https://academicworks.medicine.hofstra.edu/cgi/viewcontent.cgi?article=7158&context=articles

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases.

Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic.

Background As coronavirus disease 2019 (COVID-19) pandemic rages on, there is urgent need for identification of clinical and laboratory predictors for progression towards severe and fatal forms of this illness. In this study we aimed to evaluate the discriminative ability of hematologic, biochemical and immunologic biomarkers in patients with and without the severe or fatal forms of COVID-19. Methods An electronic search in Medline (PubMed interface), Scopus, Web of Science and China National Knowledge Infrastructure (CNKI) was performed, to identify studies reporting on laboratory abnormalities in patients with COVID-19. Studies were divided into two separate cohorts for analysis: severity (severe vs. non-severe and mortality, i.e. non-survivors vs. survivors). Data was pooled into a meta-analysis to estimate weighted mean difference (WMD) with 95% confidence interval (95% CI) for each laboratory parameter. Results A total number of 21 studies was included, totaling 3377 patients and 33 laboratory parameters. While 18 studies (n = 2984) compared laboratory findings between patients with severe and non-severe COVID-19, the other three (n = 393) compared survivors and non-survivors of the disease and were thus analyzed separately. Patients with severe and fatal disease had significantly increased white blood cell (WBC) count, and decreased lymphocyte and platelet counts compared to non-severe disease and survivors. Biomarkers of inflammation, cardiac and muscle injury, liver and kidney function and coagulation measures were also significantly elevated in patients with both severe and fatal COVID-19. Interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin were strong discriminators for severe disease. Conclusions Several biomarkers which may potentially aid in risk stratification models for predicting severe and fatal COVID-19 were identified. In hospitalized patients with respiratory distress, we recommend clinicians closely monitor WBC count, lymphocyte count, platelet count, IL-6 and serum ferritin as markers for potential progression to critical illness.

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.

To the Editor: A cluster of unexplained pneumonia cases was reported by the Peopleʼs Republic of China to the World Health Organization (WHO) on 31 December, 2019. The etiology for this outbreak was a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was responsible for the Corona Virus Disease 2019 (COVID-19). Singapore confirmed its first imported case on 23 January 2020 and local transmission was detected on 4 February, 2020. As of 28 February, 2020, Singapore had 96 confirmed cases of COVID-19 infection. SARS-CoV-2 was confirmed by real time reverse transcriptase-polymerase chain reaction (RT-PCR), performed on respiratory samples of these patients. A majority of 69 out of these 96 patients were treated at the National Centre for Infectious Diseases (NCID). We herein present a detailed analysis of the hematological parameters of the COVID-19 patients at the NCID (see Table 1). Of the 69 patients that had been admitted to the NCID, 26 patients were still hospitalized, and 43 patients had been discharged as of 28 February 2020. Also, 67 patients had at least one complete blood count (CBC) performed during inpatient stay; 65 patients had CBC performed on day of admission. We analyzed the hematological indices of all COVID-19 infected patients from day 1 of admission until 28 February 2020. We obtained data from the Laboratory Information System (LIS) exclusively which provided information on the age, gender, ethnicity and location of each patient. We divided the patients into two groups; ICU and non-ICU patients. Additionally, flow cytometry on lymphocyte subsets was performed from 24 to 28 February 2020, on a subgroup of nine COVID-19 patients; five ICU patients and four non-ICU patients (with six normal individual blood samples as controls). Immunophenotyping was performed using a Becton Dickinson FACSCanto II Flow analyzer. Most patients were of Chinese ethnicity (89.5%), while the minority were ofMalay (4.5%), Indian (1.5%) and other ethnicities (4.5%). Just 9 out of the 67 (13.4%) patients required ICU care. Notably, ICU patients were about a decade older than the non-ICU patients; the median age of ICU patients was 54 years old while the median age of non-ICU patients was 42 years old (P = .02). On admission, leukopenia was observed in 19 patients (29.2%) with only one patient presenting with severe leukopenia (WBC < 2 × 10/L). Lymphopenia featured in 24 patients (36.9%) with 19 having moderate lymphopenia (absolute lymphocyte count [ALC] 0.5-1 × 10/L), and five with severe lymphopenia (ALC < 0.5 × 10/L). Most patients had normal platelet counts, with 13 patients (20.0%) having mild thrombocytopenia (platelet count 100-150 × 10/L). Peripheral blood film review showed that a higher number of patients (69%) who were lymphopenic had the presence of a few reactive lymphocytes, of which a subset appeared lymphoplasmacytoid. This contrasts with the severe acute respiratory syndrome (SARS) outbreak in 2003 where reactive lymphocytes were not observed in a study on Haematologic parameters in SARS in Singapore and only in 15.2% of cases in a similar Hong Kong study. Our analysis revealed that on admission, most patients had a normal CBC (normal Hb, WBC and platelet count) and lactate dehydrogenase (LDH). And, no patient presented with moderate or severe thrombocytopenia that is frequently observed in other viral illnesses such as dengue fever which is endemic in our region. However, 28% of all patients presented with lymphopenia (ALC < 1 × 10/L). This number is significantly smaller compared to 63% of patients in Wuhan, China, and 42% of patients outside of Wuhan who presented with lymphopenia. This disparity in numbers may in part be reflective of the extent of epidemiological data availablewithin the surveillance pyramid in those regions. Those requiring ICU care had a lower ALC and higher LDH. These were findings also reported by Huang et al on the characteristics of COVID-19 patients inWuhan, China. Lymphopenia has beenwell described in retrospective analysis of patients in Hong Kong and Singapore afflicted with SARS-CoV in 2003, and was associated with adverse outcomes and ICU stay. Lymphopenia featured prominently in our COVID-19 ICU groupwith amedian nadir ALC of 0.4× 10/L, compared to 1.2 × 10/L in the non-ICU group. Monitoring of such hematologic parameters may help to identify patients whomay need ICU care. An ALC approaching severe lymphopenia of <0.6 × 10/L may possibly be considered as one of the indicators for early admission for supportive care in the ICU. Between the ICU (n = 9) and non-ICU (n = 58) patients, using Fisherʼs exact tests, we found that admission ALC and LDH stood out as discriminating laboratory indices with a P value of <.001 and .005 respectively. The ICU patients in general presented with more profound lymphopenia with seven out of nine being lymphopenic; four of whom had severe lymphopenia. Note, LDH was performed for 4 out of the 9 ICU patients on admission, and all four cases had a raised LDH with a median value of 1684 U/L (reference range 270-550 U/L). Comparatively non-ICU patients tend to present with a normal LDH, median value 401 U/L; with only five out of 26 non-ICU patients presenting with a Received: 2 March 2020 Revised: 3 March 2020 Accepted: 3 March 2020

https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.25774

Hematologic parameters in patients with COVID-19 infection.

COVID-19 and mycoplasma pneumoniae coinfection Bingwen Eugene Fan | Kian Guan Eric Lim | Vanessa Cui Lian Chong | Stephrene Seok Wei Chan | Kiat Hoe Ong | Ponnudurai Kuperan Department of Haematology, Tan Tock Seng Hospital, Singapore Department of Laboratory Medicine, Khoo Teck Puat Hospital, Singapore Lee Kong Chian School of Medicine, Singapore Yong Loo Lin School of Medicine, Singapore Department of Laboratory Medicine, Tan Tock Seng Hospital, Singapore

https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.25785

COVID-19 and mycoplasma pneumoniae coinfection.

From January 23 to February 27, 2020, Singapore had 96 Covid-19 cases confirmed by real time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2. We examined the peripheral blood films of 32 patients and found reactive lymphocytes as shown in the top images in 23 cases (72%). This is in stark contrast to the coronavirus responsible for the 2003 SARS outbreak where reactive lymphocytes of this type were not present in a review of 185 SARS cases in Singapore and were present in only 15.2% of 138 cases in Hong Kong (Chng et al., 2005; Lee et al. 2003).

Reactive lymphocytes in patients with COVID-19.

To the editor, COVID-19-associated coagulopathy [1] has recently been described with a globally observed increased incidence of venous thromboembolism (VTE) and arterial thrombosis which manifests as acute myocardial infarction, ischaemic stroke and acute ischaemic limb [2]. The exact pathophysiology of COVID-19 large vessel thrombosis is still under investigation and can be attributed to three plausible causes: firstly, endothelial injury by the SARS-CoV-2 virus that binds via ACE2 receptors on endothelial cells, secondly, a hypercoagulable state from an uncontrolled hyperinflammatory response and thirdly, stasis due to immobilization in critically ill patients. All three causes comprise Virchow’s triad of thrombosis. We describe a case of a 39-year-old Bangladeshi male migrant worker with no significant past medical history, who presented with fever, cough, and central abdominal discomfort. The patient required supplemental intranasal oxygen of 1.5 l/min on admission. SARS-CoV-2 PCR from nasopharyngeal swab returned positive and chest X-ray showed bilateral infiltrates. A diagnosis of COVID-19 pneumonia was made, and he was started on intravenous (IV) Remdesivir as part of a clinical trial. He remained ambulant in the general isolation ward and was not commenced on prophylactic anticoagulation upon the managing physician’s discretion. On Day 13 of illness, he developed acute right foot pain, with absent distal pedal pulses, decreased warmth, and duskiness of his toes. An acute ischaemic limb was suspected, and urgent vascular surgery consult was obtained. Global haemostatic tests [3], namely thromboelastography (TEG) (Haemonetics, TEG6s) and clot waveform analysis (CWA) on Sysmex CN-6000 automated coagulation analyser (Sysmex Corporation, Kobe, Japan) with Dade Actin FSL (Siemens Healthcare, Marburg, Germany) were performed within an hour of presentation. These tests helped in the rapid confirmation of the clinical suspicion of a hypercoagulable state in this patient. An urgently arranged CT aortogram later revealed extensive arterial thrombosis presenting as a 2 cm mobile thoracoabdominal aortic thrombus (Fig. 1), with embolization to the right profunda femoris and popliteal artery. The patient was immediately started on IV unfractionated heparin (UFH) infusion while awaiting further blood investigations and surgery. He underwent a successful endovascular stent graft exclusion of the aortic thrombus and right lower limb embolectomy. Repeat CT aortogram and angiogram on post-operative day 1 revealed no remnant mobile aortic thrombi and successful revascularisation, consistent with restoration of good capillary refill distally and palpable right foot pulses clinically. * Bingwen Eugene Fan Bingwen_Eugene_Fan@ttsh.com.sg

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Kian Guan Eric Lim

Papers

Hematologic parameters in patients with COVID-19 infection.

COVID-19 and mycoplasma pneumoniae coinfection.

Reactive lymphocytes in patients with COVID-19.

Global haemostatic tests in rapid diagnosis and management of COVID-19 associated coagulopathy in acute limb ischaemia.

Chronic dapsone use causing methemoglobinemia with oxidative hemolysis and dyserythropoiesis.