Table of Contents  
INVITED ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 5  |  Page : 6-10

D-Dimer and thrombosis in COVID-19


Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester, United Kingdom

Date of Submission17-Jun-2021
Date of Acceptance18-Jun-2021
Date of Web Publication30-Aug-2021

Correspondence Address:
Jecko Thachil
Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijves.ijves_67_21

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  Abstract 


The coronavirus disease 2019 (COVID-19) pandemic has taken medical community by surprise, but it also saw significant advances in understanding of infection induced coagulopathy. Pulmonary and macrovascular thrombosis is one of the hallmarks of this pandemic and has intrigued vascular surgeons world over. In this review, the lessons learnt from COVID-19 coagulopathy are summarised with some perspectives on role of newer concepts of immune mediated thrombosis and endothelial inflammation. D-dimers have become one of the most discussed inflammatory marker and also one of the commonest blood tests ordered in the COVID-19 pandemic. Its usefulness in management of COVID induced thrombosis has been a matter of debate and this article looks in to evidence based application of D-dimer in clinical practice. Role of Heparins, Direct Oral Anticoagulants (DOACs) and anti-platelets in prophylaxis and management of vascular thrombosis has also been summarised.

Keywords: COVID-19, COVID thrombosis, D-dimer


How to cite this article:
Thachil J. D-Dimer and thrombosis in COVID-19. Indian J Vasc Endovasc Surg 2021;8, Suppl S1:6-10

How to cite this URL:
Thachil J. D-Dimer and thrombosis in COVID-19. Indian J Vasc Endovasc Surg [serial online] 2021 [cited 2021 Nov 30];8, Suppl S1:6-10. Available from: https://www.indjvascsurg.org/text.asp?2021/8/5/6/324948




  Introduction Top


Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] Since the first case was identified in Wuhan, at the end of 2019, the disease has caused havoc around worldwide, resulting in over three million deaths. Although most people who develop COVID-19 virus will only experience mild respiratory symptoms and do not require any special treatment, a significant minority can succumb to this infection.[2] One of the most common complications which was recognized early on in this pandemic is the development of thrombosis, primarily in the lungs but also in the different circulatory beds, including both arterial and venous distributions.[3] Older people, and those with underlying medical problems such as cardiovascular disease, and diabetes, and from Asian background have been observed to be more likely to develop serious illness.[4] The best way to deal with this infection is to take precautions and thus limit individual infection and further on the spread of the virus by social distancing measures. In this invited review, a discussion is presented of the pathogenesis of thrombotic complications in COVID-19, its recognition, and possible treatments.


  Pathogenesis Top


Immunothrombosis

SARS-CoV-2 virus usually gains entry through the upper respiratory tract. Hence, the epicenter of action is the lungs. As with any other infection, this virus activates the immune system with a view to eradicate the infection.[5] In most cases, this appropriate immune response will be adequate to get rid of the virus and thus save the host. However, there are two situations where this supposedly beneficial immune response may play a role in causing harm. To understand this, we need to understand first that the immune system can trigger thrombosis. There has been tremendous amount of research on this topic in the recent era, and this bidirectional relationship is called “immunothrombosis” or “thromboinflammation.”[6] In short, many of the components of the immune system will activate the clotting system, and on the contrary, several coagulation proteins (e.g. thrombin) and platelets can activate the immune system.[6],[7] This helpful relationship exists as one and the same in the lower evolutionary animals and is called “hemolymph.” In these organisms, the hemolymph serves the purpose of providing immunity and nutrition which in “higher” organisms such as humans is provided by the immune system and blood, respectively.[8]

Concept of exaggerated thromboinflammation

There are two situations where the immunothrombosis can be pathogenic: (1) when the viral load is high and a vigorous immune response is generated, and further on, the thromboinflammation can be in large amounts and (2) whereas in some people, the viral load may not be high, but the immune response is exaggerated resulting in a similar exaggerated thromboinflammation.[5],[6] In both these situations, clots form in the microvasculature which will be termed microthrombi [Figure 1]. These small clots could be dissolved by the body's fibrinolytic system in mild and moderate COVID-19 cases without causing any harm to the host. However, in the two situations described above, the exaggerated thromboinflammation can lead to large amounts of microthrombi which would be manifested as pulmonary thrombi.[6],[7] This concept of immunothrombosis explains why children rarely get severe COVID-19 since their immune response is not usually brisk.[2] A similar explanation can be provided for pregnant women who have a temporary immunosuppressed state to eliminate the chances of “rejecting” the fetus.[2] In this context, it is useful to note that these are pulmonary thrombi and not pulmonary emboli.[9] There is a lot of confusion in the medical literature on this distinction, and as vascular surgeons know better than anyone else, emboli usually start somewhere and end somewhere else, which is not the case in COVID-19.
Figure 1: Depiction of inflammation and immunothrombosis in COVID-19. On the left of the figure, inflammation following the viral invasion is limited to small thrombi. While on the right of the figure, the outcome is acute lung injury and pulmonary thrombosis.

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Concept of endothelialitis

In extreme cases of pulmonary thromboinflammation, the activated coagulation system can spill into the circulation and cause thrombosis in arterial and venous circulatory beds.[10] However, a more common cause of these nonpulmonary clots is viral endothelialitis.[11] Several postmortem studies in this viral infection showed the presence of the SARS-CoV-2 virus in the vascular endothelium, including the coronary, renal, and cerebral microvasculature.[6] Since thrombus formation starts at the endothelial boundary in noninfective cases, endothelial invasion by an infectious organism behaves like endothelial injury and causes thrombosis. The location of clots depends on the vasculature predilection in different individuals and their underlying immune status. In other words, those who are immunocompromised tend to develop these clots more often since they cannot clear the virus easily. This hypothesis can explain the higher mortality in older individuals and in those who have underlying immunocompromised states.


  D-Dimer and COVID-19 Top


D-dimers have become one of the most common blood tests ordered in the COVID-19 pandemic. However, several misconceptions exist in using this, which needs discussion.

How D-dimer is formed

To understand the process of D-dimer formation, it is useful to review the process of fibrinolysis. Fibrin degradation products are generated from fibrinogen which naturally has a dimer and three chains.[12] The central part of fibrinogen is called the E-domain, while the two-outer structures are termed the D-domains. During the process of clot formation, thrombin acts on fibrinogen to form fibrin monomers (where the D-domains come together). Polymerization of the fibrin monomers occurs, which gives the clot strength. To enable continuous blood flow around the clot formed and not completely occlude the vessel, fibrinolytic proteins come into play. These proteins break down the crosslinked fibrin which creates different fragments including the D-dimers. D-dimer tests are monoclonal antibodies specific for these D-domains.[12] Since the D-dimers are generated by the clot breakdown, it is generally considered a marker of thrombosis, but this is not always true.

Nonthrombotic D-dimers

From a vascular surgery point of view, D-dimers can be noted to be elevated in any condition where there may be vascular injury or tissue injury (minor and major trauma and surgical or interventional procedures).[12] It may also be often noted that the normal D-dimer result is never zero. This minimal amount of D-dimer is created due to constant breakdown of thrombi formed anywhere in the body, which may not always be intravascularly. In cases of extravasation of intravascular contents which can happen in any case of inflammation to varying degrees (vasculitis process to a vascular surgeon), clotting process also seeps out along with the various inflammatory proteins. Hence, the rubor, calor, dolor, and tumor of inflammation can also be contributed by the coagulation proteins. A clot formed in the extravascular space can be used by the inflammatory proteins as a foundation to perform their proinflammatory function. These extravascular clots are lysed in a similar fashion to the intravascular ones creating “extravascular D-dimers.”[13] This concept provides the explanation for the elevated D-dimers in inflammatory conditions and malignancies.[9]

D-dimers in COVID-19

D-dimers have become one of the most requested laboratory tests in the COVID-19 era (a quick search on PubMed using keywords D-dimer and COVID-19 identified 1831 articles on May 26). One of the first publications detailing coagulopathy in COVID-19 noted very high D-dimers in these patients.[14] Based on this finding and several others who corroborated the same in quick succession, there was a sudden surge in the use of anticoagulation use in those with elevated D-dimers. There was also a trend whereby increasing doses of anticoagulation were planned based on the higher D-dimer values.[15] This practice clearly arose because of the misconception that D-dimers equals thrombosis. However, as discussed before, D-dimers do not always mean thrombosis but could be inflammation which is a very common finding in COVID-19. However, as discussed before, raised D-dimers do not always mean thrombosis and is usually just a marker of inflammation which is a very common finding in COVID-19. So much so that in some patients COVID-19 is associated with an intense inflammatory response and a higher D-dimers even when there may be no macro or pulmonary thrombi [Figure 2]. Another interesting concept here is the vascular leakage which occurs in the lungs which is otherwise termed acute lung injury or adult respiratory distress syndrome in severe cases of COVID-19.[9] It is no surprise then that D-dimers correlate with acute respiratory distress syndrome and mortality from the acute lung injury. In summary, D-dimers should not be used to decide on starting anticoagulation or escalating anticoagulation dose. If there is worsening of D-dimer values, it may however be useful to provide information on prognosis.[16] D-dimers can stay raised in long COVID syndrome although this has not been correlated to the risk of development of thrombosis. Whether the raised D-dimer would correlate with other symptoms of inflammation is not yet known. For this reason, repeating D-dimer after hospital discharge is not advisable to consider starting (or continuing) anticoagulation in the absence of other well-known risk factors for thrombosis (e.g. post-operative state, immobility).
Figure 2: Contributions of clot breakdown and inflammation on D-dimers

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  Management of Thrombosis Top


Prevention

As always in the case of medical care, prevention is better than cure. Hence, if the virus did not gain entry, there are no clots formed. If only a small load of virus managed to reach the lungs, there are no clots. Hence, social distancing and vaccination matter. In the cases where the virus has entered in sufficient amounts, or the host immune response had been vigorous, then there is a role for prophylactic anticoagulation in combination with other virus and immune control measures.[2] One of the intriguing research agenda here is the role of dexamethasone which is now standard treatment in critically ill COVID-19 patients in “reducing” the thromboinflammation and thus the thrombotic complications.[17] A similar reduction may be observed with other immunomodulatory therapies such as toclizumab, but these ideas have not been systematically studied. Until then, the standard treatment is prophylactic anticoagulation. Low-molecular-weight heparin (LMWH) has been suggested by several international guidelines as the standard prophylactic anticoagulant treatment in this setting.[2],[18] This may be based on not just the anticoagulant function of LMWH but also anti-inflammatory, antiplatelet, and antiviral and properties.[19] Heparin also has effects on the vascular endothelium (called endothelial quiescence) and promoting endothelial glycocalyx. What is not known is whether other anticoagulants such as warfarin or the direct oral anticoagulants (DOACs) have these additional antithrombotic roles.[20] Fondaparinux is often used instead of LMWH and may be preferred in those with history of heparin-induced thrombocytopenia and osteoporosis.[21] One of the issues with fondaparinux is its long duration of action (making reversal difficult) and renal clearance (much more dependent on kidney function compared to LMWH).

Heparin dosing

Early on in the pandemic, a large retrospective study of over 4000 patients confirmed the mortality benefit of LMWH prophylaxis in all patients with COVID-19 requiring hospital admission. However, soon after this, several European centers noted failure of prophylactic anticoagulation, stimulating several randomized controlled trials to identify the correct dosing.[22] The ATTACC, REMAP-CAP, and ACTIV-4a trial platforms combined their forces to assess the value of therapeutic or prophylactic heparin doses. Results showed therapeutic anticoagulation increased mortality rates compared with standard of care in severe cases where the patient required organ support or intensive care admission. On the other hand, in the moderate group, therapeutic anticoagulation increased organ support-free days and mortality was reduced. We can summarize the following about the dose [Figure 3]:[22]
Figure 3: Anticoagulation in Covid-19

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  • A definite benefit from prophylactic heparin compared with no heparin
  • Therapeutic doses in certain subsets (need supplemental oxygen but not yet receiving high-flow oxygen, continuous positive airway pressure, noninvasive ventilation, or invasive mechanical ventilation)
  • No therapeutic anticoagulation in severely ill patients without proven thrombosis
  • Treatment should be for a minimum of 14 days or until discharge.


Role of direct oral anticoagulants

DOACs have revolutionized the management of venous thromboembolism and atrial fibrillation in the last decade. They are much more convenient and do not quire monitoring and have very few drug interactions and minimal food interactions. Naturally, DOACs have been tried in the COVID-19 setting. Definite conclusions cannot be given currently, but it needs to be borne in mind that there is up to now no evidence for anti-inflammatory and nonanticoagulant functions for DOACs.[23],[24],[25] DOACs may however be used in two settings – (1) COVID-19 patients who developed thrombosis and have been treated with LMWH in the hospital and is ready for discharge – DOACs certainly make continued anticoagulation (3 months in total from the diagnosis of the clot) much simpler and easier and (2) DOACs may be given to those patients who required hospitalization but did not develop thrombosis but continue to have other risk factors for thromboembolism (reduced mobility, comorbidities, etc.).[26] It needs to be stressed however that there is no conclusive evidence to start DOAC in a patient recently noted to be COVID positive and is completely asymptomatic. A less ideal situation where DOAC may be used is if there is lack of availability of LMWH.

Role of antiplatelets

There have been several studies looking at the role of platelets in COVID-19. And unsurprisingly, platelet activation has been consistently shown to be present in hospitalized patients with this infection.[6] Logic would say that, let's give antiplatelets to these patients, but a recent large trial concluded that aspirin does not prevent hospitalization or mortality in these patients. What may be the reasons? It is possible that several different pathways are activated among the platelets and aspirin may not block them. Same may be the case with other drugs such as clopidogrel or ticagrelor. Furthermore, possibly, aspirin may need to be given with anticoagulants to get a better outcome and this has not been studied.


  Conclusion and UncertaIntIes Top


COVID-19 took us by surprise. The world was not ready, but we learned a lot in a short period of time due to the concerted efforts of worldwide healthcare professionals. However, several uncertainties still exist which are pertinent to vascular surgeons as well. Some of these are:

  • Can we predict who may develop arterial thrombosis (e.g. limb ischemia)?
  • What is the role of antiplatelets in all these – can being on certain types of antiplatelets prevent thrombosis?
  • Can antiplatelets in conjunction with anticoagulants be better than the latter on its own?
  • What about the recently described complication of vaccine-induced thrombosis thrombocytopenia?


In the authors' opinion, continued efforts as ONE WORLD is needed to break this mold of lack of understanding. While these efforts continue, I would like to conclude by bearing in mind with a lot of gratitude for the martyrdomal efforts of frontline workers around the globe in the fight back against this virus.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.  Back to cited text no. 1
    
2.
Thachil J, Agarwal S. Understanding the COVID-19 coagulopathy spectrum. Anaesthesia 2020;75:1432-6.  Back to cited text no. 2
    
3.
Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023-6.  Back to cited text no. 3
    
4.
Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol 2020;7:e438-40.  Back to cited text no. 4
    
5.
Thachil J, Srivastava A. SARS-2 coronavirus-associated hemostatic lung abnormality in COVID-19: Is it pulmonary thrombosis or pulmonary embolism? Semin Thromb Hemost 2020;46:777-80.  Back to cited text no. 5
    
6.
Thachil J. Lessons learnt from COVID-19 coagulopathy. EJHaem. 2021 May 17:10.1002/jha2.228. doi: 10.1002/jha2.228. Epub ahead of print.  Back to cited text no. 6
    
7.
Thachil J. What do monitoring platelet counts in COVID-19 teach us? J Thromb Haemost 2020;18:2071-2.  Back to cited text no. 7
    
8.
Thachil J. Platelets in inflammatory disorders: A pathophysiological and clinical perspective. Semin Thromb Hemost 2015;41:572-81.  Back to cited text no. 8
    
9.
Thachil J, Khorana A, Carrier M. Similarities and perspectives on the two C's-Cancer and COVID-19. J Thromb Haemost 2021;19:1161-7.  Back to cited text no. 9
    
10.
Thachil J. Cushman M, Srivastava A. A proposal for staging COVID-19 coagulopathy. Res Pract Thromb Haemost 2020;4:731-6.  Back to cited text no. 10
    
11.
Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020;18:2103-9.  Back to cited text no. 11
    
12.
Thachil J, Lippi G, Favaloro EJ. D-dimer testing: Laboratory aspects and current issues. Methods Mol Biol 2017;1646:91-104.  Back to cited text no. 12
    
13.
Thachil J. All those D-dimers in COVID-19. J Thromb Haemost 2020;18:2075-6.  Back to cited text no. 13
    
14.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.  Back to cited text no. 14
    
15.
Thachil J, Tang N, Gando S, Falanga A, Levi M, Clark C, et al. Laboratory haemostasis monitoring in COVID-19. J Thromb Haemost 2020;18:2058-60.  Back to cited text no. 15
    
16.
Thachil J, Longstaff C, Favaloro EJ, Lippi G, Urano T, Kim PY, et al. The need for accurate D-dimer reporting in COVID-19: Communication from the ISTH SSC on fibrinolysis. J Thromb Haemost 2020;18:2408-11.  Back to cited text no. 16
    
17.
Wagner C, Griesel M, Mikolajewska A, Mueller A, Nothacker M, Kley K, et al. Systemic corticosteroids for the treatment of COVID-19. Cochrane Database Syst Rev 2021;8:CD014963.  Back to cited text no. 17
    
18.
Spyropoulos AC, Levy JH, Ageno W, Connors JM, Hunt BJ, Iba T, et al. Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020;18:1859-65.  Back to cited text no. 18
    
19.
Thachil J. The versatile heparin in COVID-19. J Thromb Haemost 2020;18:1020-2.  Back to cited text no. 19
    
20.
Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. DOACs and “newer” hemophilia therapies in COVID-19: Reply. J Thromb Haemost 2020;18:1795-6.  Back to cited text no. 20
    
21.
Thachil J, Juffermans NP, Ranucci M, Connors JM, Warkentin TE, Ortel TL, et al. ISTH DIC subcommittee communication on anticoagulation in COVID-19. J Thromb Haemost 2020;18:2138-44.  Back to cited text no. 21
    
22.
Swan D, Carrier M, Lisman T, Thachil J. Heparin - Messias or Verschlimmbesserung? J Thromb Haemost. 2021 Jul 17. doi: 10.1111/jth.15464. Epub ahead of print.  Back to cited text no. 22
    
23.
Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020;24:360.  Back to cited text no. 23
    
24.
Thachil J. Clinical differentiation of anticoagulant and non-anticoagulant properties of heparin. J Thromb Haemost 2020;18:2424-5.  Back to cited text no. 24
    
25.
Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020;48:1358-64.  Back to cited text no. 25
    
26.
Bristogiannis S, Swan D, Thachil J. Thromboprophylaxis in COVID-19-Rationale and considerations. Adv Biol Regul 2021;81:100819.  Back to cited text no. 26
    


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