Why would a patient not respond to heparin (unfractionated heparin) therapy?

From the Guidelines

A patient may not respond to heparin therapy due to heparin resistance, which can occur in the setting of an acute phase response, such as in COVID-19 patients, where elevated levels of fibrinogen and other heparin-binding acute-phase reactants can antagonize the anticoagulant effects of heparin. Heparin resistance is defined as the requirement of high doses of unfractionated heparin (UFH) to achieve a therapeutic range, and it can be caused by various factors, including antithrombin deficiency, increased heparin clearance, or elevated levels of heparin-binding proteins 1. Other causes of apparent heparin non-response include medication interactions, incorrect dosing, laboratory errors in monitoring, or increased heparin clearance in conditions like fever, sepsis, or hyperthyroidism.

Some key points to consider when evaluating heparin resistance include:

• Elevated fibrinogen levels, which can bind to heparin and reduce its anticoagulant effect 1
• Increased levels of other heparin-binding acute-phase reactants, such as C-reactive protein 1
• Antithrombin deficiency, which can be congenital or acquired 1
• Increased heparin clearance, which can occur in conditions like fever, sepsis, or hyperthyroidism 1

Management of heparin resistance typically involves switching to alternative anticoagulants, such as direct thrombin inhibitors (bivalirudin, argatroban) or factor Xa inhibitors (fondaparinux), while investigating the underlying cause 1. It is also important to monitor the patient's aPTT and anti-factor Xa heparin levels to adjust the dose of heparin accordingly 1.

In patients with severe renal impairment, at high risk of bleeding, or in need of invasive procedures, UFH may be preferred over low molecular weight heparin (LMWH) due to its shorter half-life and ability to be rapidly reversed with protamine sulfate 1. However, LMWH can be used as an alternative to UFH in patients with normal renal function, and it has the advantage of being easier to administer and monitor 1.

Overall, heparin resistance is a complex phenomenon that requires careful evaluation and management to ensure effective anticoagulation and minimize the risk of bleeding complications. The most recent and highest quality study on this topic is the 2020 study by the ISTH Dic Subcommittee on Anticoagulation in COVID-19, which highlights the importance of considering heparin resistance in patients with COVID-19 1.

From the FDA Drug Label

If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. Resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin III deficiency.

A patient may not respond to heparin (unfractionated heparin) therapy due to:

• Heparin-induced thrombocytopenia (HIT): a serious antibody-mediated reaction that can lead to thrombocytopenia and thrombosis.
• Heparin resistance: which can occur in certain conditions such as fever, thrombosis, thrombophlebitis, infections, myocardial infarction, cancer, and postsurgical patients, as well as in patients with antithrombin III deficiency. 2

From the Research

Causes of Heparin Resistance

• Heparin resistance can be defined as the need for high doses of unfractionated heparin (UFH) to achieve a therapeutic level of anticoagulation, or the inability to do so 3.
• The most common cause of heparin resistance is a deficiency of antithrombin III (ATIII) 3, 4.
• Other conditions that can lead to heparin resistance include:
  • Congenital deficiencies 3, 4
  • Use of high doses of heparin during extracorporeal circulation 3, 4
  • Use of asparaginase therapy 3, 4, 5
  • Disseminated intravascular coagulation (DIC) 3, 4
  • Inflammatory and infectious disorders 5
  • Pregnancy 5
  • Thrombocytosis 6, 5
  • Antiphospholipid antibody syndromes 6
  • Nephrotic syndrome 5
  • Cardiopulmonary bypass 5

Diagnosis and Treatment

• Heparin resistance is often identified in the acute phase of illness, making it challenging to determine the cause 3.
• Diagnosis of heparin resistance can be made by measuring anti-Xa activity and activated partial thromboplastin time (aPTT) 7, 5.
• Treatment options for heparin resistance include:
  • Weight-based dosing and administration of additional UFH 6
  • Antithrombin supplementation 6, 4
  • Use of alternative anticoagulants such as direct thrombin inhibitors (e.g. argatroban, bivalirudin) 7, 6