Resistance is Futile!

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Picture of Lauren Igneri
Lauren Igneri
Critical care pharmacist and proud Rutgers University graduate. Enjoys rock climbing, cycling, travel, and lively discussions on the finer points of pharmacokinetics and critical care over a beer with friends.

Case

A 23-year-old woman (70 kg) struck by an automobile is admitted to the trauma ICU. She is found to have a subdural hematoma. On hospital day four, CT venogram reveals cortical vein thrombosis and suboccipital vein thrombosis with extension from the right internal jugular vein, and she is incidentally found to be COVID-19 positive. Neurosurgery clears the patient for anticoagulation on hospital day 10 with IV unfractionated heparin (UFH) protocol targeting and anti-Xa level 0.3 to 0.7 units/mL. Despite 48 hours of IV UFH dose escalation (up to 36 units/kg/hr), the patient’s anti-Xa levels remain <0.10 units/mL. 

The nurse calls the critical care pharmacist since the heparin rate is the “highest I’ve ever seen” and wants to know if there is another anticoagulant that can be used. The peripheral IV is functioning and there are no signs of extravasation.

You and the trauma team discuss the possibility of heparin resistance and develop an alternative anticoagulation plan.

The Pre-brief

  • Heparin resistance is defined as the lack of expected response to standard therapeutic doses.
    • Biological changes in IV UFH binding targets or proteins may cause resistance.
  • Standard criteria for heparin resistance are lacking, but the following have been suggested:
    • Need for more than 35,000 units/day of IV UFH to achieve anticoagulation goals.
    • Need for more than 5000 units/kg to achieve an activated clotting time (ACT) of 400-480 seconds in patients undergoing cardiopulmonary bypass.

Before you resist, take a moment to understand…

The anticoagulant properties of IV UFH ultimately result from inhibition of thrombin (factor IIa) and factor Xa. Heparin is a polysaccharide polymer with a terminal pentasaccharide sequence that binds to antithrombin. IV UFH contains polymers of varying lengths (3000-30,000 daltons) and once bound to antithrombin, inhibitory effects are exerted through either thrombin or factor Xa binding depending on a given polymer’s length. In contrast, low-molecular-weight heparins (LMWH) have shorter, uniform lengths (molecular weights 3500-5000 daltons) that are better suited to inhibit factor Xa. Therefore, LMWH inhibits factor Xa two to four times more often than thrombin. Direct thrombin inhibitors (DTI) (e.g. argatroban and bivalirudin) directly inhibit thrombin independent of antithrombin.

Causes of heparin resistance

Heparin molecules are negatively charged and bind non-specifically to many proteins (e.g. platelet factor 4, lipoproteins, collagen, fibrinogen, microbial proteins, von Willebrand factor, factor VIII, and fibrinogen) and other surfaces (e.g. monocytes, endothelial cells, growth factors, IV tubing, ECMO circuits). Non-specific binding results in great interpatient dosing variability to achieve a therapeutic response.

Antithrombin deficiency is another common cause of heparin resistance and may be acquired in patients with liver disease, sepsis, DIC, leukemia, and with the use of ECMO or cardiopulmonary bypass. Use of heparin itself can cause reductions in antithrombin levels. 

Heparin can activate platelets and result in release of platelet factor 4, formation of heparin-antibodies, and development of heparin-induced thrombocytopenia, a known cause of heparin resistance. Patients with acute inflammatory states, including COVID-19, have increased factor VIII and fibrinogen levels which shorten aPTT, but do not impact anti-Xa level. Higher IV UFH doses may be needed to achieve therapeutic anticoagulation targets if using aPTT to monitor this population. In patients with COVID-19, LMWH is preferred over UFH based on the available literature.

Additionally, patients who have been reversed with andexanet alfa prior to cardiac surgery have been shown to have increased IV UFH dosing requirements in the perioperative period.

Risk factors for heparin resistance

  • Low antithrombin levels
  • Age ≥65 years
  • Preoperative heparinization
  • Albumin ≤3.5 g/dL
  • Platelets ≥300,000/mL
  • High fibrinogen levels
  • Infective endocarditis
  • Inflammatory states, including COVID-19

Identifying and treating heparin resistance 

Heparin resistance should be suspected in critically ill patients requiring more than 35,000 units/day of IV UFH to achieve anticoagulation goals, or when very high heparin doses fail to meet anticoagulation targets. 

Switching from activated partial thromboplastin time (aPTT) to anti-Xa monitoring is preferred when heparin resistance is suspected. Anti-Xa monitoring is likely more accurate in patients with high inflammatory states, including COVID-19. Dosing of IV UFH should be optimized to achieve anti-Xa of 0.3 to 0.7 units/mL.

While antithrombin supplementation may overcome heparin resistance, improve ACT results, and reduce the dose of heparin required to achieve therapeutic anticoagulation, no robust literature exists to guide antithrombin dosing outside of cardiopulmonary bypass and is largely based on expert opinion.

When escalating heparin doses fail to meet the specified targets within a reasonable time frame or heparin-induced thrombocytopenia is suspected, alternative anticoagulation with DTIs should be considered to manage the patient. DTI selection should be based on patient comorbid conditions and/or organ dysfunction. Argatroban is hepatically metabolized and may not be suitable for those with severe liver dysfunction. Bivalirudin may be used in patients with chronic kidney disease, but renal dose adjustment is required. 

Debrief

  • Heparin resistance is commonly identified when there is a need for greater than 35,000 units/day of IV UFH to achieve anticoagulation goals.
    • In cardiopulmonary bypass, greater than 5000 units/kg to achieve an ACT of 400-480 seconds.
  • Risk factors for heparin resistance include low antithrombin levels, age ≥65 years, preoperative heparinization, albumin ≤3.5 g/dL, platelets ≥300,000/mL, high fibrinogen levels, infective endocarditis, high Inflammatory states, and potentially COVID-19.
  • Anti-Xa monitoring targeting a goal of 0.3 to 0.7 units/mL should be implemented in suspected heparin resistance.
  • Anticoagulation with DTIs should be considered when escalating IV UFH doses fail to meet the therapeutic targets or heparin-induced thrombocytopenia is suspected.
    • Base DTI selection on patient comorbid conditions and/or organ dysfunction.

References

  • Levy JH, Connors JM. Heparin Resistance – Clinical Perspectives and Management Strategies. N Engl J Med. 2021; 385(9):826-832. doi: 10.1056/NEJMra2104091.
  • Kimura Y, Okahara S, Abo K, et al. Infective Endocarditis Is a Risk Factor for Heparin Resistance in Adult Cardiovascular Surgical Procedures: A Retrospective Study. J Cardiothorac Vasc Anesth. 202; 35(12):3568-3573. doi: 10.1053/j.jvca.2021.05.024.

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