Nuts and bolts of COVID-19 associated coagulopathy: the essentials for management and treatment

Figures & data

Table 1. Major societal recommendations regarding using biomarkers to guide anticoagulation, choice of prophylactic anticoagulation and when to consider increasing intensity of anticoagulation

	How should biomarkers be used to guide management?	What are the preferred prophylactic anticoagulation regimens?	When should the intensity of anticoagulation be increased?
CDC	Insufficient data to recommend for or against using hematologic and coagulation parameters to guide management decisions.	LMWH or UFH (standard dosing). Insufficient data to recommend for or against the increase of anticoagulation intensity outside of a clinical trial.	Consider when a clinically suspected thromboembolic event is present or highly suspected despite imaging confirmation. Insufficient data to recommend for or against the increase of anticoagulation intensity outside the context of a clinical trial. Mentions patients who have thrombosis of catheters or extracorporeal filters should be treated accordingly to standard institutional protocols for patients without COVID-19.
ISTH-IG	Not mentioned	LMWH (standard dosing)	No specific recommendations
ACF	Biomarker thresholds such as D-dimer for guiding anticoagulation management should not be done outside the setting of a clinical trial.	Suggests an increased intensity of venous thromboprophylaxis be considered for critically ill patients# (i.e. LMWH 40 mg SC twice daily, LMWH 0.5 mg/kg subcutaneous twice daily, heparin 7500 SC three times daily, or low-intensity heparin infusion) that they state is based largely on expert opinion.	Consider when a clinically suspected thromboembolic event is present or highly suspected despite imaging confirmation.
ASH	No particular change to regimen recommended for patients with lupus like inhibitors. TEG and ROTEM should not be used routinely to guide management.	LMWH over UFH (standard dosing) to reduce exposure unless risk of bleeding outweighs risk of thrombosis.	Consider increasing the intensity of anticoagulation regimen (i.e. from standard to intermediate intensity, from intermediate to therapeutic intensity) or change anticoagulants in patients who have recurrent thrombosis of catheters and extracorporeal circuits (i.e. ECMO, CRRT) on prophylactic anticoagulation regimens.
ACCP	Not mentioned	LMWH (standard dosing)	Patients with PE or proximal DVT.
SCC-ISTH	D-dimer levels should not be used solely to guide anticoagulation regimens.	LMWH or UFH. Intermediate intensity LMWH can be considered in high risk critically ill patients (50% of responders) and may be considered in non-critically ill hospitalized patients (30% of respondents). Mentions that there are several advantages of LMWH over UFH including once vs twice or more injections and less heparin-induced thrombocytopenia. Regimens may be modified based on extremes of body weight (50% increase in dose if obese), severe thrombocytopenia*, or worsening renal function.	Therapeutic anticoagulation should not be considered for primary prevention until randomized controlled trials are available. Increased intensity of anticoagulation regimen (i.e. from standard or intermediate intensity to therapeutic intensity) can be considered in patients without confirmed VTE or PE but have deteriorating pulmonary status or ARDS.
ACC	Further investigation is required to determine the role of antiphospholipid antibodies in pathophysiology of COVID-19- associated thrombosis. D-dimer > 2 times the upper limit may suggest that patient is at high risk for VTE and consideration of extended prophylaxis (up to 45 days) in patients at low risk of bleeding.		Mentions that therapeutic anticoagulation is the key to VTE treatment. Does not make distinction between confirmed or suspected VTE. Hemodynamically stable patients with submassive PE should receive anticoagulation rather than thrombolytics

Table 2. Major societal recommendations regarding therapeutic anticoagulation regimens, when thrombolytics should be used and when anticoagulation should be held

	What are the preferred therapeutic anticoagulation regimens?	When should anticoagulation be held?	When are thrombolytics recommended?
CDC	Standard regimens for non-COVID-19 patients.	Active hemorrhage or severe thrombocytopenia (Platelet count not defined)	Insufficient data to recommend for or against thrombolytic therapy outside the context of a clinical trial. In pregnant patients, thrombolytic therapy should only be used for acute PE with life-threatening hemodynamic instability due to risk for maternal hemorrhage.
ISTH-IG	Not mentioned	Hold when signs of active bleeding or platelet count < 25 x 109/L. Abnormal PT or PTT is not a contraindication to thromboprophylaxis.	Not mentioned
ACF	LMWH over UFH whenever possible to avoid additional laboratory monitoring, exposure, and personal protective equipment. In patients with AKI or creatinine clearance < 15–30 mL/min, UFH is recommended over LMWH.	Active bleeding or profound thrombocytopenia (Platelet count not defined)	Consider if clinical indication such as STEMI, acute ischemic stroke, or high-risk massive PE with hemodynamic instability. Otherwise, it is not recommended outside context of a clinical trial.
ASH	LMWH or UFH over direct oral anticoagulants due to reduced drug-drug interactions and shorter half-life.	Thromboprophylaxis is recommended even with abnormal coagulation tests in the absence of active bleeding and held only if platelet count < 25 x 109/L or fibrinogen < 0.5 g/L. Abnormal PT or PTT is not a contraindication to thromboprophylaxis. Therapeutic anticoagulation may need to be held if platelet count < 30–50 x 109/L or fibrinogen < 1.0 g/L.	Not mentioned
ACCP	LMWH or fondaparinux over UFH. UFH preferred in patients at high bleeding risk and in renal failure or needing imminent procedures. Recommend increasing dose of LMWH by 25–30% in patients with recurrent VTE despite therapeutic LMWH anticoagulation.	Not mentioned	Thrombolytics over no such therapy in patients with objectively confirmed PE with hemodynamic instability or signs of obstructive shock who are not at high risk of bleeding. Peripheral thrombolysis recommended over catheter-directed thrombolysis
SCC-ISTH	Not mentioned	No specific recommendations. Reports that 50% of respondents report holding if platelet count < 25 x 109/L.	Not mentioned
ACC	Medication regimen likely to change depending on comorbidities (i.e. renal or hepatic dysfunction, gastrointestinal function, thrombocytopenia). Parenteral anticoagulation (i.e. UFH) may be preferred in many ill patients given it may be withheld temporarily and has no known drug-drug interactions with COVID-19 therapies. LMWH may be preferred in patients who are unlikely to need procedures as there are concerns with UFH regarding the time to achieve therapeutic PTT and increased exposure to healthcare workers. DOACs have advantages including lack of monitoring that is ideal for outpatient management but may have risks in settings of organ dysfunction related to clinical deterioration and lack of timely reversal at some centers.	In patients with moderate or severe COVID-19 on chronic therapeutic anticoagulation who develop suspected or confirmed DIC without overt bleeding, it is reasonable to consider the indication of anticoagulation and risk of bleeding for adjusting dose or discontinuation of anticoagulation. The majority of authors recommended reducing the intensity of anticoagulation unless there was an exceedingly high risk of thrombosis.	A multidisciplinary PERT may be helpful for intermediate and high-risk patient with VTE. For hemodynamically high-risk PE, systemic fibrinolysis is indicated with catheter-based therapies reserved for situations that are not amenable to systemic fibrinolysis. Patients with hemodynamically stable intermediate-low or intermediate-high risk PE should receive anticoagulation and rescue systemic fibrinolysis should be considered in cases of further deterioration with catheter-directed therapies as an alternative. Catheter directed therapies should be limited to most critical situations given minimal data showing mortality benefit. When considering fibrinolysis vs percutaneous coronary intervention for STEMI, clinicians should weigh risks and severity of STEMI presentation, severity of COVID-19 in patient, risk of COVID-19 to individual clinicians and healthcare system.

Table 3. Major societal recommendations regarding monitoring of anticoagulation, correction of active bleeding and prophylactic anticoagulation post-discharge

	What is the appropriate method of monitoring anticoagulation?	What is the recommended approach for correction of active bleeding?	Should patients receive post-discharge prophylactic anticoagulation
CDC	Per standard of care for patients without COVID-19	Not mentioned	Routine venous thromboprophylaxis post-discharge is not recommended. FDA-approved prophylactic anticoagulation regimen (rivaroxaban and betrixaban) can be considered if high risk for VTE and low risk for bleeding using criteria from clinical trials.
ISTH-IG	Not mentioned	Transfuse to keep platelet count > 50 x 109/L, fibrinogen > 1.5 g/L, PT ratio < 1.5	No specific recommendations
ACF	Recommend monitoring anti-Xa levels to monitor UFH due to potential baseline PTT abnormalities. Reasonable to monitor anti-Xa or PTT in patients with normal baseline PTT levels and do not exhibit heparin resistance (> 35,000 u heparin over 24 h).	Not mentioned	No evidence for anticoagulation beyond hospitalization, but reasonable to consider if low risk for bleeding and high risk for VTE including intubated, sedated, and paralyzed for multiple days.
ASH	May necessitate anti-Xa monitoring of UFH given artefactual increases in PTT.	Transfuse one adult unit of platelets if platelets < 50 x 109/L, give 4 units of plasma if INR > 1.8, and fibrinogen concentrate (4 g) or cryoprecipitate (10 u) if fibrinogen < 1.5 g/L. In patients with severe coagulopathy and bleeding can consider 4 F-PCC (25 u/kg) instead of plasma.	Reasonable to consider FDA-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) or aspirin if criteria from trials for post-discharge thromboprophylaxis are met.
ACCP	Monitor anti-Xa levels in all patients receiving UFH given potential of heparin resistance.	Not mentioned	Can be considered in patients who are at low risk of bleeding if emerging data suggests a clinical benefit.
SCC-ISTH	No specific recommendations. Mentions that expert clinical guidance statements and clinical pathways from large academic healthcare systems target an anti-factor Xa level of 0.3–0.7 IU/mL for UFH.	Not mentioned	Either LMWH or FDA-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) should be considered in patients with high VTE risk criteria. Duration is 14 days at least and up to 30 days. Of note, they report that none of the respondents recommended aspirin for post-discharge thromboprophylaxis.
ACC	Not mentioned	Transfuse platelets to maintain platelets > 50 x 109/L in DIC and active bleeding or if platelets < 20 x 109/L in patients at high risk of bleeding or requiring invasive procedures. FFP (15 to 25 mL/kg) in patients with active bleeding with either prolonged PT or PTT ratios (> 1.5 times normal) or decreased fibrinogen (< 1.5 g/L). Fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (< 1.5 g/L). Prothrombin complex concentrate if FFP is not possible. Tranexamic acid should not be used routinely in patients with COVID-19-associated DIC given the existing data.	Reasonable to consider extended prophylaxis with LMWH or DOACs for up to 45 days in patients at high risk for VTE (i.e. D-dimer > 2 times the upper limit, reduced mobility, active cancer) and low risk of bleeding.