COVID-19 Treatment Algorithms
BMC COVID-19 Anticoagulation Protocol FAQ
1. What to do when the D-dimer goes from above to below 2,000?
A key concept is that an elevated D-dimer is just a marker of increased risk for thrombosis. This is not an absolute threshold as increased risk is seen even at lower levels. This risk likely persists beyond the single lab value falling below this threshold. We would favor continuing thromboprophylaxis with the more intense regimen, assuming acceptable bleeding risk. However, it is important to look at the patient as a whole and consider other clinical features.
2. What to do with a borderline D-dimer?
The use of a D-Dimer cut-off of 2000 is somewhat arbitrary; this value was chosen given that it was >8 times the upper limit of normal and elevations such as this are associated with increased thrombosis risk.
In addition to the D-dimer level, other clinical features may help to predict risk of thrombosis, including disease severity and location of care. There is also an increased risk in those with moderate to severe disease severity [such as those with PaO2/FiO2 < or = 300 mmHg, SIC (or sepsis induce coagulopathy) score > or =4, or elevated SOFA score) or those requiring intensive unit level care. The incorporation of these clinical features may help guide to the preferred prophylaxis regimen.
3. What to do for an intermediate risk patient (D-dimer above 2,000) with higher bleeding risk (ex. concern for hemorrhagic transformation from an ischemic stroke)?
The use of the higher intensity prophylaxis regimen is based upon the observation of a high rate of VTE despite use of standard prophylaxis regimen in patients with more severe COVID disease (including those with elevated D-dimer). This approach has not been proven to be effective but is common practice. It should not be used in those with a bleeding risk that is deemed to be unacceptable or too high. As is always the case with initiating any anticoagulation, even prophylaxis, the potential benefits need to be weighed against the risk. In this case, the use of either standard prophylaxis options (either chemical or mechanical) may be considered based upon the magnitude of the bleeding risk. Risks and benefits of anticoagulation should be re-assessed daily.
4. Who should receive anticoagulation upon discharge?
This may be based upon the risk category in combination with other clinical features. There is limited guidance as its use is an extrapolation of data from other situations. It is unlikely that patients at low risk will benefit from extending prophylaxis beyond discharge. This is in contrast to patients in the “high risk group” who have an established indication for therapeutic anticoagulation (with the exception of patients on anticoagulation for HD/CVVHD clotting).
The uncertainty is primarily in the intermediate risk group. Our suggestion is that clinicians “may consider extended prophylaxis for 4 weeks upon discharge (potential agent apixaban 2.5 mg twice daily)”. This, however, remains a clinical decision that requires consideration of other issues such as the severity of illness during hospitalization and upon discharge, comorbidities, patient mobility, and bleeding risk. One should consider all these factors in estimating risks and benefits while making a decision for an individual patient. It is anticipated that most patients in this risk category will be reasonable candidates for this approach.
5. Can an alternative agent be used for extended thromboprophylaxis upon discharge?
Our recommendation would be for initiation of apixaban 2.5 mg PO BID. This is due to availability of “low dose” therapy, minimal renal clearance, and lack of need to take apixaban with food (unlike rivaroxaban) to allow for adequate bioavailability. Additionally, there is limited data that suggests use of low dose DOAC therapy in medical patients reduces risk of post-hospital discharge VTE.
In patients in whom there is a contraindication to use of apixaban for extended thromboprophylaxis, it is reasonable to consider other options. Consultation with pharmacy, hematology, or vascular medicine may be considered in this challenging subset of patients.
6. Can an alternative agent be used for therapeutic anticoagulation upon discharge?
Yes, certainly other agents may be used. The choices of agents for those that require systemic anticoagulation should be based upon the disease process being treated and comorbid illnesses, but most common either a DOAC or warfarin. For those on extended prophylaxis, we suggested low dose apixaban due to proposed efficacy and safety, even with moderate renal dysfunction.
7. How to interpret the comment about a 5-fold increase in D-dimer?
This comment was intended for the high risk category patients particularly with signs suggestive of clinically-relevant hypercoagulability. It is suggested that in such patients with a significant rapid increase (5-fold within 48 hrs) in D-dimer [and typically to levels above 2,000-4,000] that imaging for DVT or PE should be considered, if feasible.
8. If a patient is on intermediate dose anticoagulation and is found to have a confirmed VTE, how can I transition patient safely to therapeutic anticoagulation?
If a patient is on LMWH intermediate dose (0.5 mg/kg with a maximum dose of 70 mg Q12 hours) and weight allows for ongoing use of therapeutic LMWH, we would recommend transitioning to lovenox at 1 mg/kg q12 hours.
If a patient is on IV UFH intermediate dose (aPTT target of 45-65U/hr), the following scenarios may occur:
• If PTT is between 55-65s, patient is already in the “therapeutic range”. No dosage adjustment for the infusion needs to be made. The new protocol order should be placed and plan should be communicated with nursing.
• If PTT is < 55s, pt will likely require a bolus with an increase in the infusion rate of IV UFH. New order can be placed for the therapeutic IV UFH protocol. Page pharmacy (9825 off hours) to determine appropriate adjustment. Plan should be communicated with nursing.
9. When initiating anticoagulation, should therapeutic LMWH be favored over therapeutic IV UFH?
Given the coagulopathy associated with COVID and the derangements in coagulation profiles, if CrCl allows (i.e. CrCl > 30 ml/min), LMWH should be considered first line. Daily assessment of renal function is key in these patients given that patients with COVID-19 infection have been found to develop renal dysfunction.
10. When a patient is on IV UFH, what factors should prompt me to consider use of anti-Xa monitoring?
COVID-19 infection has been associated with COVID coagulopathy that has been characterized by elevations in PT/PTT (typically PT > PTT), fibrinogen and D-dimer.
Patients with severe coagulopathy may have discordance between PTT value and degree of anticoagulation with IV UFH. UFH functions by inhibiting factors II and X in the coagulation profile. In cases when there is discordance between PTT and degree of therapeutic anticoagulation, anti-Xa monitoring can be performed to measure the direct effects of IV UFH.
Clues that suggest discordance between PTT values and degree of anti-coagulation include, but are not limited to:
• Significant variability in PTT value that cannot be explained by changes in IV UFH doses.
• Recurrent thrombosis despite initiation of seemingly therapeutic anticoagulation
• Worsening clinical status despite initiation of seemingly therapeutic anticoagulation i.e. persistent tachycardia, hypoxia in someone with newly diagnosed pulmonary embolism
• “Therapeutic” PTT values at relatively low doses of IV UFH. Patients typically require 15-18 U/kg/hr for therapeutic anticoagulation.
11. What does it mean for anti-Xa and PTT values to lack concordance?
A therapeutic anti-Xa level is 0.3 – 0.7. PTT is therapeutic at a range of 55-90 seconds. To determine if the two are correlating, it is best to send both PTT and anti-Xa labs at the same time. It is simplest to check for correlation when PTT is in the therapeutic range. If PTT is therapeutic and anti-Xa is < 0.3, PTT is not a reliable marker for anticoagulation.
These labs should be drawn from the arm opposite to which IV UFH is running.
12. What should I do if anti-Xa level and PTT values are not concordant?
If a patient can be transitioned to LMWH, it would be reasonable to transition to therapeutic anticoagulation with LMWH. However, if the patient cannot be safely anticoagulated with LMWH, then IV UFH will need to be monitored by anti-Xa and the nursing driven PTT protocol should be discontinued. Unfortunately, to date, there is no anti-Xa protocol available in EPIC to guide IV UFH heparin dosing. However, there are a variety of resources available to assist with monitoring by anti-Xa. It is important to communicate with nursing about this change.
Pharmacy, hematology, and vascular medicine are all possible resources to reach out to.
Briefly, some key points regarding titration:
• Anti-Xa blood draws should ideally be drawn from the arm opposite to the heparin infusion or more distally if contralateral arm is not available.
• Therapeutic anti-Xa is 0.3 – 0.7
• Dose adjustments in IV UFH are typically made in increments of 10-20% depending on anti-Xa level. See below for a sample adjustment protocol.
• Anti-Xa is checked every 6 hours (like PTT).
• When anti-Xa is therapeutic on two consecutive draws (6 hours apart), anti-Xa can be checked daily.
Overview of Biologic Therapies Used at Boston Medical Center
Principles of therapeutics:
Unlike most other viral pneumonias, severe pulmonary symptoms in COVID-19 do not typically manifest till approximately a week after symptom onset. Many patients appear to be improving and then suddenly decompensate over hours and require intubation. Studies of inflammatory markers in COVID-19 patients suggest that the sudden decompensation is a consequence of a cytokine storm.
A proposed conceptual framework divides the disease into three stages (Siddiqi and Mehra) Stage I is dominated by viral replication and associated constitutional, respiratory, and gastrointestinal symptoms. Stage II (divided into A and B is when the host inflammation ramps up) and begins to manifest in terms of worsening dyspnea and new oxygen requirements. Stage III is marked by the cytokine storm which manifests as acute respiratory distress syndrome (ARDS) and shock.
At Boston Medical Center we have taken this framework into consideration while designing our treatment protocol.
We anticipate that drugs like Remdesivir and Selinexor have antiviral properties (through distinct mechanisms) are more effective in stage I. Our decompensating patients with accelerating oxygen requirements are likely in stage IIB and those who are in the ICU, particularly those ventilate are likely in stage III. For these patients, we have been using the following biologics.
Tocilizumab (TCZ) is a recombinant human IL-6 monoclonal antibody which binds to both cell-associated IL-6 (mIL-6R) and soluble IL-6 (sIL-6R) receptors, preventing classical and trans-IL-6 signaling. This blocks the cytokine’s mediated inflammatory response. TCZ is an approved treatment for severe life-threatening cytokine release syndrome (Xu, et al., Lee, et al., Zhang, et al.). Sarilumab is another IL-6 receptor agonist that is being considered as an alternative to Tocilizumab.
Tocilizumab (400 mg given intravenously over 1 hour) was tested in a Chinese study of 21 patients diagnosed with COVID-19. Tocilizumab was given one week after the onset of symptoms after the onset of fever caused deterioration. One day following the administration of the treatment, the temperature of all patients returned to normal and remained stable and one of the two patients on a ventilator was taken off. In the few days following the treatment administration, the peripheral oxygen saturation of all patients improved and 15 of the 21 patients lowered their oxygen intake. Both patients were taken off the ventilator within 5 days of administering the treatment. In 19 of the 21 patients, pulmonary lesions were absorbed and were later discharged (including two critical patients). No adverse drug reactions, subsequent pulmonary infections, or further deterioration was observed in any of the patients (Xu, et al., Fu, et al.).
In one study of 69 patients with severe COVID-19, subjects presented with a significantly increased baseline IL-6 (compared to their post-treatment levels of IL-6) which was correlated to the patient’s body temperature, CRP, LDH, ferritin, and D-dimer. It is suggested that baseline levels of IL-6 is correlated to the severity of the disease. The tendency showed that the lower the IL-6 level, the shorter the time from symptom onset to cure of the disease. Also, there was a tendency for the higher IL-6 levels to have a shorter lapse from symptom onset to pneumonia diagnosis. Remission of the disease presented with lower levels of IL-6 (Liu, et al.).
IL-6 has proven to enact a virus-specific humoral response (Jego, et al) which is why TCZ should not be administered in Phase I.
Our protocol is designed to give these IL-6 inhibitors during Phase IIb, prior to the hyperinflammatory phase. The reasoning is that by the time the patient is in phase III of disease, cytokine-mediated damage has largely already taken place. Observational internal data suggests that early administration of TCZ in phase IIb is associated with decreased mortality than administration is phase III.
There is now a clinical trial available to BMC patients whereby patients with lower oxygen requirements and inflammatory markers can receive tocilizumab. We expect these patients to be in Phase IIa.
Of note, tocilizumab and sarilumab both have long half-lives of 14 days.
Common adverse effects of IL6-inhibitors include transaminitis, infusion reactions, neutropenia, and ANC<1000). GI perforation has also been described and IL-6 inhibitors are avoided in patients at risk. Hepatitis B reactivation in surface antigen+ patients and TB reactivation is possible.
IL-1 is a target of interest in attempts to ameliorate the cytokine storm as it is a pro-inflammatory cytokine that induces tissue inflammation, fever, and fibrosis in viral infections. IL-1 is stimulated through activation of toll-like receptors (TLRs) and has been implicated in the hyperinflammatory response observed in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (sHLH) (Mehta et al.). Of note, IL-1 induces IL-6 and is itself induced by IL-6. Although MAS has been classically described in Epstein-Barr Virus infections, it has also been observed in other viral infections such as influenza and susceptibility to MAS may be genetic (Schulert and Cron).
It is believed that some patients with severe COVID-19 disease are exhibiting MAS and autopsy results at BMC have identified features of macrophage activation and hemophagocytosis in mediastinal lymph nodes. Such patients typically have highly elevated ferritin, triglycerides, D-dimers, decreased fibrinogen, and bicytopenia.
Anakinra is a recombinant IL-1 receptor antagonist which is routinely used for rheumatoid arthritis and has also been used for treatment of macrophage activation syndrome. (Sonmez et al) We believe that Anakinra may have a role in patients who manifest MAS due to COVID-19 and trials are already underway. Anakinra has a shorter half life (3-21h) than IL-6 inhibitors.
Like the IL-6 inhibitors, the BMC protocol has targeted Anakinra to phase IIb of disease.
We also have a trial ongoing at BMC of a monoclonal antibody called Canakinumab which blocks IL-1 signaling and has a long half-life for patients with lower oxygen requirements and inflammatory markers. We expect these patients to be in Phase IIa.
Anakinra is associated with headache, GI symptoms, nasopharyngitis, increased risk of infections, and eosinophilia.
Acknowledgements: Keianna Vogel and Chandler Annesi