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COVID-19: Hypercoagulability

COVID-19: Hypercoagulability
Authors:
Adam Cuker, MD, MS
Flora Peyvandi, MD, PhD
Section Editor:
Lawrence LK Leung, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Aug 2022. | This topic last updated: May 24, 2022.

INTRODUCTION — Individuals with coronavirus disease 2019 (COVID-19) may have a number of complex and varied coagulation abnormalities that create a hypercoagulable state, raising questions about appropriate evaluations and interventions to prevent or treat thrombosis.

This topic reviews evaluation and management of coagulation abnormalities in individuals with COVID-19. (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

Separate topics discuss management in different populations and the rare syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT):

Outpatients – (See "COVID-19: Evaluation of adults with acute illness in the outpatient setting".)

Inpatients – (See "COVID-19: Management in hospitalized adults".)

Intensive care unit (ICU) – (See "COVID-19: Management of the intubated adult".)

Children – (See "COVID-19: Management in children".)

Pregnancy – (See "COVID-19: Overview of pregnancy issues".)

Long COVID syndrome – (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

VITT – (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

PATHOGENESIS — The pathogenesis of hypercoagulability in COVID-19 is incompletely understood.

Virchow's triad — Hypercoagulability can be thought of in terms of Virchow's triad (see "Overview of the causes of venous thrombosis", section on 'Virchow triad'). All three of the major contributions to clot formation apply to severe COVID-19 infection:

Endothelial injury – There is evidence of direct invasion of endothelial cells by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, potentially leading to cell injury. Some experts have postulated that endothelial injury, microvascular inflammation, endothelial exocytosis, and/or endotheliitis play a central role in the pathogenesis of acute respiratory distress syndrome and organ failure in patients with severe COVID-19 [1-3]. (See 'VTE' below and 'Microvascular thrombosis' below and "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Clinical features in critically ill patients'.)

The contribution of complement-mediated endothelial injury has been suggested, and an in vitro study found that SARS-CoV-2 spike protein could activate the alternative complement pathway [4,5]. Studies have shown increased markers of complement activation such as C5b-9 in the circulation of individuals hospitalized with COVID-19 compared with controls (healthy people, people in the intensive care unit with non-COVID-19 respiratory failure, or people with influenza) [6-8]. Complement levels were higher in people with severe compared with moderate disease and in individuals who required mechanical ventilation compared with those who did not. Signs of complement activation in tissue biopsies have also been reported [9,10]. The role of anti-complement therapy remains investigational. (See "The endothelium: A primer", section on 'Covid-19 and endothelial injury' and "Overview and clinical assessment of the complement system", section on 'Other complement tests' and "COVID-19: Management in hospitalized adults", section on 'Others'.)

Other sources of endothelial injury include intravascular catheters and mediators of the acute systemic inflammatory response, including cytokines such interleukin (IL)-6 and other acute phase reactants [11]. (See "Overview of complications of central venous catheters and their prevention in adults" and "Acute phase reactants".)

Stasis – Immobilization can cause stasis of blood flow in all hospitalized and critically ill patients, regardless of whether they have COVID-19.

Hypercoagulable state – A number of changes in circulating prothrombotic factors have been reported or proposed in patients with severe COVID-19 [12-14]:

Elevated factor VIII

Elevated fibrinogen

Circulating prothrombotic microparticles

Neutrophil extracellular traps (NETs)

Hyperviscosity

NETs are a form of decondensed chromatin extruded by dead or dying neutrophils that may have a role in the hypercoagulable state in COVID-19 [15,16]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Extracellular DNA and NETs'.)

Hyperviscosity was demonstrated in a series of 15 critically ill patients in the intensive care unit (ICU) [17]. All 15 had elevated plasma viscosity as assessed by capillary viscometry (range, 1.9 to 4.2 centipoise [cP]; normal range, 1.4 to 1.8 cP). Hyperviscosity is thought to promote a hypercoagulable state. It is often associated with monoclonal gammopathies, especially Waldenström macroglobulinemia, but it can also be caused by polyclonal increases in gamma globulins and/or large increases in other proteins such as fibrinogen. (See "Laboratory test reference ranges in adults", section on 'Viscosity, serum'.)

Very elevated levels of D-dimer have been observed that correlate with illness severity; D-dimer is a degradation product of cross-linked fibrin indicating augmented thrombin generation and fibrin dissolution by plasmin [18]. However, high D-dimer levels are common in acutely ill individuals with a number of infectious and inflammatory diseases. Likewise, antiphospholipid antibodies, which can prolong the activated partial thromboplastin time (aPTT), are common in viral infections, but they are often transient and do not always imply an increased risk of thrombosis. (See 'Coagulation abnormalities' below and 'Clinical features' below.)

These abnormalities may differ according to the state of inflammation and how promptly treatment was initiated, especially with antiinflammatory drugs such as glucocorticoids, monoclonal antibodies, and antiviral therapies. These changes may account for differences in clinical severity and mortality between the first wave of cases and subsequent waves. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult".)

A potential role for platelet activation in promoting thrombosis has also been discussed, although data are limited [19,20].

Coagulation abnormalities — The predominant coagulation abnormalities in patients with COVID-19 suggest a hypercoagulable state and are consistent with clinical observations of an increased risk of venous thromboembolism. (See 'VTE' below.)

These are likely to vary depending on the severity of infection, which in turn depends on vaccine status and the specific variant causing the infection, as well as use of antiinflammatory therapies and other COVID-19 treatments.

Thromboinflammation — This state has been termed thromboinflammation or COVID-19-associated coagulopathy (CAC) by some experts [21,22]. It appears to be distinct from disseminated intravascular coagulation (DIC), though DIC has been reported in severely affected patients.

Abnormal laboratory markers and insights into pathophysiology of thromboinflammation were summarized in a 2022 review [23].

Laboratory findings were characterized in a series of 24 selected patients with severe COVID-19 pneumonia (intubated) who were evaluated along with standard coagulation testing and other assays including von Willebrand factor (VWF) and thromboelastography (TEG) [12]:

Coagulation testing

Prothrombin time (PT) and aPTT normal or slightly prolonged

Platelet counts normal or increased (mean, 348,000/microL)

Fibrinogen increased (mean, 680 mg/dL; range 234 to 1344)

D-dimer increased (mean, 4877 ng/mL; range, 1197 to 16,954)

Other assays

Factor VIII activity increased (mean, 297 units/dL)

VWF antigen greatly increased (mean, 529; range 210 to 863), consistent with endothelial injury or perturbation

Minor changes in natural anticoagulants

-Small decreases in antithrombin and free protein S

-Small increase in protein C

TEG findings

Reaction time (R) shortened, consistent with increased early thrombin burst, in 50 percent of patients

Clot formation time (K) shortened, consistent with increased fibrin generation, in 83 percent

Maximum amplitude (MA) increased, consistent with greater clot strength, in 83 percent

Clot lysis at 30 minutes (LY30) reduced, consistent with reduced fibrinolysis, in 100 percent

Testing in this study was performed on arterial blood because the patients had arterial catheters in place, but venous blood can be used. Heparinase was included since most patients were receiving low molecular weight (LMW) heparin.

Principles of TEG and interpretation of TEG tracings are illustrated in the figure (figure 1) and discussed in more detail separately. (See "Coagulopathy in trauma patients", section on 'Thromboelastography' and "Platelet function testing", section on 'Viscoelastic testing (TEG and ROTEM)'.)

Other studies have reported similar findings consistent with a hypercoagulable state, including very high D-dimer, VWF antigen and activity, and factor VIII activity [13,24]. One study that performed TEG on 44 ICU patients found a complete lack of clot lysis (LY30 of 0 percent) in 57 percent, referred to as "fibrinolysis shutdown" and associated with a high rate of kidney failure and thromboembolic events [25]. Another study suggested that patients with COVID-19 have higher platelet counts than patients with other coronavirus infections [26]. A series from Ireland that included 50 patients on the regular medical ward reported similar findings to those in ICU patients, including high D-dimer and fibrinogen and normal platelet counts and clotting times [27]. Another study demonstrated changes in the ratio of VWF to ADAMTS13 depending on disease severity [28].

Some of the markers of deranged coagulation appear to correlate with illness severity. D-dimer is often increased, sometimes markedly, in individuals with overt DIC and those in the ICU.

Prolonged aPTT — Early case series, including a series of 183 consecutive patients from Wuhan, China, suggested that thrombocytopenia and prolongation of the PT and aPTT were more marked [29-32]. It is not clear why these results differed somewhat from later findings of less severe PT and aPTT prolongation. One possible explanation is that these patients were sicker, perhaps because earlier in the pandemic the disease was not recognized as quickly, resulting in delays in patient presentation and/or treatment.

Another explanation for an isolated prolonged aPTT is the presence of a lupus anticoagulant (LA) (see "Clinical use of coagulation tests", section on 'Causes of prolonged aPTT'). Two studies have found a high rate of LA in patients with prolonged aPTT (50 of 57 tested individuals [88 percent] and 31 of 34 tested individuals [91 percent]) [24,33]. Another study that retested 10 LA-positive individuals with COVID-19 after one month found that 9 of the 10 had subsequently become negative [34]. The phenomenon of transient antiphospholipid antibody (aPL)-positivity is common in individuals with acute viral infections and does not constitute antiphospholipid syndrome (see "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'). However, LA-positivity may correlate with thrombosis in individuals with COVID-19 [35]. The presence of an LA may lead to an artifactual prolongation of the aPTT but does not reflect an increased bleeding risk; patients with an LA should receive anticoagulation if indicated. (See 'Management' below.)

ITP — Cases of immune thrombocytopenia (ITP) associated with COVID-19 have been reported [36-39]. In a large series of critically ill individuals, approximately 7 percent had a platelet count <50,000/microL [40]. The causes of thrombocytopenia were not described in this study.

Distinction from DIC — The hypercoagulable state associated with COVID-19 has been referred to by some as a disseminated intravascular coagulation (DIC)-like state, especially because many affected individuals are acutely ill and meet criteria for probable DIC in a scoring system published by the International Society on Thrombosis and Haemostasis (ISTH) in 2009 [41].

However, the major clinical finding in COVID-19 is thrombosis, whereas the major finding in acute decompensated DIC is bleeding. (See 'Clinical features' below.)

Likewise, COVID-19 has some similar laboratory findings to DIC, including a marked increase in D-dimer and in some cases, mild thrombocytopenia. However, other coagulation parameters in COVID-19 are distinct from DIC. In COVID-19, the typical findings include high fibrinogen and high factor VIII activity, suggesting that major consumption of coagulation factors is not occurring [12]. (See 'Coagulation abnormalities' above.)

In contrast, acute decompensated DIC is associated with low fibrinogen due to consumption of clotting factors. In one of the largest series that reported on thromboembolic events, none of the patients developed overt DIC [42].

Typically, bleeding predominates in acute decompensated DIC and thrombosis predominates in chronic compensated DIC, although there is significant overlap. Thus, the hypercoagulable state in patients with COVID-19 is more similar to compensated DIC than to acute DIC, consistent with the finding that the platelet count and aPTT are typically normal. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Pathogenesis'.)

The ISTH scoring system is based on laboratory findings and is only intended for use in patients with an underlying condition known to be associated with DIC [41]. COVID-19 would qualify based on being a severe infection. Points are given for thrombocytopenia (1 point for platelet count 50,000 to 100,000/microL; 2 points for <50,000/microL), prolonged PT (1 point for 3 to 6 seconds of prolongation; 2 points for more than 6 seconds), low fibrinogen (1 point for <100 mg/dL), and increased D-dimer (2 points for moderate increase; 3 points for "strong" increase). A score of 5 or more points suggests DIC is probable. Despite this, the diagnosis of DIC is made clinically; there is no gold standard and no single test or combination of tests that is pathognomonic. Compared with expert opinion, the ISTH scoring system is reported to have a sensitivity of 91 percent and a specificity of 97 percent [41]. (See 'Coagulation abnormalities' above.)

Regardless of whether the differences or the similarities to DIC are emphasized, many of the basic principles of DIC management apply, including the importance of treating the underlying condition, basing interventions on the clinical picture rather than on laboratory testing alone, and providing anticoagulation for thrombosis and appropriate hemostatic therapies for bleeding. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment'.)

CLINICAL FEATURES — One of the most striking features of COVID-19 is the wide spectrum of clinical manifestations and outcomes, from asymptomatic to various degrees of organ dysfunction to death. (See "COVID-19: Clinical features".)

Likewise, the spectrum of thromboembolic manifestations is broad and appears to vary widely among different individuals and different clinical studies.

VTE — Venous thromboembolism (VTE), including extensive deep vein thrombosis (DVT) and pulmonary embolism (PE), was very common in acutely ill patients with COVID-19 early in the pandemic, seen in up to one-third of patients in the intensive care unit (ICU), even when prophylactic anticoagulation was used [43-45].

However, there has been a general trend over time from a higher VTE risk in hospitalized patients earlier in the pandemic towards a lower risk later in the pandemic, although VTE risk in hospitalized patients remains a serious concern [46]. The reasons for the decrease in risk remain unclear; earlier diagnosis, improved treatment, and changes in circulating viral variants may have played a role.

The risk of VTE following discharge appears to be similar to or only mildly increased over that of acutely ill hospitalized patients without COVID-19 following discharge.

Several autopsy studies have emphasized the contributions of hypercoagulability and associated inflammation in patients who die from COVID-19:

Post-mortem examination of 21 individuals with COVID-19 found prominent PE in four, with microthrombi in alveolar capillaries in 5 of 11 (45 percent) who had available histology [47]. Three had evidence of thrombotic microangiopathy with fibrin thrombi in glomerular capillaries. The average age was 76 years, and most had a high body mass index (BMI; mean, 31 kg/m2; normal 18.5 to <25). Information on use of anticoagulation prior to death was available for 11, and all 11 were receiving some form of anticoagulation. Underlying cardiovascular disease, hypertension, and diabetes mellitus were common.

Post-mortem examination of 12 consecutive individuals with COVID-19 (8 male; 10 hospitalized) revealed DVT in 7 of 12 (58 percent) [48]. All cases of DVT had bilateral leg involvement, and none were suspected before death. Of the 12 for whom lung histology was available, 5 (42 percent) had evidence of thrombosis. PE was the cause of death in four. In those who had D-dimer testing, some had extremely high values (two >20,000 ng/mL and one >100,000 ng/mL; normal value <500 ng/mL [<500 mcg/L]). Use of anticoagulation prior to death was only reported in 4 of the 12. The mean BMI was 28.7 kg/m2; only three patients had a normal BMI, and they had cancer, ulcerative colitis, and/or chronic kidney disease.

An autopsy study that compared pulmonary pathology from seven individuals who died of COVID-19 found a severe endothelial injury (endotheliitis), widespread thrombosis with microangiopathy and alveolar capillary microthrombi, and increased angiogenesis, all of which were significantly more prominent in the lungs of the patients who died of COVID-19 compared with the lungs of controls who died of influenza or other causes [49]. Endothelial injury is a well-established component of hypercoagulability. (See 'Virchow's triad' above.)

These studies have noted the preponderance of males with a high prevalence of obesity and other chronic medical comorbidities, especially cardiovascular disease, hypertension, and diabetes mellitus. Subsequent studies have demonstrated similar findings [50].

In a large study that involved over 3000 individuals admitted to the hospital, most of whom received prophylactic-dose anticoagulation, risk factors for VTE on multivariate analysis were older age, male sex, Hispanic ethnicity, coronary artery disease, prior myocardial infarction, and higher D-dimer (>500 ng/mL) at hospital presentation [51]. VTE was associated with an increased mortality rate (adjusted hazard ratio [HR], 1.37; 95% CI 1.02-1.86).

Thrombosis as a very rare complication of certain vaccines for COVID-19 is discussed separately. (See "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia'.)

ICU — Case series of intensive care unit (ICU) patients have reported high rates of VTE during the early stages of the pandemic (range, 20 to 43 percent), mostly pulmonary embolism (PE), and often despite prophylactic-dose anticoagulation, with a decline in rates of VTE over time:

A large database review involving 637 patients who required mechanical ventilation documented VTE in 45 (7.2 percent) [52]. A series that included 829 ICU patients with severe COVID-19 reported VTE in 13.6 percent (PE in 6.2 percent and DVT in 9.4 percent) [51]. A series of 102 ICU patients reported a 14-day cumulative incidence of VTE of 9.3 percent, versus no VTE in 108 concurrent ward patients [53]. These rates of VTE are lower than reported in studies from earlier in the pandemic. The reason for lower incidence of VTE during later stages of the pandemic is not known; it might include improved medical care based on incorporation of new evidence, incorporation of new therapies directed at the virus or the resulting inflammation, increased use of anticoagulation, or reduced testing for VTE due to a high patient volume.

A series of 184 sequential patients with severe COVID-19 in the ICU reported PE in 25 (14 percent), DVT in 1, and catheter-associated thrombosis in 2 [42]. The cumulative incidence of VTE (based on different durations of follow-up) was calculated at 27 percent. All were receiving at least standard dose thromboprophylaxis.

Earlier series of ICU patients reported VTE in 22 to 39 percent of individuals, often despite prophylactic anticoagulation [54-56]. A series of 150 ICU patients published in the spring of 2020 reported VTE in 64 (43 percent, mostly PE) and clotting of the extracorporeal circuit in 28 of 29 receiving continuous renal replacement therapy and 2 of 12 undergoing extracorporeal membrane oxygenation (ECMO) [24]. All patients were receiving thromboprophylaxis (mostly low molecular weight [LMW] heparin), 70 percent with prophylactic dose and 30 percent with therapeutic dose. These rates are higher than seen in matched cohorts from comparable populations (individuals in the ICU during the same time interval in the previous year, concurrent patients with influenza rather than COVID-19, and concurrent patients with non-COVID-19 acute respiratory distress syndrome [ARDS]), all of which were below 8 percent [24,54]. Some of the ICU patients have had additional comorbidities including cancer and kidney failure [42].

Rates of DVT are higher in studies that perform routine surveillance with bilateral leg ultrasounds. Two small studies that screened all patients with bilateral leg ultrasounds (34 and 26 patients) observed DVT in 65 to 69 percent, with one showing bilateral clots in 38 percent [57,58]. Some of the DVTs occurred despite the use of anticoagulation prior to admission or institution of prophylactic anticoagulation on admission to the ICU.

Inpatients (non-ICU) — The rate of VTE in non-ICU inpatients is increased, but to a lesser extent than ICU patients.

A database study involving >6500 patients with COVID-19 found a VTE rate of approximately 3 percent in those who were hospitalized (most on general medical wards) [52].

A retrospective study that included 1240 hospitalized, non-ICU patients documented PE using computed tomography with pulmonary angiography (CTPA) in 103 (8.3 percent) [59]. On multivariable analysis, the risk factors for PE included male sex, high C-reactive protein, and longer delays between symptom onset and hospitalization; however, the magnitude of increased risk was relatively small (odds ratios, approximately 1.03). Anticoagulation was associated with a lower risk of PE.

A study that included 2505 hospitalized, non-ICU patients reported VTE in 3.6 percent (PE in 2.2 percent and DVT in 2.0 percent) [51]. Patients were only evaluated if symptomatic.

Earlier studies evaluating symptomatic patients reported slightly higher rates of VTE (approximately 3 to 6 percent) [55,60]. Some developed clots while receiving prophylactic anticoagulation. In one of the studies, half of the VTE events were documented within the first 24 hours after admission, suggesting that thromboprophylaxis might be ineffective because the VTE had already occurred.

Higher rates of VTE are seen in studies that screen all patients for VTE regardless of symptoms. A study that systematically evaluated 71 non-ICU patients who were hospitalized with COVID-19 for more than 48 hours by performing bilateral lower extremity duplex ultrasounds at the time of discharge found a higher rate of DVT (21 percent) [61]. Only 2 of 15 patients with DVT were symptomatic; five had bilateral involvement. PE occurred in 10 percent, one of which was fatal. Another study involving 84 non-ICU inpatients who were receiving prophylactic-dose anticoagulation used compression ultrasonography of the leg veins to screen, and it documented DVT in 12 percent [62].

Outpatients — Thrombotic events have been observed in COVID-19 patients who were not admitted to the hospital but appear to be rare. In the ACTIV-4B trial, a randomized trial of outpatient thromboprophylaxis, there was only a single VTE among 558 participants (0.2 percent), and there were no arterial thromboembolic events [63].

An earlier observational study of 72 outpatients with COVID-19 pneumonia who presented to the emergency department and were referred for CTPA identified pulmonary embolism (PE) in 13 (18 percent) [63,64].

Arterial events — There are also reports of arterial thrombosis, including in the central nervous system (CNS). The largest study, which included 3334 individuals (829 ICU and 2505 non-ICU) reported stroke in 1.6 percent and myocardial infarction in 8.9 percent [51]. Risk factors for arterial thrombosis included older age, male sex, Hispanic ethnicity, history of coronary artery disease, and D-dimer >230 ng/mL on presentation. Arterial thrombotic events were associated with increased mortality (adjusted HR 1.99; 95% CI 1.65-2.40).

Other studies have provided additional information on selected types of arterial thrombosis; our approach to evaluation and management of these events is discussed in the linked topic reviews:

Stroke – In one of the series of ICU patients discussed above, ischemic stroke was observed in 3 of 184 (cumulative incidence, 3.7 percent) [42]. In another one of the series discussed above, cerebral ischemia was seen in 3 of 150 [24]. In the series that included 314 non-ICU inpatients, six (2 percent) had ischemic strokes; an additional three in the ICU had an ischemic stroke [60].(See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.)

Limb ischemia – (See "COVID-19: Acute limb ischemia".)

Myocardial infarction – (See "COVID-19: Myocardial infarction and other coronary artery disease issues", section on 'Impact on the cardiovascular system'.)

Microvascular thrombosis — Autopsy studies in some individuals who have died from COVID-19 have demonstrated microvascular thrombosis in the lungs [4,22,47,49]. (See 'VTE' above.)

Other reports have described perfusion abnormalities in the lung that were explained by thromboembolic disease [65].

The mechanism is unclear and may involve hypercoagulability, direct endothelial injury, complement activation, or other processes.

In the absence of more definitive data regarding mechanisms or therapy, we would not pursue specialized testing for thrombotic microangiopathies (eg, ADAMTS13 activity, complement studies) or specialized therapies (eg, plasma exchange, anti-complement therapy) outside of a research study.

Bleeding — Bleeding is less common than clotting in patients with COVID-19, but it may occur, especially in individuals receiving anticoagulation or those with thrombocytopenia.

Anticoagulation

In a subset of 25 ICU patients who were evaluated for abnormal neurologic findings, one had evidence of intracranial hemorrhage as well as ischemic lesions [24]. Three other patients in this series also had hemorrhagic complications, including two intracerebral bleeds associated with head trauma and one with hemorrhagic complications of extracorporeal membrane oxygenation (ECMO). Three others in this series had evidence of intracerebral ischemia. (See 'Arterial events' above.)

In a series of individuals with suspicion for heparin-induced thrombocytopenia (HIT), three of five who were treated with a parenteral direct thrombin inhibitor had a major bleeding event [66].

These observations emphasize the importance of limiting anticoagulation to appropriate indications and, in individuals with suspected stroke, documentation of whether it is ischemic versus hemorrhagic.

Thrombocytopenia − Case series have summarized findings in small numbers of individuals with COVID-19 who developed immune thrombocytopenia (ITP) with bleeding complications [67,68]. Minor bleeding was common; major bleeding, including critical and fatal bleeding, occurred rarely. Management is similar to individuals without COVID-19. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Initial treatment of immune thrombocytopenia (ITP) in adults".)

EVALUATION — The evaluation of patients with COVID-19 and coagulation abnormalities (suspected or documented) can be challenging due to the limited data on which clinical parameters or coagulation abnormalities should be acted upon.

A general approach is as follows, although other decisions may be made by the treating clinicians based on their evaluation of the patient. This approach is consistent with guidance from the International Society on Thrombosis and Haemostasis (ISTH), the American Society of Hematology (ASH), and the American College of Cardiology (ACC) [21,69,70].

Routine testing

Inpatients (routine laboratory testing) — We assess the following in inpatients with COVID-19:

Complete blood count (CBC) including platelet count

Coagulation studies (prothrombin time [PT] and activated partial thromboplastin time [aPTT])

Fibrinogen

D-dimer

C-reactive protein (CRP), as a marker of inflammation

Repeat testing is reasonable on a daily basis or less frequently, depending on the acuity of the patient's illness, the initial result, and the trend in values. The aPTT or anti-factor Xa activity can be used to monitor therapeutic dosing of unfractionated heparin [23]. The purpose of the D-dimer is to assist in assessing disease severity; changes in management are based on clinical features rather than on D-dimer measurements. As such, frequent (daily) measurements of D-dimer are generally not indicated to guide decision-making related to hypercoagulability. Viscoelastic testing (thromboelastography [TEG]) may be useful in some cases but has not been validated in prospective trials [23].

Other routine testing (not specifically related to hypercoagulability) is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Evaluation'.)

As noted above, common laboratory findings include (see 'Coagulation abnormalities' above):

High D-dimer

High fibrinogen

Normal or mildly prolonged PT and aPTT

Mild thrombocytopenia or thrombocytosis, or normal platelet count

We do not intervene for these abnormal coagulation studies in the absence of clinical indications. However, these findings may have prognostic value and may impact decision-making about the level of care and/or investigational therapies directed at treating the infection. As an example, increasing D-dimer is associated with poor prognosis, especially if levels are increased several-fold [71].

Atypical findings such as a markedly prolonged aPTT (out of proportion to the PT), low fibrinogen, or severe thrombocytopenia suggest that another condition may be present and additional evaluation may be indicated. (See 'Role of additional testing' below.)

We do not routinely test for thrombotic thrombocytopenic purpura (TTP), other thrombotic microangiopathies, or antiphospholipid antibodies (aPL). There are no therapeutic implications of transiently positive aPL in the absence of clinical findings. Transient aPL positivity is often seen in acute infections. (See "Diagnosis of antiphospholipid syndrome", section on 'Other conditions associated with aPL'.)

We do not routinely perform imaging for screening purposes, as there is no evidence that indicates this practice improves outcomes. However, imaging is appropriate in individuals with symptoms, as discussed below. (See 'Role of additional testing' below.)

Outpatients (routine coagulation testing not required) — For outpatients, routine coagulation testing is not required. Evaluation of abnormal symptoms or findings on examination is similar to inpatients. (See 'Role of additional testing' below.)

Role of additional testing

Diagnosis of DVT or PE — Evaluation for deep vein thrombosis (DVT) or pulmonary embolism (PE) may be challenging because symptoms of PE overlap with COVID-19, and imaging studies may not be feasible in all cases. The threshold for evaluation or diagnosis of DVT or PE should be low given the high frequency of these events and the presence of additional venous thromboembolism (VTE) risk factors in many individuals. (See 'VTE' above.)

DVT – Individuals with suspected DVT should have compression ultrasonography when feasible according to standard indications. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

PE – We agree with guidance from the American Society of Hematology (ASH) regarding diagnosis of PE, which includes the following [72]:

A normal D-dimer (unusual in critically ill individuals with COVID-19) is sufficient to exclude the diagnosis of PE if the pretest probability for PE is low or moderate but is less helpful in those with a high pretest probability. An increase in D-dimer is not specific for VTE and is not sufficient to make the diagnosis. (See "Overview of acute pulmonary embolism in adults", section on 'Clinical presentation, evaluation, and diagnosis'.)

In patients with suspected PE due to unexplained hypotension, tachycardia, worsening respiratory status, or other risk factors for thrombosis, computed tomography with pulmonary angiography (CTPA) is the preferred test to confirm or exclude the diagnosis. A ventilation/perfusion (V/Q) scan is an alternative if CTPA cannot be performed or is inconclusive, although V/Q scan may be unhelpful in individuals with significant pulmonary involvement from COVID-19. Consultation with the pulmonary embolism response team (PERT) in decision-making is advised if possible. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

The role of full-dose anticoagulation if CTPA or V/Q scan is not feasible is discussed below. (See 'Documented or presumed VTE' below.)

Infection control procedures should be followed in patients undergoing imaging studies. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Infection control in the health care setting'.)

Evaluation of atypical laboratory findings — As noted above, certain laboratory tests are monitored in inpatients for their prognostic value. (See 'Inpatients (routine laboratory testing)' above.)

Laboratory findings that are atypical for COVID-19, such as severe thrombocytopenia (platelet count <50,000/microL), prolonged aPTT out of proportion to the PT, or a markedly reduced fibrinogen, should be evaluated as done for individuals without COVID-19. Details are discussed in separate topic reviews:

Thrombocytopenia – (See "Diagnostic approach to the adult with unexplained thrombocytopenia".)

Abnormal coagulation tests – (See "Clinical use of coagulation tests", section on 'Evaluation of abnormal results'.)

Evaluation of bleeding — The evaluation is discussed separately. (See "Approach to the adult with a suspected bleeding disorder" and "Clinical use of coagulation tests", section on 'Patient on anticoagulant'.)

Management of bleeding depends on the underlying cause. (See 'Treatment of bleeding' below.)

MANAGEMENT

General considerations for management — A series of decisions need to be made, as described in the sections below:

Should anticoagulation be used?

Which agent(s) are appropriate?

What is the appropriate dose level (prophylactic dose, intermediate dose, or therapeutic dose)?

What is the appropriate duration of therapy?

Our approach is summarized in the table (table 1) and depicted in the algorithm (algorithm 1).

Regardless of the approach used, clinicians should be familiar with potential drug interactions between oral anticoagulants and investigational therapies for COVID-19 [73,74].

Individuals with a history of heparin-induced thrombocytopenia (HIT) or active HIT should not receive low molecular weight [LMW] heparin or unfractionated heparin. Alternatives are discussed separately. (See "Management of heparin-induced thrombocytopenia", section on 'Anticoagulation'.)

Resources and other guidance — Guidance and frequently asked questions have been published by the following organizations:

International Society on Thrombosis and Haemostasis (ISTH), with guidance on recognition and management [69,75,76]

Anticoagulation forum [77,78]

American Society of Hematology (ASH), with frequently asked questions (FAQs) and guidance on anticoagulation [79-81]

American College of Cardiology (ACC) [70]

American College of Chest Physicians (ACCP) [82]

National Institutes of Health (NIH) [83]

For the most part, these guidelines were published before emergence of the omicron variant and subvariants, which appear to be associated with less inflammation than variants in the earlier waves of the pandemic.

Inpatient VTE prophylaxis — Venous thromboembolism (VTE) prophylaxis is appropriate in all hospitalized medical, surgical, and obstetric patients with COVID-19 (algorithm 1), unless there is a contraindication to anticoagulation (active bleeding or serious bleeding in the prior 24 to 48 hours) or to the use of heparin (history of heparin-induced thrombocytopenia [HIT], in which case an alternative agent such as fondaparinux may be used). This includes patients admitted for COVID-19 and those admitted for another condition and incidentally found to have SARS-CoV-2 infection. (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

The intensity of anticoagulation for thromboprophylaxis (prophylactic dose, therapeutic dose, or something in between) is based on an individualized risk-benefit assessment. (See 'ICU patients' below and 'Hospitalized medical patients (non-ICU) admitted for COVID-19' below and 'Dosing' below.)

Recommendations for dose intensity are dynamic and have shifted over the course of the pandemic. During the first year of the pandemic, before COVID-19-specific therapies were available and many individuals presented with an exuberant inflammatory response, higher doses of anticoagulation may have saved the lives of many individuals with severe COVID-19.

Subsequent dosing recommendations have evolved to reflect available evidence (see 'Supporting evidence' below). As an example, prophylactic dose anticoagulation was initially recommended for all patients hospitalized for COVID-19; subsequent data suggesting that therapeutic-dose anticoagulation may improve outcomes in hospitalized medical patients (but not ICU patients) led several groups to change their recommendations and advise therapeutic dosing for hospitalized medical patients with acute COVID-19 [81,83]. Much of the evidence regarding intensity of anticoagulation was collected earlier in the pandemic. Given dramatic changes in circulating viral variants, patient populations, and other treatments (vaccines, antiviral therapies, monoclonal antibodies, glucocorticoids) over the course of the pandemic, it is uncertain to what extent those findings are applicable to individuals infected with later variants such as omicron and omicron subvariants.

Patients already on an anticoagulant — Individuals hospitalized with COVID-19 who are already receiving therapeutic-dose anticoagulation for stroke prophylaxis in atrial fibrillation or a recent VTE event should continue this dose level (do not reduce dose based on level of care), unless they have contraindications such as active bleeding; the anticoagulant may be changed to a shorter acting agent such as LMW heparin to allow more rapid changes if needed.

ICU patients — All patients with COVID-19 in the intensive care unit (ICU) require thromboprophylaxis unless they have a contraindication.

We use prophylactic-dose anticoagulation for people with COVID-19 in the ICU who do not have a suspected or documented VTE. Examples include individuals requiring hemodynamic or ventilatory support. Each patient requires an individualized risk-benefit assessment; higher intensity dosing may be appropriate for individuals with a high thrombotic risk and low bleeding risk. This is consistent with advice from ASH and the NIH. (See 'Resources and other guidance' above.)

Occasionally, an individual may be treated with higher-dose anticoagulation. Examples include people for whom there is a high suspicion for VTE that cannot be documented. Individuals already receiving another anticoagulant may be switched to LMW heparin for greater ease of management.

Supporting evidence is presented below. (See 'Supporting evidence' below.)

Hospitalized medical patients (non-ICU) admitted for COVID-19 — All hospitalized medical patients with COVID-19 require thromboprophylaxis unless they have a contraindication. This includes patients admitted with dyspnea or hypoxia that cannot be managed as an outpatient, or those with a concern for development of more serious features of the disease, or those admitted with another acute medical illness and found incidentally to be infected with SARS-CoV-2.

For people admitted for COVID-19, we generally prefer therapeutic intensity (full-dose) anticoagulation for thromboprophylaxis, although all individuals require an individualized risk-benefit assessment. This is based on possible small improvements in certain outcomes such as organ support-free days, which were seen in some trials (other trials may have shown a trend that did not reach statistical significance). Prophylactic dosing may be appropriate for individuals deemed to be at a higher bleeding risk. However, individuals infected with the omicron variant or subvariants appear to have less inflammation and less thrombosis, and prophylactic dosing may also be reasonable.

Supporting evidence is presented below. (See 'Supporting evidence' below.)

Patients hospitalized for another medical illness with incidental finding of SARS-CoV-2 infection

Medical – For people admitted for another medical illness and found incidentally to be infected with SARS-CoV-2 (the virus that causes COVID-19), prophylactic dose anticoagulation is generally preferred for thromboprophylaxis. Details depend on the reason for hospitalization and are discussed separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Surgical – Perioperative VTE prophylaxis is especially important for patients with COVID-19 who are hospitalized for a surgical procedure. Details of the timing and choice of agent are discussed separately. (See "Prevention of venous thromboembolism in adult orthopedic surgical patients" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Obstetric – We would also use VTE prophylaxis in obstetric patients with COVID-19 who are in the hospital prior to or following delivery. LMW heparin is appropriate if delivery is not expected within 24 hours and after delivery; unfractionated heparin is used if faster discontinuation is needed (eg, if delivery, neuraxial anesthesia, or an invasive procedure is anticipated within approximately 12 to 24 hours or at 36 to 37 weeks of gestation). (See "Use of anticoagulants during pregnancy and postpartum".)

Dosing — Dosing is summarized here and discussed separately:

Therapeutic dosing

LMW heparin – Low molecular weight (LMW) heparin is generally given at a fixed dose without monitoring (eg, enoxaparin 1 mg/kg every 12 hours). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing and monitoring'.)

Unfractionated heparin – Unfractionated heparin is titrated based on laboratory testing. The table lists target values for the aPTT and anti-factor Xa activity (use one or the other not both) (table 2). For those receiving unfractionated heparin who have either a prolonged aPTT at baseline or heparin resistance (see 'Ongoing clotting or heparin resistance' below), the aPTT may be unreliable, and anti-factor Xa activity should be monitored to guide dosing [77]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing and monitoring'.)

Prophylactic dosing – Prophylactic dosing (subcutaneous LMW heparin) is generally as follows:

Enoxaparin – For patients with creatinine clearance (CrCl) >30 mL/min, 40 mg once daily; for CrCl 15 to 30 mL/min, 30 mg once daily. European dosing is based on units rather than mg. A typical prophylactic dose is 4000 units once daily, or 100 units/kg once daily [84,85].

Dalteparin – 5000 units once daily.

Nadroparin – For patients ≤70 kg, 3800 anti-factor Xa units once daily; for patients >70 kg, 5700 units once daily. In some cases, doses up to 50 anti-factor Xa units/kg every 12 hours are used.

Tinzaparin – 4500 anti-factor Xa units once daily.

Adjustment for body weight is also appropriate, although details are controversial. As an example, for individuals with a weight >120 kg or body mass index (BMI) >35 kg/m2, prophylactic dosing of enoxaparin 40 mg twice daily can be used [86].

For patients with CrCl <15 mL/min or renal replacement therapy, we use unfractionated heparin, which is much less dependent on elimination by the kidney. The tables have more information about adjustments for kidney impairment (table 3), obesity (table 4), and pregnancy (table 5).

Supporting evidence

Evidence for ICU patients – Analysis from three randomized trials (REMAP-CAP, ACTIV-4a, and ATTACC) in 1207 critically ill individuals assigned to full therapeutic dosing versus prophylactic dose anticoagulation indicated that survival to hospital discharge was not statistically different (65 versus 63 percent; odds ratio [OR] 0.84, 95% CI 0.64-1.11) between the two dose intensities [87]. Therapeutic dosing was associated with slightly lower rates of thrombosis (7.2 versus 11.1 percent) and major thrombosis (6.4 versus 10.4 percent). There were slight differences, not statistically significant, in bleeding rates (3.8 percent with therapeutic versus 2.3 percent with prophylactic; OR 1.48, 95% CI 0.75-3.04) and organ support-free days (one day with therapeutic versus four days with prophylactic; OR 0.83, 95% CI 0.67-1.03). The percentage of people in the prophylaxis arm who received intermediate dosing was high (52 percent), which may have blunted the differences in outcomes. An editorial suggested that critically ill individuals may have developed thrombotic or inflammatory changes too severe for anticoagulation to be effective, or that regional differences in management may have played a role [88].

The INSPIRATION trial, which randomly assigned 600 people with critical COVID-19 in the ICU to receive enoxaparin at intermediate dose or standard prophylactic dosing (1 mg/kg daily versus 40 mg daily, in both cases adjusted for weight and kidney function), found that the escalation to intermediate dosing did not improve a composite outcome of thrombosis, use of ECMO, or mortality (hazard ratio [HR] 1.06; 95% CI 0.83-1.36) [86,89]. The composite outcome was common (occurring in 44 to 46 percent of participants), emphasizing the acuity of disease in this population, but the rates of adjudicated VTE were low (3.3 and 3.5 percent). Individual outcomes and other endpoints such as 30-day mortality were also similar between groups. There was a trend towards increased bleeding in the intermediate-dose group that did not reach statistical significance. The weight-based dosing for individuals with weight >120 kg or BMI >35 kg/m2 was 0.6 mg/kg twice daily for intermediate dose and 40 mg twice daily for prophylactic dose. (See 'Inpatient VTE prophylaxis' above.)

HESACOVID, a small trial that randomly assigned 20 individuals with severe COVID-19 to receive therapeutic-dose anticoagulation (enoxaparin, 1 mg/kg twice daily) or prophylactic-dose anticoagulation (enoxaparin, 40 mg once daily or unfractionated heparin, 5000 units three times daily), found that those assigned to therapeutic dosing had fewer days on the ventilator [90]. However, confidence in the results is hampered by the open-label design and small size.

Evidence for hospitalized medical patients – Analysis from three randomized trials (REMAP-CAP, ACTIV-4a, and ATTACC) in 2244 patients with moderate illness (hospitalized, not in the ICU) found therapeutic dosing to be superior to prophylactic dosing in reducing the number of organ support-free days (80 percent without organ support in the therapeutic dosing arm, versus 76 percent in the prophylactic arm; OR 1.27, 95% CI 1.03-1.58), although the difference barely crossed the threshold for statistical significance [91]. Other outcomes were not statistically different, including thrombosis (1.1 versus 2.1 percent), survival to hospital discharge (93 versus 92 percent; OR 1.21, 95% CI 0.87-1.68), and bleeding (1.9 versus 0.9 percent; OR 1.80, 95% CI 0.90-3.74).

The ACTION trial, which randomly assigned 615 people over age 18 who were hospitalized with COVID-19 and had an elevated D-dimer to receive therapeutic dose anticoagulation (mostly rivaroxaban 15 or 20 mg once daily) or prophylactic dose anticoagulation (mostly prophylactic LMW heparin), found no major differences in efficacy between therapeutic and prophylactic dosing [92]. The efficacy outcome was a composite of survival, duration of hospital stay, and duration of supplemental oxygen, analyzed using a "win ratio" method that prioritizes the most important outcome (survival) within a composite endpoint [93]. A better outcome with therapeutic anticoagulation was designated a win ratio >1; in this analysis, the win ratio was 0.86 (95% CI 0.59-1.22; p = 0.4). The risk of bleeding was higher in the therapeutic dosing group (relative risk [RR] 3.64; 95% CI 1.61-8.27).

A trial that randomly assigned 176 hospitalized patients (admitted to the ICU or with evidence of coagulopathy) found similar all-cause mortality with intermediate dose versus standard dose LMW heparin (30-day mortality, 15 versus 21 percent; OR 0.66, 95% CI 0.30–1.45) [94]. Thrombosis occurred in 13 percent in the intermediate dose arm and 9 percent in the standard dose arm; major bleeding occurred in two percent in both arms.

The RAPID trial, which randomly assigned 465 adults with COVID-19 and high D-dimer admitted to the hospital ward to receive therapeutic or prophylactic dose heparin, found a trend towards better outcomes with therapeutic dosing [95]. The composite endpoint (death, ICU admission, or mechanical ventilation at 28 days) occurred in 16 percent of the therapeutic group and 22 percent of the prophylactic group (OR 0.69; 95% CI 0.43–1.10; p = 0.12). Four patients assigned to therapeutic heparin died (1.8 percent) versus 18 assigned to prophylactic heparin (7.6 percent; OR 0.22; 95% CI 0.07-0.65; p = 0.006). Major bleeding was rare (1 and 2 percent) and not statistically different between groups.

The HEP-COVID trial, which randomly assigned 253 adults with COVID-19 and high D-dimer or sepsis coagulopathy score (approximately one-third in the ICU) to receive prophylactic or standard dose heparin versus therapeutic dose LMW heparin, found a benefit of therapeutic dose heparin that just met statistical significance [96]. The composite endpoint (death, VTE, or arterial thromboembolism) occurred in 29 percent of the therapeutic group and 42 percent of the prophylactic/intermediate group (RR 0.68; 95% CI 0.49-0.96; p = 0.03). A statistical benefit was only seen in the non-ICU patients (17 versus 35 percent); ICU patients had similar rates of the composite endpoint (51 versus 55 percent). The rate of thromboembolism was statistically reduced with therapeutic dosing (11 versus 29 percent, RR 0.37, 95% CI 0.21-0.66; p <0.001). Major bleeding was uncommon (5 and 2 percent) and not statistically different.

Documented or presumed VTE — Therapeutic-dose (full-dose) anticoagulation is appropriate for documented VTE, similar to individuals without COVID-19 (algorithm 1). (See 'Diagnosis of DVT or PE' above.) (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

Full-dose anticoagulation is also reasonable in some cases of suspected VTE in which standard confirmatory testing is not available or feasible, including the following:

Confirmed diagnosis – In patients for whom computed tomography with pulmonary angiography (CTPA) or ventilation/perfusion (V/Q) scan is not feasible, the following may be sufficient to initiate treatment:

Confirmation of deep vein thrombosis (DVT) using bilateral compression ultrasonography of the legs.

Transthoracic echocardiography or point-of-care ultrasound that demonstrates clot in transit in the main pulmonary artery.

Presumptive diagnosis – In patients for whom no confirmatory testing is possible, it may be reasonable to treat empirically with full-dose anticoagulation based on one or more of the following:

Sudden deterioration in respiratory status in an intubated patient consistent with pulmonary embolism (PE), especially when chest radiography and/or inflammatory markers are stable or improving and the change cannot be attributed to a cardiac cause.

Otherwise unexplained respiratory failure (eg, not due to fluid overload or acute respiratory distress syndrome [ARDS]), especially if the fibrinogen and/or D-dimer is very high.

Physical findings consistent with thrombosis (superficial thrombophlebitis or retiform purpura not explained by other conditions).

The choice of anticoagulant is similar to individuals with DVT or PE caused by other acute medical illnesses.

The duration of anticoagulation is similar to individuals with DVT or PE caused by other acute medical illnesses. As an example, an individual with an uncomplicated DVT or PE who did not have any ongoing risk factors for VTE would be anticoagulated for three months and then could discontinue anticoagulation, provided they have largely recovered from COVID-19. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Duration of treatment'.)

Clotting of intravascular access devices — Full-dose anticoagulation is appropriate for individuals with recurrent clotting of intravascular access devices (arterial lines, central venous catheters) despite prophylactic-intensity anticoagulation.

Full-dose anticoagulation is also appropriate in those with clotting in extracorporeal circuits (continuous renal replacement therapy, extracorporeal membrane oxygenation [ECMO]). Details are discussed separately. Management of coagulation abnormalities in patients with COVID-19 receiving ECMO is discussed separately. (See "COVID-19: Extracorporeal membrane oxygenation (ECMO)".)

Ongoing clotting or heparin resistance

Ongoing clotting despite therapeutic anticoagulation – If an individual develops new or progressive thrombosis while receiving therapeutic-intensity anticoagulation, it may be prudent to evaluate for the following:

Heparin-induced thrombocytopenia (HIT). HIT can occur in individuals with COVID-19, but the incidence is not increased; the rate is comparable to other populations who are acutely ill and receiving heparin [97]. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Evaluation'.)

The possibility that anticoagulation is not actually at therapeutic intensity. Often it is helpful to check an anti-factor Xa activity level. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring/measurement (LMW heparins)'.)

The possibility of an ongoing thrombotic process (including COVID-19-associated inflammation) that has not been adequately treated. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)

If clotting continues after these considerations are addressed, consideration of increased dosing may be appropriate, often in consultation with a hemostasis and thrombosis expert. Aggressive treatment of COVID-19 should continue based on disease severity.

Heparin resistance – Heparin resistance (requirement for very high doses of heparin to achieve a therapeutic aPTT or anti-factor Xa activity) might be a concern in acutely ill patients with COVID-19. A series of 15 individuals in the ICU anticoagulated for VTE noted a very high requirement for unfractionated heparin (8 of 10 required more than 35,000 units per day) or LMW heparin (5 of 5 receiving dalteparin had anti-factor Xa peak below expected [<0.6 international units/mL for twice daily dosing or <1 international units/mL for once daily dosing]) [98]. The reason for heparin resistance was unclear; the authors stated it did not correlate with increased fibrinogen or factor VIII or with decreased antithrombin. Heparin is negatively charged and can interact with a variety of positively charged plasma proteins, some of which behave like acute phase reactants and will compete for heparin binding, accounting for heparin resistance. However, these results have not been confirmed. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Heparin resistance/antithrombin deficiency'.)

Indications for tPA — Tissue plasminogen activator (tPA) is appropriate for usual indications, unless there is a contraindication:

Limb-threatening DVT – (See "Catheter-directed thrombolytic therapy in deep venous thrombosis of the lower extremity: Patient selection and administration".)

Massive PE – (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration".)

Acute stroke – (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".)

Acute myocardial infarction – (See "Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy".)

Consultation with the pulmonary embolism response team (PERT) or stroke team in decision-making is advised if possible.

In contrast, we are not using tPA in individuals with nonspecific findings such as hypoxia or laboratory evidence of hypercoagulability.

Small case series (three to five patients) have described administration of tPA to individuals with ARDS associated with COVID-19 and have reported improvement in some cases [99-101].

Aspirin/antiplatelet agents — We do not prescribe aspirin or other antiplatelet agents for individuals with COVID-19 (inpatients or outpatients), although we continue to use aspirin for standard indications. Aspirin increases the risk of bleeding and does not appear to improve COVID-19 outcomes. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)

Inpatients – The RECOVERY trial randomly assigned 14,892 individuals hospitalized with COVID-19 to receive or not receive aspirin 150 mg in addition to standard care during hospitalization [102]. By 28 days, 17 percent of participants had died in both groups (rate ratio [RR] 0.96; 95% CI 0.89-1.04). Progression to mechanical ventilation occurred in 11 percent receiving aspirin and 12 percent not receiving aspirin (RR 0.95; 95% CI 0.87-1.05). Results were largely consistent across subgroups and other endpoints. Aspirin was associated with a small reduction in thrombosis (4.6 versus 5.3 percent) and a small increase in major bleeding (1.6 versus 1.0 percent).

The ACTIV-4a trial randomly assigned 562 individuals who were hospitalized with COVID-19 but not critically ill to receive or not receive the antiplatelet agent ticagrelor (or another P2Y12 inhibitor, clopidogrel or prasugrel); all received therapeutic dose heparin [103]. Outcomes were not statistically different in the two groups, including survival to hospital discharge, organ support-free days, thrombosis, or major bleeding. This trial also evaluated heparin dose-level for VTE prophylaxis. (See 'Supporting evidence' above.)

Outpatients – The ACTIV-4B Outpatient Thrombosis Prevention Trial randomly assigned outpatients with symptomatic COVID-19 to receive aspirin 81 mg per day, apixaban at prophylactic dose (2.5 mg twice daily), apixaban at therapeutic dose (5 mg twice daily), or placebo [63]. Compared with placebo, aspirin did not improve the composite outcome (mortality at 45 days, hospitalization for cardiovascular or pulmonary symptoms, symptomatic venous or arterial thromboembolism). The number of events was very small (one event each in the aspirin, prophylactic apixaban, and placebo groups; two events in the therapeutic apixaban group), leading the trial to be stopped after only 657 individuals were enrolled rather than the planned 7000. Bleeding complications were highest with therapeutic dose apixaban (9.2 percent), followed by prophylactic apixaban (6.7 percent) and aspirin (4.2 percent); the rate in the placebo group was 2.2 percent. All bleeding events were minor or clinically relevant nonmajor bleeding, and there were no deaths in any group.

The unexpectedly low rate of thromboembolic complications in ACTIV-4B suggests that antithrombotic therapy is not warranted in most ambulatory outpatients with COVID-19 [63]. (See 'Clinical features' above.)

It is reasonable to continue antiplatelet therapy if the individual is already receiving it for another indication and to use antiplatelet therapy for standard indications. (See "COVID-19: Management in hospitalized adults", section on 'Statins and aspirin'.)

There is also no role for aspirin following COVID-19 vaccination. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Prevention (common questions)'.)

Outpatient thromboprophylaxis

Patients discharged from the hospital — Individuals with documented VTE require a minimum of three months of anticoagulation, as discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Duration of therapy' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Some individuals who have not had a VTE may also warrant extended thromboprophylaxis following discharge from the hospital [73]:

Based on the low incidence of VTE despite infrequent use of post-discharge prophylactic anticoagulation in available studies such as those mentioned below, we do not use routine post-discharge thromboprophylaxis. We do not monitor laboratory tests such as D-dimer, as we would not alter management based on the results.

We consider post-discharge thromboprophylaxis in patients with major prothrombotic risk factors such as a history of VTE or recent major surgery or trauma, as long as they are not at high bleeding risk. Options for post-discharge prophylaxis include those used in clinical trials, such as rivaroxaban 10 mg daily for 31 to 39 days [104].

A potential benefit for post-discharge thromboprophylaxis in high-risk individuals was demonstrated in the MICHELLE trial; in this trial, 320 individuals hospitalized with COVID-19 who were at high risk for VTE but did not have a thromboembolic event were randomly assigned to receive rivaroxaban 10 mg daily or no anticoagulant for 35 days following hospital discharge [105]. All received inpatient thromboprophylaxis. The composite endpoint of VTE (symptomatic or asymptomatic, identified by bilateral leg ultrasound or computed tomography pulmonary angiography), symptomatic arterial thromboembolism, or any fatal cardiovascular event or VTE, occurred in 3 percent of the patients in the rivaroxaban arm and 9 percent in the nonpost-discharge anticoagulation arm, a statistically significant difference (RR, 0.33, 95% CI 0.12-0.90). There was no major bleeding in either arm. The trial was open-label, and over two-thirds of patients screened were excluded; the most common reasons were that the patient declined to participate or their thromboembolic risk was too low. Editorialists commented that more studies are awaited, and most clinicians are unlikely to start providing post-discharge thromboprophylaxis based on results of a trial this small [106].

The overall risk of post-discharge VTE appears to be similar to that of individuals hospitalized for acute medical illnesses other than COVID-19 [107].

A study that followed 4906 individuals discharged from the hospital following admission for COVID-19 found a VTE rate of 1.6 percent [108]. Post-discharge thromboprophylaxis was used in 13 percent. The rate of thrombosis was lower in those treated with post-discharge thromboprophylaxis, but this may have been due to patient selection (those with a higher thrombotic risk likely also had a higher bleeding risk, and anticoagulation may have been avoided). The rate of major bleeding in this study was 1.7 percent overall.

A study that followed 1877 individuals discharged from the hospital following admission for COVID-19 who did not use post-discharge thromboprophylaxis, VTE was diagnosed in only nine (0.48 percent) [109]. This was similar to the likelihood of VTE in a pre-COVID-19 population (56 events in 18,159 individuals [0.31 percent]). In the patients with COVID-19, the median interval between discharge and VTE diagnosis was eight days (range, 3 to 33 days).

A study that followed a cohort of 163 individuals discharged from the hospital after a COVID-19 admission found four thrombotic events (cumulative incidence of VTE within 30 days of discharge, 0.6 percent; cumulative incidence of any thrombosis, 2.5 percent) [110]. Post-discharge thromboprophylaxis was used in only 8 percent of patients. This study also documented two major bleeding events (cumulative risk of major bleeding, 0.7 percent).

This subject is discussed in more detail separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Duration of prophylaxis'.)

Patients not admitted to the hospital — The vast majority of outpatients with COVID-19 do not require anticoagulation. However, outpatient thromboprophylaxis may be appropriate in selected individuals with COVID-19 who are not admitted to the hospital, especially those with prior VTE or recent surgery, trauma, or immobilization, noting that this practice is based on clinical judgment. The practice of not using anticoagulation in most outpatients is consistent with several expert panels. (See 'Resources and other guidance' above.) (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

Data from the ACTIV-4B Outpatient Thrombosis Prevention Trial, which was stopped early due to a very low number of events, support the practice of not using anticoagulation (or aspirin) in stable symptomatic outpatients with COVID-19 [63]. This trial, which randomly assigned 657 of a planned 7000 outpatients with COVID-19 who were symptomatic and clinically stable to receive apixaban at therapeutic dose (5 mg twice daily), prophylactic dose (2.5 mg twice daily) or placebo, found very low event rates and no benefit from either dose of apixaban. The composite endpoint (death, VTE or arterial thromboembolism, stroke, myocardial infarction, or admission for cardiovascular or pulmonary complications) only occurred in one patient in each group, which led to the early stopping of the trial. Major bleeding did not occur. Results for aspirin are discussed above. (See 'Aspirin/antiplatelet agents' above.)

In the rare case that thromboprophylaxis is used in an outpatient, we would use an anticoagulant regimen such as rivaroxaban 10 mg daily for 31 to 39 days [104].

Available data do not support use of aspirin or other antiplatelet agents in outpatients (see 'Aspirin/antiplatelet agents' above).

Sulodexide, an orally administered heparin-like molecule (not available in the United States), may provide antithrombotic and/or antiinflammatory activity and is also under investigation, with a preliminary trial suggesting benefit [111]. However, further data are needed for confirmation. Details and clinical implications are presented separately. (See "COVID-19: Evaluation of adults with acute illness in the outpatient setting".)

We do not monitor laboratory tests such as D-dimer in outpatients, as we would not alter management based on the results. Outpatients who develop symptoms of VTE should be evaluated as described above. (See 'Diagnosis of DVT or PE' above.)

Treatment of bleeding — Bleeding does not appear to be a major manifestation of COVID-19. However, patients may have bleeding for other reasons, including trauma and/or treatment with anticoagulation. (See 'Bleeding' above.)

The approach to bleeding is similar to individuals without COVID-19 and may involve anticoagulant reversal and/or discontinuation, transfusions for thrombocytopenia or hypofibrinogenemia, or specific therapies such as factor replacement.

Anticoagulant-associated bleeding – (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants" and "Reversal of anticoagulation in intracranial hemorrhage".)

Trauma coagulopathy – (See "Coagulopathy in trauma patients".)

An underlying bleeding disorder such as immune thrombocytopenia (ITP), hemophilia, or von Willebrand disease (VWD) – (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Treatment of bleeding and perioperative management in hemophilia A and B" and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery".)

Antifibrinolytic agents (tranexamic acid, epsilon aminocaproic acid) are generally not used in patients with disseminated intravascular coagulation (DIC), due to the concern that they may tip the balance towards thrombosis. Thus, they should be avoided in patients in whom the COVID-19-associated hypercoagulable state is the predominant finding. (See 'Distinction from DIC' above and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of bleeding'.)

Fibrinogen is often increased in COVID-19, and supplementation with fibrinogen is not required unless there is bleeding that is attributable to hypofibrinogenemia or dysfibrinogenemia (fibrinogen activity level <150 to 200 mg/dL). (See 'Coagulation abnormalities' above and "Disorders of fibrinogen", section on 'Treatment/prevention of bleeding'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics" and "Society guideline links: COVID-19 – Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

Hypercoagulable state – Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, especially with viral variants that were circulating early in the pandemic. The degree of hypercoagulability depends on the magnitude of the systemic inflammatory response. Fibrinogen and D-dimer may be increased and there may be modest prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and mild thrombocytosis or thrombocytopenia. A lupus anticoagulant (LA) is common in individuals with a prolonged aPTT. The pathogenesis of these abnormalities is incompletely understood. (See 'Pathogenesis' above.)

Thrombosis risk – The risk for venous thromboembolism (VTE) was markedly increased in the early pandemic, before vaccines and medical therapies were available, especially in patients in the intensive care unit (ICU). Later studies have reported risks in the range of 5 to 10 percent in ICU patients and <5 percent in hospitalized medical patients; rates may be lower with omicron and omicron subvariants. Pulmonary microvascular thrombosis and arterial thrombotic events such as stroke, myocardial infarction, and limb ischemia are increased to a lesser extent than venous thrombosis. (See 'Clinical features' above.)

Evaluation

Laboratory testing – All patients admitted to the hospital for COVID-19 should have a baseline complete blood count (CBC) with platelet count, PT, aPTT, fibrinogen, and D-dimer. Repeat testing is done according to the patient's clinical status. Laboratory abnormalities that are not typical of COVID-19 should be evaluated. Outpatients do not require coagulation testing. (See 'Routine testing' above.)

Imaging – Imaging studies are appropriate for suspected VTE. (See 'Role of additional testing' above.)

Management – Our general approach is summarized in the table (table 1) and depicted in the algorithm (algorithm 1).

Thromboprophylaxis – All individuals hospitalized with COVID-19 should receive thromboprophylaxis unless contraindicated. Low molecular weight (LMW) heparin is preferred, but unfractionated heparin can be used. Dose intensity is based on an individualized thrombotic and bleeding risk assessment; evidence continues to evolve. Aspirin is not used outside of standard indications. (See 'Inpatient VTE prophylaxis' above and 'Dosing' above and 'Supporting evidence' above and 'Aspirin/antiplatelet agents' above.)

-Critically ill/ICU – For critically ill patients, we suggest prophylactic dosing rather than more intensive (intermediate or therapeutic) dosing (Grade 2C). Dosing for enoxaparin is 40 mg once daily. Some institutions use higher dosing for individuals with weight >120 kg or BMI >35 kg/m2 (40 mg twice daily). (See 'ICU patients' above.) (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

-Hospitalized (non-ICU) – For moderately ill patients admitted for COVID-19, we suggest therapeutic dose anticoagulation (Grade 2C). Therapeutic dose anticoagulation may be appropriate for individuals with a high suspicion for (but inability to document) VTE. (See 'Hospitalized medical patients (non-ICU) admitted for COVID-19' above.)

-Hospitalized for another reason with incidental finding of SARS-CoV-2 infection – For individuals hospitalized for another condition and found incidentally to be infected with SARS-CoV-2, prophylactic anticoagulation is generally appropriate; details are determined based on the reason for hospitalization. (See 'Patients hospitalized for another medical illness with incidental finding of SARS-CoV-2 infection' above.)

-Other underlying indication – Therapeutic dose anticoagulation is also appropriate for individuals who have an underlying indication apart from hospitalization for COVID-19, such as atrial fibrillation. (See 'Patients already on an anticoagulant' above.)

Individuals who have not had a VTE are not routinely given thromboprophylaxis after discharge from the hospital. A period of thromboprophylaxis following discharge may be appropriate in selected individuals. Outpatients are not given anticoagulants or aspirin, with rare exceptions. (See 'Outpatient thromboprophylaxis' above.)

VTE treatment – Therapeutic-dose (full-dose) anticoagulation is continued for at least three months. (See 'Documented or presumed VTE' above.)

Bleeding – Bleeding is less common but can occur. Treatment may include transfusions, anticoagulant reversal or discontinuation, or specific products for underlying bleeding disorders. (See 'Treatment of bleeding' above.)

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Topic 127926 Version 65.0

References