Back in February, when the first cases of COVID-19 were detected in Vancouver and we were worried that Chinese New Year celebrations might fuel the spread of this dreaded disease in our community, there were persistent questions around what would be in store for our service. There were scarce publications, but through our hematology lens, we saw that COVID-19 was associated with lymphopenia and mild thrombocytopenia, and disseminated intravascular coagulation occurred in end-stage disease in some patients.1 None of these signals seemed unusual with severe viral pneumonia, which can result in severe acute respiratory distress syndrome in some patients and trigger an overwhelming inflammatory response and cytokine storm. We’ve seen all that before in some hematologic diseases. So, we asked our intensive care unit (ICU) colleagues not to measure ferritin because it could generate unnecessary consults for hemophagocytic lymphohistiocytosis. We thought our work was done.
Then, as the wave of infection spread to Europe, North America, and most of the world, medical literature started trickling out from China that suggested a different story. Retrospective studies highlighted that many patients had very high levels of D-dimer and fibrinogen.2,3 However, these appeared to occur with only moderate thrombocytopenia and near-normal prothrombin time/partial thromboplastin time (so not a consumptive coagulopathy), and without common reports of peripheral cell fragmentation or intravascular hemolysis (so not a microangiopathic coagulopathy). This constellation of findings is unlike other coagulopathies or hypercoagulable state patterns that we recognize; notably, it is not sepsis-related coagulopathy. Nor is it disseminated intravascular coagulation, thrombotic thrombocytopenic purpura/atypical hemolytic uremic syndrome/hemolysis, elevated liver enzymes, low platelet count, antiphospholipid antibody syndrome, cancer-associated thrombosis, or even cytokine-release syndrome following chimeric antigen receptor T-cell therapy.4
As the pandemic grew, reports of hypercoagulopathy emerged. Colleagues from China observed an alarming association between high D-dimer levels and disease severity, need for critical care support, and all-cause mortality.5 One study showed that in 191 patients, D-dimer greater than 1.0 μg/mL on admission was associated with in-hospital death (odds ratio, 18.4; 95% CI, 2.6-128.6).6 Another found that among 311 patients who had a D-dimer level greater than 3.0 μg/mL (sixfold higher than upper limit of normal), better survival was observed in those selected to received anticoagulant prophylaxis (mainly with low-molecular-weight heparin).7 These studies did not report the incidence of thrombotic events, and routine thromboprophylaxis is not standard in China because of a baseline relatively low risk of venous thromboembolism (VTE).8,9 They also did not account for any differences in clinical characteristics, underlying comorbidities, or treatments that could have influenced the risk of death. It is well established that D-dimer elevation is nonspecific for thrombosis, and very high levels are commonly found in other disease states (e.g., sepsis, cancer) and even healthy physiological conditions (e.g., second and third trimester of pregnancy).10-12 Conversely, elevated D-dimer has been associated with an increased risk of thrombosis and poor overall survival in cancer patients.13,14 Moreover, hypercoagulability resulting in an 18-fold risk of VTE has been previously described in critically ill patients with H1N1 acute respiratory distress syndrome.15 Is critical illness driving the risk for thrombosis, or is thrombosis causing the multisystem organ failure seen in COVID-19?
We anxiously awaited more data while the death toll climbed in Italy and other parts of Europe. We wondered if high rates of thrombosis would be observed with routine thromboprophylaxis. The first publications from the Netherlands, France, and Italy all reported a high incidence of venous and possibly arterial thrombosis, despite standard thromboprophylaxis.16-19 These largely retrospective analyses estimated incidence rates ranging from 16.7 to 27.6 percent in critical care patients, and approximately 6.5 percent in medical ward patients. Unfortunately, all of these studies had very short-term follow-up, some used screening ultrasonography, and some included suspected but unconfirmed pulmonary embolism (imaging not feasible due to isolation). It is also challenging to interpret the data when centers have different criteria for hospital and ICU admission, when to perform imaging, thromboprophylaxis strategies, and other therapies (e.g., hydroxychloroquine, anti-IL-6 medications, anti-complement therapies, and antivirals). Patients across studies may not have comparable comorbidities and severity of illness (and hence overall risk for thrombosis). Some clinicians at hospitals that have faced a tsunami of COVID-19 admissions have escalated thromboprophylaxis up to full therapeutic intensity based on laboratory parameters and their local experience. Excessive clotting of arterial and venous catheters, extracorporeal filters, and circuits also seem to be problematic. However, could the observation of excessive clotting events be due to clinicians being faced with an overwhelming number of patients? Or perhaps the thrombosis risk is, in fact, similar to that of other high-risk groups that are less prevalent? In a prospective study of 113 consecutive patients in the ICU with severe sepsis and septic shock, with all patients receiving guideline-recommended thromboprophylaxis, the incidence of VTE was 37.2 percent (95% CI, 28.3-46.8).20 Science is still lagging behind in confirming the VTE observations in COVID-19, establishing the varying risks of VTE in the spectrum of disease from mild to critical, and determining if these rates are higher than in other types of severe infection.20,21
Adding fuel to the fire, the news media has reported a higher incidence of stroke in young patients who have no underlying risk factors,22 and the possibility of antiphospholipid antibody syndrome has been raised as a contributing factor to the hypercoagulability observed in these patients.17,23 It is worrisome that perhaps fear is feeding fiction. More robust evidence is desperately needed to help us provide evidence-based care to our patients.
Despite the massive scale of infection and mortality impact of COVID-19, the pathophysiology of organ damage remains elusive. Limited autopsy data are available, but understanding the earlier phases of the disease is even more critical.24,25 Is microvascular thrombosis exacerbating the hypoxemic respiratory failure and end-stage multiorgan failure seen in COVID-19, or is it a consequence? More importantly, will intervening with therapeutic-intensity anticoagulation reduce morbidity and mortality?26,27 We must not forget that anticoagulant therapy is a double-edged sword — the risk of thrombosis must be balanced with the risk of bleeding.
It is now well documented that some patients with severe or critical COVID-19 have an unregulated immune response and exhibit biochemical patterns consistent with cytokine storm: high ferritin, extremely high levels of C-reactive protein, and high levels of IL-2R, IL-6, IL-10, and tumor-necrosis factor α cytokines.28 These patients also have very high levels of factor VIII and von Willebrand factor, consistent with extensive endothelial injury.17 Given the entangled and synergistic relationships between the immunologic, inflammatory, coagulation, and complement pathways, it is reasonable to assume that we cannot slay the multiheaded monster by targeting one system. Although heparin has pleotropic effects,29 we know that as with other coagulopathies, controlling the underlying disease is likely the only curative solution. In these times of uncertainty, we need to rely on first principals and sound science. ASH has collated FAQs in different hematology disciplines to help clinicians navigate in their daily practice. These consensus statements highlight what we do and do not know and encourage participation in clinical trials and robust research.
Multicenter international trials are underway to understand the risks and benefits of different therapeutic approaches. As clinicians and scientists, we need to continue to battle bravely, armed with facts and figures, not fear, fiction, nor fantasy. COVID-19, be warned!
Dr. Lee and Dr. Baumann Kreuziger indicated no relevant conflicts of interest.