Thursday, November 15, 2012

Immunogenicity of Alteplase: Never Say Never

A few weeks ago, we received an interesting question from one of the ED attending physicians regarding the immunogenicity of alteplase. Providing him with an answer made me realize to not take for granted the information available regarding the differences between the various thrombolytic agents, and reading more about this topic made me a bit humbled by the years of research and clinical experience that went into what we currently know today about these agents.

Streptokinase was developed in the 1930s as a product derived from various polypeptide chains that originated from beta-hemolytic streptococci. Shortly after its discovery, it was found that patients with recent streptococcal infections may develop antibodies against streptokinase, causing an immune complex to form between the circulating antibodies and streptokinase. This may potentially invoke an immune system response characterized as a type III allergic reaction, especially with frequent administration of streptokinase. In addition, a type I IgE-mediated reaction to steptokinase may develop within minutes of its infusion that can manifest as a full-blown anaphylactic reaction. Because streptokinase is not fibrin-specific, its infusion can induce rapid activation of plasminogen to plasmin, which can lead to generalized depletion of plasminogen, leading to histamine release secondary to activation of the complement cascade and production of bradykinin; this may induce marked facial flushing and hypotension. The rate of immunogenicity in patients who receive streptokinase is reported as upwards of 6%, based on the results of the GUSTO-I trial.

The search began for the ideal thrombolytic agent that was less likely to induce an immunogenic response and possess more specificity for fibrin, and decades later, alteplase was developed. Because alteplase is a genetically engineered version of endogenous human tissue plasminogen activator obtained from the human melanoma cell line produced via recombinant DNA technology, the likelihood of it inducing an immunogenic response in patients receiving the product should theoretically be lower than streptokinase. In addition, because alteplase is more specific for the activation fibrin-bound plasminogen to fibrin-bound plasmin, this allows for local fibrinolysis while minimizing bradycardia and hypotension.

This all sounds good and well for alteplase...until further research in the literature regarding the actual incidence of immunogenic reactions is done. Somewhat surprisingly, the incidence of an immunogenic response associated with alteplase is reported to be 0.1 to 2%. The type of response seen in published case reports has widely varied and includes urticaria, rash, hypotension, oropharyngeal swelling, and facial angioedema. Even more interesting is the fact that it has been hypothesized that because angiotensin-converting enzyme (ACE) inhibitors inhibit the action of kininases that normally break down bradykinin, these agents may exacerbate angioedema that occurs in the setting of alteplase infusion.

What is one to do? In most of the case reports, patients were adequately managed with the administration of fluids, antihistamine, corticosteroid, and/or vasopressor therapy; however, in nearly half of all reported cases, emergent intubation was necessary as a life-saving intervention. Simply put, be on the lookout for this as a possible complication of alteplase (not to mention the risk for bleeding). Should a patient begin to experience respiratory distress, facial angioedema, or other clinical signs and symptoms suggestive of anaphylaxis with the administration of alteplase, immediate management of the immunogenic reaction should be instituted as appropriate and a decision of whether or not the infusion is to be continued should be determined on a case-by-case basis.


I would like to acknowledge the efforts of Rana Abdeljabbar, Pharm.D. Candidate 2013 and John Youhanna, Pharm.D. Candidate 2013 for their contributions to this blog post.

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