key: cord-0998447-y23i8tkl
authors: Sahu, Kamal Kant; Cerny, Jan
title: A review on how to do hematology consults during COVID-19 pandemic
date: 2020-11-08
journal: Blood Rev
DOI: 10.1016/j.blre.2020.100777
sha: c0ff1609b2de83a946deca1b6272efb13e9a2235
doc_id: 998447
cord_uid: y23i8tkl

The ongoing COVID-19 pandemic is the most trending and talked topic across the World. From its point of origin in Wuhan, China to clinical laboratory at NIH, a mere six-month-old SARS-CoV-2 virus is keeping the clinicians, and scientists busy at various fronts. However, COVID-19 is an emerging and evolving disease and each day brings in more data, new figures, and findings from the field of clinical practice. The role of hematologists has been increasingly recognized during the current pandemic because of several reasons. Most important of them are the characteristic hematological findings of COVID-19 patients that also have prognostic implications and that were not seen in other viral infections. The treatment of hematological complications in COVID-19 patients is very challenging given the critical care setting. There are interim and limited guidelines thus far due to the novelty of the disease. As this remains to be a quite fluid situation, all the appropriate medical societies including the major hematology bodies are proposing initial and interim guidelines (e.g. ASH guideline). This puts a hematologist on consult service in a dubious position where, he/she must tailor the recommendations on case to case basis. The purpose of this review is to provide the background context about the impact of COVID-19 on the blood system and to summarize the current interim guidelines to manage the associated hematological issues in COVID-19 infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been recently recognized as a new human infectious virus (1) . Starting early December 2019 as a local outbreak, now coronavirus disease has turned to a pandemic status with more than 13,800,016 cases and 589,114deaths (as on July 16 , 2020) (2) . The clinical continuum of COVID-19 varies from asymptomatic form to critically ill requiring intensive care. Recent studies have found a specific trend of laboratory abnormalities in patients with COVID-19. The initial reports noted the following common hematological changes lymphopenia (82.1%), thrombocytopenia (36.2%), and leukopenia (33.7%) (3) . Similarly, coagulopathies with prolonged prothrombin time, and D dimer elevation have been observed in patients with more critical clinical picture (4) . It is expected that we will have to learn how to live with coronavirus infection risk for the foreseeable future. It is very likely that patients with various clinical pictures will need to be evaluated by a hematologist and thus we feel this review of known hematological abnormalities associated with COVID-19 is going to be important for routine clinical practice (5) . Multiple hematologic parameters in COVID-19 patients can predict prognosis as well as severity of illness thus may help with proper triage of patients within the hospital.

(15/23 patients) were noted to have double the risk to develop thrombosis. Improved prediction scores also showed a higher risk of bleeding while on VTE prophylaxis in 9 out of 138 (6.52%) patients. Contrary to prediction, thrombotic events were noted only in 4 out of 138 patients (2.9%), 3 of them were critically ill. Upon treatment for VTE, one critically ill patient also suffered a massive hemorrhage. Postmortem findings of variable degrees of hemorrhagic pulmonary infarction, occlusion, and micro thrombosis formation have also been noted by Luo et al (9) . Cui et al did their study exclusively in 81 intensive care unit (ICU) patients with COVID- 19 . 20 out of the 81 patients (25%) developed VTE, of which 8 patients ultimately died. They found D-dimers >1.5 µg/mL to a good prognostic indicator to develop VTE in critically ill patients (10) .

Based on the increased risk of thrombosis the current consensus is to consider judicious use of anticoagulants for VTE prophylaxis in all hospitalized patients especially the ones who are critically ill (11) . Another group of researchers suggests using low molecular weight heparin (LMWH) as it might have inhibitory potential against SARS-CoV-2 replication (12, 13) . This is based on the observation of FXa and FIIa induced activation of SARS-CoV-2 Spike protein which promotes infectivity. Recently, Kim et al reported a potential link between host cell surface glycosaminoglycan (GAGs) and SARS-CoV-2 viral entry into the cell (14) . They further indicated heparan interaction with the GAG-binding motif that could potentially block the SARS-CoV-2 pathogenesis. Hence the use of anticoagulation especially during the early phase of viremia might inhibit SARS-CoV-2 replication. Tang et al studied 449 patients with severe COVID-19, 99 of them received LMWH for 7 days or more (15) . In patients with sepsis-induced coagulopathy (SIC score) ≥4, the 28-day mortality of heparin users was lower than nonusers (40.0% vs 64.2%, P=0.029), or D-dimer > 6- Empirical Therapeutic-intensity anticoagulation:

Once acquired, SARS-CoV-2 infection initiates a complex systemic inflammatory response.

Activation of host defense mechanisms including the coagulation cascade and complement system prompts thromboinflammation or immunothrombosis. The severity of this phenomenon correlates with the severity of the critical illness of the patients. Postmortem series have confirmed evidence of multi-organ and disseminated microvascular thrombosis in various organs (19, 20) . This has served as a platform for a few ongoing clinical trials to try prophylactic high-intensity prophylaxis in critically ill patients with COVID-19 with no known thrombosis.

Few medical centers are using full-dose anticoagulation through their institutional protocol but so far, no data support it for the prevention of microvascular thrombosis in patients suffering from severe COVID-19 infection(21). As per the latest ASH guidelines (Version 3.0; last reviewed June 23, 2020), therapeutic-dose heparin should only be limited to clinical trials than empiric use (22) .

There are anecdotal reports of transient benefits of using tissue plasminogen activator (tPA) in critically ill patients with Acute respiratory distress syndrome (ARDS) (23) . However, there is not enough data to suggest using more innovative therapies like tPA outside of a clinical trial and most centers recommend against using them (22).

In general, patients with impending multiorgan failure who develop disseminated intravascular coagulation (DIC) have the worst prognosis. In DIC, one can see various combinations of exaggerated thrombotic and/or fibrinolytic phase (24, 25) . Studies so far have suggested that J o u r n a l P r e -p r o o f coagulopathy associated with COVID-19 (CAC) is predominantly a pro-thrombotic DIC with elevation in D-dimer levels, and fibrinogen levels, and a decrease in anti-thrombin levels. A critical evaluation of coagulogram of patients with COVID-19 has shown a spectrum of the coagulopathic pattern from CAC to frank DIC (24) . The clinical implications of these coagulopathy perturbations are pulmonary congestion with microvascular thrombosis and micro occlusion with an increased rate of thromboembolic events, central line thrombosis, and strokes. (26) . Based on these findings, D-dimer has become a reliable marker of prognosis, hospital mortality, and need for ICU level care (3, 15, 26) .

Though not significant, modestly prolonged prothrombin time (PT) was noted in non-survivors (15.5 seconds) than in survivors (13.6 seconds) by Huang et al (26) . Rovina et al. suggested in their small study (57 patients) the use of measurement of soluble urokinase plasminogen activator (suPAR) within first 24 hours that can be predictive of severe respiratory failure and identify patients at high risk early. The urokinase plasminogen activator receptor (uPAR) that is bound on the endothelium is cleaved as SARS-CoV-2 activates endothelial cells (27) . The endothelial activation is an early step in COVID process. While this parameter of endothelial activation has been described in several settings predicting kidney injury or progression of sepsis J o u r n a l P r e -p r o o f it may not be readily available as a routine test and we need to see further studies in COVID-19 patients as well.

As discussed, patients can be anywhere in the spectrum of coagulopathy from mild to severe, and from CAC to DIC. The nature of the disease, viral load, and spread in the body, cytokine storm, etc. are a few of the many factors that help to assess the actual patient's situation. The American Society for Hematology (ASH) recommends regular monitoring of platelet count, PT/aPTT, Ddimer, and fibrinogen levels to guide how aggressive critical care needs to be and when to scale up or scale down the level of care.

So far, there are no high-quality data to guide management for coagulopathy in patients with COVID-19. Therefore, both International Society of Thrombosis and Haemostasis (ISTH) and ASH suggest managing coagulopathy in COVID-19 just like any in other non-COVID-19 patient, that primarily includes treating the underlying disease (15, 28) . Unfortunately, for COVID-19, we do not have any specific treatment to mitigate the viremia and organ dysfunction.

Current literature from clinical experience with COVID-19 patients suggests bleeding not be a major concern(22,24,29) ASH committee strongly suggests a tailored approach and clinical judgment on case to case basis while deciding for the use of blood components (Figure 1) .

Based on the recommendations by ASH and ISTH, Table 1 describes the various types of anticoagulants and the possible scenarios for using them (15, 28, 30) (Table 1 ).

Antiphospholipid antibodies are classically discussed in context to their role in laboratory diagnosis of antiphospholipid syndrome. However, these antibodies are well known to rise Similarly, Li et al reported an incidence of stroke as 5% among hospitalized patients (37) . Large vessel stroke in 5 COVID-19 patients younger than 50 yrs was recently reported by Oxley et al (25) . None of these three studies evaluated their patients for the presence of antiphospholipid antibodies. Hence, so far significance of antiphospholipid antibodies in precipitating ischemic/thrombotic events in COVID-19 patients is unknown and needs further evaluation.

Abnormal platelet count is often associated with a viral illness and that is not COVID-19 specific (38) (39) (40) (41) . Similarly, the importance of low platelet in prognostication is well described in multiple studies in critically ill patients. Various patterns such as low nadir platelet count, or rapid decline in platelet count have proven significance based on several studies (42, 43) . The evidence so far has confirmed a low platelet count as an important prognostic indicator of J o u r n a l P r e -p r o o f severity and mortality in COVID-19 patients (44) . While thrombocytopenia may be associated with significant bleeding events, a reactive thrombocytosis could be associated with heightened hypercoagulability or/and thrombogenesis (45, 46) .

Thrombocytopenia is the one of the most common reasons hematologists are being consulted on critically ill patients. Unfortunately, a thrombocytopenia in an ICU patient is often multifactorial and thus it is often difficult to pinpoint one and only factor. Similarly, in COVID-19 as well, combination of various factors could be responsible for low platelets. Underlying liver issues, drug side effects, heparin-related thrombocytopenia (HIT), primary hematological disease (Immune thrombocytopenia, Thrombotic thrombocytopenic purpura etc.), impending DIC, viral infection and overt inflammatory response are few of the many such causes (39, 47) .

Pathophysiology: Studies from previous viral outbreaks might help to understand the possible mechanism behind SARS-CoV-2 induced thrombocytopenia (44, 48) .

Few of the potential mechanisms proposed are:

 Endothelial damageplatelet activation, aggregation, and thrombosis (predominantly in lungs) consumptive thrombocytopenia.

 Deranged platelet defragmentation from mature megakaryocytes due to pulmonary capillary bed morphologic alternationreduced release in the peripheral circulation.

 Robust auto-immune response against plateletsplatelet destruction.

 Virus directly infecting the hematopoietic stem cells, megakaryocytes, and platelets (via CD13 or CD66a) apoptosis.

Prognostic value of thrombocytopenia: As discussed previously thrombocytopenia especially the declining trend has been consistently studied in many studies as a poor indicator of survival.

Lippi et al in their recent meta-analysis of 9 studies and 1779 COVID-19 patients studied thrombocytopenia in COVID-19 infections (44) . Their meta-analysis showed that thrombocytopenia was associated with increased severity of illness, and dismal survival. They however admitted their study had limitations including arbitrary cutoff for low platelet count in various studies thereby making interpretation difficult. Qu et al also reported a high platelet to lymphocyte ratio as an independent prognostic factor for prolonged hospitalization and a more pronounced cytokine storm in COVID-19 patients(49).

Newly diagnosed ITP (Outpatient): Treatment options for newly diagnosed ITP remains the same. Rather, the frequency of lab draws, and office visits should be minimized as much as possible. COVID-19 patients who need urgent platelet count increase (e.g. major bleeding or wet purpura or platelet count), Intravenous immune globulin (IVIg) therapy (1gm/kg for 1-2 days), and oral thrombopoietic (TPO) agents like eltrombopag or avatrombopag. Both IVIg and TPO agents have the advantage of not being immunosuppressive agents unlike other ITP drugs like steroids, and cyclosporine.

If a patient is critically ill, extremely thrombocytopenic to less than 20,000/ microliter, treatment with IVIg and oral thrombopoietic (TPO) agents (eltrombopag or avatrombopag) may be considered. If a patient is already on a TPO agent from before, the trial of dose increment or adding a second TPO agent could be considered. A trial of short-term steroids (1-5 days) has not been studied in COVID-19, hence it is difficult to recommend for or against it (41) .

Journal Pre-proof Chronic ITP: As of now, there is no evidence of increased incidence of COVID-19 in known ITP patients (38) . Patients with stable disease and receiving lower doses of immunosuppressants do not need any modification. However, patients receiving higher doses of steroids may benefit by attempting to replace with TPO agents and/or IVIg. Rituximab may need to be possibly avoided.

An increased platelet count has also been seen in association with respiratory viral illnesses.

Based on previous studies, the stand of secondary thrombocytosis (ST) as a prognostic marker in viral diseases is controversial with contrasting results for and against both (50, 51) . As of now, only a few studies so far have discussed ST in patients with COVID-19. Chen at al identified thrombocytosis in a small proportion~4% of cases (52) . Further significance is yet to be studied.

Both ASH and ISTH have no specific recommendations with regards to ST. From the hematology consult angle, in our opinion we can say that ST is something that should be kept in mind, the increase in the number of platelets counts per se may not matter unless there is clinical evidence of thrombotic state. Previous studies showed increased circulating cytokines, such as thrombopoietin, interleukin 6/8/1a, and tumor necrosis factor as responsible agents to cause ST (53, 54) . Hence, to our assumption, once the cytokine storm subsides, the platelet counts are expected to go down. 

Hence, there is no clear evidence to recommend for or against GM-CSF and the ongoing clinical trials might be helpful to guide us.

FN is one of the serious treatment-related toxicities of chemotherapy for cancer. It is associated with a mortality rate ranging from 2% to 21% (76) . While G-CSF in FN has not shown any mortality benefit it reduces the hospital stay, which can be beneficial especially during current COVID-19 due to limited resources. However, at the same time there are reports which have shown that G-CSF-induced neutropenia recovery coincides with respiratory deterioration due to acute lung injury or ARDS (77) . 

Lymphopenia is one of the common hematological findings in viral illnesses and other immunological disorders. It has been well described during previous coronavirus outbreaks as well.

Most of the studies from the beginning of the pandemic have found lymphopenia in a significant patient population (7, 26, 80) . Huang 

Eosinophils are known for their role in host defense against infections, immunological and allergic disorders, and various hematological disorders and cancers (84) . Eosinopenia, has been also studied as an early marker of increased mortality in critically ill patient's medical intensive 

In recent years, many simple elements reported in the routine laboratory results have been investigated for their role to predict systemic inflammation. Some of these biomarkers are;

Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCR), plateletto-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil CD64 expression, mean cell volume of neutrophils and monocytes, delta neutrophil index immature granulocyte fraction, and monocyte distribution width (MDW). So far, except for a handful of studies, we do not have any good data on any of them for their usability in the COVID-19 pandemic(56,90). Tocilizumab, a recombinant humanized monoclonal antibody against the human IL-6 receptor is currently approved for chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (97) . Early studies from China showed the benefit of tocilizumab administration in patients with severe or critical illnesses (98, 99) . Currently, the Food and Drug Administration's (FDA) has approved this drug for the phase III trial study which would provide us more data regarding this indication. From the hematologist's perspective, all consults for suspected sHLH should be thoroughly investigated and COVID-19 might be considered as a potential trigger. As of now, in the United States, use of tocilizumab in critically ill COVID-19 cases with raised IL-6 levels is based on compassionate ground and no recommendations could be given(100).

Like other hematological parameters, hemoglobin levels and its significance has also been studied in COVID-19 patients. Studies conducted in the past on hospitalized patients with pneumonia have found low hemoglobin to be independently associated with increased patients with the severe disease than in those with mild cases (104, 105) . Although, not looked in detail so far in any of the above-mentioned studies, it is expected that multiple factors would be contributing to anemia in COVID-19 patients who are critically ill and/or in intensive care.

Basics remain the same while consulting for anemia in patients with COVID-19, that is to look for [1] Loss of blood due to phlebotomy and bleeding [2] Decreased erythropoiesis secondary to bone marrow suppression [3] Increased destruction of RBCs, or [4] nutritional deficiency (82, 106, 107) . 

We have mentioned the importance of peripheral smear film (PBF) examination as one of the easiest, cheapest, basic, and quickly available tests already several times. We believe that the 

Patients with sickle cell disease (SCD) are at increased risk of infections. In general, SCD patients have underlying cardiopulmonary co-morbidities that predisposes them to respiratory illnesses more than the general healthy population (110) . Another serious complication of SCD is acute chest syndrome (ACS), which is often provoked by a respiratory infection like viral illnesses. Previous studies during the 2009 H1N1 influenza pandemic found SCD patients to be at risk for developing more complications (111, 112) . The SARS-CoV-2 virus seems to also to Unlike SCD, patients with thalassemia have comparatively a lower risk of lung infections but, an overall compromised cardiopulmonary system, diabetes, and hemochromatosis secondary to severe iron overload increase the vulnerability to complications of the virus. Another concern of hypoadrenalism in thalassemia secondary to iron overload may merit using rescue steroids as a stress dose (115) . Concerns over chelation related side effects also merit discussion on case to case basis. Deferiprone carries the risk of reversible agranulocytosis and neutropenia while deferoxamine is known for its association with bacterial infections (notably Yersinia and Klebsiella).

Individual's susceptibility to infections based on their blood groups has always been a matter of epidemiological investigations for immunohematology. Many blood groups can facilitate the infectious process by acting as receptors thereby facilitating cell invasion and evasion of host defense. One of the classical observations is a correlation between ABO type and norovirus infection (32, 116) . Hutson 

Hypogammaglobulinemia is a condition with reduced immunoglobulins in the serum, which can be a primary or secondary phenomenon (119) . The primary antibody deficiency syndromes are extremely rare and hence, malnutrition, plasma cell, or B cell-directed therapy as in patients (121) . Given the limited data, we can only speculate that the immunosuppressed state caused by inborn defects leading to hypogammaglobulinemia maybe perhaps protective. It is possible that in patients with severe COVID-19 aberrant B-cell signaling is detrimental. This theory is further supported by preliminary reports showing that BTK inhibitors were able to curtail inflammatory responses in patients with COVID-19 (122) . BTK inhibitors create a pharmacologically acquired "absence" of B cells or B cell signaling, which essentially resembles Bruton's agammaglobulinemia (123) . On the other hand, profound secondary hypogammaglobulinemia (< 400 mg/dL) in multiple myeloma patients (n=54) was associated with more likely hospitalization and mortality in a study by Wang et al So it appears that the risk factor may not be hypogammaglobulinemia itself, but rather how a specific patient becomes hypogammaglobulinemic in terms of COVID-19 severity and outcome(124).

The preliminary observations from China and Europe suggested that COVID-19 patients with cancer overall faced much higher morbidity and mortality. This has led to the initial wave of recommendations of delaying therapy cycles, switching to less myelosuppressive regimens, and delaying stem cell transplantations (and related immunosuppression) whenever clinically acceptable (125) (126) (127) . More recently single-institution studies seem to suggest however that immunosuppression and anti-cancer therapy can be delivered safely as long as aggressive nonpharmacological intervention (NPI) protocols are followed to prevent COVID-19 transmission.

Besides these aggressive NPI protocol individualized approach is paramount as various factors like the type of cancer, stage, and prognosis, comorbidities (hypertension, diabetes remain the key risk factors for COVID-19 outcome across all diseases), performance status, treatment options, the local situation of the pandemic as it relates to the availability of ICU level of care and blood product supply in case of complications, patient's preference, and specialists' experience play important role in deciding the approach (128, 129) . And at least until further studies are available case to case basis evaluation is most likely going to be the prevalent approached, which may be modified as the interim recommendations by hematology and oncology societies may be changed based on data available from larger cohorts of patients such as ASH, ASCO, and CIBMTR databases (14, 25, (130) (131) (132) .

COVID-19 has emerged as an unparalleled health care crisis that represents a challenge for all medical specialties by its pervasive presence and by its novel clinical symptomatology and syndromes. The role of a hematology expert is paramount in managing clotting conditions, associated cytopenias. Furthermore, hematologists with expertise in handling Cytokine release syndrome (CRS) that occurs in patients receiving cellular therapies (CAR T cells) or hematopoietic stem cell transplants may provide key insights into the appropriate management of cytokine storm associated with severe COVID-19. Last, but not least as many patients may present to the hospital in the presymptomatic phase a unique constellation of hematological abnormalities that are recognized by hematology specialists may thus lead to proper COVID diagnosis and in turn prevent potential unnecessary SARS-CoV-2 exposures and transmissions. 

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