To the Editor,

Table APTT and anti-Xa assay values as well as factor VIII, fibrinogen, and antithrombin levels of the patient described
Full size table

Coagulation derangements commonly observed in critically ill patients can result in both true and pseudo heparin resistance. Failure to correctly identify the underlying mechanism of action can lead to inappropriate dosing of heparin and potentially devastating complications. We describe a case of a patient with pseudo heparin resistance caused by elevated factor VIII to review current methods of heparin monitoring and the diagnostic approach to heparin resistance.

A 57-yr-old male underwent a Bentall procedure to repair an enlarged aortic root and bicuspid aortic valve. Postoperatively, his respiratory status declined requiring mechanical ventilation. His clinical deterioration was thought to be multifactorial (pneumonia, congestive heart failure, and chronic obstructive pulmonary disease exacerbation). On postoperative day 22, heparin was started for atrial fibrillation with a target activated partial thromboplastin time (APTT) of 70–90.9 sec. On postoperative day 27, there was difficulty obtaining therapeutic APTT values with persistently subtherapeutic results despite high heparin usage. At the same time, bleeding was noted from the sternal wound and heparin was held. In the preceding 24 hr, the patient had received 56,000 units of heparin (average 2,333 units·hr−1, patient weight 113 kg). To investigate for heparin resistance, anti-Xa assay levels were sent. A discordance was repeatedly observed between APTT values, which remained subtherapeutic, and the anti-Xa values, which were supratherapeutic. The patient’s factor VIII level was consistently above 5.5 IU·mL−1 (normal reference interval > 0.50 IU·mL−1). Lab values are summarized in the Table.

Heparin resistance is defined as the need for greater than 35,000 units of heparin in 24 hr to reach therapeutic APTT levels.1 When discovered, the first step is to determine whether there is true heparin resistance (in vivo blunting of heparin’s anticoagulant effect) or pseudo (also known as apparent) heparin resistance, where there are subtherapeutic APTT values despite therapeutic in vivo anticoagulation. To help differentiate true from pseudo heparin resistance, the APTT and anti-Xa assay levels should be measured on the same sample. The anti-Xa assay relies on free factor Xa (i.e., not bound by the antithrombin-heparin complex) interacting with a substrate and producing a measurable colour change. The anti-Xa assay, unlike the APTT assay, is not affected by other clotting factors (e.g., factor VIII) or acute-phase reactants.

True heparin resistance, where the APTT and anti-Xa levels are concordantly lower than expected, is commonly associated with decreased antithrombin and this should be measured as part of the diagnostic evaluation.2 While heparin itself can lower antithrombin activity levels directly by up to 30% through increasing the enzyme’s clearance, this rarely requires antithrombin replacement.3 Other causes of true heparin resistance include increased clearance of heparin4 and increased non-specific protein binding.5 The latter can be induced by inflammatory states.

In our case, given the discrepancy between APTT and anti-Xa assay results, pseudo heparin resistance was suspected. Notably, the patient was bleeding from his sternal wound, suggesting supratherapeutic anticoagulation and strengthening the case for pseudo heparin resistance. Relying on the APTT results may have led to inappropriate escalations of his heparin dose and catastrophic bleeding. The patient’s pseudo heparin resistance was likely secondary to extremely elevated factor VIII levels, which can shorten the APTT but do not affect anti-Xa assay results. Acute increases in factor VIII levels can be a marker of generalized inflammation and often correlate with other acute-phase reactants.

Heparin resistance is a complex but underappreciated complication of heparin use. We advocate for a multifaceted approach to the diagnosis of heparin resistance that includes bedside examination as well as assessment of antithrombin and factor VIII levels.