key: cord-0686764-qdgif1q7 authors: Thachil, Jecko; Khorana, Alok; Carrier, Marc title: Similarities and perspectives on the two C’s—Cancer and COVID‐19 date: 2021-03-31 journal: J Thromb Haemost DOI: 10.1111/jth.15294 sha: f8acc70bd8d846a5d0c07325802081f14d14deac doc_id: 686764 cord_uid: qdgif1q7 COVID‐19 continues to dominate the health‐care burden in the twenty‐first century. While health‐care professionals around the world try their best to minimize the mortality from this pandemic, we also continue to battle the high mortality from different types of cancer. For the hemostasis and thrombosis specialist, these two conditions present some unusual similarities including the high rate of thrombosis and marked elevation of D‐dimers. In this forum article, we discuss these similarities and provide some considerations for future research and therapeutic trials. The year 2020 was different from any other in the last 100 years with the impact the COVID-19 pandemic had on the global population. This viral infection has caused enough morbidity and mortality in such a short period as malignancies have done to the human population over many decades. When we look forward to a post--COVID-19 era with "respair" (a fourteenth-century word meaning "the return of hope after a period of despair"), it would be worthwhile looking at these two C's-COVID-19 and cancer-to see if there may be any common factors and whether we can learn from the latest scourge to inform us of the age-old menace. Some of the similarities between these two conditions are the very high D-dimers, markedly elevated thrombotic risk including multi-system thrombosis, and inadequacy of anticoagulation in certain cases. [1] [2] [3] We provide some perspectives on these laboratory abnormalities and clinical features to assist future basic science research and clinical trials. D-dimers are created during the process of fibrinolysis when covalently bound D-domains of adjacent fibrin monomers are created by plasmin degradation of cross-linked fibrin. 1 D-dimers were developed as a laboratory marker for the exclusion of venous thrombosis and indeed have a very good predictive potential in this clinical endpoint. 4 Despite its admirable role as a negative predictive marker, unfortunately, it is often used as a positive diagnostic marker for thrombosis in patients including those with COVID-19. 5, 6 Markedly elevated D-dimers were noted early on in patients with Different authors correlated very high D-dimers with mortality and suggested particular cut-off levels as a prognostic indicator. [6] [7] [8] [9] For example, a cut-off value of 2.0 µg/ml was shown to have a sensitivity of 92.3% and a specificity of 83.3% in predicting hospital mortality. 10 A pooled analysis of the literature at the time of publication also identified D-dimer to be associated with the severity of COVID-19 (weighted mean difference: 2.97 mg/L; 95% confidence interval [CI] 2.47-3.46 mg/L between COVID-19 patients with or without severe disease). 11 However, one of the misunderstood aspects of this laboratory marker is to consider all the D-dimers in COVID-19 result from intravascular clot breakdown and thus behave as a marker of thrombosis. 12 D-dimer is generated by the breakdown of cross-linked fibrin that can happen inside the blood vessels but also in the extravascular space 4,13 (see Figure 1 ). In patients affected by severe COVID-19, a considerable amount of D-dimers may be generated in the extravascular space; specifically in the alveolar space. 12, 14 In patients who develop acute lung injury with infectious or inflammatory conditions including COVID-19, one of the characteristic features is the leakage of plasma proteins into the alveolar space (sometimes termed "wet lung"). 15 These plasma proteins, which may include inflammatory cytokines, may help in the local defense mechanism against airwayborne pathogens. 15 But in addition to the inflammatory cytokines, the leaked plasma proteins also include fibrinogen and thrombin. 16 Just as much as these proteins participate in clot formation in the vascular space, they also create fibrin in the alveolar space. Fibrin may serve the purpose of acting as a scaffold for the inflammatory cytokines to act out their defense function. 17 Breakdown of this fibrin, which is necessary to main adequate gas exchange (the lungs have a vigorous fibrinolytic system), also creates D-dimer, which is reabsorbed into the vasculature and can be detected in blood samples. But the key difference here is that these D-dimers do not signify intravascular clot formation and thus do not behave as a marker for thrombosis. On the other hand, the increase in D-dimers would correlate with worsening acute lung injury, which may clinically manifest as increasing hypoxia and can thus be a useful prognostic indicator. 18 Postmortem studies of COVID-19 patients have shown the exudative pattern (in keeping with the wet lung description) in all cases with hyaline membranes composed of serum proteins and fibrin. 19 Polak et al. in their systematic review of the pathological findings in COVID-19 described a vascular pattern in which diffuse intra-alveolar fibrin deposition was noted in addition to microvascular thrombi; and intra-alveolar fibrin balls filling alveoli in conjunction with organizing pneumonia. 20 In a recent study of just over 120 patients with COVID-19, D-dimer values at peak were shown to be an independent predictor of critical lung injuries irrespective of the inflammatory markers assessed by C reactive protein. D-dimer was also associated with increased in-hospital death or need for critical care support even in the absence of thrombotic events. 21 The malignant process very much mimics an inflammatory reaction with chronic inflammation suggested to be a risk factor for some types of cancers (see Figure 1 ). 22 The inflammatory part of the tumors is the stromal component, which functions as the tumor nourisher with its rich supply of blood vessels. 23 In addition to new blood vessels, the other constituents of the stroma include connective tissue (which makes the tumor palpable), and a fibrin-gel matrix, which determines the stromal size. 24 Initial skeptics considered the presence of fibrin in tumor tissue as an epiphenomenon of ischemic necrosis or representative of the clot formed during removal of the tumor. 23 But, the identification of a process similar to that of vascular leakage in inflammatory processes (as described above in the lungs) has given proof to the concept of fibrin being a significant part of the stroma. 25 Increased vascular permeability allows extravasation of fibrinogen, which is acted on by the cancer procoagulants to create cross-linked fibrin. 26 The cross-linked fibrin in the stroma is degraded rapidly by the extensive fibrinolysis instigated by tumor-secreted plasminogen activators. 27 The key difference between inflammatory and tumor fibrin deposition is that the latter is an ongoing process due to the continued release of vascular permeability factor by the tumors. 28 The tumor-associated fibrin in high concentrations can prevent inflammatory cells reaching the tumor (detrimental to the host), although in low concentrations would have facilitated inflammatory function (beneficial to the host). 23 These observations would suggest that aggressive tumors and those who may be "resistant" to anti-cancer therapy may be associated with increased extravascular fibrin and subsequent fibrinolysis and hence raised D-dimers (see Table 1 ). F I G U R E 1 D-dimer production in acute lung injury and malignancies. Fibrinolysis in both these cases occurs in the extravascular spaces and intravascularly created using BioRender tool • Because D-dimer can signify continuing inflammation, increasing Ddimers can be considered a prognostic factor in inflammatory conditions (in combination with other markers such as C-reactive protein). • Serial monitoring of D-dimers may assist in predicting the development of acute respiratory distress syndrome in critically ill patients with underlying inflammation. • Similarly increasing D-dimers may be considered a tumor marker indicating progression and/or metastasis in solid cancers. • It would be interesting to see whether decrease in D-dimer values with anti-inflammatory therapies mirror clinical improvement. • In the same manner, it would be useful to examine whether decrease in D-dimer is one of the markers of clinical efficacy of anticancer therapies. One of the well-known clinical complications of COVID-19 is the markedly increased risk of thrombosis. This is similar to what has been observed in patients with malignancies with cancer-associated thrombosis now considered a speciality in itself. Some of the unusual thrombotic manifestations of the two C's are the development of pulmonary thrombosis in the absence of lower limb deep vein thrombosis and the simultaneous development of clots in various circulatory beds (Table 1 ). scans. These incidental pulmonary "thrombi" are often detected in patients with cancer and critically ill patients. 34 But radiological examination cannot conclusively determine whether these constitute a bland embolus, or they may be tumor thrombi. Anatomical distribution of the human circulatory system has positioned lungs as a very effective filter by having all the systemic venous blood tracking to the pulmonary circulation prior to being oxygenated. It can play one of the crucial non-respiratory roles by filtering out thrombus material, fibrin clumps, and possibly other exogenous materials from the venous circulation. 35 The tendency for cancers to disseminate means that cancer particulate matter may escape into the venous circulation and may get lodged in the narrow-lumen pulmonary microcirculation. 36 These tumor emboli are not thrombotic in nature and thus reporting them as thrombo-emboli may not be correct. CT reports should ideally term them pulmonary filling defects rather than PE. This distinction between tumor and non-tumor emboli is clinically important because while the thrombo-embolic process is best managed by anticoagulation, tumor emboli will not be treated with blood thinners. 37 Because platelets play a major role in tumor metastasis, tumor--platelet hetero-aggregates formed can circulate and lodge in pulmonary vasculature and can mimic tumor thrombi. 38 In the COVID-19 setting, pulmonary thrombi can start as microthrombi secondary to thrombo-inflammation. 39 The multisystem thrombosis would once again point to systemic coagulation activation in both the C's with all three constituents of the Virchow's triad coming into play. In relation to cancer, endothelial damage is caused by the tumor itself, chemotherapeutic agents, surgical interventions, and radiotherapy procedures, and stasis can occur from compression of vessels and immobility following surgery and general weakness and hypercoagulability from cancer procoagulants. 45 In COVID-19, thromboinflammation (hypercoagulability) is currently considered the key pathogenic factor for the development of thrombosis in addition to endothelialitis (vascular damage) from direct viral invasion. 46 In addition, stasis can be caused by immobility from the extreme fatigue and enforced social isolation in mild cases and the critical illness state in the severe cases. 46 The clinical relevance of heightened awareness of multisystem thrombosis is that anticoagulant drugs may be inadequate in preventing arterial clots based on the adage that venous thrombi are caused by coagulation factors and arterial clots are caused by platelet thrombi. • Regular ultrasound screening of the lower limbs in critically ill patients may miss cases of pulmonary thrombosis. • Pulmonary filling defects may be the appropriate terminology instead of pulmonary emboli in patients with cancer-associated thrombosis. • Future studies with more sophisticated imaging techniques able to distinguish tumor (and non-thrombotic) emboli from thromboemboli would be welcome to select appropriate patients for anticoagulation. • Arterial thrombosis is not rare in patients with systemic activation of coagulation and preventive strategies may need to include additional therapeutic measures to anticoagulants (e.g., antiplatelets and anti-inflammatory/antineoplastic agents). Several current trials are exploring the role of intensified anticoagulation in patients with COVID-19. Although the early publications from China showed that prophylactic anticoagulation can translate to reduced mortality in these patients, a plethora of papers was published soon after that demonstrated that prophylactic anticoagulation is not enough to prevent thrombosis in COVID-19 settings, especially in those who require critical care support. [47] [48] [49] In the cancer context, failure of thrombo-prophylaxis was observed in a phase 2 trial of 50 hospitalized cancer patients with high risk for thrombosis (based on Padua risk score). 50 These patients were randomized to fixed-dose or weight-adjusted low molecular weight heparin regimens wherein the cumulative incidence of DVT of 22% was noted in those assigned to fixed-dose enoxaparin (40 mg daily) compared to one incidentally identified pulmonary embolus in the weight-adjusted enoxaparin (1 mg/kg daily) group. 50 Figure 2 ). • More research is needed to understand the exact mechanisms of thrombosis in the two C's, which would help identify therapeutic strategies. • Interesting research prospects in this context are whether early MC reports grants and personal fees from Leo Pharma, grants and personal fees from BMS, grants and personal fees from Pfizer, personal fees from Bayer, personal fees from Servier, and personal fees from Sanofi, outside the submitted work. JT conceived the paper and wrote the first draft. AK and MC critically reviewed the manuscript and gave comments. All authors approved the final manuscript. 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