COVID-19 Hematologic Complications
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: : Ifrah Fatima, M.B.B.S[2],Shakiba Hassanzadeh, MD[3],Ramyar Ghandriz MD[4],Oluwabusola Fausat Adogba, MD[5]
Synonyms and keywords: :
The novel COVID-19 infection has multi-systemic complications. The most common hematologic complications of COVID-19 are lymphopenia, neutrophilia and thrombocytopenia. Some other hematological findings include: decrease in hemoglobin, coagulopathy, DIC and several other laboratory abnormalities.It is also suggested that the blood group may have an association with COVID infection. It is seen that individuals with the anti-A antibody are less susceptible to COVID-19.COVID-19 induces a hypercoagulable state in the body. Leukocytosis, increase in C-reactive protein (CRP), increase in procalcitonin, increase in ferritin, LDH, ALT, AST are other complications of the disease. The main feature of COVID-19 coagulopathy is thrombosis
Complications
COVID- 19 Coagulopathy and DIC
The main feature of COVID-19 coagulopathy is thrombosis while the acute phase of DIC presents with bleeding: [1]
- Similar laboratory findings are marked increase in D-dimer and normal/slightly low platelets and prolonged PT.
- Findings distinct in COVID 19 are high fibrinogen and high factor VIII activity
- The scoring system of the International Society on Thrombosis and Hemostasis should be used to detect DIC (platelet count, PT, fibrinogen, D‐dimer, antithrombin and protein C activity monitoring), but the diagnosis and subsequent treatment should be done clinically. [2]
Pathophysiology
COVID-19 induces a hypercoagulable state in the body. An increased risk of mortality has been noted in patient’s with coagulopathy in COVID-19. [3]The factors that contribute to this state are:
- Virchow’s triad [4]
- Vascular endothelial damage
- Endothelitis- direct invasion of endothelial cells by SARS-CoV-2
- Complement mediated damage to pericytes
- Pro-inflammatory cytokines- IL-1, IL-6, and TNF- α, that activate the coagulation pathway and the fibrinolytic system
- Stasis- Prolonged hospital admissions causing immobilization of the patient
- Hypercoagulabe state- Evidenced by elevated fibrinogen, prothrombotic factors and hyperviscosity [5]
- Some patients have been found to have Lupus anticoagulant (anti-cardiolipin) and anti-β2GP1 antibodies that may be contributory. [6]
Clinical Features
- Thrombotic complications : [4] [7]
- Deep Vein Thrombosis
- Pulmonary Embolism
- Ischemic stroke
- Myocardial infarction
- Ischemic limbs
- Systemic arterial events
- Clotting of central venous catheters, dialysis catheters, and dialysis filters
Laboratory Findings
Thrombocytopenia
- There is an association between severe COVID-19 infection and thrombocytopenia.[8]
- Thrombocytopenia is seen in 57.7% of patients with severe COVID-19 infection compared to 31.6 % of patients with non-severe infection.[9]
The pathogenesis of thrombocytopenia in COVID-19 infection is due to several factors:[10]
- Decrease in primary platelet production due to infection of bone marrow cells by coronaviruses[11] and inhibition of bone marrow growth,[12] which lead to abnormal hematopoietic function.[10]
- Decrease in circulating platelet due to lung injury which causes megakaryocyte fragmentation and decreases platelet production, because lung is a reservoir for megakaryocyte and hematopoieitic progenitor cells and has a role in platelet production.[10][14]
- In addition, decrease in platelets may be due to activation of platelets that result in platelet aggregation and formation of micro-thrombus which increase platelet consumption.[10][15]
Neutrophilia
- The human body fights infections by recruiting neutrophils early to the sites of infection by oxidative burst and phagocytosis. [16]
- New evidence suggests that the severe symptoms of COVID-19, including Acute Respiratory Distress Syndrome (ARDS), could be caused by Neutrophil Extracellular Traps (NETs). Acute Respiratory Distress Syndrome (ARDS), pulmonary inflammation, thick mucus secretions in the airways, extensive lung damage, and blood clots are suggested to be as a result of the action of Neutrophils. When neutrophils detect pathogens, they can expel their DNA in a web laced with toxic enzymes (called a NET- Neutrophil Extracellular Trap) to attack them.
- These NETs capture and digest the unwanted pathogen but in cases of ARDS (Covid-19 manifestation) they cause damage to the lungs and other organs. [17]
- The neutrophil-to-lymphocyte ratio (NLR) has been identified as the independent risk factor for severe illness in patients with the 2019 novel coronavirus disease.[18] A higher NLR at hospital admission in patients has been associated with a more severe outcome. An NLR of >4 has been identified as a predictor of admission to the ICU.[19]
Hemoglobin decrease
- Although anemia is not a common finding in patients with COVID-19 infection, decrease in hemoglobin in patients with severe COVID-19 infection has been reported.[15][9]
- The median hemoglobin is lower in patients with severe COVID-19 (12.8 g/dL) compared to patients with non-severe infection (13.5 g/dL).[9]
- Pathophysiology:[15]
- Erythropoiesis may be affected by inflammation during COVID-19 infection which leads to decrease in hemoglobin.[15]
- Anemia is not a common finding probably due to the compensation of erythrocyte proliferation caused by pneumonia-induced hypoxia and the long life span of erythrocytes.[15]
Lymphopenia
- COVID-19 infection cause many hematologic effects such as lymphopenia. It was shown that lymphocyte count decrease to 5% before death. [20]
- Low lymphocyte is an indicator of severity of disease. It is suggested to indicate the severity of disease
- There are four hypothetical mechanisms regardin lymphopenia:[21][22]
- Direct infection of Lymphocytes
- Direct destroying lymphatic organs
- Inflammatory cytokines such as TNF ἀ, IL-6 , etc inducing lymphopenia
- Inhibition of lymphocytes by metabolic molecules such as hyperlactic acidemia
COVID-19 ARDS was found to have an association with procoagulants and acute phase reactants, unlike non-COVID ARDS. [23]
Coagulation testing: Pro-coagulant profile: [24]
- Platelet counts- normal or increased
- Prothrombin time (PT)- normal or slightly prolonged
- Activated partial thromboplastin time (aPTT)- Normal or slightly prolonged (can be due to Lupus Anticoagulant)[6]
- Fibrinogen- increased, especially in nonsurvivors
- D-dimer - increased - The level of D‐dimer has shown to reflect the severity and is associated with adverse outcomes.
TEG findings: [25]
- Reaction time (R)- decreased
- Clot formation time (K)- decreased
- Maximum amplitude (MA) increased
- Clot lysis at 30 minutes (LY30) reduced
Other findings:
- Factor VIII activity- increased
- Factor V activity- increased [23]
- VWF antigen- increased
- Protein C- increased or normal
- Antithrombin and Protein S- slightly decreased/ normal
Other Laboratory Findings
Leukocytosis
- Leukocytosis is seen in 11.4% of patients with severe COVID-19 infection compared to 4.8% of patients with non-severe infection.[9]
- In patients with COVID-19 infection, leukocytosis may be an indication of a bacterial infection or superinfection.[26]
Increase in C-reactive protein (CRP)
- Increase in CRP is seen in 81.5% of patients with severe COVID-19 infection compared to 56.4% of patients with non-severe infection.[9]
- CRP is an acute phase reactant that increases in conditions with inflammation.[27]
- In patients with COVID-19 infection, increase in CRP may be an indication of severe viral infection or sepsis and viremia.[26]
Increase in procalcitonin
- Increase in procalcitonin is seen in 13.7% of patients with severe COVID-19 infection compared to 3.7% of patients with non-severe infection.[9]
- In sepsis, the activation and adherence of monocytes increase procalcitonin, therefore procalcitonin in a biomarker for sepsis and septic shock.[28]
- In patients with COVID-19 infection, increase in procalcitonin may be an indication of bacterial infection or superinfection.[26]
Increase in ferritin
- There have been different reports regarding the association of increase in ferritin with death in COVID-19 infection; for example, there has been a report that increase in ferritin is associated with acute respiratory distress syndrome (ARDS) but not death[29], while another one reports an association between increase in ferritin and death in COVID-19 infection[30].
Increase in aspartate aminotransferase (AST)
- Increase in AST is seen in 39.4% of patients with severe COVID-19 infection compared to 18.2% of patients with non-severe infection.[9]
- In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.[26]
Increase in alanine aminotransferase (ALT)
- Increase in ALT is seen in 28.1% of patients with severe COVID-19 infection compared to 19.8% of patients with non-severe infection.[9]
- ALT is produced by liver cells and is increased in liver conditions.[27]
- In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.[26]
Increase in lactate dehydrogenase (LDH)
- Increase in LDH is seen in 58.1% of patients with severe COVID-19 infection compared to 37.2% of patients with non-severe infection.[9]
- LDH is expressed in almost all cells and an increase in LDH could be seen in damage to any of the cell types.[27]
- In patients with COVID-19 infection, increase in LDH may indicate injury to the lungs or multi-system damage.[26]
Increase in monocyte volume distribution width (MDW)
- MDW was found to be increased in all patients with COVID-19 infection, particularly in those with the worst conditions.[26]
Increase in total bilirubin
- Increase in total bilirubin is seen in 13.3% of patients with severe COVID-19 infection compared to 9.9% of patients with non-severe infection.[9]
- Bilirubin is produced by liver cells and increases in liver and biliary conditions.[27]
- In patients with COVID-19 infection, increase in total bilirubin may indicate injury to the liver.[26]
Increase in creatinine
- Increase in creatinine is seen in 4.3% of patients with severe COVID-19 infection compared to 1% of patients with non-severe infection.[9]
- Creatinin is produced in the liver and excreted by the kidneys; creatinine increases when there is decrease in glomerular filtration rate.[27]
- In patients with COVID-19 infection, increase in creatinine may indicate injury to the kidneys.[26]
Increase in cardiac troponins
- In myocardial infarction and acute coronary syndrome are used for diagnosis.[27]
- In patients with COVID-19 infection, increase in cardiac troponins may indicate cardiac injury.[26]
Decrease in albumin
- Albumin may be decreased in many conditions such as sepsis, renal disease or malnutrition.[27]
- In patients with COVID-19 infection, decrease in albumin may indicate liver function abnormality.[26]
Increase in interleukin-6 (IL-6)
Thrombocytosis
Thrombocytosis has been reported in 4% of patients with COVID-19 infection.[31]
References
- ↑ Levi M, Thachil J, Iba T, Levy JH (2020). "Coagulation abnormalities and thrombosis in patients with COVID-19". Lancet Haematol. 7 (6): e438–e440. doi:10.1016/S2352-3026(20)30145-9. PMC 7213964 Check
|pmc=value (help). PMID 32407672 Check|pmid=value (help). - ↑ Levi M, Toh CH, Thachil J, Watson HG (2009). "Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology". Br J Haematol. 145 (1): 24–33. doi:10.1111/j.1365-2141.2009.07600.x. PMID 19222477.
- ↑ Tang N, Li D, Wang X, Sun Z (2020). "Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia". J Thromb Haemost. 18 (4): 844–847. doi:10.1111/jth.14768. PMC 7166509 Check
|pmc=value (help). PMID 32073213 Check|pmid=value (help). - ↑ 4.0 4.1 Becker RC (2020). "COVID-19 update: Covid-19-associated coagulopathy". J Thromb Thrombolysis. doi:10.1007/s11239-020-02134-3. PMC 7225095 Check
|pmc=value (help). PMID 32415579 Check|pmid=value (help). - ↑ Maier CL, Truong AD, Auld SC, Polly DM, Tanksley CL, Duncan A (2020). "COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia?". Lancet. 395 (10239): 1758–1759. doi:10.1016/S0140-6736(20)31209-5. PMC 7247793 Check
|pmc=value (help). PMID 32464112 Check|pmid=value (help). - ↑ 6.0 6.1 Bowles L, Platton S, Yartey N, Dave M, Lee K, Hart DP; et al. (2020). "Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19". N Engl J Med. doi:10.1056/NEJMc2013656. PMC 7217555 Check
|pmc=value (help). PMID 32369280 Check|pmid=value (help). - ↑ Barrett CD, Moore HB, Yaffe MB, Moore EE (2020). "ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A comment". J Thromb Haemost. doi:10.1111/jth.14860. PMID 32302462 Check
|pmid=value (help). - ↑ Lippi G, Plebani M, Henry BM (2020). "Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis". Clin Chim Acta. 506: 145–148. doi:10.1016/j.cca.2020.03.022. PMC 7102663 Check
|pmc=value (help). PMID 32178975 Check|pmid=value (help). - ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX; et al. (2020). "Clinical Characteristics of Coronavirus Disease 2019 in China". N Engl J Med. 382 (18): 1708–1720. doi:10.1056/NEJMoa2002032. PMC 7092819 Check
|pmc=value (help). PMID 32109013 Check|pmid=value (help). - ↑ 10.0 10.1 10.2 10.3 Xu P, Zhou Q, Xu J (2020). "Mechanism of thrombocytopenia in COVID-19 patients". Ann Hematol. 99 (6): 1205–1208. doi:10.1007/s00277-020-04019-0. PMC 7156897 Check
|pmc=value (help). PMID 32296910 Check|pmid=value (help). - ↑ Yang M, Ng MH, Li CK (2005). "Thrombocytopenia in patients with severe acute respiratory syndrome (review)". Hematology. 10 (2): 101–5. doi:10.1080/10245330400026170. PMID 16019455.
- ↑ Yeager CL, Ashmun RA, Williams RK, Cardellichio CB, Shapiro LH, Look AT; et al. (1992). "Human aminopeptidase N is a receptor for human coronavirus 229E". Nature. 357 (6377): 420–2. doi:10.1038/357420a0. PMC 7095410 Check
|pmc=value (help). PMID 1350662. - ↑ Nardi M, Tomlinson S, Greco MA, Karpatkin S (2001). "Complement-independent, peroxide-induced antibody lysis of platelets in HIV-1-related immune thrombocytopenia". Cell. 106 (5): 551–61. doi:10.1016/s0092-8674(01)00477-9. PMID 11551503.
- ↑ Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM; et al. (2017). "The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors". Nature. 544 (7648): 105–109. doi:10.1038/nature21706. PMC 5663284. PMID 28329764.
- ↑ 15.0 15.1 15.2 15.3 15.4 Liu X, Zhang R, He G (2020). "Hematological findings in coronavirus disease 2019: indications of progression of disease". Ann Hematol. doi:10.1007/s00277-020-04103-5. PMC 7266734 Check
|pmc=value (help). PMID 32495027 Check|pmid=value (help). - ↑ "Targeting potential drivers of COVID-19: Neutrophil extracellular traps | Journal of Experimental Medicine | Rockefeller University Press".
- ↑ "Severe COVID-19 symptoms may be caused by overactive neutrophils".
- ↑ Akagi Y, Itoi M, Sano Y, Andonian MR, Barrett AS, Vinogradov SN, Moroi K, Sato T, Gheorghescu B, Baghurst PA, Nichol LW, Rainsford KD, Akagi Y, Itoi M, Sano Y (August 1980). "[Monoaminergic neurons of monkey retina (author's transl)]". Nippon Ganka Gakkai Zasshi (in Japanese). 84 (8): 771–80. doi:10.1016/0005-2795(75)90035-5. PMID 7211594.
- ↑ Tan, Li; Wang, Qi; Zhang, Duanyang; Ding, Jinya; Huang, Qianchuan; Tang, Yi-Quan; Wang, Qiongshu; Miao, Hongming (2020). "Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study". Signal Transduction and Targeted Therapy. 5 (1). doi:10.1038/s41392-020-0148-4. ISSN 2059-3635.
- ↑ Fischer, Karin; Hoffmann, Petra; Voelkl, Simon; Meidenbauer, Norbert; Ammer, Julia; Edinger, Matthias; Gottfried, Eva; Schwarz, Sabine; Rothe, Gregor; Hoves, Sabine; Renner, Kathrin; Timischl, Birgit; Mackensen, Andreas; Kunz-Schughart, Leoni; Andreesen, Reinhard; Krause, Stefan W.; Kreutz, Marina (2007). "Inhibitory effect of tumor cell–derived lactic acid on human T cells". Blood. 109 (9): 3812–3819. doi:10.1182/blood-2006-07-035972. ISSN 0006-4971.
- ↑ Liao, Yuan-Chun; Liang, Wei-Guang; Chen, Feng-Wei; Hsu, Ju-Hui; Yang, Jiann-Jou; Chang, Ming-Shi (2002). "IL-19 Induces Production of IL-6 and TNF-α and Results in Cell Apoptosis Through TNF-α". The Journal of Immunology. 169 (8): 4288–4297. doi:10.4049/jimmunol.169.8.4288. ISSN 0022-1767.
- ↑ 23.0 23.1 "Correction". Circulation. 131 (24): e535. 2015. doi:10.1161/CIR.0000000000000219. PMID 26078378.
- ↑ Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli M, Resta M; et al. (2020). "The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome". J Thromb Haemost. doi:10.1111/jth.14854. PMID 32302448 Check
|pmid=value (help). - ↑ Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V; et al. (2020). "Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis". J Thromb Haemost. doi:10.1111/jth.14850. PMID 32302438 Check
|pmid=value (help). - ↑ 26.00 26.01 26.02 26.03 26.04 26.05 26.06 26.07 26.08 26.09 26.10 Lippi G, Plebani M (2020). "The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks". Clin Chem Lab Med. 58 (7): 1063–1069. doi:10.1515/cclm-2020-0240. PMID 32191623 Check
|pmid=value (help). - ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 Frater JL, Zini G, d'Onofrio G, Rogers HJ (2020). "COVID-19 and the clinical hematology laboratory". Int J Lab Hematol. 42 Suppl 1: 11–18. doi:10.1111/ijlh.13229. PMC 7264622 Check
|pmc=value (help). PMID 32311826 Check|pmid=value (help). - ↑ Meisner M (2014). "Update on procalcitonin measurements". Ann Lab Med. 34 (4): 263–73. doi:10.3343/alm.2014.34.4.263. PMC 4071182. PMID 24982830.
- ↑ 29.0 29.1 Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S; et al. (2020). "Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China". JAMA Intern Med. doi:10.1001/jamainternmed.2020.0994. PMC 7070509 Check
|pmc=value (help). PMID 32167524 Check|pmid=value (help). - ↑ Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z; et al. (2020). "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study". Lancet. 395 (10229): 1054–1062. doi:10.1016/S0140-6736(20)30566-3. PMC 7270627 Check
|pmc=value (help). PMID 32171076 Check|pmid=value (help). - ↑ Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y; et al. (2020). "Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study". Lancet. 395 (10223): 507–513. doi:10.1016/S0140-6736(20)30211-7. PMC 7135076 Check
|pmc=value (help). PMID 32007143 Check|pmid=value (help).