|Year : 2021 | Volume
| Issue : 3 | Page : 181-186
COVID-19 and Blood Disorders
Sheeba Khan1, Sunita Aggarwal2, Ankitesh Kumar3, Sandeep Garg2, Praveen Bharti2, Deepshikha Choudhary2
1 Room Number 330, LNRDH Maulana Azad Medical College, New Delhi, India
2 BL Taneja Block, Department of Medicine, MAMC and LNH, New Delhi, India
3 B22 Hudco Place Extension, New Delhi, India
|Date of Submission||20-Jul-2021|
|Date of Decision||01-Oct-2021|
|Date of Acceptance||19-Oct-2021|
|Date of Web Publication||24-Dec-2021|
Dr. Sunita Aggarwal
Department of Medicine, MAMC and LNH, B L Taneja Block, New Delhi-110002
Source of Support: None, Conflict of Interest: None
In December 2019, a new type of coronavirus, severe acute respiratory syndrome coronavirus 2 was detected in Wuhan, Hubei province, China. It is currently a pandemic, with more than 185 million cases and roughly 4 million deaths globally as of July 9, 2021, with the United States and India leading the way. Coronavirus disease 2019 (COVID-19) may show multisystem involvement with significant impact on hematopoietic system and hemostasis. Blood count abnormalities, that is, lymphopenia (83.2%) and neutrophilia (34.5%), are of prognostic significance. Changes in hemostatic biomarkers represented by increase in D-dimer (23.3%) and associated thrombocytopenia (36.3%) indicate the essence of coagulopathy reported in these patients leading to fatal implications such as disseminated intravascular coagulation and serious thrombotic complications. Hence, accurate evaluation of laboratory indicators at the beginning and during COVID-19 can help health professionals in adjusting appropriate treatment and providing special and prompt care for those who need it. This study aims to highlight these abnormalities and appropriate interventions aimed to reduce the associated mortality of the disease. The effect of COVID-19 in patients with hematologic abnormalities and role of vaccination are also outlined.
Keywords: Coagulopathy, COVID-19, laboratory findings, vaccination
|How to cite this article:|
Khan S, Aggarwal S, Kumar A, Garg S, Bharti P, Choudhary D. COVID-19 and Blood Disorders. MAMC J Med Sci 2021;7:181-6
| Introduction|| |
Coronavirus disease 2019 (COVID-19) is a multisystemic infectious disease caused by a newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an incubation period of 1 to 14 days. Fever, dry cough, and tiredness are common symptoms of COVID-19. However, a subset of patients develops a more severe form of the disease, characterized by acute respiratory distress syndrome (ARDS), neurologic, cardiac, renal, hematopoietic, and immune complications. SARS-CoV-2 enters the host cells through angiotensin-converting enzyme 2 (ACE2) receptors that are expressed in the alveolar epithelial cell types 2 and 1, myocytes, vascular endothelial cells, hematopoietic stem cells, and progenitors. SARS-CoV-2 may also attack host cells via the CD147-spike protein pathway. Hematologic abnormalities lymphopenia, thrombocytopenia, and elevated D-dimer levels are significantly prominent in patients with severe COVID-19 and may serve as a biomarker for those who need hospitalization and intensive care unit. This study summarizes the hematologic abnormalities with their pathogenesis and management along with vaccination in COVID-19 and the effect in patients with underlying hematologic disorder.
| Hematologic Profile in COVID-19|| |
During the course of the disease, longitudinal evaluation of hematologic parameters such as lymphocyte count dynamics and inflammatory indices, including lactate dehydrogenase, C-reactive protein, and interleukin-6 (IL-6) may help to spot cases with dismal prognosis and early intervention to improve outcomes [Table 1].
Hematologic abnormalities were also witnessed with other coronaviruses. In patients with SARS-CoV-1 infections, lymphopenia (69.6–100%) and thrombocytopenia (20–55%) have been reported. The corresponding rates in Middle East respiratory syndrome coronavirus (MERS-CoV) infections were as follows: lymphopenia (44–60%) and thrombocytopenia (31–40%). Coagulation abnormalities, that is, elevated D-dimer level and prolonged prothrombin time (PT) ensuing SARS-CoV-1 and MERS-CoV infections were observed in several studies. For instance, 45% of patients with SARS-CoV-1 had elevated D-dimer levels. It was also reported that 20.5% of patients had deep vein thrombosis, and 11.4% showed clinical evidence of pulmonary embolism (PE) with SARS-CoV-1 infection.
| Effects on White Blood Cells|| |
Due to the high prevalence of lymphopenia (40–91.6%) in patients with COVID-19 and its strong association with the severity of the disease, lymphocytes count can be used as a predictive biomarker for the severity of the disease. Lymphopenia in these patients leads to a reduction of the total number of lymphocytes, TCD4+, TCD8+, B cells, and natural killer cells, where the reduction of CD8+ T cells more significant. Zhao et al. in a meta-analysis study demonstrated that the risk of severe COVID-19 increased by about threefold in patients with lymphopenia. Fan observed that 69% of patients with lymphopenia had reactive lymphocytes (lymphoplasmacytoid) and lower levels of CD45+, CD19+, CD8+, CD4+, and CD16/56+ in intensive care unit (ICU) admitted patients than non-ICU patients. Multiple studies revealed that there could be a link between lymphopenia severity and COVID-19 severity, as well as the requirement for ICU admissions.,,,,
It is hypothesized that SARS-CoV-2 may directly invade lymphocytes, leading to lysis of lymphocytes and lymphopenia, as they express ACE2 and CD147 on their membrane. There is a negative relationship between serum levels of IL-6, IL-10, and tumor necrosis factor-alpha with the number of lymphocytes.
The neutrophil-to-lymphocyte ratio (NLR ratio) was higher in patients with severe COVID-19 is calculated by dividing the absolute number of neutrophils by the absolute number of lymphocytes and is of great importance in expressing the general inflammatory condition of the patient. NLR is used for classifying the severity of COVID-19 disease [Table 2].
Currently, corticosteroids are used to reduce COVID-19-related inflammation. Dexamethasone 0.1 to 0.2 mg/kg or methylprednisolone 0.5 to 1 mg/kg for 5 days in moderate cases and dexamethasone 0.2 to 0.4 mg/kg or methylprednisolone 1.0 to 2.0 mg/kg for 10 days in severe cases.
Neutrophilic leukocytosis was linked with a high risk of the acute respiratory syndrome, risk of death, and elevated troponin levels. In addition, neutrophil infiltration into the pulmonary capillaries, extravasation of neutrophils into the alveolar space, and neutrophilic mucositis were found in the autopsy report of patients with COVID-19.
For the development of severe complications of COVID-19, including ARDS, increased neutrophil counts (by cytokines such as granulocyte colony-stimulating factor), and their inflammatory activities (production) as well as neutrophil extracellular traps from overactive neutrophils may be responsible.
Therefore, the neutrophil count not only determines the prognosis of COVID-19 but also plays an important role in the immunopathology of severe COVID-19.
Thrombocytopenia is reported in 5% to 40% of patients, and platelet count <200 × 109/L at admission was associated with three times higher mortality although the degree of thrombocytopenia observed is generally mild. Platelet counts were found to decrease from around day 4 of symptoms.
Mechanisms of development of thrombocytopenia are the direct and indirect effect of SARS-CoV-2 on the hematopoietic cells and endothelial cells, which can be associated with increased platelet activation, increased platelet aggregation, impaired megakaryocyte maturation, and platelet consumption in the microcirculation of damaged lung tissue. Inflammatory cytokines by destroying progenitors in the bone marrow and reducing platelet production can cause thrombocytopenia.
Finally autoantibodies against platelets may lead to thrombocytopenia by platelet destruction. Case studies of patients developing idiopathic thrombocytopenia purpura (ITP) and thrombotic thrombocytopenic purpura following SARS-CoV-2 infection have been published with the likely mechanism being the molecular mimicry between the antigens of SARS-CoV-2 and platelet glycoproteins.,
Lippi et al. demonstrated a relationship between platelet count at the time of hospitalization and the severity of the disease in their meta-analysis and this has been confirmed by several other studies. Furthermore, according to Yang and his colleagues, thrombocytopenia is a common finding in patients with COVID-19 and is linked to an elevated risk of mortality.
| Coagulopathy in COVID-19|| |
Recent data suggest increased incidence of thromboembolism in patients with COVID-19 and elevated D-dimer (23.3%), prolonged PT (2.1%), prolonged activated partial thromboplastin time (aPTT; 9.7%) serve as markers of negative prognosis. The imbalance between coagulation and fibrinolysis in the pulmonary circulation and bronchoalveolar space are likely to be important factors in the pathogenesis of ARDS in COVID-19. Tang et al. found differences in coagulation parameters between survivors and nonsurvivors in a study of 183 COVID-19 pneumonia patients, with increases in PT, aPTT, fibrinogen, D-dimer, and fibrin degradation products, and a sharp decline in antithrombin levels among nonsurvivors compared to survivors. The same findings were also observed in study by Yu et al. [Table 3].
|Table 3 Comparison of coagulation parameters in coronavirus disease 2019|
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The exact mechanism of coagulation dysfunction in patients with COVID-19 is unknown. The combined effect of the significant inflammatory response, thromboinflammation, and endothelial damage is primarily responsible for this thrombogenic potential of the virus, although virus itself does not possess any intrinsic procoagulant activity. In certain patients, especially those with severe illnesses, SARS-CoV-2 has been shown to cause endothelial dysfunction via an ACE2-mediated pathway with an increased inflammatory response. Inhibition of the plasminogen system, platelet dysfunction and complement activation in COVID-19 are other factors that lead to the development of hypercoagulable state. To further support the hypercoagulable state, lupus anticoagulant (LAC) has been detected with an incidence as high as 90%. Bowles et al. found the presence of LAC in 31 of 34 diagnosed patients with elevated aPTT. Antiphospholipid antibodies in affected patients may also contribute to coagulopathy via secondary antiphospholipid syndrome.
Malas et al. reported in a meta-analysis that the rate of arterial thromboembolism (ATE) in patients infected with SARS-CoV-2 was 2%, the rate of venous thromboembolism (VTE) was 21%, the rate of deep venous thrombosis (DVT) was 20%, the rate of PE was 13% and in ICU-admitted patients, the rates were ATE (5%), VTE (31%), DVT (28%), and PE (19%), respectively. Bleeding is uncommon in the patients with COVID-19 with disseminated intravascular coagulation (DIC) which is similar to the SARS-CoV-1 infection; however, the rate of thrombosis is three to six times higher.
Patients with COVID-19 admitted to the ICU may have other risk factors (such as old age, obesity, and smoking) that may aggravate coagulopathy. Patients with comorbid conditions (e.g., systemic disease, obesity); a sepsis-induced coagulopathy (SIC) score ≥4 and elevated levels of D-dimer [>6 times ULN (upper limit of normal) D-dimer is 500 ng/ml], C-reactive protein, troponins; and other markers of DIC are associated with a worse prognosis.
The routine use of antithrombotic prophylaxis with low-molecular-weight heparin (LMWH) is recommended for inpatients by the International Society on Thrombosis and Hemostasis given the relatively high rates of VTE. LMWH has advantages over unfractionated heparin with once daily versus twice or thrice daily injections and less heparin-induced thrombocytopenia (HIT). However, they are contraindicated in ESRD (end stage renal disease- egfr less than 15 ml/min), active bleeding, platelets <20,000/mm3, and blood pressure >200/120 mmHg. Direct oral anticoagulants (DOACs; rivaroxaban, apixaban) are approved for in-hospital prophylaxis; however, these agents should be considered with caution in patients with COVID-19 in whom coadministration of immunosuppressant, antiviral, and other experimental therapies may hamper with DOAC therapeutic activity. Dosing of anticoagulants is based on the severity of the disease as given in [Table 4].
Duration of Anticoagulation
In the absence of COVID-19-specific data, the rationale behind extended duration thromboprophylaxis with LMWH or a DOAC for at least 2 weeks is due to high rates of VTE observed in patients. Prolonged anticoagulation is recommended for 6 weeks posthospital discharge in selected patients with COVID-19 with significant VTE-risk factors such as advanced age, stay in the ICU, cancer, a prior history of VTE, thrombophilia, severe immobility, an elevated D-dimer (>2 times ULN), and an IMPROVE VTE score of 4 or more and who are at low risk of bleeding. In the case of confirmed VTE, the duration of treatment should be at least 3 months.
Effects on Red Blood Cells and Hemoglobin
Reduced hemoglobin levels have been noted in some patients with severe COVID-19. No significant effects on red blood cell (RBC) counts have been found, but structural changes have been noted with the resultant increase in red cell distribution width (RDW). RBCs of patients with COVID-19 had altered lipid metabolism and increased oxidation of structural proteins.
Peripheral Blood Film
Examination of the peripheral blood smear reported an increased frequency of reactive and plasmacytoid lymphocytes, significant left-shifted granulopoiesis with hypergranular, occasionally vacuolated neutrophils, and leukoerythroblastic features. The presence of schistocytes or red cell fragments has not been reported.
Effect on Bone Marrow
Bone marrow aspirates of patients with severe COVID-19 show an increase in pleomorphic megakaryocytes, plasma cells, and macrophages along with hemophagocytosis. Rare virions were also identified in bone marrow megakaryocytes using electron microscopy. Direct viral effects on the hematopoietic stem cells may affect hematopoiesis.
COVID-19 in Hematologic Disorders
In hematologic disorders including RBC disorders and hemophilia, the COVID-19 clinical manifestations were similar to other patients. As hematologic malignancies directly affect the immune system, these patients are at significantly higher risk of a variety of severe infections including COVID-19. Therapeutic side effects such as myelosuppression and lymphodepletion and direct immunosuppression may make such patients more prone to infections. Patients with hematologic, lung, or metastatic (stage IV) cancer had more severe disease and higher mortality than those without malignancy. It is important to individually evaluate the necessity of active intervention, postponing elective surgery or adjuvant chemotherapy for patients with low risk of progression, and minimizing outpatient visits for mitigating exposure and transmission.
| Vaccination in COVID-19|| |
COVID-19 vaccination campaigns with several vaccine types are currently underway worldwide to combat COVID-19. The vaccines that have been developed are highly effective with minimal adverse effects. Currently, Astazenca (Astazenca and Serum institute of India PVT Ltd as ChAdOx1-nCoV-19 corona virus vaccine) and Covaxin (Bharat biotech and is inactivated virus based vaccine) vaccines have been approved to be administered to the Indian population and they are given as an intramuscular injection.
Individuals receiving direct oral anticoagulant (apixaban, dabigatran, edoxaban, and rivaroxaban) or warfarin in therapeutic international normalized ratio (INR) range or on full-dose heparin or fondaparinux injections can all receive the COVID-19 vaccination. It is recommended to apply prolonged pressure (at least 5 minutes) to the injection site after vaccination to reduce bruising. Patients taking warfarin with supratherapeutic INR should delay vaccination until their INR is <3.
Patients with low-platelet disorders such as ITP, platelet function disorders (such as Glanzmann thrombasthenia, Hermansky–Pudlak syndrome, Gray platelet syndrome), or platelet disorders caused by medications (such as aspirin, clopidogrel, and ticagrelor) should take extra precautions when receiving the vaccine to prevent hematoma formation. A fine-gauge needle (25 or 27 gauge) should be used for the vaccination, followed by pressure on the site, without rubbing, for at least 10 minutes. Platelet count should not be less than 50,000/mm3.
Patients with hemophilia should get a prior dose of factor concentrates before vaccination.
Vaccination can be administered to patients with malignancies including hematologic malignancies with a prior complete blood count profile.
Vaccine-induced immune thrombotic thrombocytopenia
Recently, the Astazenca vaccine and Johnson & Johnson (J&J) vaccine (Janssen biotech Inc. and is adenoviral based vaccine), both of them adenoviral vector-based vaccines, have raised a public alarm with concerns regarding the rare, but serious, development of thrombotic events such as cerebral sinus vein and splanchnic vein thrombosis, now known as vaccine-induced immune thrombotic thrombocytopenia (VIITT) or thrombosis thrombocytopenia syndrome (TTS). These thrombotic events appear similar to HIT, both clinically and pathologically with the presence of high-titer anti-PF4/heparin antibodies that cause platelet activation in functional assays. The risk of developing the HIT-like clotting syndrome is very low, with 86 potential cases reported in Europe out of 25 million people vaccinated as on March, 2021 [Figure 1].
|Figure 1 Diagnosis of vaccine-induced immune thrombotic thrombocytopenia. CBC, complete blood count; HIT, heparin-induced thrombocytopenia; VIITT, vaccine-induced immune thrombotic thrombocytopenia.|
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Interim case definition of TTS has been proposed by Brighton collaboration which states any patient with a platelet count of less than 150,000/ μL of new onset without history of receipt of heparin within 100 days and Imaging study, surgical, or pathology findings consistent with thrombosis/thromboembolism constitute case criteria for the syndrome.
The VIITT is treated with high-dose intravenous immunoglobulin and nonheparin anticoagulation after high clinical suspicion and positive laboratory parameters.
| Conclusion|| |
Lymphocytopenia, thrombocytopenia, and increased D-dimer are common hematologic abnormalities in COVID-19 and are utilized for both diagnosis and prognosis. Attention needs to be paid to coagulation abnormalities and steps taken to prevent the complications related to it. Vaccines are efficacious and safe against COVID-19, thereby they can be administered to all individuals irrespective of underlying hematologic condition with due precautions.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Amiral J, Vissac AM, Seghatchian J. Covid-19, induced activation of hemostasis, and immune reactions: can an auto-immune reaction contribute to the delayed severe complications observed in some patients? Transfus Apher Sci 2020;59:102804.
Ulrich H, Pillat MM. CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement. Stem Cell Rev Rep 2020;16:434-40.
Agbuduwe C, Basu S. Haematological manifestations of COVID‐19: from cytopenia to coagulopathy. Eur J Haematol 2020;105:540-6.
Yang M, Li CK, Li K et al.
Hematological findings in SARS patients and possible mechanisms. Int J Mol Med 2004;14:311-5.
Al-Tawfiq JA, Hinedi K, Abbasi S, Babiker M, Sunji A, Eltigani M. Hematologic, hepatic, and renal function changes in hospitalized patients with Middle East respiratory syndrome coronavirus. Int J Lab Hematol 2017;39:272-8.
Lee N, Hui D, Wu A et al.
A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1986-94.
Chong PY, Chui P, Ling AE et al.
Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 2004;128:195-204.
Zhao Q, Meng M, Kumar R et al.
Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a systemic review and meta-analysis. Int J Infect Dis 2020;96:131-5.
Fan BE. Hematologic parameters in patients with COVID-19 infection: a reply. Am J Hematol 2020;95:E215.
Terpos E, Ntanasis-Stathopoulos I, Elalamy I et al.
Hematological findings and complications of COVID-19. Am J Hematol 2020;95:834-47.
Lovato A, de Filippis C. Clinical presentation of COVID-19: a systematic review focusing on upper airway symptoms. Ear Nose Throat J 2020;99:569-76.
Huang C, Wang Y, Li X et al.
Clinical features of patients infected with2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Yang M, Ng MH, Li CK. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2005;10:101-5.
Zhang H, Cao X, Kong M et al.
Clinical and hematological characteristics of 88 patients with COVID-19. Int J Lab Hematol 2020;42:780-7.
Liu Y, Du X, Chen J et al.
Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect 2020;81:e6-12.
Karimi Shahri M, Niazkar HR, Rad F. COVID-19 and hematology findings based on the current evidences: a puzzle with many missing pieces. Int J Lab Hematol 2021;43:160-8.
Rahman A, Niloofa R, Jayarajah U, De Mel S, Abeysuriya V, Seneviratne SL. Hematological abnormalities in COVID-19: a narrative review. Am J Trop Med Hyg 2021;104:1188-201.
Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta 2020;506:145-8.
Yang X, Yang Q, Wang Y et al.
Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020;18:1469-72.
Wu C, Chen X, Cai Y et al.
Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-43.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.
Yu HH, Qin C, Chen M, Wang W, Tian DS. D-dimer level is associated with the severity of COVID-19. Thromb Res 2020;195:219-25.
Chandra A, Chakraborty U, Ghosh S, Dasgupta S. Anticoagulation in COVID-19: current concepts and controversies. Postgrad Med J 2021, postgradmedj-2021-139923.
Bourgonje AR, Abdulle AE, Timens W et al.
Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease2019 (COVID-19). J Pathol 2020;251:228-48.
Helms J, Tacquard C, Severac F et al.
High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020;46:1089-98.
Bowles L, Platton S, Yartey N et al.
Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med 2020;383:288-90.
Cavalli E, Bramanti A, Ciurleo R et al.
Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: diagnostic and therapeutic perspectives (review). Int J Mol Med 2020;46:903-12.
Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis. EClinicalMedicine 2020;29:100639.
Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID‐19. J Thromb Haemost 2020;18:2103-9.
Spyropoulos AC, Levy JH, Ageno W et al.
Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020;18:1859-65.
Thomas T, Stefanoni D, Dzieciatkowska M et al.
Evidence of structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients. J Proteome Res 2020;19:4455-69.
Schapkaitz E, De Jager T, Levy B. The characteristic peripheral blood morphological features of hospitalized patients infected with COVID-19. Int J Lab Hematol 2021;43:e130-4.
Debliquis A, Harzallah I, Mootien J et al.
Haemophagocytosis in bone marrow aspirates in patients with COVID-19. Br J Haematol 2020;190:e70-3.
Cui D, Zhang A, Liu A, Hu Q. Clinical findings in a patient with haemophilia A affected by COVID‐19. Haemophilia 2020;26:e214–6.
He W, Chen L, Chen L et al.
COVID-19 in persons with haematological cancers. Leukemia 2020;34:1637-45.
Nazy I, Sachs UJ, Arnold DM et al.
Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: communication from the ISTH SSC Subcommittee on Platelet Immunology. J Thromb Haemost 2021;19:1585-8.
[Table 1], [Table 2], [Table 3], [Table 4]