COVID-19 and Coagulopathy: Frequently Asked Questions
(Version 7.0; last updated January 29, 2021)
Input from Agnes Y. Y. Lee, MD, MSc; Jean M Connors, MD; Lisa Baumann Kreuziger, MD; Mike Murphy, MD; Terry Gernsheimer, MD; Yulia Lin, MD; Menno Huisman, MD; and Maria DeSancho, MD.
What is COVID-19-associated coagulopathy? Is it any different from disseminated intravascular coagulopathy (DIC)?
The most common pattern of coagulopathy observed in patients hospitalized with COVID-19 is characterized by elevations in fibrinogen and D-dimer levels, and mild prolongation of PT/aPTT. This correlates with a parallel rise in markers of inflammation (e.g. CRP). Unlike the pattern seen in classic DIC from bacterial sepsis or trauma, prolongation of the aPTT and/or PT is minimal, thrombocytopenia is mild (platelet count ~100 x109/L), and lab results supporting microangiopathy are infrequent.
Rarely patients with severe COVID-19 infection and multiorgan failure progress to coagulopathy meeting criteria for overt DIC per ISTH criteria. This is suggested by moderate to severe thrombocytopenia (platelet count <50 x109/L), prolongation of the PT and aPTT, extreme elevation of D-dimer, and decreased fibrinogen (< 1.0 g/L.1 The utility of viscoelastic testing [i.e. ThromboElastoGraphy (TEG) and ROtational ThromboElastoMetry (ROTEM)] is under investigation for COVID-19 associated coagulopathy/DIC but should not be used routinely for patient management.
Lupus anticoagulants (LA) have been reported in some patients with COVID-19 as the reason for aPTT prolongation. Generally, LA are not associated with bleeding unless they are masking an underlying bleeding tendency or have associated hypoprothrombinemia (in which case the PT will be prolonged). The aPTT prolongation may necessitate using an anti-Xa activity assay to monitor unfractionated heparin. Clinical significance of LA in COVID-19 is unknown and limited evidence suggests that it is a transient laboratory abnormality.
What is the prognosis in a patient with COVID-19-associated coagulopathy/DIC?
Patients with a serious infection are more likely to have COVID-19 associated coagulopathy than patients with a mild infection and those who die from COVID-19 are more likely to have met the ISTH criteria for DIC compared to survivors. Elevated D-dimer at admission and markedly increasing D-dimer levels (3- to 4-fold) over time are associated with high mortality, likely reflecting coagulation activation from infection/sepsis, cytokine storm and impending organ failure.
In hospitalized patients with COVID-19-associated coagulopathy/DIC, which lab parameters should be followed?
We recommend monitoring platelet count, PT and/or aPTT, D-dimer, and fibrinogen. Worsening of these parameters, specifically the D-dimer, indicates progressive severity of COVID-19 infection and predicts that more aggressive critical care may be needed; experimental therapies for COVID-19 infection might be considered in this setting. Improvement of these parameters along with stable or improving clinical condition provides confidence that stepping down of aggressive treatment may be appropriate.
How should an elevated D-dimer be interpreted in a patient with COVID-19?
Because D-dimer is a product of cross-linked fibrin, it is a sensitive biomarker to rule out venous thromboembolism. However, while a normal level of D-dimer excludes VTE in patients with a low clinical probability, an elevated D-dimer does not necessarily indicate that a patient has VTE. In addition, an elevated D-dimer in a patient with COVID-19 should not be used as a sole criterion for hospital admission or mandate imaging for DVT/PE unless other signs or symptoms of VTE are present. VTE may be suspected if D-dimer levels change from normal to abnormal, there is a rapid increase in D-dimer on serial monitoring, and/or clinical signs or symptoms occur. Imaging studies to diagnose PE or DVT should be pursued in these scenarios.
What treatment or intervention should we give in someone with COVID-19-associated coagulopathy/DIC?
As for all coagulopathies, treatment of the underlying condition is paramount. Experience to date suggests that COVID-19 infection infrequently leads to bleeding despite abnormal coagulation parameters. Supportive care including blood product transfusion should be individualized. Blood component therapy should not be instituted on the basis of laboratory results alone, but reserved for those who are bleeding, require an invasive procedure, or who are otherwise at high risk for bleeding complications. Traditional risk factors for bleeding apply. There are no data to support any particular “safe” cut-off for hematological parameters and the thresholds below are for guidance only.
In patients who are not bleeding, there is no evidence that correction of laboratory parameters with blood products improves outcomes. Replacement might worsen disseminated thrombosis and further deplete scarce blood products. In a patient who is experiencing clinically relevant bleeding, transfuse platelets (one adult dose) if the platelet count is less than 50 x 109/L, give plasma (4 units) if the INR is above 1.8 and order fibrinogen concentrate (4 grams) or cryoprecipitate (10 units) if the fibrinogen level is less than 1.5 g/L. For patients with severe coagulopathy and bleeding, consider 4F-PCC (e.g. 25 Units/kg) instead of plasma, as volume status appears to be a significant factor associated with respiratory compromise. The hemostatic effectiveness of tranexamic acid (TXA) is unknown in this setting.
Should we give therapeutic anticoagulation in someone with COVID-19-associated coagulopathy/DIC? What about those who are already on anticoagulation for atrial fibrillation or another indication?
A large NIH multiplatform, adaptive-design trial that incorporates 3 global studies/networks (REMAP-CAP, ATTACC and ACTIV-4A) was set up to address this question. ACTIV-4A Inpatient and ATTACC enrolled patients within first 72 hours of hospitalization, while REMAP-CAP used a 48-hour cut-off for those needing organ support on admission and up to 14 days for those who were moderately ill. Patients were randomized in an adaptive fashion to receive different intensities of anticoagulation and/or antiplatelet agents. The primary outcome was a composite of 21-day “organ support-free” days, defined as number of hospital days not requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO support and in-hospital mortality. Thrombosis, bleeding and overall mortality were secondary outcomes. Patients who required therapeutic anticoagulation for other indications (e.g., mechanical heart valves) were excluded.
For patients requiring ICU level of care at enrollment (severe state): As of December 21, 2020, enrollment of patients requiring ICU level of care was paused due to an interim pooled analysis demonstrating futility (OR 0.76; 0.60 – 0.97) of full dose anticoagulation in reducing the need for organ support and mortality, compared with usual care prophylactic dose anticoagulation, in this specific subgroup. ICU level of care was defined as requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO support. Peer-reviewed publication is pending (see preliminary data in table). However, given the concern for safety (numerically higher mortality and bleeding; probability of therapeutic dose is harmful is 98.5%), we discourage the empiric use of full dose heparin or LMWH in this specific subgroup of COVID-19 patients who do not have other indications for therapeutic anticoagulation, outside of a clinical trial.
For hospitalized patients not requiring ICU level of care at enrollment (moderate state): On January 22, 2021, the NIH announced that full dose anticoagulation is superior to usual care prophylactic dose anticoagulation (proportional OR 1.5; 1.1 – 2.2) in reducing the need for organ support and mortality in moderately ill hospitalized COVID-19 patients. Moderately ill patients were defined as those who required hospitalization but not ICU level of care (see above) at the trial enrollment time point. Preliminary, non-adjudicated data on thrombotic and bleeding outcomes have been made public (see Table). Consequently, until peer-reviewed data are available, we recommend using clinical judgment, with careful consideration of the risk of bleeding and the eligibility criteria used in these studies, in managing individual patients.
Table: Pre-publication, interim, non-peer reviewed data from the Multiplatform Trial
|Moderate State||Severe State|
|Therapeutic||Usual Care||Therapeutic||Usual Care|
|Need for organ support*||~16%||~23%||N/A||N/A|
|Mortality||40/699 (5.7%)||54/699 (7.7%)||160/453 (35.3%)||144/442 (32.6%)|
|Thrombotic events ƚ||16/853 (1.9%)||24/742 (3.2%)||31/460 (6.7%)||53/448 (11.8%)|
|ISTH Major bleeding||14/853 (1.6%)||7/742 (0.9%)||17/460 (3.7%)||8/448 (1.8%)|
*a post-hoc analysis, ƚ includes DVT, PE, MI, ischemic stroke, other thrombotic event
Planning for continuing enrollment in these multiplatform trials is in process, while other studies are continuing in evaluation of other dosing regimens and interventions, such as intermediate dose anticoagulation or antiplatelet agents. We encourage participation in ongoing clinical trials and epidemiologic studies, and will update this FAQ as more data become available.
What are reasonable cut-off values for platelet count or other coagulation parameters to consider withholding anticoagulation in patients with COVID-19?
In patients already on anticoagulation for VTE or atrial fibrillation, therapeutic doses should continue, but may need to be held if the platelet count is less than 30-50 x 109/L or if the fibrinogen is less than 1.0 g/L. Individual patient assessment is required to balance risks of thrombosis and bleeding.
Thromboprophylaxis with LMWH is recommended for all hospitalized COVID-19 patients in the absence of bleeding, despite abnormal coagulation tests, and held only if platelet counts are less than 20 - 30 x 109/L, or fibrinogen less than 0.5 g/L. Abnormal PT or aPTT is not a contraindication for pharmacological thromboprophylaxis. Mechanical thromboprophylaxis should be used when pharmacological thromboprophylaxis is contraindicated. The impact of dose intensity used for pharmacological thromboprophylaxis on patient outcomes is under investigation in many prospective trials.
For additional information see:
- NIH ACTIV Trial of blood thinners pauses enrollment of critically ill COVID-19 patients
- Moores et al Prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19: CHEST Guideline and Expert Panel Report
- Thromboembolism and Anticoagulant Therapy During the COVID-19 Pandemic: Interim Clinical Guidance from the Anticoagulation Forum
- COVID recommendations from the International Society for Thrombosis and Hemostasis
- Antithrombotic therapy in patients with COVID-19