COVID-19 Hematologic Complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ramyar Ghandriz MD[2], Ifrah Fatima, M.B.B.S[3],Shakiba Hassanzadeh, MD[4],Oluwabusola Fausat Adogba, MD[5]

Overview

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 blood group may have association to COVID infection.

Blood type and COVID-19

• Two pre-print articles from China in early 2020 suggested the association of ABO blood group with a risk of COVID-19 infection- Blood group A was associated with a higher risk of infection and Blood Group O was associated with a lower risk. These studies were non-peer reviewed and had their own limitations.
• A more recent Genome-wide Association Study done in patients with severe respiratory failure (requiring mechanical ventilatory support) also found a higher risk of infection among people with blood group A, compared to non-A blood groups and a lower risk for blood group O as compared with non-O blood groups.

• However, once infected, blood group type does not seem to influence clinical outcome.
• The GWA study also identified the genetic susceptibility locus (3p21.31) that places patients at a higher risk for severe COVID-19 infection.

• A study has reported that individuals with anti-A antibodies (in those with blood groups O and B) are less susceptible to COVID-19 infection, with anti-A in blood group O being more protective compared to anti-A in blood group B.
  • Pathophysiology:
    • Anti-A antibody blocks viral attachment to its cell receptor and  inhibits the virus–cell adhesion, and this could be the reason for anti-A protection against COVID-19 infection.(Gerard)
    • In blood group types A and B, the predominant isotype of immunoglobulin in anti-A or anti-B is IgM, where as in blood group type O it is IgGFung, Mark (2014). Technical manual. Bethesda, Md: American Association of Blood Banks. ISBN 1563958880., which could be the reason why anti-A in blood group O (IgG) is more protective in COVID-19 infection than anti-A in blood group B (IgM). (Gerard)

Complications

Lymphopenia

There is an association between COVID-19 infection and lymphopenia.There are four hypothetical mechanisms for this matter:

• Direct infection of Lymphocytes
• Directly destroying lymphatic organs
• Inflammatory cytokines such as TNF ἀ, IL-6 , etc inducing lymphopenia
• Inhibition of lymphocytes by metabolic molecules such as hyperlactic acidemia

Neutrophilia

• The human body fights infections by recruiting neutrophils early to the sites of infection by oxidative burst and phagocytosis.
• 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.
• 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. 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.

Thrombocytopenia

• There is an association between severe COVID-19 infection and thrombocytopenia.
• Thrombocytopenia is seen in 57.7% of patients with severe COVID-19 infection compared to 31.6 % of patients with non-severe infection.

The pathogenesis of thrombocytopenia in COVID-19 infection is due to several factors:

• Decrease in primary platelet production due to infection of bone marrow cells by coronaviruses and inhibition of bone marrow growth, which lead to abnormal hematopoietic function.

• Increase in platelet destruction due to increase in auto-antibodies and immune complexes.

• 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.
• 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.

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.
• 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).
• Pathophysiology:
  • Erythropoiesis may be affected by inflammation during COVID-19 infection which leads to decrease in hemoglobin.
  • 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.

Coagulopathy

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. The factors that contribute to this state are-

• Virchow’s triad
  • 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
• Some patients have been found to have Lupus anticoagulant (anti-cardiolipin) and anti-β2GP1 antibodies that may be contributory.

Clinical Features

Thrombotic complications like:

• Deep Vein Thrombosis
• Pulmonary Embolism
• Ischemic stroke
• Myocardial infarction
• Ischemic limbs
• Systemic arterial events
• Other features like clotting of central venous catheters, dialysis catheters, and dialysis filters were also seen.

Laboratory Findings

COVID-19 ARDS was found to have an association with procoagulants and acute phase reactants, unlike non-COVID ARDS.

Coagulation testing: Pro-coagulant profile:

• 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)
• 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:

• 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
• VWF antigen- increased
• Protein C- increased or normal
• Antithrombin and Protein S- slightly decreased/ normal

COVID- 19 Coagulopathy and DIC

The main feature of COVID-19 coagulopathy is thrombosis while the acute phase of DIC presents with bleeding:

• 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.

Other hematological 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.
• In patients with COVID-19 infection, leukocytosis may be an indication of bacterial infection or superinfection.

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.
• CRP is an acute phase reactant that increases in conditions with inflammation.
• In patients with COVID-19 infection, increase in CRP may be an indication of severe viral infection or sepsis and viremia.

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.
• In sepsis, the activation and adherence of monocytes increase procalcitonin, therefore procalcitonin in a biomarker for sepsis and septic shock.
• In patients with COVID-19 infection, increase in procalcitonin may be an indication of bacterial infection or superinfection.

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, while another one reports an association between increase in ferritin and death in COVID-19 infection.

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.
• In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.

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.
• ALT is produced by liver cells and is increased in liver conditions.
• In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.

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.
• LDH is expressed in almost all cells and an increase in LDH could be seen in damage to any of the cell types.
• In patients with COVID-19 infection, increase in LDH may indicate injury to the lungs or multi-system damage.

Increase in monocyte volume distribution width (MDW)

• MDW (Beckman Coulter, Brea, CA, USA) was found to be increased in all patients with COVID-19 infection and particularly in those with the worst conditions.

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.
• Bilirubin  is produced by liver cells and increases in liver and biliray conditions.
• In patients with COVID-19 infection, increase in total bilirubin may indicate injury to the liver.

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.
• Creatinin is produced in the liver and excreted by the kidneys; creatinine increases when there is decrease in glomerular filtration rate.
• In patients with COVID-19 infection, increase in creatinine may indicate injury to the kidneys.

Increase in cardiac troponins

• In myocardial infarction and acute coronary syndrome are used for diagnosis.
• In patients with COVID-19 infection, increase in cardiac troponins may indicate cardiac injury.

Decrease in albumin

• Albumin may be decreased in many conditions such as sepsis, renal disease or malnutrition.
• In patients with COVID-19 infection, decrease in albumin may indicate liver function abnormality.

Increase in interleukin-6 (IL-6)

• Increase in IL-6 has been reported to be associated with death in COVID-19 infection.