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Hematologic Findings And Consequences Of Novel Coronavirus (SARS-COV-2) Infection
At the end of 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lead to a cluster of infections in Wuhan. China. The disease caused by this virus was designated as coronavirus-disease-2019 (COVID-19) by the World Health Organization (WHO). COVID-19 spread globally and went on to infect millions of people on all continents except Antarctica, causing an unprecedented global impact. As of February 2021, over one hundred million COVID-19 cases have been reported globally, with well over two million deaths attributed to the virus. Updated figures can be found on the WHO website: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports . The true extent of the pandemic is likely not yet fully appreciated, as only a fraction of cases are evaluated by medical professionals, diagnosed, and reported. Using the prevalence of seropositivity in a population with reported positive cases, it is estimated that the number of infections may be 6 to 24 times higher than reported. The reported death toll is also likely a significant underestimate. A US-based study that assessed excess deaths in 2019–2020 indicated that as many a quarter of all COVID-19 related deaths may not be officially counted.
Clinical manifestations of COVID-19 are primarily respiratory, including dyspnea and hypoxemia, and in many cases can progress to acute respiratory distress syndrome (ARDS). However, manifestations may be varied and multisystemic, and presentations are heterogeneous and range from asymptomatic to fatal ( Fig. 153.1 ). Although healthy patients at any age are susceptible to severe disease, advanced age and comorbidities are clear risk factors for poor outcomes in COVID-19. In a study of 17 million patients in the United Kingdom, the following risk factors were identified to be significantly associated with COVID-19 mortality: age >60; male sex; BMI >30 mg/kg 2 ; tobacco use; non-White ethnicity; asthma; diabetes; non-hematological cancer diagnosed within the last 5 years; hematologic cancer; reduced kidney function; liver disease; stroke or dementia; prior organ transplant; rheumatoid arthritis, lupus, or psoriasis; and other immunosuppressed states. Patients with hematologic malignancies, in particular, may have perturbations in myeloid and lymphoid maturation that leave them especially susceptible to the exuberant cytokine storm associated with severe disease. Evidence suggests these patients have very poor outcomes if infected with COVID-19.
THE CLINICAL MANIFESTATIONS OF COVID-19 MAY AFFECT A WIDE RANGE OR ORGAN SYSTEMS.
Although respiratory failure is likely the primary driver of morbidity and mortality in the majority of COVID-19 cases, mounting experience indicates that severe COVID-19 can be a multisystem syndrome capable of involving multiple organ systems. The hematologic complications of COVID-19 are particularly prominent and have drawn significant interest. Early in the pandemic, clinicians reported thromboembolic complications including pulmonary embolism, deep vein thrombosis, thrombosis of intravascular access catheters, and stroke. In addition, laboratory parameters including some coagulation assays (particularly D-dimer), blood counts (including the lymphocyte count among others), and inflammatory markers (such as ferritin) have been noted to be characteristically altered in COVID-19 ( Table 153.1 ). This chapter reviews the hematologic manifestations of COVID-19 and discusses their significance.
Table 153.1
Common Hematologic Manifestations of COVID-19
| Prevalence (%) | Prognostic implications | Suspected Pathophysiology | |
|---|---|---|---|
| Venous thrombosis | 5–30 (in severe disease) | May predict mortality | Heightened inflammation, critical illness, prolonged hospitalization |
| Arterial thrombosis | Likely rare, not well described | May predict mortality | Poorly understood, perhaps vascular inflammation |
| Elevated D-dimer | 50–80 (among hospitalized patients) | May be associated with though not strongly predictive of mortality | Inflammation-driven acute phase reactant Possibly increased fibrinogenesis/fibrinolysis in some instances |
| Hyperferritinemia | 55–80 | May predict severe disease | Inflammation-driven acute phase reactant |
| Lymphopenia | 35–85 | May predict mortality | Cytokine-driven apoptosis, direct infection of lymphocytes, or destruction of lymphatic organs |
| Thrombocytopenia | 30–40 | May predict morality | Infection of megakaryocytes, immune mediate destruction |
| Anemia | 20–35 | May predict severe disease and mortality | Decreased production |
Thrombosis in Covid-19
Evidence for Thromboembolic Disease as a Pathophysiologic Factor in COVID-19
There has been evidence to suggest that, at least among some patients, a pathophysiologic component of severe COVID-19 disease may be related to a provoked thrombophilic state ( Table 153.2 ). Critically ill patients with COVID-19 have demonstrated high rates of overt venous thromboembolism (VTE) in sizable cohorts. In a prospective cohort study of 150 patients with COVID-19 and ARDS, 64 thromboembolic complications were identified, most often pulmonary embolism (PE). Notably, the rate of PE was significantly increased as compared with a propensity-matched non-COVID historical prospective ARDS cohort. A series of 184 consecutive ICU patients with COVID-19 on appropriate thromboprophylaxis yielded a cumulative VTE incidence of 27% (higher than typically seen in comparable non-COVID ICU populations). In a retrospective study of 3334 hospitalized COVID-19 patients, the diagnosis of VTE was associated with an increased risk of mortality (adjusted hazard ratio [HR], 1.37; 95% CI 1.02 to 1.86). Additionally, high rates of central venous catheter clotting have been reported among COVID-19 patients, particularly with regard to hemodialysis access.
Table 153.2
Frequently Cited Evidence Supporting the Central Role of an Acquired Thrombophilic State in the Pathophysiology of COVID-19
| High observed rates of venous thromboembolism (VTE) in many severe coronavirus-disease-2019 (COVID-19) cohorts. |
| Association between VTE incidence and mortality in some cohorts. |
| High observed rates of central venous catheter clotting. |
| Autopsy studies demonstrating evidence of occult pulmonary thrombosis, microthrombosis, and thrombotic angiopathy. |
| Pulmonary physiology reminiscent of pulmonary vascular disease among some mechanically ventilated patients. |
| Frequently elevated D-dimers and their association with outcomes. |
| Reports of otherwise unexplained arterial thrombotic events. |
Beyond overt venous thromboembolic disease, there has been interest in the role of occult VTE, including microthrombosis, contributing to adverse outcomes. Autopsy studies of COVID-19 patients have revealed extensive micro and macro pulmonary emboli that had been undiagnosed prior to death. For instance, a post-mortem examination of 21 COVID-19 patients yielded 4 instances of overt PE, 5 of diffuse alveolar capillary microthrombosis, and 3 cases demonstrating stigmata of thrombotic microangiopathy in glomerular capillaries. Another small autopsy study reported severe endothelial injury, microangiopathy, and microthrombosis in the lungs of 7 patients who died of COVID-19 (findings that were not present in controls who had died from influenza or other non-COVID causes). Some mechanically ventilated COVID-19 patients have manifested pulmonary physiology more consistent with pulmonary vascular disease rather than pure ARDS, suggesting that a diffuse thrombotic process may contribute to respiratory decompensation among a subset of patients. Interest has also arisen regarding D-dimer levels, which are frequently elevated among COVID-19 patients, and has been associated with poor outcomes and been posited as possible laboratory indicators of thrombotic microangiopathy or other forms of microthrombosis. Observational studies have also noted increased levels of factor VIII and von Willebrand factor among patients with severe COVID-19.
In addition to high rates of VTE, high rates of arterial thrombosis have been reported among COVID-19 cohorts. In a highly publicized single-institution series, 5 cases of acute ischemic stroke were identified among COVID-19 patients within a 2-week period (with all patients younger than 50 years of age, and with generally minimal vascular risk factors). Similarly, 20 COVID-19 patients with acute limb ischemia were reported by a single institution over a 3-month period. A large retrospective study of over 3000 hospitalized COVID-19 patients reported myocardial infarction among 8.9%.
Limitations to Current Evidence Regarding Thromboembolic Disease in COVID-19
The perception that acquired hypercoagulability and thromboembolic disease (both micro and macro) may play a role in the pathophysiology of COVID-19 has to date been based largely on anecdotal observations that are hampered by numerous limitations ( Table 153.3 ). It is certainly well established that critical illness and prolonged hospitalization are major risk factors for VTE, and in this sense, the finding that VTE is common among severely ill COVID-19 patients is neither novel nor surprising. Although some of the aforementioned studies report VTE rates among critically ill COVID-19 patients that may be higher than historical non-COVID controls, several other COVID-19 studies report more moderate rates that are more in line with historical standards. The high frequency of VTE encountered in some cohort studies may have been overestimated in the setting of inconsistently reported thromboprophylaxis practices and the extensive and nonsystematic use of diagnostic imaging studies. Systematic comparisons of VTE rates among COVID-19 and non-COVID-19 patients are not yet available, and it is presently difficult to assert that COVID-19 is significantly “more thrombophilic” than other comparatively severe respiratory illnesses.
Table 153.3
Limitations to Available Evidence Supporting the Notion That an Acquired Thrombophilic State May Play a Major Role in the Pathophysiology of COVID-19
| Rates of VTE may be similar to those in comparably severe illnesses of other etiologies. |
| Lack of systematic comparisons of VTE rates among COVID-19 and non-COVID-19 patients. |
| Observations of high rates of central venous catheter clotting remain anecdotal and not yet rigorously studied. |
| Autopsy studies implicating the role of occult thrombotic disease are very few in number and subject to selection bias. |
| Reports of pulmonary physiology similar to that of pulmonary vascular disease remain few, unsystematic, and speculative. |
| Elevated D-dimers, though often present, are non-specific and likely represent acute phase response to heightened inflammation. |
| Arterial thrombotic events have been reported in a small number of series, most ischemic cardiac events represent “demand ischemia.” |
Autopsy studies demonstrating occult pulmonary thromboembolic disease and thrombotic microangiopathy among COVID-19 patients remain few, with the number of confirmed reports paling in comparison to the number of known COVID-19 related fatalities. Further, there may be selection bias in these autopsy reports, with only the most idiosyncratic and otherwise inexplicable deaths preferentially selected for autopsy. Elevated D-dimer, though increasingly interpreted as a measure of occult thrombotic burden in COVID-19 at some centers, is a highly non-specific marker of VTE and may be a manifestation of inflammation rather than thrombosis. In a study of 449 COVID-19 patients, there was no difference in admission D-dimer levels as compared with 104 patients with a non-COVID pneumonia. In a study of 1065 hospitalized COVID-19 patients, although D-dimer levels and trends were associated with poor outcomes, they proved poor predictors both when taken in isolation and when incorporated into multivariable models. Similarly, elevations of factor VIII and von Willebrand factor are likely reflective of the highly proinflammatory nature of COVID-19 and not indicative of any unique prothrombotic process.
Series describing arterial thrombotic complications such as stroke and limb ischemia have been small and few, and it is difficult to form meaningful conclusions from the limited cases available for study. Reported rates of myocardial infarction (MI) have likely included large quantities of cases of type 2 MI (or “demand ischemia”), with cases of true acute thrombotic coronary obstruction likely rare. Like many other purported manifestations of “COVID-19 hypercoagulability,” such demand ischemia is a common feature of critical illness across etiologies. Reports of pulmonary physiology reminiscent of venous thromboembolic disease remain purely anecdotal with limited published data to date.
The Role of Anticoagulation in COVID-19
Some limited data suggest that anticoagulation may improve outcomes in COVID-19. In an often-cited study reported early in the course of the pandemic, the use of prophylactic heparin was associated with improvement in mortality in a very specific subgroup (those with a sepsis-induced coagulopathy score ≥4) of 449 patients with severe COVID-19. However, it was unclear why this specific subgroup was chosen, why the rate of prophylactic anticoagulation was so low (only 99 patients received it), and why prophylactic anticoagulation was offered in some cases and not others. In addition, the baseline characteristics of the two groups were not well described and not compared, and the analysis favoring anticoagulation was univariable. In a large single-hospital system retrospective study, therapeutic dose anticoagulation was associated with improved in-hospital survival among intubated patients; however, some potentially significant clinical factors were not controlled for, and the benefit conferred by anticoagulation was not observed in non-intubated patients. A follow-up study from the same group using a largely overlapping retrospective cohort found that prophylactic dose anticoagulation was associated with lower rates of intubation and in-hospital mortality than the group not receiving anticoagulation. However, given that prophylactic anticoagulation is already the established standard of care for the vast majority of hospitalized patients (unless contraindicated), the clinical utility of such a finding is not readily apparent. It should be observed that in such studies that those patients who do not receive prophylactic anticoagulation likely carry contraindications for prophylaxis (such as active bleeding, coagulopathy, or severe thrombocytopenia) which may themselves be associated with poor outcomes. Such deeply ingrained practices may be difficult to account for. Notably, in this study, therapeutic dose anticoagulation did not yield significantly improved outcomes relative to prophylactic anticoagulation.
There is currently no truly rigorous data that offer convincing evidence that anticoagulation beyond what is typically recommended for generic (non-COVID) hospitalized patients is of benefit in COVID-19. For the time being, it remains unclear whether anticoagulation may truly have a protective effect on COVID-19 infections and if so whether any particular group of COVID-19 patients may benefit most. A propensity-matched analysis of 4343 COVID-19 patients demonstrated no outcome-benefit among those patients who were on anticoagulation for other indications prior to COVID-19 diagnosis. Such finding suggest that if there is benefit to be derived from anticoagulation, it may be more likely later in the disease course and/or among sicker patients (such as those requiring hospitalization). However, some studies investigating intervention with anticoagulation among critically ill COVID-19 patients have demonstrated similarly negative results. For instance, in a multicenter target trial emulation among 2809 critically ill COVID-19 patients, those who received early therapeutic anticoagulation had a similar risk for death as those who did not. A smaller observational study actually demonstrated worse survival outcomes among inpatients empirically treated with therapeutic dose anticoagulation compared to those treated with prophylactic dose anticoagulation. More recently, three large-scale prospective international trials investigating preemptive use of therapeutic heparin among critically ill COVID patients were halted after their data safety monitoring boards determined that such interventions appeared futile and possibly unsafe in interim analyses (although the specific data prompting these decisions are not available at the time of this writing, concerns regarding safety were presumably based on excess bleeding risk detected in the treatment groups).
In spite of the lack of convincing evidence, many clinicians and centers have pursued and advocated for therapeutic (or sometimes intermediate dose) anticoagulation for critically ill patients with COVID-19 in the absence of documented thromboembolism. While it is certainly true that some critically ill patients with high clinical suspicion for VTE may be too unstable or otherwise unable to undergo confirmatory testing, and empiric therapeutic anticoagulation may be reasonable among such patients, routine use of therapeutic anticoagulation among COVID-19 patients with clearly negative VTE testing is not presently evidence based and should be pursued with caution outside the context of a clinical trial. It should also be noted that decision tools employed by some centers to identify those COVID-19 patients who may benefit from therapeutic anticoagulation frequently employ unfounded and seemingly arbitrary criteria such as specific D-dimer cutoffs or thresholds of respiratory support requirement, which have not been validated. Current guidelines for anticoagulation among COVID-19 patients from the International Society of Thrombosis and Hemostasis (ISTH) as well as the American Society of Hematology (ASH) are very similar to the established standards used among all hospitalized patients ( Table 153.4 ). Specifically, they state that hospitalized COVID-19 patients should generally receive prophylactic dose anticoagulation unless contraindicated and that therapeutic dose anticoagulation should be used among those with demonstrated thromboembolism unless contraindicated. Notable differences from standard anticoagulation protocols acknowledged as reasonable in the ISTH guidelines include consideration of intermediate-dose low-molecular-weight (LMW) heparin prophylaxis among some “high-risk” hospitalized patients and consideration of extended VTE prophylaxis following hospital discharge (this likely based on reports of post-discharge VTE among some COVID-19 patients) (see Table 153.4 ). It should be noted however that these specialized prophylaxis considerations are not based on strong evidence and highlight current uncertainty in clinical practice.
Table 153.4
Clinical Guidance on the Diagnosis, Prevention,and Treatment of Venous Thromboembolism in Hospitalized Patients With COVID-19 From the International Society of Thrombosis and Hemostasis
Adapted from Spyropoulos AC, Levy JH, Ageno W, 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(8):1859–1865.
| Diagnosis of VTE in hospitalized COVID-19 patients | Practitioners should use standard-of-care objective testing (i.e., computed tomography pulmonary angiogram [CTPA], ventilation/perfusion [V/Q] scan, magnetic resonance imaging [MRI] venography, Doppler ultrasonography) to diagnose venous thromboembolism (VTE) based on clinical index of suspicion. A pragmatic approach (i.e., point-of-care bedside ultrasonography or echocardiography) can also be combined with standard-of-care objective testing (50% of respondents). |
| Routine screening for VTE using bedside Doppler ultrasonography of the lower extremities or based on elevated D-dimer levels is not recommended. | |
| VTE prophylaxis in non-ICU hospitalized COVID-19 patients | A universal strategy of routine thromboprophylaxis with standard-dose UFH or LMWH should be used after careful assessment of bleed risk, with LMWH as the preferred agent. Intermediate-dose LMWH may also be considered (30% of respondents). |
| VTE prophylaxis recommendations should be modified based on extremes of body weight, severe thrombocytopenia or deteriorating renal function. | |
| VTE prophylaxis in sick ICU hospitalized COVID-19 patients | Routine thromboprophylaxis with prophylactic-dose UFH (unfractionated heparin) or LMWH (low molecular weight heparin) should be used after careful assessment of bleed risk. Intermediate-dose LMWH (50% of respondents) can also be considered in high risk patients. Patients with obesity as defined by actual body weight or BMI should be considered for a 50% increase in the dose of thromboprophylaxis. Treatment-dose heparin should not be considered for primary prevention until the results of randomized controlled trials are available. |
| Multi-modal thromboprophylaxis with mechanical methods (i.e., intermittent pneumonic compression devices) should be considered (60% of respondents). | |
| Duration of VTE prophylaxis for hospitalized COVID-19 patients | Either LMWH (30%) or a DOAC (direct oral anticoagulant) (i.e., rivaroxaban or betrixaban; 30% of respondents) can be used for extended-duration thromboprophylaxis. |
| Extended post-discharge thromboprophylaxis should be considered for all hospitalized patients with COVID-19 that meet high VTE risk criteria. The duration of post-discharge thromboprophylaxis can be approximately 14 days at least (50% of respondents), and up to 30 days (20% of respondents). | |
| VTE treatment in hospitalized COVID-19 patients | Established guidelines should be used to treat patients with confirmed VTE, with advantages of LMWH in the inpatient setting and DOACs in the post-hospital discharge setting. A change from treatment-dose DOAC or vitamin K antagonists (VKA) to in-hospital LMWH should be considered especially for patients in critical care settings or with relevant concomitant medications, and dependent on renal function and platelet counts. Anticoagulant regimens should not change based solely on D-dimer levels. |
| A change of anticoagulant regimen (i.e., from prophylactic or intermediate-dose to treatment-dose regimen) can be considered in patients without established VTE but deteriorating pulmonary status or ARDS (50% of respondents). | |
| The duration of treatment should be at least 3 months (50% of respondents). |
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