Heparin

Mechanism

Unfractioned heparin (UFH) has a pentasacharide sequence that binds to antithrombin to form a complex. The UFH-antithrombin complex is better at inactivating factor Xa then antithrombin alone. This is because once bound to UFH, antithrombin undergoes a conformational change. The UFH-antithrombin complex can also inactivate thrombin by binding to it.

Low moleculer weight heparin (LMWH) also has a pentasaccharide sequence that binds to antithrombin to form a complex. The LMWH-antithrombin complex also inactivates factor Xa, however, it doesn't work on thrombin. This is because the pentasaccharide sequence on LMWH is too short to both complex with antithrombin and bind thrombin. LMWHs typically end in "parin", examples include enoxaparin and dalteparin.

Adverse effect:  Heparin-Induced Thrombocytopenia (HIT)

Heparin is a common cause of thrombocytopenia. LMWH (e.g. enoxaparin) is less likely than unfractioned heparin to cause HIT. There are two main types of heparin-induced thrombocytopenia, type 1 HIT and type 2 HIT. 

Type 1 Heparin-induced thrombocytopenia (HIT)

Within 2 days of exposure to heparin, patient develops a mild drop in the platelet count due to a non-immune mediated aggregation of platelets. Platelet counts return to normal spontaneously and heparin does not need to be stopped. 

Type 2 Heparin-induced thrombocytopenia (HIT)

5-10 days after exposure to heparin, patient develops a drop in the platelet count of 50% or more. Type 2 HIT may be sooner, sometimes within the first day of use, in patients who were exposed to heparin before. They may also have arterial or venous thrombosis which can be life-threatening (e.g. stroke), necrotic skin lesions at the heparin injection site, as well as an acute anaphylactoid reaction. 

Type 2 HIT is immune-mediated. Heparin causes a conformational change in platelets exposing and binding to platelet factor 4 (PF4) then IgG antibodies bind to this heparin-PF4 complex forming immune complex. The heparin-PF4-IgG immune complex then activates platelets causing platelet aggregation as well as release of procoagulant microparticles which results in thrombosis. The heparin-PF4-IgG immune complex is removed from the blood as it goes through the spleen by splenic macrophages leading to a reduction in the platelet count. The combination of platelets in the complex being removed by the spleen and platelets being consumed in thrombus formation results in a significant, usually 50% or more, reduction in the platelet count i.e. severe thrombocytopenia. 

Treatment should be started based on clinical presentation before any confirmation tests are done. Stop all heparin products and give another type of anticoagulant to prevent the HIT related thromboses. Direct thrombin inhibitors (e.g. argatroban) are usually the anticoagulant of choice, however, factor Xa inhibitors (e.g. fondaparinux, rivaroxaban) may also be used. Afterwards, diagnosis can be confirmed with a serotonin release assay (functional assay), which is the gold standard. Confirmation can also be done using a high titer immunoassay. Platelet counts will usually return to normal 2-7 days after stopping heparin.

Once the platelet count is greater than 150,000 then warfarin can be used for maintenance. However, do not give warfarin as part of the initial treatment as it rapidly lowers protein C levels which can lead to an increased risk of thrombus formation. 

Key Points for Type 2 HIT:

• heparin-PF4-IgG immune complexes --> 1. platelet aggregation resulting in thrombosis, 2. platelets with the immune complexes destroyed by spleen, 3. Net result is severe thrombocytopenia
• 50% or greater reduction in platelet count 5-10 days after heparin started
• Most dangerous presentation is arterial and venous thrombosis, patients may also have skin necrosis at injection site, or an anaphylactoid reaction. 
• Treat first by stopping heparin and giving another form of anticoagulant (argatroban, fondaparinux)
• Diagnosis confirmed by serotonin release assay (gold standard) or high-titer immunoassay

Adverse Effect:  Bleeding

Heparin toxicity presents can present with bleeding. Protamine Sulfate is a heparin antagonist that works well against unfractioned heparin toxicity, but unfortunately not as well with LMWH toxicity.