CE Article: Spotting the Clotting—Hypercoagulopathy in COVID-19

Objectives

After reading this article, the learner will be able to:

• Delineate that COVID-19 is not just a disease that attacks the lungs, but one that can create widespread inflammation and hypercoagulability that can lead to significant multi-system organ damage;
• Explain why COVID-19 may be more of a disease of blood vessels than the respiratory system and why lungs can still suffer as a result.
• Catalog the various complications of COVID-19 associated with hypercoagulable states, ranging from microinfarctions and blood clots in extremities and vital organs to outright brain injury and stroke;
• Recite why point coagulation profile testing, ranging from D-dimer assays and thromboelastography (TEG) with platelet mapping, may help target the appropriate patients for possible anti-coagulant and/or antiplatelet therapy and also differentiate those who should not;
• Detail “10 Golden Considerations” for out-of-hospital providers with respect to identifying potential excessive clotting complications. 

A few months ago the SARS-CoV-2 virus was a readily dismissed concern in the minds of most Americans and many others worldwide. While the first U.S. case was reported back in January, by March 1 there were still only two reported U.S. deaths and 89 confirmed cases nationwide. 

Insidiously, within another 90 days, 100,000 U.S. citizens succumbed despite ambitious efforts to impose physical distancing and stay-at-home policies across the country and abroad. More concerning, many of those dying were young, previously healthy persons, including frontline first responders, doctors, nurses, and many other healthcare colleagues.

Early on COVID-19 was largely described as a severe respiratory illness characterized by cough, fever, and flulike symptoms. Those seeking hospital care generally were described as having severe dry cough, dyspnea, fever, and pleuritic chest pain or tightness. Many were also found to have arterial oxygen desaturation, even in the absence of dyspnea. Some patients remained minimally symptomatic, but others showed they could rapidly decompensate into a severe respiratory failure requiring ventilator support, with a radiographic picture often resembling adult respiratory distress syndrome (ARDS).

Considering these overt pulmonary disease presentations, a focus on the pulmonary disease process has become central in discussions regarding management of the virus, not only among clinicians and public health officials but also the media and public at large. As often seen in ARDS, the severe lung disease cases are also frequently associated with renal demise, liver enzyme elevations, myocardial dysfunction, and other general signs of so-called “cytokine storm.” Thus this multiorgan failure has been widely accepted as a secondary complication of the more overt pulmonary symptoms and hypoxemia—until recently.

More Than the Lung

Severe COVID-19 illness may not just be primarily a pulmonary problem but rather a broad systemic infection that involves a spectrum of widespread inflammatory processes and highly unusual vascular disorders that not only contribute to respiratory dysfunction but also create many other pathological findings. Specifically, in many affected patients the virus seems to cause widespread clotting of capillaries and smaller blood vessels, accompanied by concomitant inflammatory processes that suffocate previously healthy tissues. In some patients, clotting in larger vessels may result in deep-vein thrombosis, pulmonary embolism, stroke, and even myocardial injury. 

While many hypotheses already exist, a well-accepted consensus on the cause of the clotting disorders remains elusive to date. As has been emphasized more recently with respect to children, a widespread systemic inflammatory response can occur with COVID-19. Typically occurring a little later in the clinical course of symptomatology, this complication is often characterized as a “cytokine storm,” usually marked by high levels of inflammatory proteins in the bloodstream. This pathological development is now well-associated with processes like myocarditis, encephalitis, and diffuse vasculitis. It is speculated, therefore, that the vasculitis could potentially trigger widespread clotting. 

However, for many other reasons, including the observation of clotting problems in the absence of distinct systemic inflammatory complications, the precise cause still remains unclear. In fact, it is also speculated the clotting and associated microinfarcts in various body tissues could be, in turn, a key contributor to the inflammatory processes.

Overall, the current common clinical opinions of frontline practitioners are that the clotting and inflammatory complications are likely intertwined processes but may also be independently acting complications in some cases, and both need to be addressed accordingly. In that respect, the purpose of this discussion is to specifically examine an approach to hypercoagulable states associated with COVID-19.

The consequences of this diffuse clotting disorder can be grave and yet not readily recognized. In turn, this more sublime pathological aspect of COVID-19 has ramifications for providers who may first encounter possible COVID-19 patients in the out-of-hospital setting. Be they first responders, paramedics, medical directors, nursing practitioners, primary care physicians, or public health officials, awareness of this clotting process is essential. Early recognition and appropriately directed treatment are believed to be key to preventing further disease progression. A cognitive appreciation for this more subtle yet quite detrimental complication of COVID-19 may be instrumental in mitigating its more serious sequelae. 

Much of the current knowledge regarding this so-called “vascular plugging” complication of COVID-19 emanates from autopsy reports in which postmortem examinations revealed widespread microthrombi (small blood clots) associated with platelet clumping throughout the body, as well as clots in larger vessels too. With respect to the more overt pulmonary disease processes, microthrombi may create pulmonary microinfarcts (leading to tissue demise and death). Accumulation of dying tissue debris in the lung appears to be further exacerbated by inflammatory white cells infiltrating the lung airspaces (much like pus) along with associated edematous changes further complicating lung function. 

While these pathological processes lead to respiratory compromise, similar processes can also occur in vessels that supply the central nervous system or other key organ systems. The circulatory compromise in neurological tissue is thought to cause a multitude of manifestations ranging from isolated altered smell and taste disturbances to a significant number of brain tissue infarcts (strokes), some minor, some major. These neurological complications can be associated with accompanying inflammatory responses resembling encephalitis in many cases. 

Similar effects of this clotting complication attack the heart, gastrointestinal tract, kidneys, liver, and even skin, particularly in the fingertips and toes. There are also reports of thrombi formation in dialysis circuits and ECMO pumps, which can be life-threatening if not addressed expediently. Recently reports have even shown venous and arterial clotting resulting in limb loss. A major concern is that this clotting disorder may also lead to unanticipated lethal pulmonary embolus or cardiac arrest with no heralding signs or symptoms.

Spotting and Blotting the Clotting

Physical distancing and shelter-at-home strategies have slowed the spread of the infection, but once a person acquires it, is there a way to slow the disease process, its complications, and even associated deaths? If multiorgan damage is primarily due to persistent clotting, then perhaps antiplatelet therapy or anticoagulant interventions may be helpful in slowing or even reversing the process.

In an attempt to begin to understand the pathophysiology, prevalence, and management of COVID-19, a coalition of EMS, emergency medicine (EM), and critical care clinician researchers was formed in early March in South Florida. This de facto collaborative featured representation from a number of EMS agencies, emergency departments, and critical care units across three counties (Broward, Miami-Dade, and Palm Beach). The group adopted the moniker SoFloCo (South Florida Collaborative). Even as the first autopsy data were beginning to appear, many of the SoFloCo team members had already started to evaluate the clotting parameters of patients, including those with and without specific signs or symptoms of a clotting diathesis. 

Communicated through messaging apps and twice-weekly video conferences, the exchange of information and debates across the coalition became a constant cognitive “neighborhood sandbox”—a virtual think-tank initiative that addressed evolving observations regarding COVID-19 and its assessment and management. 

The importance of the clotting disorder, its prevalence, and considerations for empiric treatment became early topics of discussion. At first it was recommended that patients would receive a “clotting workup” after arriving at the hospital. But typical clotting parameters such as D-dimer measurements, prothrombin time, and INRs (international normalized ratios) did not appear to be specific enough and often were simply considered to be compatible with a massive inflammatory response, similar to elevated C-reactive protein (CRP) counts and ferritin levels.

Thanks to recent advances in trauma care, however, the group was able to rapidly consider and turn to the early use of thromboelastography (TEG) as a better test of whole blood clotting in any individual patient. Over the past few months TEG evaluations have shown many COVID-19 patients are indeed hypercoagulable (“hyperclotters”). This finding was therefore consistent with evolving pathological data reporting widespread microthrombi formation. But, at the same time and very notably, TEG has also shown a certain percentage of patients also can be hypocoagulable and thus more prone to bleeding. In other cases, the patients may be hypercoagulable but are also found to have low platelet levels.

Accordingly, empiric anticoagulation or antiplatelet therapies, which are currently performed at many institutions to prevent these clotting complications of COVID-19, could therefore be harmful if a patient is found to be in a hypocoagulable state. Using TEG with platelet mapping, however, frontline clinicians may be able to create a more individualized approach to ascertain the right therapy for the right patient. If indicated, therapies to prevent clotting can be instituted—and if not, avoided.

But TEG with platelet mapping also provided an even better guide to help us achieve best-practice therapies, be it the specific targeted use of antiplatelet interventions (e.g., aspirin) or the use of anticlotting factor medications (e.g., heparins). In that respect TEG may arise as the single most helpful tool in slowing the formation of thrombi while preventing bleeding in this vulnerable population. Unfortunately, to date TEG generally is only available in hospital (and largely trauma center) settings. Nevertheless, with this current experience and evolving trauma care practices, it may become a consideration for future prehospital advances.

The Important Role of EMS 

While TEG with platelet mapping was becoming a breakthrough clinical consideration, our experience with it also demonstrated that many COVID-19 patients with TEG abnormalities, be they hyper- or hypocoagulable, had no signs or symptoms of a clotting or bleeding disorder at the time of evaluation or any profound inflammatory complications. Many patients with milder to moderate symptoms, and those who simply had positive tests for COVID-19, are now routinely being managed outside the hospital based on their pulmonary symptoms and signs. Therefore, the clotting problem may go unrecognized altogether—or perhaps underappreciated.

With those concerns, the goal of this current communication was not only to provide a better awareness of these common and underrecognized complications of COVID-19 but also to convey to out-of-hospital care personnel “10 golden considerations” in their evaluation of patients in this era of COVID-19.

Concluding Thoughts

Evolving experience with TEG, clotting parameters, treatment considerations, and ongoing data gathering will help us better understand if antiplatelet therapy with aspirin or clopidogrel or anticoagulant treatment with traditional or low-molecular-weight heparin can change outcomes positively in cases where hypercoagulable states can be identified. TEG may be a pivotal test in helping us distinguish the need for such interventions, but for now, as TEG remains an in-hospital tool, it will take careful prehospital assessment to help identify those who may need such a targeted evaluation.

Although most people infected with this novel virus will either be asymptomatic or have a less severe clinical course, those who do become ill and hospitalized can experience serious and life-threatening complications. As emphasized by this discussion, many of these complications may be the result of a COVID-driven hypercoagulable state associated with a significant inflammatory response. These complications can have significant consequences. While it is not always clear who has developed or will develop this clotting diathesis, awareness is key.

What does remain clear is that COVID-19 is not simply a flulike illness or a stronger version of the common cold, and serious infection with SARS-CoV-2 is much more than an isolated pulmonary process. 

Also keep in mind that any current understandings regarding the pathophysiology of COVID-19 may change as our experience with the virus expands. In addition, presumptive future mutations of SARS-CoV-2 may also change the perspectives provided in the current discussion. With that understanding, the authors and their team members will do their best to keep frontline heroes informed with the most available and reliable information possible.  

10 Golden Considerations for EMS Regarding COVID-19 Thrombotic Complications

1. Patients with baseline cardiovascular disease, such as hypertension, diabetes, or obesity, appear to be at increased risk for complications from COVID-19.

2, Microthrombi in cardiac or pleural tissue may manifest as chest tightness that may be positional in nature or change with deep respirations even in the face of normal oxygen saturations or unremarkable electrocardiographs.

3. Microthrombi formation may play a role in multiorgan dysfunction that can first present in an isolated manner in one organ system or as multiple symptoms and signs, be they in the lungs, brain, heart, gastrointestinal tract, kidneys, skin, or even as a cardiac arrest.

4. Intuitively, as is the case with pulmonary embolism, leg pain or swelling may be a manifestation of a blood clot within the venous circulation of the leg, but arterial clots may also cause the involved extremity to lose pulses with or without associated pain, discoloration, or loss of motor/sensory function. Such an arterial complication can lead to a potential loss of the extremity if not recognized and treated quickly enough. Asymmetric distal pulses may not be appreciated and are usually a late sign.

5. Signs or symptoms of neurological deficits such as those seen in a stroke could be another manifestation of blood clotting triggered by COVID-19. Young patients can have such deficits, and a presentation of confusion or altered mental status, such as that seen in any encephalopathy, may be another sign of neurologic involvement. Changes in smell or taste, even if isolated symptoms, also should not be ignored.

6. COVID-related blood clotting problems and respiratory distress may contribute to preterm labor in pregnant women.

7. Responders should look for strange rashes, hematomas, petechiae, and purpura (bruiselike findings) they may not see on a regular basis. These findings may be a sign of cutaneous injury due to microthrombi formation, especially at the fingertips and toes. In addition, reddened conjunctiva, erythematous skin blotches, and strawberry-colored tongue appearance may be manifestations of COVID-19 in children, resembling the syndrome of inflamed arteries often seen with Kawasaki disease, including coronary artery involvement.

8. Diarrhea and cramping can be associated with COVID-19 and may not be a benign process. Abdominal pain with a minimally tender abdominal exam, whether in a younger or older person, may actually be due to blood clot formation in the vessels supplying blood to the intestines. This could be catastrophic if not appreciated early, and in the setting of COVID-19, it needs to be considered.

9. Flank pain could be a manifestation of renal microinfarction and swelling from microembolic ischemia in the kidney. At the same time COVID-19 could also be creating microinfarct-induced myonecrosis (muscle cell injury), either in the flank or elsewhere.

10. COVID-19 is a great masquerader, and its clotting complications can lead to pulmonary, cardiac, neurologic, gastrointestinal, cutaneous, genitourinary, renal, musculoskeletal, face, eye, nose, and tongue problems—whether individually or in conjunction with one another. Overall, the most predictable pattern in COVID-19 is that the signs and symptoms of SARS-CoV-2 infection are often not predictable. Awareness needs to remain at a heightened level.

The main contributing members of the South Florida Collaborative (SoFloCo) include: Boaz S. Rosenblat, MD; James P. Roach, DO; Peter M. Antevy, MD; Randy S. Katz, DO; Antonio Gandia, MD; Kenneth A. Scheppke, MD; John P. Cunha, DO; Wayne Lee, MD; David A. Farcy, MD; Armando Clift, MD; and Paul J. Adams, DO.

Acknowledgements: The authors thank Drs. Jonathan Jui and Amal Mattu for their thoughtful reviews of the manuscript and their perennial major contributions to the knowledge of medical professionals.

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Michael Estreicher, MD, is assistant EMS medical director for Hollywood, Fla., and assistant medical director at the Memorial Hospital Pembroke ED in Pembroke Pines, Fla.

Tjasa Hranjec, MD, a board-certified trauma/critical care and transplant surgeon, is the vice chief of surgery at Memorial Regional Hospital in Hollywood, Fla.

Paul E. Pepe, MD, MPH, is the medical director for EMS and public safety for Dallas County, Tex., as well as medical director for EMS research, education, and special operations for nine South and Central Florida counties and municipalities.