disease, which in severe cases can increase the risk of thrombosis (Figure 1). Increased pro-thrombotic characteristics of COVID-19 likely results from (a) severe and prolonged hypoxemia that stimulates thrombosis, (b) cytokine storms in critically ill patients, and (c) a presumed role of local pulmonary thrombotic phenomena. It is presumed that prothrombotic pulmonary endothelial dysfunction leads to severe acute inflammation (through release of complement and cytokines) and blood coagulation activation with vascular microthrombosis that triggers further coagulopathy, leading to disseminated intravascular coagulation (DIC) [10].

**Figure 1.** Mechanisms of COVID-19 associated coagulopathy.

Post-mortem histological similarities suggest that Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV), the cause of a previous endemic between 2002 and 2003, also causes ARDS with visible localized pulmonary hemorrhage, pulmonary oedema, desquamation with hyaline membrane formation and interstitial mononuclear inflammatory infiltrates. Localized pulmonary arteriolar thrombosis observed with SARS has not yet been described in autopsy reports of patients with COVID-19 [11]. Pulmonary vasculature thrombosis is likely to result from severe hypoxia, which is a powerful stimulant of coagulation.

#### **3. Biomarkers of Hemostasis**

Thrombocytopenia and increased D-dimer levels are consistently associated with an increased need for mechanical ventilation, admission to the intensive care unit (ICU) or death [12,13]. The severity of COVID-19 is frequently associated with prolongations of prothrombin time (PT), international normalized ratio (INR) and thrombin time (TT), and a trend of increases in activated partial thromboplastin time (aPTT) [14–16]. Retrospective analysis of hospitalized patients with COVID-19 indicates high levels in D-dimers and fibrin degradation products, prolonged PTs and aPTT in non-survivors compared to survivors. It is estimated that 71% of patients succumbing to the complications of COVID-19 met the International Society on Thrombosis and Haemostasis (ISTH) criteria for DIC, compared to just 0.6% for survivors [17,18].

#### **4. Potential Role of Complement Inhibition in COVID-19**

Thrombotic microangiopathy (TMA) can occur in many different clinical conditions, including pathogenic complement activation. The complement system mediates the innate immune response that promotes inflammation, defends against bacterial infections, and often neutralizes infectious viruses [19]. Two murine studies investigated complement activation in coronavirus infections to determine whether activation of the system could be protective or pathogenic. In a murine model lacking C3 and unable to activate the common complement pathway, SARS-CoV infection severity was decreased with less respiratory dysfunction and lower cytokine levels despite equal viral loads [20], suggesting that a significant portion of SARS-mediated disease is likely immune mediated. There were increased concentrations of C5a and C5b-9 in sera and lung tissues in a mouse model of MERS-CoV infection [21]. Blocking C5a with an antibody alleviated lung and spleen damage, with decreased cytokine response and viral replication. Evidence is emerging that the complement system is overactivated in SARS-COV-2 as noted in previous coronavirus infections and this may play a central role in thrombosis and unbalanced immune response [22].

Excessive complement activation occurs in humans in a number of pathological settings, leading to diffuse TMA and end-organ dysfunction, e.g., atypical hemolytic-uremic syndrome (aHUS), a rare disorder of uncontrolled complement activation characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. TMA in aHUS results in renal dysfunction and, in rare cases, cardiac dysfunction. Importantly, aHUS is treatable with eculizumab, a C5 complement inhibitor. Early treatment with eculizumab can reverse both renal and cardiac dysfunction [23]. Although the use of complement inhibitors is limited to rare diseases, it should also be actively investigated in the treatment of COVID-19.

#### **5. Role for Antivirals and Immunomodulatory Agents to Reduce the Development of Immunothrombosis**

There are several potential control points in the pathophysiological cascade COVID-19, starting from the initial infection to later development of ARDS where targeted therapeutic interventions could reduce the severity of disease. There is a role for dexamethasone in the treatment of ARDS in moderate to severe COVID-19 infection; dexamethasone reduces mortality and has become the standard of care in addition to using anti-viral and immunomodulatory therapies. Excessive systemic inflammation in patients with severe COVID-19 is likely to deplete levels of Vit C, Vit D and Zn in many individuals. Several human and animal studies highlight the potential efficacy of supplementation with a combination of Zn, intravenous Vit C and oral Vit D. Inhibition of IL6 by tocilizumab shows beneficial effects in several clinical trials and could reduce microthrombosis. Moreover, when used at appropriate doses, these treatments generally have an exceptionally good

safety record. Aspirin (acetylsalicylic acid), the macrolide antibiotic azithromycin, oral or intravenous administration of NAC (N-acetylcysteine) has a role in inhibiting NF-κB and reducing the activation of the coagulation cascade in severe cases of COVID-19 [24].

#### **6. D-Dimer in COVID-19 and Coagulations Disturbances**

Patient health can deteriorate rapidly in severe cases of COVID-19, leading to ARDS, septic shock, metabolic acidosis and coagulopathy including DIC. Levels of D-dimers, which originate from the breakdown of cross-linked fibrin and are related to activation of coagulation and fibrinolysis, are often markedly elevated in severe COVID-19 patients (Table 1) [25,26]. A retrospective cohort study of 191 patients reported that D-dimer levels greater than 1.0 µg/mL were associated with increased mortality (*p* = 0.0033) in patients with COVID-19 [8]. Levels of 2.0 µg/mL or more on admission were reported as the optimum cut-off for predicting in-hospital mortality for COVID-19 [27]. Nearly 90% of inpatients with pneumonia have increased coagulation activity as marked by elevated D-dimer levels. The levels of D-dimers on admission can be used to triage patients into critical care [8,14]. Increased D-dimer levels are associated with worse outcomes even though many patients may not have full blown DIC and have near normal levels of PT, aPTT and TT.


**Table 1.** Levels of D-Dimers in Patients with COVID-19.

#### **7. COVID-19, Elevated Troponin and Thrombotic Disease**

Increased troponin levels in patients with COVID-19 are associated with poor outcomes [30], but the differential diagnosis for elevated troponin levels in patients with COVID-19 is broad [31] and ranges from nonspecific myocardial injury, impaired renal function (leading to troponin accumulation), myocarditis, pulmonary embolism (PE) and types 1 and 2 myocardial infarction (MI) [32,33]. Similarly, elevated natriuretic peptide levels is nonspecific [32] and consideration for thrombotic events such as PE should always be guided by clinical findings. Mortality rates are higher in patients with underlying cardiovascular disease due to COVID-19 infection [34]. Levels of high-sensitivity cardiac troponin I (hs-TnI) are useful in monitoring disease progression and mortality [35]. A retrospective study of hs-TnI levels and death in patients with COVID-19 (based on SARS-CoV-2 RNA detection) reported a univariable odds ratio of 80.1 (95% CI 10.3–620.4, *p* < 0.0001), which was higher compared to other biomarkers such as D-dimers and lymphocyte counts [8]. Another study of 416 hospitalized patients reported that hs-TnI was elevated in 20% of COVID-19 patients on presentation [36]. These patients were more likely to require invasive (22% vs. 4%, *p* < 0.001) or non-invasive (46% vs. 4%, *p* < 0.001) ventilation, develop complications such as ARDS (59% vs. 15%, *p* < 0.001) or acute kidney injury (9% vs. 0%, *p* < 0.001). Clinicians should remain alert that increased levels of hs-TnI can also be related to non-ischemic causes of myocardial injury and thereby avoid inappropriate use of other resources [37].

#### **8. Venous Thromboembolism**

Venous thromboembolism (VTE) is common in patients with COVID-19, although the prevalence remains unknown. A recent scoping review reported the incidence of VTE to be 20%, with a risk of stroke of 3%; both VTE and risk of stroke are increased in severely ill patients [38]. ARDS in patients with COVID-19 can cause hypoxic pulmonary vasoconstriction, pulmonary hypertension, and right ventricular failure; further injury from severe PE can be irreversible. Risk of VTE can be screened by levels of D-dimer and fibrinogen; a retrospective study suggests that D-dimer concentrations greater than 1.0 µg/mL predicted the risk of VTE [39]. Patients with one or more predisposing factors for VTE (such as being older, elevated CRP, increased D-dimers, high fibrinogen levels, tachypnea, fever, critical illness, infectious etiology and immobility) are at greater risk of such events during hospitalization and require close monitoring.

#### **9. Management of VTE in Patients with COVID-19**

Therapeutic anticoagulation is the mainstay of VTE management in patients either with or without COVID-19 [40–42]. Prescribing an anticoagulant agent should take into consideration underlying comorbidities; bleeding risk and the treatment choices can change during hospital stay or at discharge. Parenteral anticoagulation, for example with unfractionated heparin (UFH), is preferable in some inpatients with VTE as it can be temporarily withheld or reversed as no significant interactions have been reported with investigational COVID-19 therapies. However, using UFH has some disadvantages such as the variable times to achieve therapeutically activated partial thromboplastin time ratios and increased risks of infection to health care workers during frequent blood draws. Using lowmolecular-weight heparin (LMWH) may be preferred in patients who are unlikely to need further procedures. Advantages of oral anticoagulation with direct oral anticoagulant therapy (DOACs) includes minimal monitoring, improved discharge planning and outpatient management, while potential disadvantages include clinical deterioration and an inability to access reversal agents in a timely manner. Use of DOACs or LMWH is preferable in patients who are ready for discharge as it can minimize contact with health care personnel during INR monitoring. Catheter driven reperfusion and thrombolysis therapy is often recommended for management of patients with an unstable and large PE, but many patients with COVID-19 can have absolute or relative contraindications (such as coagulopathy, thrombocytopenia, a recent invasive procedure, pericarditis, age > 75 years) to thrombolysis [43,44].

#### **10. Outpatient Management with Mild COVID-19**

Patients with mild symptoms of COVID-19 should stay at home and the routine use of thromboprophylaxis is not recommended; they should be assessed for potential risks of VTE or bleeding and should continue anticoagulant treatment for other indications. Such patients should be counselled on the transition to DOAC after considering the risks of bleeding, potential drug interactions, affordability and availability of drugs, and recent INR status. There may be limitations to monitoring INR at home or at nearby laboratories due to the risk of exposure to SARS-CoV-2. Patients not suitable for treatment with DOAC

should use LMWH as a reasonable alternative. Patients with a stable INR and who did not require changes in dosage within the last six months can safely continue warfarin therapy [45].

#### **11. Management of Hospitalized Patients with Moderate or Severe COVID-19 without DIC**

Hospitalized patients with moderate to severe COVID-19 should be assessed for risks of VTE and DIC. Routine screening for VTE (e.g., with bilateral lower extremity ultrasound) in hospitalized patients with COVID-19 with elevated D-dimer levels (>1500 ng/mL) is not currently recommended. Signs of active bleeding should be monitored if DIC is suspected or confirmed. Every patient with moderate to severe symptoms should be offered thromboprophylaxis if not strictly contraindicated (for example, with severe thrombocytopenia, grossly deranged coagulation profiles or active bleeding). The choice of drugs, the dose and duration of treatment should follow national guidelines. Laboratory data monitoring, especially of D-dimers, should be checked every 2−3 days. Intermediate or therapeutic doses of thromboprophylaxis should be used at the discretion of the treating physician based on the risk of bleeding. A study of 92 ICU patients indicates a 21% overall rate of hemorrhagic events, of which nearly half (48%) received anticoagulation treatment [38]. Parenteral LMWH is the preferred choice for thromboprophylaxis due to its advantages related to dosing schedule and monitoring compared to intravenous heparin. Compliance is an important consideration in anticoagulant therapy; LMWH is administered mostly as a single daily dose, which improves compliance and thus outcomes. Drug interactions between antiviral treatments and DOACs, and the difficulty in maintaining stable INRs in patients prescribed vitamin K antagonists, means that LMWHs or UFH are preferable alternative treatments, either with or without mechanical prophylaxis.

#### **12. Hospitalized Patients with Moderate or Severe COVID-19 and with Suspected or Confirmed DIC**

Prophylactic anticoagulation should be administered to patients with moderate or severe COVID-19 diagnosed with DIC but without significant bleeding. There are currently insufficient data to consider routine therapeutic or intermediate-dose parenteral anticoagulation with UFH or LMWH in hospitalized patients with COVID-19 with suspected or confirmed DIC but with no overt bleeding. It is reasonable to consider the indications for anticoagulation therapy during dose adjustment or discontinuation in patients with moderate or severe COVID-19 already receiving chronic anticoagulation treatment and who develop suspected or confirmed DIC without overt bleeding. A common recommendation in such conditions is to reduce the dose of anticoagulant if the thrombotic risk is not excessive [45,46]. Patients with moderate or severe COVID-19 and receiving dual antiplatelet therapy (e.g., percutaneous coronary intervention within the past three months or recent myocardial infarction) should be assessed on an individual basis and serial platelet counts should be considered when making decisions on dose adjustments or discontinuation of treatment. In general, it is advisable to continue dual antiplatelet therapy if the platelet count is >50,000, reduce to single antiplatelet therapy if the platelet count is between 25,000 and 50,000, and discontinue antiplatelet therapy if the platelet count is below 25,000. These guidelines should be reviewed according to the risk of bleeding vs risk of thrombosis [17].

Risk assessment of VTE is reasonable when using pharmacological prophylaxis for up to 45 days post discharge. Pharmacological prophylaxis should be considered if there is an elevated risk for thrombotic events without a high bleeding risk. Patients should be counselled on the importance of ambulation and physical activity at home [45].

#### **13. Patients with COVID-19 Presenting with Acute Coronary Syndrome (ACS)**

Decisions regarding percutaneous coronary intervention or fibrinolytic therapy should be taken after assessing the severity of ST-elevation myocardial infarction (STEMI) and potential COVID-19 in patients and transmission risk to clinicians and healthcare providers [47].

#### **14. Extended (Post-Discharge) VTE Prophylaxis**

Post discharge extended thromboprophylaxis is recommended with LMWH or DOACs; even though these therapies reduce the risk of VTE, there remains the risk of bleeding events, including major bleeding [48–54]. Although there is little data specifically related to COVID-19, an individualized approach should be used after balancing the risks of hemorrhage and thrombosis, followed by extended prophylaxis (for up to 45 days) for patients at increased risk of VTE (e.g., reduced mobility, comorbidities such as active cancer, and elevated D-dimer levels more than twice higher than normal) but who are at a low risk of bleeding [50,55]. There is no clear guidance on thromboprophylaxis in patients quarantined with mild COVID-19 but having significant comorbidities, or for those without COVID-19 but who are less active because of quarantine measures. Such patients should be counselled about the importance of remaining physically active at home. Until more high-quality data are available, pharmacological prophylaxis should be reserved for patients with the highest risk, including those with limited mobility and a history of prior VTE or active malignancy.

#### **15. Role for Empiric Therapeutic Anticoagulation without a Diagnosis of VTE**

In view of the hemostatic derangements discussed above and from observations of other viral illnesses, some clinicians prefer the use of intermediate- or full-dose parenteral anticoagulation (rather than prophylactic dosing) for routine care of patients with COVID-19 based on the hypothesis that it could prevent microvascular thrombosis [56,57]. However, data to support this premise are primarily based on a subgroup analysis (n = 97) from a single retrospective study having limited control for potential confounders [17]. Another single-center study with 81 patients suggested that D-dimer levels greater than 1500 ng/mL have a sensitivity of 85.0% and specificity of 88.5% for detecting VTE events [58]. Many physicians prefer prophylactic anticoagulation treatment, while others consider the short-term use of intermediate or therapeutic doses as a reasonable approach. While physicians currently use a variety of prophylactic, intermediate, or therapeutic doses of anticoagulants in patients, the optimal dosing in patients with severe COVID-19 remains unknown.

#### **16. Managing the Risk of Hospital-Associated VTE**

Hospital-associated venous thromboembolism (HA-VTE) includes VTE presentation while hospitalized, and for up to 90 days post-discharge. Patients infected with COVID-19 are at increased risk of HA-VTE, especially if they become immobilized during critical care. It is unclear if hospitalized patients with COVID-19 are at increased risk for VTE compared to other patients with chest infections and elevated D-dimer values. Elevated D-dimer levels can also be used in a scoring system to identify those at increased risk of VTE [50,59]. Patients with severe COVID-19 are immobile, leading to an acute inflammatory state with a hypercoagulable state. There is also the possibility of endothelial cell activation/damage due to binding of the virus to ACE2 receptors [60].

#### **17. COVID-19 and Interventional Therapies for VTE**

The management of PE requires a multidisciplinary team [40,61–63]. It is important to note that there are limited data demonstrating lower mortality rates due to the routine use of advanced VTE therapies [64]. Therefore, the use of catheter-directed therapies during the current outbreak should be reserved for the most critical cases.

#### **18. Additional Considerations**

A lack of data makes it difficult to recommend transfusion thresholds in patients with COVID-19 that differ from those recommended for other critically ill patients. The prophylactic transfusion of platelets, use of fresh frozen plasma, fibrinogen, and prothrombin complex concentrate may be considered if invasive procedures are planned [18]. Lastly, patients requiring targeted temperature management often have prolongations of both PT and

aPTT without evidence of bleeding diathesis [65]. Therefore, correction of coagulopathy in unselected patients without overt bleeding is not advisable.

#### **19. Management of Bleeding That Occurs in COVID-19**

Clinically overt bleeding is uncommon in patients with COVID-19. Bleeding in COVID-19-associated DIC requires support with blood products and should be managed as per local guidelines [66]. The guidelines for blood product transfusion are as follows: (a) maintain platelet count >50 <sup>×</sup> <sup>10</sup>9/L in DIC patients with active bleeding or >20 <sup>×</sup> <sup>10</sup>9/L in those with a high risk of bleeding or requiring invasive procedures, (b) fresh frozen plasma (15 to 25 mL/kg) in patients with active bleeding with either prolonged PT or aPTT ratios (>1.5 times normal) or decreased fibrinogen (<1.5 g/L), (c) fibrinogen concentrate, or cryoprecipitate in patients with persisting severe hypofibrinogenemia (<1.5 g/L), and (d) prothrombin complex concentrate if fresh frozen plasma transfusion is not possible. Tranexamic acid is not recommended for routine use in COVID-19-associated DIC.

#### **20. Management of Patients with Thromboembolic Disease without COVID-19**

The main management goals for patients with pre-existing or new onset thrombotic disease but without COVID-19 is to provide adequate antithrombotic protection, while minimizing physical contact between patients and healthcare workers. Outpatient management or early discharge for acute VTE is recommended whenever possible [57], and it is reasonable to plan early discharge after medication stabilization for low-risk ACS or PCI for high-risk ACS [67,68].

In general, pharmacotherapy in patients without COVID-19 but with thrombotic disease should be provided according to usual management plans. There is little evidence that antiplatelet agents or anticoagulants increase vulnerability to infection with COVID-19, or of developing severe COVID-19. Patients education on (a) self-monitoring of symptoms is important, and (b) visits to the emergency department for minor bleeding is discouraged.

Patients receiving vitamin K antagonist who need frequent INR checks face logistical challenges due to the lockdowns, with an increased risk of exposure to SARS-CoV-2 in public places. It is useful to consider alternatives such as extended INR testing intervals if previous INR values were stable [69]. Other alternatives include home-based INR checks (provided this is promptly enabled), drive-through INR testing, or switching to a DOAC or LMWHs when clinically appropriate [45].

Whenever switching of anticoagulant is planned, care should be taken to ensure the patients of affordability and accessibility of the agent. DOACs should be used with caution in the elderly (greater risk of bleeding, especially gastrointestinal bleeding) and those with acute kidney injury/renal impairment. Contraindications to treatment with DOACs include patients with mechanical heart valves, valvular atrial fibrillation (AF), antiphospholipid syndrome (APLS), concomitant use of drugs that inhibit cytochrome P450 family 3-subfamily A, and P-glycoprotein and patients who are pregnant or breastfeeding. Patient education on appropriate dietary habits while receiving vitamin K antagonists is also important. The use of LMWHs should be considered in cases where DOACs are not available or not approved by insurance providers.

#### **21. International Travel and COVID-19**

Multiple studies reported that environmental and physiological changes occur during routine commercial flights that could lead to mild hypoxia and gas expansion, and which can exacerbate chronic medical conditions or even induce acute in-flight medical events. Long-haul flights increase the risk of VET several fold. COVID-19 has at least two effects relevant to air travel. Unlike normal pneumonia, in which patients experience cough, chest discomfort and significant breathing difficulties, patients with COVID-19 pneumonia initially may not always experience such symptoms, causing a condition termed "silent" or "happy" hypoxia. This may be aggravated by the hypobaric cruising cabin altitude pressure. Silent hypoxia occurs because the virus only causes the air sacs to collapse to reduce oxygen

levels without affecting the removal of carbon dioxide. It is important to detect hypoxia in these patients before they begin to experience dyspnea so that an early intervention can prevent the lungs from deteriorating further. Secondly, COVID-19 is associated with coagulopathy and endothelial damage resulting in VTE. As many economies return to normal, commercial aircrafts will resume operations whilst implementing preventative strategies. Pre- and on-board pulse oximetry screening can be used for early detection of silent hypoxia in unwell passengers boarding aircrafts. This is a simple procedure and can avoid on-flight emergencies. Identified risk factors may be accentuated by the procoagulant effects of undiagnosed COVID-19 that can increase the risk of VTE's. The "new normal" pre- and post-travel consultation will need to take all these considerations into account. Travelers with known risk factors (e.g., obese, male, pregnant, smoking history, previous/family history of VTE) should consider appropriate thromboprophylaxis [70].

#### **22. Public Health Considerations Related to Care for Thrombotic Disease**

Governments have enacted mandatory home quarantine for all non-essential personnel in areas most affected by COVID-19. There are several issues to consider related to thrombotic disease at a community level:


#### **23. Conclusions**

More information and data are needed to better define thromboembolic disease due to de novo COVID-19 and differentiate it from pre-existing thrombotic disease to guide optimal management strategies. A large international registry is currently accruing data from COVID-19 patients with VTE [66,67] and another adjudicated prospective registry is incorporating COVID-19 outcomes with cardiovascular risks (CORONA-VTE registry; BWH Thrombosis Research Group). A multicenter, multinational ACS registry has also been initiated, in addition to the new American Heart Association registry for cardiovascular care and outcomes in these patients. Special attention should also be given to patients with pre-existing thromboembolic diseases and with limited access to care due constraints on access to the health care system. The guidance provided in this review for thrombotic disease and antithrombotic therapy during the COVID-19 pandemic (summarized in Table 2) should supplement rather than substitute for clinical decision making. Nuances in conversations between patients and practitioners should be considered when making appropriate patient-centered decisions. Thrombotic diseases may be existing factors or incident complications in patients with COVID-19. Mindful prescribing of preventive and therapeutic doses of antithrombotic agents will mitigate the potentially lethal thrombotic and hemorrhagic events in these high-risk patients. Collaboration between funding agencies, professional societies, patients, clinicians and investigators is needed to address current knowledge gaps on coagulopathies inpatients with COVID-19 patients. Lastly, as governments ease lockdowns, international travel will impact on how we manage and advise patients who remain at risk of, or who are recovering from, COVID-19.


**Table 2.** Summary of management guidelines for thrombotic disease in patients with COVID-19.

DOAC: Direct oral anticoagulants; DIC: Disseminated intravascular coagulation; VTE: Venous thromboembolism; INR: International normalized ratio; LMWH: Low-molecular weight heparin.

> **Author Contributions:** Conceptualization, A.I. and S.K.; resources, S.K., A.I., S.R., I.L.; writing—A.I. and S.K., writing—review and editing S.R., I.L.; supervision, S.K.; All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding. Institutional Review Board Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

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