Individuals with COVID-19 may have a number of coagulation abnormalities (in the direction of an underlying hypercoagulable state), raising questions about appropriate evaluations and interventions to prevent or treat thrombosis.

Interim guidance has been published by the International Society on Thrombosis and Haemostasis (ISTH), and frequently asked questions are posted on the websites of the American Society of Hematology (ASH) and the American College of Cardiology (ACC).

This topic reviews evaluation and management of coagulation abnormalities in individuals with COVID-19.

Separate topics discuss the following:

• General management : See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”.
• Critical care : See “Coronavirus disease 2019 (COVID-19): Critical care and airway management issues”.
• Extracorporeal membrane oxygenation (ECMO) : See “Extracorporeal membrane oxygenation (ECMO) in adults”.
• Pregnancy : See “Coronavirus disease 2019 (COVID-19): Pregnancy issues”.
• Anesthesia : See “Coronavirus disease 2019 (COVID-19): Anesthetic concerns, including airway management and infection control”.

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’s 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. Other sources of endothelial injury include intravascular catheters and mediators of the acute systemic inflammatory response such as cytokines (eg, interleukin [IL]-6) and other acute phase reactants [1]. The contribution of complement-mediated endothelial injury has been suggested [2]. (See “The endothelium: A primer” and “Complications of central venous catheters and their prevention” 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
  • Elevated factor VIII
  • Elevated fibrinogen
  • Circulating prothrombotic microparticles
  • Neutrophil extracellular traps (NETs)

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. 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.)

Coagulation abnormalities : The predominant coagulation abnormalities in patients with COVID-19 suggest a hypercoagulable state and are consistent with uncontrolled clinical observations of an increased risk of venous thromboembolism (see ‘VTE’ below). This state has been termed thromboinflammation or COVID-19-associated coagulopathy (CAC) by some experts [5,6]. It appears to be distinct from disseminated intravascular coagulation (DIC), though DIC has been reported in severely affected patients.

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)

• 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.

Other studies have reported similar findings consistent with a hypercoagulable state, including very high D-dimer, VWF antigen and activity, and factor VIII activity. One study suggested that patients with COVID-19 have higher platelet counts than patients with other coronavirus infections

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. 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]) . 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.)

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

Principles of TEG and interpretation of TEG tracings are illustrated in the figure (figure 1) and discussed in more detail separately. (See “Platelet function testing”, section on ‘Thromboelastography (TEG) and ROTEM’ and “Acute coagulopathy associated with trauma”, section on ‘Thromboelastography’.)

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

However, the major clinical finding in COVID-19 is thrombosis, whereas the major finding in acute decompensated DIC is bleeding.

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. 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

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. However, in COVID-19, the platelet count and aPTT are typically normal. (See “Disseminated intravascular coagulation (DIC) in adults: Evaluation and management”, section on ‘Pathogenesis’.)

This 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. 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. (See ‘Coagulation abnormalities’ above.)

Regardless of whether the differences from DIC or the similarities are emphasized, many of the basic principles of DIC management apply, including the importance of treating the underlying condition, the importance of basing interventions on the clinical picture rather than on laboratory testing alone, and the need to provide anticoagulation for thrombosis and appropriate hemostatic therapies for bleeding. (See “Disseminated intravascular coagulation (DIC) in adults: Evaluation and management”, section on ‘Treatment’.)

CLINICAL FEATURES

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

Two autopsy studies emphasize 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 [17]. 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) [18]. 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.

Both of these studies noted the preponderance of males with a high prevalence of obesity and other chronic medical comorbidities, especially cardiovascular disease, hypertension, and diabetes mellitus.

ICU – Case series of intensive care unit (ICU) patients have reported high rates of VTE (range, 20 to 43 percent), mostly pulmonary embolism (PE), and often despite prophylactic-dose anticoagulation:

• A series of 184 sequential patients with severe COVID-19 in the ICU reported PE in 25 (14 percent), deep vein thrombosis (DVT) in 1, and catheter-associated thrombosis in 2. 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. The group as a whole was very ill, with 13 percent requiring renal replacement therapy and 13 percent mortality. Three-fourths of the patients were male, and several had active cancer (independent VTE risk factors).
• A series of 150 ICU patients 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) [7]. All patients were receiving thromboprophylaxis (mostly low molecular weight [LMW] heparin), 70 percent with prophylactic dose and 30 percent with therapeutic dose.This study also compared the subgroup of 77 patients with COVID-19-associated acute respiratory distress syndrome (ARDS) to a matched cohort of 145 patients with non-COVID-19-ARDS and found the rate of thrombotic complications (mostly PE) to be higher in the COVID-19 patients (12 versus 2 percent).
• A series of 107 ICU patients reported PE in 22 (21 percent; cumulative incidence at 15 days, 20 percent). Of the 22 patients with PE, 20 were receiving prophylactic anticoagulation and 2 were receiving therapeutic-dose anticoagulation (for prior VTE and atrial fibrillation). By comparison, the incidence of PE in two matched cohorts (one from the same time interval in the previous year and one from concurrent patients with influenza rather than COVID-19) were 6 and 8 percent, respectively.
• A series that included 74 ICU patients reported VTE in 29 (39 percent), with a cumulative incidence of 25 percent at 7 days and 48 percent at 14 days. All of these individuals were receiving anticoagulation, most at prophylactic levels. None of the patients receiving therapeutic level anticoagulation at admission developed VTE.
• An earlier series of 81 patients with severe COVID-19 pneumonia reported VTE in 20 (25 percent)
• A study that performed screening leg ultrasounds in 26 individuals with COVID-19 in the ICU who were all receiving either prophylactic-dose or therapeutic-dose anticoagulation found VTE in 18 (69 percent), including bilateral clots in 10 (38 percent). Some of these individuals had additional VTE risk factors including cancer, recent surgery, high BMI, or prior VTE; 7 (27 percent) were receiving anticoagulation prior to admission.

VTE risk is in the range where some experts would suggest more aggressive thromboprophylaxis dosing of anticoagulants or even empiric therapeutic-dose anticoagulation for VTE prevention. Some of these studies noted a higher than average body mass index in affected individuals, suggesting that obesity, along with other risk factors, may warrant consideration in decision-making regarding the intensity of anticoagulation. (See ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ below.)

Inpatients (non-ICU) – Data are more limited regarding the rate of VTE in inpatients who are not in the intensive care unit (ICU).

The series with a 39 percent rate of VTE in ICU patients above also included 124 non-ICU patients, and of those, only 4 (3 percent) were diagnosed with VTE

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.

Outpatients – We are aware that thrombotic events have been observed in COVID-19 patients who were not admitted to the hospital, but data on the incidence are not available.

Arterial events – There are also reports of arterial thrombosis, including in the central nervous system (CNS). As examples:

• CNS : A single health system identified five cases of acute ischemic stroke associated with COVID-19 over a two-week period, with symptoms suggesting large-vessel occlusion; all patients were under 50 years of age. In other time periods before the pandemic, there were approximately 0.7 large vessel strokes per two-week interval in individuals under age 50. In one of the series of ICU patients discussed above, ischemic stroke was observed in 3 of 184 (cumulative incidence, 3.7 percent). In another one of the series discussed above, cerebral ischemia was seen in 3 of 150
• Limbs : A report described 20 patients with COVID-19 who developed acute limb ischemia at a single institution over a three-month period. This represented a significant increase in limb ischemia over the previous year (16 percent, versus 2 percent in early 2019). Most were male (18 of 20), and the average age was 75 years. Surgical revascularization procedures were performed in 17, of which 12 (71 percent) were successful, a lower-than-expected success rate. Individuals who received postoperative heparin did not require reintervention, although the benefits of postoperative heparin did not reach statistical significance.

Another report described four patients with acute limb ischemia due to thrombosis, two of whom were young and did not have any comorbidities (a 53-year-old man who developed aorto-iliac thrombosis and a 37-year-old man who developed humeral artery thrombosis). Both were receiving prophylactic-dose LMW heparin at the time thrombosis developed and both had very high D-dimer (>9000 ng/mL).

Myocardial infarction has also been reported but not emphasized in available series.

Microvascular thrombosis – Autopsy studies in some individuals who have died from COVID-19 have demonstrated microvascular thrombosis in the lungs. 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 the setting of anticoagulation. As an example, 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. 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.)

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 and the concerns related to performing diagnostic imaging procedures on acutely ill and potentially contagious patients. 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)

Routine testing (all patients)

Inpatients – 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

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. Measurement of the D-dimer more than once per day is generally not indicated. 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. (See ‘Investigational therapies’ below.)

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, and it may unnecessarily expose health care workers to additional infectious risks. However, imaging is appropriate in individuals with symptoms, as discussed below. (See ‘Role of additional testing’ below.)

Outpatients – 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 – e agree with guidance from the American Society of Hematology (ASH) regarding diagnosis of PE, which includes the following :

• A normal D-dimer is sufficient to exclude the diagnosis of PE. An increase in D-dimer is not specific for VTE and is not sufficient to make the 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. 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 “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Infection control in the health care setting’.)

Evaluation of atypical laboratory findings —As noted above, typical laboratory findings of COVID-19 are monitored for their prognostic value. (See ‘Routine testing (all patients)’ above.)

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

• Thrombocytopenia : (See “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

Overview of management considerations — Management can be challenging. Hypercoagulability appears to adversely impact prognosis, but there are no high-quality studies to support interventions that go beyond standard indications, and antithrombotic therapies carry risks of increased bleeding [30]. In the absence of high-quality data to guide management, institutions may vary in how aggressively they approach prevention and treatment of thromboembolic complications. Enrollment in clinical trials is encouraged to help determine the best approach

Regardless of clinical trial enrollment, adherence to institutional protocols and input from individuals with expertise in hemostasis and thrombosis is advised to balance the risks of thrombosis and bleeding and guide decisions about antithrombotic therapy; bleeding caused by administration of excessive antithrombotic therapy may require prothrombotic treatments that further increase thrombotic risk.

Acknowledging the lack of evidence, we agree with interim guidance from the International Society on Thrombosis and Haemostasis (ISTH). Our approach is summarized in the table (table 1) and discussed in the following sections.

Management of coagulation abnormalities in patients with COVID-19 receiving extracorporeal membrane oxygenation (ECMO) is discussed separately. (See “Coronavirus disease 2019 (COVID-19): Critical care and airway management issues”, section on ‘Additional options’ and “Extracorporeal membrane oxygenation (ECMO) in adults”.)

Inpatient VTE prophylaxis

Indications – 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 (eg, active bleeding or serious bleeding in the prior 24 to 48 hours) or to the use of heparin (eg, history of heparin-induced thrombocytopenia [HIT], in which case an alternative agent such as fondaparinux may be used).

• ICU : All patients with COVID-19 in the intensive care unit (ICU) require thromboprophylaxis. As discussed below, some would empirically use intermediate-dose or therapeutic-dose anticoagulation in severely ill individuals in the absence of documented VTE. (See ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ below.)
• Medical (non-ICU) : All hospitalized medical patients should be treated with prophylactic-dose low molecular weight (LMW) heparin (or unfractionated heparin if LMW heparin is unavailable) for thromboprophylaxis.
• 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 “Coronavirus disease 2019 (COVID-19): Pregnancy issues”, section on ‘Medical and obstetric care of hospitalized patients’ and “Use of anticoagulants during pregnancy and postpartum”.)

Dosing – Dosing (subcutaneous) is generally as follows; however, many experts are recommending higher doses for critically ill individuals, especially those in the ICU (see ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ below):

• 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.
• Dalteparin – 5000 units once daily.
• Nadroparin – For patients ≤70 kg, 3800 or 4000 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.

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 2), obesity (table 3), and pregnancy (table 4).

Supporting evidence –LMW heparin is known to reduce the risk of VTE and may have antiinflammatory properties. In a retrospective series of 2773 individuals hospitalized with COVID-19, in whom 786 (28 percent) received systemic anticoagulation, anticoagulation was associated with improved in-hospital survival in intubated patients (71 percent, versus 37 percent for those who were not anticoagulated) [33]. Intubated patients represented approximately 14 percent of the cohort; in the cohort as a whole, anticoagulation was not associated with better in-hospital survival (78 versus 77 percent). Bleeding events occurred in 3 percent of the anticoagulated patients and 2 percent of those who were not anticoagulated (not a statistically significant difference). In a retrospective study of 449 individuals with severe COVID-19, enoxaparin (40 to 60 mg once daily) appeared to be associated with improved survival when compared with no pharmacologic prophylaxis, especially in those with a high D-dimer

• The survival difference was only seen in a subset of individuals with a high sepsis-induced coagulopathy score (28-day mortality, 40 percent with heparin versus 64 percent without) or a high D-dimer, not in the cohort as a whole.
• The magnitude of benefit was greater in those with higher D-dimer values. The reduced mortality became statistically significant at six times the upper limit of normal (33 versus 52 percent).

One small series (16 patients) used higher prophylactic doses of nadroparin along with clopidogrel and did not report any VTE events; the small size of the study and lack of a control group limits interpretation

As discussed above, a high percentage (25 to 43 percent) of individuals with COVID-19 in the ICU had VTE despite prophylactic-dose anticoagulation, prompting many experts to suggest higher doses. (See ‘VTE’ above and ‘Indications for full-dose anticoagulation’ below.)

One study monitored antithrombin (AT) levels and provided AT concentrate for those with decreased levels [4]. However, we generally would not measure AT levels or consider AT concentrate unless an individual was known to have inherited AT deficiency or exhibited heparin resistance in association with a very low AT level. (See “Antithrombin deficiency”, section on ‘Heparin resistance’.)

Indications for full-dose anticoagulation — Therapeutic-dose (full-dose) anticoagulation (eg, enoxaparin 1 mg/kg every 12 hours) is appropriate in the following settings, unless there is a contraindication to anticoagulation (eg, active bleeding or serious bleeding in the prior 24 to 48 hours) or to the use of heparin (eg, history of heparin-induced thrombocytopenia [HIT], in which case an alternative agent such as fondaparinux may be used) (algorithm 1):

Documented or presumed VTE —Therapeutic-dose (full-dose) anticoagulation is appropriate for documented venous thromboembolism (VTE), similar to individuals without COVID-19. (See ‘Diagnosis of DVT or PE’ above.)

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:

• 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.
• 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).

For patients with acute VTE who are discharged from the hospital, extended thromboprophylaxis may be reasonable. (See ‘Patients discharged from the hospital’ below.)

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. (See “Extracorporeal membrane oxygenation (ECMO) in adults”.)

Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients —The question of treatment-dose anticoagulation for thromboprophylaxis has also been raised in critically ill individuals and those in the ICU who have not had confirmed or suspected acute VTE but are at high risk, as described above. (See ‘VTE’ above.)

Many centers are recommending intermediate-dose or even therapeutic-intensity anticoagulation in these individuals (see “Coronavirus disease 2019 (COVID-19): Critical care and airway management issues”, section on ‘Venous thromboembolism prevention’). There are no data comparing different levels of anticoagulation in these patients (prophylactic, intermediate, or therapeutic dosing), and clinical trials are in progress. Enrollment in such a trial is encouraged.

As stated by the American Society of Hematology (ASH), empiric full-dose anticoagulation for individuals who do not have VTE remains controversial, since data demonstrating improved outcomes are lacking, and some of the risk factors for VTE are also risk factors for increased risk of bleeding [29]. Thus, if VTE is suspected, confirmatory testing should be obtained or other indications for full-dose anticoagulation should be sought if possible, especially in individuals who are not in the ICU. This testing and other findings that support therapeutic-dose anticoagulation are discussed above. (See ‘Diagnosis of DVT or PE’ above.)

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”.
• 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.

A case series described administration of tPA to three individuals with ARDS associated with COVID-19 who did not have access to or were not eligible for other interventions such as ECMO [34]. One individual had transient improvement in laboratory parameters but ultimately died. The other two had improvement in laboratory parameters; clinical outcomes were not described

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:

• We would be most likely to use post-discharge prophylactic anticoagulation in individuals with other risk factors for VTE such as immobilization, recent surgery, or trauma.
• We would use other criteria similar to those used in the APEX and MARINER trials, including immobility and older age. Most hospitalized patients with COVID-19 would meet these criteria.
• However, bleeding risk also needs to be incorporated into decision-making.
• Options for post-discharge prophylaxis include those used in clinical trials, such as rivaroxaban 10 mg daily for 31 to 39 days

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 —Outpatient thromboprophylaxis may also be appropriate for selected individuals with COVID-19 who are not admitted to the hospital, especially those with other thrombotic risk factors such as prior VTE or recent surgery, trauma, or immobilization, noting that this practice is based on clinical judgment. There are no trials that address thromboprophylaxis in outpatients with COVID-19.

If thromboprophylaxis is used in an outpatient, we would use a regimen such as rivaroxaban 10 mg daily for 31 to 39 days

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 “Acute coagulopathy associated with trauma”.)
• An underlying bleeding disorder such as immune thrombocytopenia (ITP), hemophilia, or von Willebrand disease (VWD) – (See “Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis” 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 “Disseminated intravascular coagulation (DIC) in adults: Evaluation and management”, 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’.)

Investigational therapies —A number of therapies for COVID-19 are under investigation, some of which may impact thrombotic risk. However, effects of these treatments on hemostasis in this patient population have not been well studied. (See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘COVID-19-specific therapy’.)

Participation in clinical trials is encouraged in order to improve understanding of the most effective and safest means of preventing and treating thrombotic complications of COVID-19. Investigational therapies may be appropriate in life-threatening situations or as part of a clinical trial, and markedly increased D-dimer may be used as one criterion for identifying individuals with a worse prognosis.

Close monitoring for clinical signs of thrombosis or bleeding is advised in all individuals with COVID-19, with input from an individual with expertise in hemostasis and thrombosis in those with severe or unusual presentations.

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: Coronavirus disease 2019 (COVID-19) – International and government guidelines for general care” and “Society guideline links: Coronavirus disease 2019 (COVID-19) – Guidelines for specialty care”.)

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: Coronavirus disease 2019 (COVID-19) overview (The Basics)”)
• Society guidelines for patients (see “Society guideline links: Coronavirus disease 2019 (COVID-19) – Resources for patients”)

SUMMARY AND RECOMMENDATIONS

• Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state associated with acute inflammatory changes and laboratory findings that are distinct from acute disseminated intravascular coagulation (DIC), save for those with very severe disease. Fibrinogen and D-dimer are increased, with typically only modest prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and mild thrombocytosis or thrombocytopenia. The presence of a lupus anticoagulant (LA) is common in individuals with a prolonged aPTT. The pathogenesis of these abnormalities is incompletely understood, and there may be many contributing factors related to the acute inflammatory response to the disease. (See ‘Pathogenesis’ above.)
• The risk for venous thromboembolism (VTE) is markedly increased, especially in patients in the intensive care unit (ICU), with case series reporting prevalences of 25 to 43 percent in ICU patients, often despite prophylactic-dose anticoagulation. The risk for other thrombotic events (stroke, microvascular thrombosis) is less clear. (See ‘Clinical features’ above.)
• 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. Outpatients do not require coagulation testing. The main purpose of this testing is to obtain prognostic information that may be used to inform level of care. (See ‘Routine testing (all patients)’ above.)
• Imaging studies are appropriate for suspected VTE if feasible. If standard diagnostic studies are not feasible, other options for determining the need for therapeutic-dose anticoagulation are available, as discussed above. Laboratory abnormalities that are not typical of COVID-19 should be further evaluated, as described above. (See ‘Role of additional testing’ above.)
• Management is challenging due to the acuity of the illness and a paucity of high-quality evidence regarding efficacy and safety of different approaches to prevent or treat thromboembolic complications of the disease. Our general approach, which is summarized in the table (table 1) and depicted in the algorithm (algorithm 1), includes:
  • All inpatients should receive thromboprophylaxis unless contraindicated. Low molecular weight (LMW) heparin is preferred, but unfractionated heparin can be used if LMW heparin is unavailable or if kidney function is severely impaired. Some institutional protocols include more aggressive anticoagulation with intermediate-dose or even therapeutic-dose anticoagulation for thromboprophylaxis. (See ‘Inpatient VTE prophylaxis’ above and ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ above.)
  • Bleeding is unusual but can occur. If it occurs, treatment is similar to non-COVID-19 patients and may include transfusions, anticoagulant reversal or discontinuation, or specific products for underlying bleeding disorders. (See ‘Treatment of bleeding’ above.)
  • Participation in clinical trials is encouraged in order to improve understanding of the most effective and safest means of preventing and treating thrombotic complications of COVID-19. Disease-specific therapies under investigation may impact thrombotic risk, but the effects of these treatments on hemostasis in this patient population have not been well documented. (See ‘Investigational therapies’ above.)

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GRAPHICS

Thromboelastography (TEG) tracing parameters