THE COVID-19 PANDEMIC AND THE ISSUE(S) OF ANTICOAGULATION-Part I
We are now experiencing a once in a lifetime health issue that has not been seen since the Spanish Flu of the early 20th century. A pandemic of epic proportions has infected millions of people worldwide and taken over 300,000 lives, with the largest number of infections taking place in the United States, as of this writing.
The novel coronavirus pneumonia (NCP) now named COVID-19 apparently emerged in November 2019 in Wuhan, China. COVID-19 stands for Coronavirus Infectious Disease-2019 and belongs to the Coronavirus genus in the Coronaviridae family which has large RNA genomes. The virus is also referred to as SARS-CoV-2. It has been suggested that it emerged from an animal, likely a bat as has been shown with SARS-CoV. The origin has not been confirmed, however, and has been the subject of much conjecture. Whatever the creation or cause, this has presented mankind with a severe problem that not only can take innocent lives, but wreck the world’s economies in a manner not seen since the Great Depression.
This presents the medical community with a number of problems in diagnosis and treatment of patients afflicted with this virus. The medical laboratory has been thrust to the forefront of the battle in performing large numbers of assays for identification of the afflicted and the management of what appears to be the thrombi that this disease causes. This topic will be covered in this issue of Clot Club.
Abnormal Coagulation Parameters associated with COVID-19
One of the first papers that discuss the effects of the virus on the coagulation system was by a group of physicians on the initial frontlines of the pandemic in Wuhan, China. Tang et al. observed significantly elevated coagulation levels in subjects with severe pneumonia connected to the coronavirus.1 They looked at regular coagulation screening assays such as prothrombin times (PT), activated partial thromboplastin time (aPTT), D-dimers (D-D), and fibrin degradation products (FDPs).
Hemostasis Changes in COVID-19 Patients
The medical team observed the coagulation test results and disease outcomes in subjects with confirmed COVID-19. The results were as follows: The overall mortality was (11.5%). This group had significantly higher D-D, FDP levels with prolonged PT, and aPTT times when compared to the survivors when admitted (p,0.05): 71.4% of non-survivors and 0.6% survivors meet the DIC score2 to determine the diagnosis of DIC. They concluded that abnormal coagulation results, in particular those patients who had markedly elevated D-D and FDP results, went hand in hand with a higher risk of mortality associated with COVID-19. 1
The DIC score is calculated from measurement of the platelet count, D-D, fibrinogen, and prothrombin times.
|>100 x 109/L||0|
|50-100 x 109/L||1|
|<50 x 109/L||2|
|Moderate (1-10 times upper limit of normal)||2|
|Strong increase (>10 times upper limit of normal||3|
|Prothrombin time prolongation|
|Overt Disseminated Intravascular Coagulation||≥5|
ISTH DIC Score table2
It is surprising to note that the Tang study used both FDPs and D-D because in the United States there are currently no automated FDP assays that have been FDA cleared for use.
At the ISTH Paris meeting in 2001, I presented the following paper: McGlasson DL, Bessmer DS, Neuhauser TS. Do We Still Need to Perform FDP Assays in Conjunction With D-Dimers? Supplement to the Journal of Thrombosis and Haemostasis, July 2001 (ISSN 0340-6245). We reviewed several hundred simultaneously run FDP and D-D tests found that only 3 FDP tests did not correlate with a positive range D-D and all of the elevated FDP subjects had some form of end-stage cancer.
The DIC score used by the ISTH did not use the FDP method to determine DIC. The DIC score however has been shown in these studies to be of prognostic value in COVID-19 pneumonia.
The clinical symptoms of this new disorder are a myriad of observations which include fever, myalgia, cough and dyspnea, and lesser symptoms of headaches, nausea, diarrhea, and vomiting. When subjects display clinical features of the COVID-19 disorder, a rapid onset of severe pneumonia can occur, causing respiratory issues. Much is being learned, but this seems to occur in 30% of patients; 30% may be transferred to ICU units, and 10-15% of patients may die from this disorder, according to current statistics as of this writing.4
D-dimer levels in COVID-19 patients
A retrospective study of 191 patients in China showed D-dimer levels in COVID-19 survivors were markedly decreased compared to D-D levels in non-survivors. Older aged patients with D-dimer levels greater than 1 μg/L, and organ failure using the Sequential Organ Failure Assessment (SOFA score, which predicts ICU mortality on admission based on lab results and clinical picture) were associated with higher odds of in-hospital death5.
D-dimer levels in COVID-19 Patients at Admission:
In another retrospective study of 343 patients in China, D-dimer levels at admission of > 2.0 µg/mL were linked to mortality; ROC analysis showed 92.3% sensitivity and 83.3% specificity (ROC AUC = 0.89).6
In a prospective study of 83 patients in Ireland, D-dimer and fibrinogen were significantly elevated in ICU vs. Non-ICU patients.7
The above examples are just a few of a myriad of studies that have been observed in the COVID-19 coagulopathy pattern.
COVID-19 Associated Coagulopathy (CAC): Is it any different from DIC?
Elevated levels of D-D and fibrinogen are common markers of the disease state and are proportional to increased levels of CRP. Other inflammatory markers that may be elevated are IL-6, ferritin, Pro-calcitonin, antithrombin, LDH (lung tissue damage), troponin, and Pro-BNP. Elevated PT and aPTT times are also observed, although times can be shortened by the elevation of fibrinogen and FVIII levels. However, levels of fibrinogen <100mg/dl can be seen along with elevated D-D levels. In severe cases, marked thrombocytopenia less than 50 x 109/L can be observed.8,9
The ISTH published interim guidelines on how to recognize and manage the coagulopathy in COVID-19. Their recommendation of coagulation markers on admission are first, elevated D-D. They note that the elderly and subjects with co-morbidities have higher D-D levels and have a greater chance of dying from the COVID-19 virus. They reported on the largest data set on clinical observation to date, which included over 550 facilities in China. A D-D ≥0.5 mg/L was seen in 46.4% of the patients tested. Only 43% had raised D-D if the disease was non-severe, and about 60% had the more severe stage of the illness.11 As discussed earlier, Tang and associates found that have a 3 to 4 fold increase from normal should be admitted to the hospital even with the lack of severe symptoms, since this marked elevation show increased thrombin generation.
Other tests looked at are the PT and the platelet count. In the Tang study, PT was also prolonged in the non-survivors on admission, but only slightly, with a range of 14.4-16.3 seconds. This was slightly lower in survivors, with a range of 13.0-14.3 sec. One thing they stressed was that the PT time should only be used to report results and not the international normalized ratio (INR). They noted that the subtle changes that would occur in the INR versus the two groups may not be noticed. Even though thrombocytopenia is often evident in sepsis, this was not apparent with many of the COVID-19 patients. In the study published in the Lancet, a platelet count <100 x 109/L was only evident in 5% of subjects, in a study of 40 subjects. In the two subjects with lower platelet count, one was in the ICU and one was not.
In other studies, similar data was seen in non-survivors with thrombocytopenia, and is not considered a great predictor on admission.
Based on the current data, the ISTH recommends measuring D-D, PT, and platelet count in decreasing order of importance in all subjects who present with the COVID-19. They also stress that any patients who have underlying issues such as liver disease, types of medication, particularly anticoagulants, could affect the parameters when patients need to be ranked for severity of treatment protocols. The fibrinogen levels should also be monitored throughout the treatment of all subjects.
ISTH Guidelines for Management of COVID-19 Coagulopathy. Controversy over anticoagulation?
There is not a lot of evidence yet on how to anticoagulate patients afflicted with this disorder. Two recent publications discuss this issue.8.12 While we are still compiling data to treat the COVID-19 virus, we target the treatment of the DIC occurrence to limit the mortality of subjects who are the most severely infected.
Several treatments have been proposed to manage the coagulopathy, including low molecular weight heparin (LMWH), unfractionated heparin (UFH), tissue plasminogen activator (tPA), direct oral anticoagulants (DOACs), Vitamin-K antagonists (oral dosing coumadin derivatives). There are pros and cons for all. However, the most common suggestions seem to be that LMWH prophylactic anticoagulation as the way to treat the coagulopathy seen with this disorder. This includes both the non-severe and severe subjects who need to be hospitalized for COVID-19. Co-morbidities should be taken into account, including active hemorrhage and a platelet count <25×109/L, or abnormal renal function. A prolonged PT or aPTT is not considered a complication in starting to treat with LMWH. Tang, in an abstract submitted, reviewed, and accepted, but not yet published, saw the benefit of this algorithm in a study that monitored 449 patients with the severe stage of COVID-19. This included 99 subjects that received primarily LMWH at prophylactic dosing. No significant difference was seen in a 28-day mortality observation in those patients who received heparin vs those who did not. However, if a Sepsis-Induced Coagulopathy Study score (SIS) ≥4 was applied to patients/anticoagulant therapy with LMWH those subjects had a better prognosis in regards to mortality (40.0% vs 64.2%, p=0.029). In those patients who had a D-D level >6 fold of upper limit of normal a similar benefit (32.8% vs 52.4%, p=0.017). The use of LMWH will also protect critically ill patients against VTE. LWMH also has been shown to have anti-inflammatory benefits that could benefit in patients with the COVID-19 infections that have proinflammatory cytokines that are elevated.4,11,15
But as we are all too familiar, with new situations there are always those with another set of data and other opinions. This is the case with heparin therapy. In a letter to the editor on reference #7 on the paper by J Thachil et al CD Barrett et a #16l: these authors state that they do not believe the use of prophylactic LWMH to treat severe COVID-19 coagulopathy is a convincing strategy to employ. They state “patients that are critically ill with COVID-19 have hallmark signs of DIC, and as noted in the ISTH interim guidance and our own clinical practice, thrombosis is the overwhelming phenotype with rare bleeding complications. We address this concern with the existing data on the severe hypercoaguable state of COVID-19 victims and advocate for consideration of systemic anticoagulation with unfractionated heparin to prevent life threatening micro- and macrovascular thrombosis to mitigate their associated consequences, up and including progression of respiratory and organ failure.”15
So, we in the laboratory are at a point and counterpoint on treatments and methods for monitoring subjects and managing their hemostatic state. There will be more to come in my next posting in July. Hopefully we will have a better handle on this topic.
Thrombosis is more of a problem than bleeding in COVID-19. If you have any comments please contact me at firstname.lastname@example.org.
- Tang N, Dengju L, Wang X et al: abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost.2020;00:1-4.
- Taylor J, Toh CH Hoots WK et al: Towards definition, clinical and laboratory criteria and a scoring system for disseminated intravascular coagulation. : On behalf of the scientific on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis.2001 86(5): 1327-1330.
- Lillicrap D. Disseminated Intravascular coagulation in patients with 2019-nCoV pneumonia. J Thromb Haemost. 2020;18:786-787.
- Huang C, Wang Y, Li X, et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(101223):497-506.
- Zhou F, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062.
- Zhang L, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020 Apr 19. doi: 10.1111/jth.14859. [Epub ahead of print.
- Fogarty H, et al. COVID-19 Coagulopathy in Caucasian patients. Br J Haematol. 2020 Apr 4. doi: 10.1111/bjh.16749. [Epub ahead of print]
- Thachil J, Tang N, Gando S et al: ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 May;18(5):1023-1026
- Webinar Coagulation alterations and management of patients with CVID-19 infection. Stago special event on demand presented by Prof. Armando D’Angelo, Director of the Coagulation Service and Thrombosis Unit Ospedale San Raffael, Milano Italy.
- Zhang J, Zhou L, Yang Y et al: Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics. Lance epublished doi.org/10.1016/S2213-2600(20)30071-0.
- Guyan WJ, Ni ZY, Hu Y et al: China Medical Treatment Expert Group for COVID-19. Clinical characteristics of Coronavirus Disease 2019 in China. N. Engl J Med, 2020doi: 10.1056/NEJMoa2002032.
- ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A Comment.
- Shankar-Hari, Phillips GS, Levy ML et al: Sepsis Definitions Task Force. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock Sepsis-3). JAMA. 2016 315(8):775-87.
- Iba T, Levy JH, Warkentin TE et al: Scientification and Standardizationon Perioperative and Critical Care of the International Society on thrombosis and Haemostasis. Diagnosis and Management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J thromb Haemost 2019. 17(11):1989-1994.
- Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammator effects? Thromb Haemost. 2017;117(3)L437-444.
- Barrett CD, Moore HB, Yaffe MB and EE Moore. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A Comment. J Thromb Haemost. 2020 Apr 17. Doi: 10.1111/jtbh.14860 [Epub ahead of print].