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Heparin Resistance in COVID‑19 Patients.pptx
- 1. Heparin Resistance in COVID-19 Patients
- 2. Learning Objectives Recall the mechanism of action of Unfractionated Heparin (UFH) 1 Explain the mechanisms of action of Heparin resistance 2 Recall the clinical evidence related to COVID-19 and Heparin resistance 3
- 3. Patient Case #1 O2 sats: 91% on room air HR: 130 RR: 22 Temp 98.9 WBC 16.01 Procal 0.53 Lactic Acid 1.24 COVID-19 positive Initial vitals and labs:
- 4. Imaging Studies Chest CT: Acute pulmonary embolus to the left posterior basilar segmental and subsegmental pulmonary arterial branches. Small clot burden with no evidence of right heart strain.
- 5. Initial Coagulation Labs Lab Value PT 12.3 (9.5-11.6) INR 1.2 (0.9-1.1) APTT 29.0 (26.0-39.0) Fibrinogen 274 (170-400) D-Dimer 6.39 (0-0.50) Anti-Xa < 0.10 (0.3-0.7)
- 6. Per MMC Protocol, What Would be our Initial Bolus and Drip? *** ROUND TO THE NEAREST 100 *** Heparin bags are 25,000 units/250 mL
- 7. Per MMC Protocol, What Would be our Initial Bolus and Drip? 60.6 kg 62 kg 59.2 kg 4800 900 9 *** ROUND TO THE NEAREST 100 *** Heparin bags are 25,000 units/250 mL
- 9. Patient Case #2 O2 sats: 72% on room air HR: 114 RR: 24 Temp 97.9 WBC 13.32 Procal 0.10 Lactic Acid 0.93 COVID-19 positive Initial vitals and labs:
- 10. Imaging Studies Chest CT: Small left lower lobe peripheral pulmonary embolism, with evidence of right heart strain
- 11. Initial Coagulation Labs Lab Value PT 11.9 (9.5-11.6) INR 1.1 (0.9-1.1) APTT 33.4 (26.0-39.0) Fibrinogen None D-Dimer 3.07 (0-0.50) Anti-Xa < 0.10 (0.3-0.7)
- 12. Anti-Xa Trend
- 13. When assessing the patients’ trends of Anti-Xa lab results, what may you think is causing the consistent subtherapeutic levels?
- 14. When assessing the patients’ trends of Anti-Xa lab results, what may you think is causing the consistent subtherapeutic levels?
- 15. Background
- 16. Review of COVID- 19 and possible mechanisms for hypercoagulability
- 17. What is Heparin’s Mechanism of Action?
- 18. What is Heparin’s Mechanism of Action?
- 21. Mechanisms of Heparin Resistance Pseudo heparin resistance: Titrating Heparin using PTT. High levels of factor VIII and/or fibrinogen can decrease the PTT value. Artificially low PTT values make it appear as if heparin isn’t working. Antithrombin III deficiency: caused by many things (e.g., liver disease, acute thrombosis, disseminated intravascular coagulation). Since heparin works via binding to antithrombin III, this deficiency leads to true physiological heparin resistance. Low heparin concentration due to binding by acute-phase proteins: Systemic inflammation increases the production of proteins that bind heparin (e.g., platelet factor 4).
- 22. Heparin Resistance in COVID-19 Patients in the Intensive Care Unit Retrospective cohort study in May 2020 • Objectives: • To review the clinical and laboratory evidence for heparin resistance in patients with COVID-19 at the Intensive Care Unit at Addenbrooke’s Hospital (Cambridge, United Kingdom). • 69 patients who had been admitted with COVID-19 to the ICU in the study period • 15 had been on treatment doses of either unfractionated heparin (UFH) or low molecule weight heparin (LMWH) White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;50(2):287-291. doi:10.1007/s11239-020-02145-0
- 23. Heparin Resistance in COVID-19 Patients in the Intensive Care Unit • Of the 10 infusions of UFH, 8 patients had heparin resistance (> 35,000 units/day) and of these 8 patients, 3 required > 50,000 units heparin per day to maintain the target APTR. White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;50(2):287-291. doi:10.1007/s11239-020-02145-0
- 24. Heparin Resistance in COVID-19 Patients in the Intensive Care Unit • UFH may be desirable for thrombosis in the ICU in COVID-19 to ensure therapeutic anticoagulation • Further studies are required to determine the best option for thromboprophylaxis and management of thrombosis in patients with COVID-19 as well as to determine the mechanism of heparin resistance White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;50(2):287-291. doi:10.1007/s11239-020-02145-0
- 25. What is the Mechanism of Heparin Resistance Seen in COVID Patients? • Likely that the main mechanism is that Heparin may be bound by proteins circulating in the blood (rather than being adsorbed and exerting its effect in the body). In vitro studies using blood from COVID patients have shown that adding heparin produces lower anti-Xa activity than expected. • May have some antithrombin III deficiency, but studies reported that the levels are not reduced enough to cause heparin resistance on its own. • May be a mix of mechanisms. Further evidence is needed to determine a true mechanism of heparin resistance in COVID-19 patients.
- 26. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2 • Case report of four patients with an indication for therapeutic anticoagulation. • Treatment in all four patients was complicated by requiring high UFH doses in order to achieve adequate coagulation, based on the aPTT ratio. • Factor VIII, fibrinogen and d-dimer were found to be elevated in these patients, while almost all the antithrombin levels were in the normal range. Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. International Journal of Laboratory Hematology. 2020;42(S1):19-20. doi:10.1111/ijlh.13230
- 27. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2 • Authors explained the increased Factor VIII levels seem to decrease or normalize the in vitro anticoagulant activity of heparin (measured by aPTT assay), while the in vivo antithrombotic activity of heparin remains unaffected (measured by anti-Xa assay). • Authors suggest to monitor the heparin activity of UFH treatment based on anti-Xa levels with a target value of 0.3-0.7 U/L in all patients with SARS-CoV-2 instead of treatment based on aPTT levels, as it appeared to show more accurate levels. Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. International Journal of Laboratory Hematology. 2020;42(S1):19-20. doi:10.1111/ijlh.13230
- 28. How can we manage a patient with Heparin resistance?
- 29. Management of Heparin Resistance • Heparin doses may need to be aggressively escalated to achieve a therapeutic effect • Argatroban as a possible alternative to heparin for treatment dosing of anticoagulants in COVID-19 patients • Treatment dose Enoxaparin
- 30. Heparin drip may be the optimal treatment for our COVID-19 patients. The drip will allow for immediate detection of heparin resistance and higher titration as necessary to achieve therapeutic levels. Monitoring of anti-Xa levels is likely superior to monitoring of PTT levels, as it does not have the potential factors that affect the levels (liver disease, etc). If using Enoxaparin for COVID-19 patients with Heparin resistance, it may be of benefit to monitor Anti-Xa to ensure that patients are not receiving subtherapeutic dosing. It is important to complete case reports, when they occur, to allow for this potential problem to be brought to the attention of the medical community Applying to Practice
- 31. Summary of Patient Cases • Both Heparin drips were changed to treatment dose Enoxaparin (Case #1: 60 mg SC twice daily and Case #2: 70 mg twice daily) • What labs would you monitor while patient is on Enoxaparin?
- 32. Post Presentation Questions • What is the mechanism of action of Unfractionated Heparin (UFH)? • What is one possible mechanism for heparin resistance? • Based on the clinical evidence that is currently published, what would you recommend for management of a COVID-19 patient with heparin resistance (Utilizing > 35,000 units/day).
- 33. Post Presentation Questions • What is the mechanism of action of Unfractionated Heparin (UFH)? Heparin + Anti-thrombin III → [Heparin-Antithrombin-III complex] → Prevents formation of clots • What is one possible mechanism for heparin resistance? • Pseudo heparin resistance • Antithrombin III deficiency • Low heparin concentration due to binding by acute-phase proteins • Based on the clinical evidence that is currently published, what would you recommend for management of a COVID-19 patient with heparin resistance (Utilizing > 35,000 units/day). Answers may vary. Increase the Heparin drip dose, change to treatment Enoxaparin, consider Argatroban
- 34. Questions?
- 35. References • Antithrombotic Therapy. COVID-19 Treatment Guidelines. Accessed February 6, 2022. https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy/ • White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;50(2):287-291. doi:10.1007/s11239-020-02145-0 • Perepu US, Chambers I, Wahab A, et al. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial. Journal of Thrombosis and Haemostasis. 2021;19(9):2225-2234. doi:10.1111/jth.15450 • Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin. Handb Exp Pharmacol. 2012;(207):43-61. doi:10.1007/978-3-642-23056-1_3 • Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. International Journal of Laboratory Hematology. 2020;42(S1):19-20. doi:10.1111/ijlh.13230
Editor's Notes
- Decision was to start patient on heparin gtt. While on the heparin gtt, this was our trend in Anti-Xa…
- So patient gets started on a heparin drip and the team notices…
- That despite being on heparin and titrating per protocol, the lab value stayed subtherapeutic.
- Decision was to start patient on heparin gtt. While on the heparin gtt, this was our trend in Anti-Xa…
- COVID-19 has been associated with inflammation and a prothrombotic state, with increases in fibrin, fibrin degradation products, fibrinogen, and D-dimers.
- There has been discussion on COVID-19 and its hypercoagulable state. It is thought that there is a cascading relationship between endothelial injury, inflammatory and immune activation, and coagulation. SARS-CoV-2 enters host cells via an interaction between the viral spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor expressed in numerous organs and tissues, including pulmonary alveolar type 2 epithelial cells (which produce surfactant), the brain, heart, kidney and endothelium. ACE2 normally degrades angiotensin II, and SARS-CoV-2–mediated downregulation of ACE2 may lead to accumulation of angiotensin II, which may contribute to a procoagulant state. Injury to the endothelium initiated by SARS-CoV-2 entry into these cells is thought to play a key role, and likely explains the pathologic evidence of diffuse endotheliitis (or inflamed endothelium) in multiple organs, including lungs, kidneys, heart and intestines. The endotheliopathy may lead to an inflammatory host response characterized by excessive immune activation and cytokine storm, which promotes hypercoagulability and thrombosis. Pseudo heparin resistance: Titrating Heparin using PTT. High levels of factor VIII and/or fibrinogen can decrease the PTT value. Artificially low PTT values make it appear as if heparin isn’t working. To remedy this, the use of anti-Xa levels avoids the issue of pseudo resistance entirely since it is not specifically looking at factor VIII or fibrinogen.
- Give me an example of a drug from answer B, C, D…
- Heparin Intrinsic pathway inhibited = prolongs PTT
- Also inhibits factors 9, 10, 11 and 12 in addition to II and Xa
- Of the 10 infusions of UFH, 8 patients, or 80%, had heparin resistance (which was defined as using > 35,000 units/day) and of these 8 patients, 3 required > 50,000 units heparin per day to maintain the target APTR (and this was not including the 5000 unit loading dose).
- APTR therapeutic range was 1.5–2.5 APTR, defined as the activated partial thromboplastin time (APTT) divided by the mean of the reference range
- With higher levels of factor VIII and fibrinogen, some amount of pseudo resistance might be expected. A few patients did seem to exhibit some pseudo-resistance (subtherapeutic APTT ratio despite a therapeutic anti-Xa level). Study may not be large enough to make a clinical conclusion. Use of anti-Xa levels avoids the issue of pseudo resistance entirely. Numerous studies have reported on antithrombin III level and authors have concluded that these levels, although slightly reduced, was not reduced enough to cause heparin resistance (e.g., not <50% activity).
- Heparin doses may need to be aggressively escalated to achieve a therapeutic effect. One study had greater than 64,500 units/day heparin in one patient with COVID-19. Argatroban is a direct thrombin inhibitor- does not use any cofactors, binds to the catalytic site of thrombin to exert its anticoagulant action. Downfall is you may have this return mechanism of pseudo-resistance with the aPTT monitoring of Argatroban Treatment dose Enoxaparin with Anti-Xa monitoring
- Limitations: New disease state for us to understand Not many studies out that identify heparin resistance in COVID-19 patients Enox: If enoxaparin is used without anti-Xa level monitoring, it’s possible that patients could have occult heparin resistance and ineffective treatment.
- Heparin doses may need to be aggressively escalated to achieve a therapeutic effect. One study had greater than 64,500 units/day heparin in one patient with COVID-19. Argatroban is a direct thrombin inhibitor- does not use any cofactors, binds to the catalytic site of thrombin to exert its anticoagulant action. Downfall is you may have this return mechanism of pseudo-resistance with the aPTT monitoring of Argatroban Treatment dose Enoxaparin with Anti-Xa monitoring
- Pseudo heparin resistance: Titrating Heparin using PTT. High levels of factor VIII and/or fibrinogen can decrease the PTT value. Artificially low PTT values make it appear as if heparin isn’t working. Antithrombin III deficiency: caused by many things (e.g., liver disease, acute thrombosis, disseminated intravascular coagulation). Since heparin works via binding to antithrombin III, this deficiency leads to true physiological heparin resistance. Low heparin concentration due to binding by acute-phase proteins: Systemic inflammation increases the production of proteins that bind heparin (e.g., platelet factor 4).