Heparin Resistance

Heparin resistance is a challenging condition that occurs when unusually large doses of heparin are needed to achieve the desired level of blood thinning. This problem has gained increased attention in intensive care units, particularly during the COVID-19 pandemic, when many critically ill patients required anticoagulation but failed to respond to standard heparin doses.

Table of contents

• What Is Heparin Resistance?
• How Common Is Heparin Resistance?
• What Causes Heparin Resistance?
• How Is Heparin Resistance Diagnosed?
• Treatment Options

What Is Heparin Resistance?

Heparin resistance occurs when the anticoagulant response to heparin is inadequate, requiring higher doses than usual to achieve the blood-thinning effect needed for treatment.^[1] In simple terms, it means that heparin medication does not work as well as expected, and doctors need to use much more of it to prevent blood clots.^[2]

There is no universal agreement on the exact definition of heparin resistance. Different medical centers use different criteria. Some define it as requiring more than 35,000 units of unfractionated heparin (a type of blood-thinning medication) per day, while others use weight-based definitions such as more than 20 units per kilogram of body weight per hour.^[1] For patients undergoing heart surgery with cardiopulmonary bypass, heparin resistance is more specifically defined as needing more than 500 units per kilogram of heparin to achieve proper anticoagulation levels.^[4]

Unfractionated heparin remains the anticoagulant of choice in many intensive care unit patients, particularly those with severe multi-organ failure or those requiring extracorporeal circuits like extracorporeal membrane oxygenation (ECMO).^[1] This is because it has rapid onset and offset of action, and can be fully and rapidly reversed with protamine when needed.

How Common Is Heparin Resistance?

The reported incidence of heparin resistance ranges between 4% and 26%, depending on the initial heparin dose given and the target level of anticoagulation required.^[4] The variation in these numbers reflects differences in how heparin resistance is defined and measured in different clinical settings.

During the COVID-19 pandemic, heparin resistance was increasingly reported in critically ill patients.^[1] This highlighted the importance of understanding and managing this condition in intensive care settings, where patients are often very sick and have multiple medical problems.

What Causes Heparin Resistance?

Heparin works by binding to a protein called antithrombin (formerly known as antithrombin III) in the blood. When heparin binds to antithrombin, it makes antithrombin much more effective at stopping blood clots from forming.^[4] Heparin resistance can occur when this process is disrupted.

The most common cause of heparin resistance is antithrombin deficiency.^[4] If a patient does not have enough antithrombin in their blood, heparin cannot work properly because it needs antithrombin to produce its blood-thinning effect.

Other causes of heparin resistance include:^[2][4]

• Increased levels of proteins that bind to heparin, reducing the amount of free heparin available to work
• Increased clearance of heparin from the body
• Hypercoagulability, a state where blood clots more easily than normal
• Use of certain medications like andexanet alfa
• Thrombocytosis, which is an elevated platelet count
• Antiphospholipid antibody syndromes

Systemic inflammation, which is common in intensive care unit patients, increases the production of proteins that bind heparin. This makes heparin resistance particularly common among sicker patients with more severe inflammation.^[4] This is one reason why heparin resistance is frequently seen in critically ill patients.

How Is Heparin Resistance?

Heparin resistance should be suspected when usual heparin doses fail to prolong blood clotting time tests to the desired therapeutic range.^[4] Diagnosis generally involves clinical suspicion and laboratory confirmation.

Several laboratory tests can help diagnose heparin resistance:^[4]

• Activated partial thromboplastin time (aPTT): a clot-based test used for patients on the ward or in intensive care units
• Activated clotting time (ACT): used for patients undergoing vascular interventions and cardiopulmonary bypass
• Antithrombin activity levels: can be measured using specialized assays
• Heparin levels: can be measured directly
• Anti-factor Xa testing: increasingly used for heparin monitoring as it may be less affected by other factors

Traditional clot-based tests like aPTT may be highly influenced by other factors occurring in many patients, especially those with inflammation or acute infection.^[2] This is particularly important because inflammation can make these tests show falsely low anticoagulation levels even when heparin is working properly, a situation sometimes called “pseudo heparin resistance.”

Treatment Options

Several approaches can be used to manage patients with heparin resistance. The choice of treatment depends on the underlying cause and the clinical situation.^[2]

Common management strategies include:^[4]

• Administration of additional heparin: This is often the first step. If blood clotting tests show inadequate anticoagulation, additional heparin is typically given, sometimes up to 500 units per kilogram of body weight
• Weight-based dosing: Using the patient’s body weight to calculate the heparin dose may be more appropriate than fixed daily doses
• Antithrombin supplementation: This is the treatment of choice when heparin resistance is due to antithrombin deficiency. Antithrombin administration is highly recommended to reduce the need for fresh frozen plasma transfusion in certain situations
• Fresh frozen plasma (FFP): Can be used if antithrombin concentrates are not available, though much larger volumes may be required (more than 500-1000 milliliters), which increases risks
• Alternative anticoagulants: If antithrombin supplementation and increased heparin doses do not work, alternative medications that do not require antithrombin may be used, such as the direct thrombin inhibitors bivalirudin or argatroban

Higher doses of heparin may increase the risk of bleeding due to heparin rebound and the nonspecific binding of heparin to plasma proteins.^[4] Therefore, careful monitoring is essential when using increased doses of heparin.

The management of heparin resistance requires careful consideration of the individual patient’s situation, the availability of laboratory testing, and the potential risks and benefits of different treatment approaches.^[2]