How does heparin (unfractionated heparin) cause hyperkalemia (elevated potassium levels)?

From the Guidelines

Heparin causes hyperkalemia by inhibiting aldosterone production in the adrenal glands, leading to decreased potassium excretion in the kidneys, as noted in a study published in the European Heart Journal 1. This effect is dose-dependent and occurs with both unfractionated heparin and low-molecular-weight heparins, though it's more common with unfractionated heparin. Some key points to consider include:

• Hyperkalemia typically develops after several days of heparin therapy and is more likely in patients with risk factors such as renal impairment, diabetes, or those taking other medications that can raise potassium levels.
• The potassium elevation is usually mild to moderate (typically 0.5-1.5 mEq/L above baseline) but can occasionally be severe.
• Monitoring potassium levels is important for patients on prolonged heparin therapy, especially those with risk factors, as emphasized in a study published in the Mayo Clinic Proceedings 1.
• The hyperkalemia generally resolves within 1-3 days after discontinuing heparin.
• For patients requiring continued anticoagulation with hyperkalemia, switching to direct oral anticoagulants or fondaparinux may be considered as these agents don't typically affect potassium levels. It's also worth noting that heparin is listed as a drug that may cause hyperkalemia due to decreased potassium excretion in the European Heart Journal study 1. Additionally, a study published in Diabetes Care highlights the importance of monitoring serum creatinine and potassium levels after initiation of treatment with an ACE inhibitor or ARB, MRA, or diuretic, particularly among individuals with reduced glomerular filtration who are at increased risk of hyperkalemia and AKI 1. Overall, the most recent and highest quality study, published in 2021 in the Mayo Clinic Proceedings, supports the notion that heparin can cause hyperkalemia by inhibiting aldosterone production, leading to decreased potassium excretion 1.

From the Research

Mechanism of Heparin-Induced Hyperkalemia

• Heparin is a predictable and potent inhibitor of aldosterone production, which can lead to hyperkalemia 2, 3, 4.
• The inhibitory effect of heparin on aldosterone production is specific to the zona glomerulosa and occurs within a few days of initiation of therapy 2.
• The mechanism of aldosterone inhibition by heparin involves reduction in both the number and affinity of angiotensin-II receptors in the zona glomerulosa 2.
• Heparin-induced aldosterone suppression results in natriuresis and decreased excretion of potassium, leading to hyperkalemia 2, 5, 6.

Risk Factors for Heparin-Induced Hyperkalemia

• Prolonged use of heparin increases the risk of hyperkalemia 2, 3, 4.
• Patients with renal insufficiency, diabetes mellitus, or those taking certain medications are at higher risk of developing hyperkalemia while on heparin therapy 2, 3, 6, 4.
• The use of unfractionated heparin (UH) may be associated with a higher risk of hyperkalemia compared to low molecular weight heparin (LMWH) 5.

Clinical Implications

• Serum potassium levels should be monitored periodically in patients receiving heparin for 3 or more days, especially in those at high risk of hyperkalemia 2, 3.
• Clinicians should be aware of the potential for heparin-induced hyperkalemia and take steps to prevent and manage it 2, 3, 4.