What causes heparin resistance in critically ill patients with sepsis and multiple organ dysfunctions?

Heparin Resistance in Sepsis

Heparin resistance in sepsis occurs primarily because elevated acute phase reactants—particularly fibrinogen, C-reactive protein, and other heparin-binding proteins—bind to and neutralize heparin, creating a prohemostatic environment that antagonizes its anticoagulant effects. 1

Primary Mechanisms

Acute Phase Protein Binding

• Hyperfibrinogenemia is the key factor causing heparin resistance in septic patients, as elevated fibrinogen levels directly bind to heparin molecules and reduce their bioavailability 1
• C-reactive protein and other heparin-binding acute phase reactants are markedly elevated during the inflammatory response in sepsis, creating additional binding sites that sequester heparin away from its anticoagulant targets 1
• These proteins compete with antithrombin III for heparin binding, reducing the formation of the heparin-antithrombin complex necessary for anticoagulation 1

Cellular Sequestration

• Activated macrophages and endothelial cells—both prominently activated in sepsis—bind and internalize heparin, further reducing circulating bioavailable drug 1
• The systemic inflammatory response characteristic of sepsis causes widespread endothelial activation, creating numerous additional binding sites for heparin on vascular surfaces 1

Antithrombin Depletion

• While moderate to severe antithrombin deficiency is uncommon in most septic patients (levels typically remain around 80%), antithrombin levels can fall below 60% in critically ill patients with multiple organ dysfunction 1
• Antithrombin levels decrease in sepsis through multiple mechanisms: increased vascular permeability causing extravasation, consumption by pathologically activated coagulation, cleavage by proteases, and decreased hepatic synthesis during acute hepatic dysfunction 1
• Since heparin requires antithrombin to exert its anticoagulant effect, even modest reductions in antithrombin levels can contribute to apparent heparin resistance 1

Additional Contributing Factors

Thrombocytosis

• Excessive thrombopoietin production by the liver during sepsis can cause thrombocytosis, which has been suggested as an additional mechanism for heparin resistance 1
• Elevated platelet counts provide more surface area for thrombin generation, potentially overwhelming heparin's anticoagulant capacity 1

Hypercoagulability

• The FDA label specifically notes that heparin resistance is frequently encountered in fever, thrombosis, thrombophlebitis, and infections with thrombosing tendencies 2
• Sepsis-induced coagulopathy involves systemic activation of coagulation with suppression of fibrinolysis, creating a prothrombotic state that requires higher heparin doses to overcome 1

Clinical Definition and Recognition

• Heparin resistance is defined as requiring daily UFH doses exceeding 35,000 units to achieve therapeutic aPTT or the inability to achieve therapeutic anticoagulation despite high doses 1, 3
• The FDA label recommends close monitoring of coagulation tests in patients with fever, thrombosis, and infections, as these conditions frequently cause heparin resistance 2

Practical Management Strategies

Monitoring Approach

• Measure both aPTT and concomitant anti-factor Xa heparin levels when heparin resistance is suspected, as aPTT may be unreliable in inflammatory states 1
• The FDA label recommends adjustment of heparin doses based on anti-Factor Xa levels in cases of suspected resistance 2
• Point-of-care aPTT testing may be influenced by elevated acute phase reactants, making anti-Xa monitoring more reliable in septic patients 1, 4

Alternative Anticoagulation

• If monitoring is impractical or resistance persists, consider longer-acting, non-aPTT adjusted subcutaneous fondaparinux or danaparoid if renal function is normal 1
• Prophylactic-dose LMWH (dalteparin) has been studied in critically ill patients with markedly impaired renal function without adverse effects 1
• Direct thrombin inhibitors (bivalirudin or argatroban) represent alternative options when heparin resistance cannot be overcome 4

Antithrombin Supplementation

• While antithrombin supplementation is theoretically attractive for overcoming heparin resistance, large trials have not demonstrated mortality benefit, and concomitant heparin administration may impair antithrombin's beneficial effects 1
• Subgroup analyses suggest antithrombin may be effective in septic patients with coagulopathy who are not receiving concurrent heparin 1

Common Pitfalls

• Do not assume therapeutic anticoagulation based solely on aPTT in septic patients—inflammatory mediators can prolong aPTT independent of heparin effect, while acute phase reactants can normalize aPTT despite subtherapeutic anticoagulation 1, 4
• Avoid attributing all cases of elevated heparin requirements to "resistance"—ensure weight-based dosing is being used, as early reports of resistance used total daily doses without weight adjustment 4
• Consider that lupus anticoagulants and antiphospholipid antibodies can develop during severe infections and may confound aPTT-based monitoring 1, 4