COVID-19 infection is associated with lymphopenia, occasional thrombocytopenia, and overall leukopenia at hospital admission. ICU admission and mortality risk are associated with an elevated D-dimer (dimerized plasmin fragment D) level and a decreasing lymphocyte count. Platelet count was not a discriminating test on ICU admission or during the hospitalization. Additional routine biomarkers for infected patient risk stratification and for early admission for supportive care in the ICU are urgently needed.
Abbreviations: ISTH: International Society on Thrombosis and Hemostasis; RDW: Red Blood Cell Distribution Width; ALC: Absolute Lymphocyte Count; AMC: Absolute Monocyte Count; ANC: Absolute Neutrophil Count; JAK-STAT3: Janus kinases and Signal Transducer and Activator of Transcription 3 Proteins; FDP: Fibrin Degradation Products
Endothelial cell injury induced by viral infection activates a multitude of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumour necrosis factor alpha (TNF-alpha) . IL-6 plays a significant role through its effect on JAK-STAT3 pathway‘ IL-6 also enhances secretion of vascular endothelial growth factor and IL-8 but reduces E-cadherin expression on endothelial cells . The proinflammatory cytokines in combination with numerous immune-active molecules including chemokines, other interleukins, colony stimulating factors and interferons contribute to a cytokine storm . The cytokine storm and hyper-inflammatory state results in a prothrombotic state and likely endothelial and platelet activation . A subgroup of patients with COVID-19 disease may experience a fatal hypercytokinemia that often lead to multi-organ dysfunctional syndrome . COVID-19 has a high rate of hospitalization and mortality . Biomarkers are urgently needed for patient risk stratification .
RDW greater than 14.5% at the time of admission for SARS-CoV-2 infection was associated with an increase in mortality risk (from 11% to 31%). Increased RDW during admission also associated with an increased mortality risk. The mortality risk is
higher in patients (<70 years) than older patients. The mechanism (s) for RDW alteration associated with COVID-19 remain unclear. Reports (on inflammation in non–COVID-19 cohorts), suggested that RDW become elevated when RBC production kinetics have slowed in the setting of increased WBC and platelet kinetics .
Leucopenia, lymphopenia and COVID-19
Leucopenia or normal total white cell count, lymphopenia (ALC <1.0 x109/L) are noted in COVID-infected patients. Lymphopenia is believed to result from defective immune response to the virus. In addition, SARS-CoV-2 is thought to inhibit bone marrow haematopoiesis through certain receptors resulting in lymphopenia (1). Medications used for COVID-19 treatment like steroids can also cause lymphopenia .
Thrombocytopenia and COVID-19
Data on thrombocytopenia in COVID-19 patients are variable. The medium nadir platelet counts remained in the normal range in ICU and non-ICU patients . The preservation of platelet count is possibly attributed to the large amounts of platelets produced in response to increased thrombopoietin formation from liver stimulation and megakaryocytes in the lung . Thrombocytopenia was described in 36% of COVID-19 hospitalised patients in one study . The incidence of thrombocytopenia could be as high as 57% amongst non-survivors . Subsequent studies have not confirmed this high frequency . Mild to
moderate thrombocytopenia (platelet count > 50 x 109/L) are
commonly seen . Count below 100 x 10 9/l occurs in around
5% of hospitalised patients .
Potential causes of thrombocytopenia in COVID-19
Thrombocytopenia is multifactorial. It could be explained by
use of antibiotics, antivirals, heparin, and other commonly used
agents, as well as haemodialysis and extracorporeal membrane
oxygenation (ECMO). Platelet production may be affected by direct
viral insult to the bone marrow and by impaired fragmentation
of megakaryocytes due to COVID-19 induced damage to the lung
and pulmonary capillary bed . Stimulation of anti-platelet
autoantibodies by SARS-Cov-2 will trigger immune-mediated
platelet destruction. The antibodies and immune complexes
deposited on the surfaces of platelets predispose to platelets
destruction by the reticuloendothelial system . In end
stage COVID-19 infection multi organ failure may exacerbate
thrombocytopenia . Dysfunctional platelets can also contribute
to increased bleeding despite being in the normal range .
Fibrinogen levels may fall with disease progression resulting in a
hypercoagulable state and increased bleeding risk .
Thrombosis in COVID-19 patients
COVID-19 infection is associated with arterial and venous
thrombosis . The incidence of cerebral infarction in COVID-19
infected patients is 4.5% The incidence of DVT, PE or thrombosis
elsewhere in the body has not been studied well . Patients on
extracorporeal membrane oxygenation and/or continuous renal
replacement therapy have a higher risk of thromboembolism due
to increased inflammatory process .
Coagulation changes in COVID-19 positive patients
There are prolongation of prothrombin time (PT) and
activated partial thromboplastin time (aPTT), elevations of D
dimer, fibrinogen and FDP and decreased levels of antithrombin
III. aPTT prolongation is caused by increased Factor VIII level
and Factor XII deficiency secondary to the presence of factor XII
inhibitors. Von Willebrand factor is quantitatively increased. Lupus
anticoagulant (LA) is positive in 91% of those with prolonged
aPTT. The presence of both LA and Factor XII deficiency are not
associated with bleeding tendency. Overt DIC (ISTH score of 5 and
higher) is seen more frequently in non-survivors . ADAMTS13
levels of 20-40%, typical of other inflammatory states was found
in COVID-19 without TTP .
Mechanisms of thrombosis in COVID-19 positive
The increase in inflammatory activity contributes to
microvascular thrombosis including plugging of the pulmonary
microvasculature and pulmonary embolism. The upregulation
of tissue factor (TF) - activated VIIa complex is associated with
thrombin generation and fibrin deposition in various organs
including the bronchoalveolar system. Hyperactive fibrinolysis
increases plasmin cleavage activity and D-dimers which correlates
linearly with disease severity .
Prophylactic anticoagulation should be given to all
hospitalised patients without evidence of active bleeding even
if PT and aPTT are prolonged. The anticoagulant of choice is
low molecular weight heparin, unfractionated heparin (UFH)
or subcutaneous fondaprinux. UFH has little interaction with
COVID-19 drugs’ treatment. Its thromboprophylaxis usage
is limited by the requirement for frequent aPTT monitoring.
Mechanical thromboprophylaxis such as intermittent pneumatic
devices should only be used if pharmacological anticoagulation
is contraindicated. The use of concomitant pharmacological and
mechanical anticoagulation should be avoided .
COVID-19 infection differs from other infections
Unlike other viral infections such as human immunodeficiency
virus and cytomegalo-virus infections, the CD4/CD8 ratio was
not inverted in in COVID-19 infection . The aPTT may be less
prolonged in COVID-19 infection as compared to typical sepsis
induced disseminated intravascular coagulopathy (DIC) .
ICU and covid 19
Those requiring ICU care had a lower ALC and higher LDH.
The median nadir of ALC is 0.4× 109/L, compared to 1.2 × 109/L
in the non-ICU group . Severe lymphopenia in critically ill
patients is explained by lymph node destruction, suppression of
lymphocytes during lactic acidosis and binding of SARS-CoV-2
to angiotensin-converting enzyme 2 receptors on lymphocytes
. Flow cytometry on peripheral blood lymphocytes in the ICU
patients demonstrate significantly lower CD45+, CD3+, CD4+,
CD8+, CD19+and CD16/56+ count . The CD4/CD8 ratio was
not inverted. There is activation of T-helper-1 (Th1) function due
to the increased concentration of inflammatory mediators such as
IL-1B, IL-6, IL-12, IL-18, IL-33, CXCL10, CCL2 and TNF-alpha .
During the patient stay in ICU, more profound, decrements in
the level of haemoglobin, ALC and AMC occurs compared to non-
ICU group. The median nadir of AMC was 0.2 × 109/L in the ICU
group, compared to 0.4 × 109/L in the non-ICU group. ICU patients
tend to develop neutrophilia during the hospitalization (ANC
of 11.6×109/L, compared to 3.5×109/L in the non-ICU group).
The median nadir platelet count remained in the normal range
(above150×109/L) for both groups .
• Patients with elevated RDW at admission were 6.12
times more likely to die within 48 hours (4.9%) than patients
with a normal RDW (0.8%). RDW may be helpful for prioritizing
patients for early, aggressive intervention .
• Lymphopenia appears to predict COVID-19 severity .
An ALC approaching <0.6 × 109/L may be considered as one of
the indicators for early admission for supportive care in the ICU.
The ICU patients had severe lymphopenia. Lymphopenia was
associated with adverse outcomes and ICU stay .
• Relative lymphocytosis is often associated with a milder
disease and faster onset of spontaneous recovery .
• Platelet count was not a discriminating test on ICU
admission or during the hospitalization .
• Thrombocytopenia is a marker of poor clinical outcome
and was associated with a three-fold enhanced risk of worsening
disease. the platelet count was lower in patients with very severe
COVID-19. Twenty percent of COVID-19 patients who died had a
platelet count <100 x 10 9/l, compared with 1% of survivors. Very
low platelet counts of <20 x 109/l, or a sudden fall in the platelet
count >50% over 24-48 hours can occur in the pre-terminal stages
of COVID-19 .
• Increasing values in WBC, ALC, AMC, and down trending
LDH was noted in ICU as clinical condition improve .
• Coagulopathic features are associated with a more
severe outcome in COVID-19 infection . A high D-dimer value
correlates with ICU requirement and higher mortality compared
to individuals with normal/mild elevation of the D-dimer levels
 A fourfold increase in D-dimer predicts mortality in COVID-19
infection due to the increased risk of venous thrombosis and
cytokine storm .
• Serum ferritin levels were significantly associated with
disease severity and outcome .
• Other biochemical markers associated with a more
severe presentation are elevations in lactate dehydrogenase
(LDH), C reactive protein, procalcitonin, Troponin T, creatinine,
and liver enzymes .
• Almost 30% of adults and many children infected by
COVID-19 are asymptomatic . A proportion of asymptomatic
patients with positive RT-PCR results are admitted during
contact tracing. They may not have significant CBC anomalies at
presentation. This may result in lower haematological indices on
admission compared to patients in critical condition .
• Further studies should be conducted correlating the
clinical condition to laboratory findings  in patients with low
viral load during the early phase of the disease (Day 1–4) and
also in patients who are recovering from the infection but still
• Recognizing how many patients had hemato-oncological
disorders at baseline like immune thrombocytopenia, or any
cancer receiving chemotherapy affecting the bone marrow
haematopoiesis is essential .
It is recommended that every patient diagnosed with
COVID-19 infection should have a baseline PT/aPTT, D dimer and
platelet count. Monitoring of hematologic parameters may help to
identify patients who may need ICU care.