With input from Dr Monica Vasudev

1138: COVID-19 is associated with a hypercoagulable state

1. Associated with acute inflammatory changes.
2. Lab findings are distinct from acute DIC except for those with very severe disease.
3. Fibrinogen and D-dimer are increased in COVID-19.
4. Only modest prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT).
5. Mild thrombocytosis or thrombocytopenia.
6. The presence of a lupus anticoagulant (LA) is common in individuals with a prolonged aPTT.
7. The risk for venous thromboembolism is 25 to 43% in ICU patients, often despite prophylactic-dose anticoagulation.
8. Pulmonary microvascular thrombosis is also heightened.
9. The risk for arterial thrombotic events, like stroke, myocardial infarction, and limb ischemia, seems to be increased.
10. All inpatients should receive thromboprophylaxis unless contraindicated.
11. Individuals who have not had a VTE do not routinely receive thromboprophylaxis after discharge from the hospital. A period of thromboprophylaxis after discharge may seem appropriate in selected individuals.
12. High IL-6 is liked with high C-reactive protein (CRP).

CRP

1. CRP =  the upper limit of the reference range (mg/dL) equals (age in years)/50 for men and (age in years/50) + 0.6 for women[J Rheumatol. 2000;27(10):2351,  J Rheumatol. 2005;32(6):1040. ]
2. CRP over 10 mg/L = clinically significant inflammation while concentrations between 3 and 10 mg/L indicate what is commonly referred to as low-grade inflammation [Ann Intern Med. 2015;163(4):326]
3. Minor CRP elevation (between 3 and 10 mg/L) has been considered as a marker of low-grade inflammation. This is not a well-defined state and is sometimes referred to as mini-inflammation or subclinical inflammation. It is seen in many conditions in which there are minor degrees of metabolic dysfunction, such as obesity and insulin resistance, unlike inflammation as it has traditionally been understood.
4. Markedly elevated levels of CRP are strongly associated with infection. Infections, most often bacterial, were found in approximately 80% of patients with values in excess of 10 mg/dL (100 mg/L) and in 88 to 94% of patients with values over 50 mg/dL (500 mg/L) [Eur J Intern Med. 2006;17(6):430; Pathol Biol (Paris). 2011 Dec;59(6):319-20.]
5. Levels of CRP may also be elevated in patients with viral infections, although usually not to the degree seen in patients with bacterial infection [Clin Infect Dis. 2004;39(2):206.]
6. CRP over 40 mg/L had a sensitivity and specificity for bacterial pneumonia of 70% and 90%, respectively [Am J Med. 2004;116(8):529.] 
7. Median CRP level in pneumococcal pneumonia was 166.0 mg/L and in L pneumophila 178.0 mg/L [Chest. 2004;125(4):1335-42.]
8. CRP appears to be less sensitive than procalcitonin for the detection of bacterial pneumonia [Intensive Care Med. 2006;32(3):469.]. 
9. CRP levels that rapidly return to baseline point to resolving tissue damage as may occur with favorable patient responses to treatments. At the early stage of COVID-19, CRP levels have been shown to positively correlate with lung lesions.
10. In COVID-19 patients, minimally elevated CRP levels (10 - 20 μg/mL) can suggest mild viral disease.
11. COVID-19 patients with moderate increase in CRP levels (Over 20–40 μg/mL) may develop some level of (reversible) tissue damage associated with the natural response to fight the disease. If these levels are measured relatively early in disease progression, before a cytokine storm response, it may suggest a confounding bacterial infection or more significant tissue involvement.
12. COVID-19 patients with significantly raised CRP levels (e.g., > 100 μg/mL) suggest advanced tissue damage and pathologies associated with cytokine storm, coagulation abnormalities, and multiple organ failure. Such high CRP levels correlate with a fatal prognosis.[Am J Trop Med Hyg. 2020 Aug; 103(2): 561–563.]

CRP cut offs

10. CRP levels can be used for early diagnosis of pneumonia[PloS one, 11 (3) (2016), p. e0150269, 10.1371/journal.pone.0150269]
11. 11mg / L: ROC curves showed a sensitivity of 75% and specificity of 70% for the LDH cut-off value of 450 U/L and a sensitivity of 72% and specificity of 71% for the CRP cut-off value of 11 mg/dl to identify COVID-19 with moderate-severe ARDS. [Clinica Chimica Acta, Volume 509, October 2020, Pages 135-138]
12. 16.60 mg/L: Moderate-severe vs mild [77.0% sensitivity, 72.0% specificity).[Annals of Clinical Microbiology and Antimicrobials volume 19, Article number: 18 (2020)]
13. 20.42 mg/L: Area under the curve of CRP on the first visit for predicting severe COVID‐19 was 0.87 (95% CI 0.10–1.00) at 20.42 mg/L with sensitivity and specificity 83% and 91%, respectively.CRP in severe COVID‐19 patients increased to a significant level at the initial stage, before CT findings. CRP predicted early severe COVID‐19.  [https://doi.org/10.1002/jmv.25871 Journal of Medical Virology]
14. Only CRP was found to be significantly associated with the progression of non-severe COVID-19 patients (OR, 1.056; 95% CI, 1.025–1.089; P = .000) as determined by multivariate analysis - for every 1-unit increase in CRP level, the risk of developing severe events increased by nearly 5%. [Open Forum Infectious Diseases, Volume 7, Issue 5, May 2020, ofaa153].
15. KM curve showed that patients with high levels of CRP (≥26.9 mg/L) had significantly elevated risks of developing into severe cases when compared with patients with low levels (24.5% vs 1.9%; log-rank P < .001)  [Open Forum Infectious Diseases, Volume 7, Issue 5, May 2020, ofaa153].
16.    40-50 mg/L:      Chinese guideline: For follow-up
17. 41.4 mg/L: CRP exhibited sensitivity 90.5%, specificity 77.6%, positive predictive value 61.3%, and negative predictive value 95.4%. [doi: https://doi.org/10.1101/2020.03.21.20040360]
18. Over 100 mg/L: At admission associated with increased ICU admissions and 30-day mortality [J Crit Care 2020; 56: 73 – 9]

D-dimer over 1000 ng/ml (Less than 500)

CRP over 100 mg/L (Less than 8)

LDH over 245 units/ L (Less than 110-210)

Troponin over 2 x ULN (F 0-9 ng/L, Males 0-14 ng/L)

Ferritin over 500 mcg/L (F 10-200, M 30-300]

CPK over 2 x ULN (40-150 units/L)

Reduced absolute lymphocyte count: Less than 800/microl [18 to 7700 in over 21 years age]

References:

1. Guan WY, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497.
3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054.
4. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020.
5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020.
6. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020.

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA