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Clinical Update for Physical Therapists: Coagulopathy and COVID-19

Abstract Physical therapists have a unique role in both prevention of VTE through the promotion of early mobility and physical activity and diagnosis through discovery of signs and symptoms of VTE. This Perspective updates clinicians on the latest information regarding pathophysiology of coagulopathy associated with COVID-19 and applies VTE clinical practice guidelines to COVID-19 in order to provide guidance on physical therapist management.

, including patients in the acute phase while hospitalized and during the recovery phase in the inpatient rehabilitation, skilled care, home health, and outpatient settings. 1 The effect of the virus on the respiratory system appears to range from a simple respiratory tract infection to acute respiratory distress syndrome (ARDS) with multiorgan failure. 1 People with COVID-19 may also develop coagulopathy that can lead to venous thromboembolism (VTE) and microvascular thrombosis throughout the body. 1 Physical therapists have a unique role in both prevention of VTE through the promotion of early mobility and physical activity and diagnosis through discovery of signs and symptoms of VTE. Therefore, it is critical physical therapists are aware of the clinical implications of this unique coagulopathy and the prevalence of VTE in patients diagnosed with and recovering from COVID-19.

[H1] Pathophysiology of COVID-19 Coagulopathy
The COVID-19 virus causes an acute inflammatory response throughout the entire body upon entering via the angiotensin-converting enzyme 2 (ACE2) receptors, 1,2 which are expressed in multiple organs and endothelial cells. [1][2][3][4] In fact, some have referred to COVID-19 as COVID endothelialitis due to the effect the virus has on the endothelium of all tissues in the body and especially on the arterial and venous endothelium. 2 The coagulation abnormalities found in COVID-19 appear as a hypercoagulable state, including widespread microvascular thromboses that compromise the blood flow to small blood vessels in multiple organs. 10 Retrospective studies of medical records from hospitalized patients who tested positive for COVID-19 have revealed that COVID-19 coagulopathy presents with profoundly elevated fibrinogen and D-dimer, abnormalities in platelet counts, and (in some cases) mild prolongation in prothrombin time (PT). 11 Elevations in fibrinogen and D-dimer are common with severe inflammatory disease and are associated with significant clotting and even disseminated intravascular coagulopathy (DIC). 3 Tang et al 10  Greatly elevated D-dimer (3.5-fold increase above normal) and elevated fibrinogen (1.9 X normal levels) in patients with COVID-19 were significantly related to an increased risk of mortality. 8,10 Despite the association between elevated D-dimers and poor patient prognosis, 10 elevated D-dimer is so common in hospitalized patients with COVID-19 that elevated D-dimers alone would be insufficient to warrant further testing for VTE, including a duplex ultrasound. In a meta-analysis of 9 studies including 1779 patients with COVID-19, Lippi et al 12 found the platelet count was significantly lower in patients with severe disease (mean = 31,000/L), with an even lower platelet count associated with mortality (mean = 22,000/L). 12 As there are no data on laboratory values from patients who tested positive for COVID-19 but were not hospitalized, identifying less severe patients at increased risk for VTE is more challenging.

[H1] Risk Factors and Prevalence of Coagulopathy
Although available data on COVID-19 are still sparse, the evidence in support of this severe COVID-19 coagulopathy continues to emerge. In the study by Helms et al 13 from France, thrombus was found in dialysis catheters and extracorporeal membrane oxygenation (ECMO) catheters. In one autopsy study, 4 out of 21 individuals demonstrated significant pulmonary embolism, 5 of 21 had microthrombi in alveolar capillaries, and 3 had thrombotic microangiopathy in glomerular capillaries. 13,14 In multiple studies and in spite of anticoagulation, VTE occurred in 27% of the population hospitalized with severe COVID-19. 15 Microvascular thrombosis has also been found in small vessels, including the pulmonary capillaries, distal digits in extremities, and other organs. 14,16 Microvascular thrombosis is a potential cause of elevations in cardiac enzymes (troponin and proBNP), need for dialysis due to renal dysfunction or failure, and other organ dysfunctions. 14,16 The risk of VTE is increased in all individuals who are critically ill but appears to be even higher in those with COVID-19. 14,15 In addition to the systemic inflammation already mentioned, patients with COVID-19 may have additional risk factors for VTE if certain medical interventions were required, such as mechanical ventilation and central venous catheters. There are reports of nutritional deficiencies and liver dysfunction that can interfere with the production of coagulation factors. [17][18][19][20] Furthermore, patients who are older with multiple comorbidities are more likely to experience more severe clinical symptoms of COVID-19, adding additional risk factors for VTE to the clinical picture. 6 Finally, the limited supply of personal protective equipment (PPE) has forced facilities to limit health care workers' interactions with patients who have COVID-19, including those of physical therapists. Concerns regarding emergent needs to access patients who pull out lines and tubes have led the medical team to favor sedation for protection of both patient and worker, leading to increased amount and length of sedation. 21 The culmination of these decisions has ultimately reduced the total mobility of these patients, therefore increasing the risk of VTE.

[H1]Prevention of Venous Thromboembolism (VTE)
Clinical practice guidelines currently exist, notably the guideline from the American College of Chest Physicians, to provide direction on the management and prevention of VTE; however, these guidelines do not specifically address the unique concerns of COVID-19 given its novel status. 22 When the disease first emerged in other countries (China, South Korea), routine chemical prophylaxis was not provided. 8,9 However, since learning about the risk of thrombosis and coagulopathy, prophylactic doses of anticoagulation are now a standard part of the protocol on admission for individuals diagnosed with COVID-19, unless there is an absolute contraindication to anticoagulation. If contraindication to anticoagulation is present, then mechanical prophylaxis (intermittent pneumatic compression) is strongly recommended. 4 This practice was instituted based upon clinical evidence of the risk of thrombotic events described above, as there have not been any randomized clinical trials to substantiate this practice to date.
In addition, assessment of VTE risk of all patients with COVID-19 on admission is the current recommendation, as elevated risk may require a therapeutic dose of anticoagulation rather than a prophylactic dose. 3,4 Current studies are reporting the use of the IMPROVE and Padua risk assessment models (RAMs) for patients with COVID-19, and the Caprini Risk Assessment for all patients who have surgery or trauma. 4 These RAMs include additional risk information-such as history of active cancer or heart failure and severe loss of mobility-that contribute to the clinical picture of the patient with COVID-19.
As mentioned above, all patients with COVID-19 admitted to the hospital should be receiving prophylactic anticoagulation; 6 however, there are cases of increased risk or medical team preference where patients are receiving therapeutic doses prophylactically. 6 Unfractionated heparin (UFH) is a common treatment option because of its short half-life and reduced drug-drug interactions with investigational COVID-19 therapies and is the primary drug to be used when the patient has decreased creatinine clearance (renal dysfunction). 3,23,24 The need to reduce exposure to health care providers and use of PPE equipment, however, may present challenges given the frequent blood draws required with UFH. For this reason, if it is deemed unlikely a patient will be requiring a procedure, low molecular weight heparin (LMWH) may be preferable. Although it is outside the scope of this article, it is important to note that the coagulation abnormalities may also be affecting the arterial side of the vascular system, causing stroke, myocardial injury, and peripheral arterial embolisms. 15,26,27 At this time, the prevalence of arterial thrombosis does not appear to be as high as VTE, but there have been some alarming reports of stroke as the presenting sign of COVID-19 in a small group of young patients. 26,27 For these reasons, health care practitioners should consider COVID-19 a risk factor for thrombotic complications and be vigilant in their assessment of patients presenting with risk of or signs/symptoms of cerebral vascular injury or myocardial injury.

[H1]Indicators of Coagulopathy and Likelihood Assessment
For physical therapists treating this patient population who encounter physical signs suggestive of lower extremity (LE) DVT (ie, pain, unilateral swelling, warmth, tenderness below knee), the clinical practice guidelines (CPG) on VTE should be following, and the Wells criteria should be 10 used to determine the likelihood of LE DVT. 23 If an upper extremity DVT is suspected (Tab. 1), the Constans criteria should be utilized. 28 Although all providers should remain vigilant in looking for these common DVT signs, the increased risk of VTE in patients with COVID-19 most often presents as pulmonary embolism rather than DVT. 29 At the earliest possible stage, it is critical to identify patients that may be presenting with massive pulmonary embolism. Any patient that has hemodynamic instability should be immediately considered to have a high-risk pulmonary embolism and referred to emergency care. 30 Patients that present with right ventricular dysfunction on transthoracic echocardiogram or computed tomographic pulmonary angiography, elevated cardiac biomarkers, and/or PESI > III (sPESI ≥ 1) should be considered low intermediate risk for early death (in-hospital or 30day). 31 If patients present with the aforementioned findings and elevated cardiac troponin levels, this would increase the patient's risk of early death to high intermediate risk. 31 If the patient is hemodynamically stable, lacks evidence of right ventricular dysfunction, has normal cardiac troponins, and has PESI I or II (sPESI = 0), the patient is at a low risk of early death. 31  Table 2 lists current anticoagulation doses regularly reported in the treatment of COVID-19 patients. Dosages may be adjusted posthospitalization based upon presence of VTE during hospitalization, but direct oral anticoagulants (DOACs) often have been prescribed posthospitalization due to lack of need to be followed for blood therapeutic levels and due to inability of patients to have caregivers to administer shots. 22

[H1]Long-Term Management
For mild-to-moderate COVID-19, patients should be instructed on the importance of hydration and mobility for prevention of VTE and to watch for new signs of VTE. Therapists can use the Physical Activity Guidelines for Americans as a reference for activity guidelines. 31 In individuals who were considered to be at increased risk for VTE with mild-to-moderate COVID-19, continuation of some dosage of anticoagulation is recommended, as well as instruction in how to avoid sedentary behavior and appropriate exercise prescription to keep these individuals active. 6 Anticoagulation may be necessary for up to 3 months post-COVID-19; 6 Once the patient's VTE has been medically managed and the individual is medically stable, the patient can return to physical activity. As addressed by Hillegass et al, 23 once therapeutic dosages of medications have been reached, mobility should be encouraged. Physical therapists should advocate for these individuals to begin an exercise program or adjust their previous program given their current medical state. 23 In those individuals who are currently being treated for VTE, the current medical management should be identified on the initial visit, including anticoagulation, length of treatment, or the need for mechanical intervention. 22 Practitioners need to remember that even with prophylaxis medications, the risk of VTE is still present. 15 Patients need to be educated on the risk for bleeding with anticoagulants and how to take precautions, especially when they cut themselves or fall.
Knowing the risks for VTE and the appropriate treatment are essential parts of physical therapist assessment and intervention because this knowledge could save lives. As movement specialists, physical therapists need to encourage mobilization to help prevent the initial VTE and to help decrease the risk of a recurrent VTE. The unique nature of COVID-19 may force us to deliver physical therapy services within a confined space due to isolation protocols, or we may have to provide education instead of hands-on treatment to keep ourselves safe. However, it is the role of physical therapists to promote a culture of mobility to help patients with COVID-19 maintain function and possibly decrease their risk of VTE. 23 We are learning more information on this critical illness daily that may provide better information on the mechanisms involved and possible markers for screening those patients more likely to present with coagulopathies. Until more is known, our best course of action is to use previously published clinical practice guidelines on the prevention, screening, and management of those with VTE combined with our clinical expertise. 22,23,31 Physical therapists need to stay current with the literature as more is published and information is shared about COVID-19 and coagulopathy.