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Friday, June 5, 2015

Platelets in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is an acquired syndrome that is irreversible and debilitating. A chronic inflammatory disease characterized by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after the ingestion of aspirin, it presents with an onset in young adulthood. Estimations indicate there are approximately 1.2 million adults in the United States living with AERD. Its pathogenesis likely involves disturbances in the mechanisms that regulate tissue recruitment of immune effector cells and activity of the 5-LO/LTC4S pathway. There is substantial evidence that platelets contribute to these mechanisms. Laidlaw et al review the evidence regarding asthma in general and AERD in particular (J Allergy Clin Immunol 2015; 135(6): 1407-14).

Platelets lack a nucleus and have no DNA. They are derived from cytoplasmic fragments of megakaryocytes and have a life span in the circulation of approximately 8-10 days before being removed by the spleen. In addition to their role in hemostasis, activated platelets can activate other immune cells, and upon adhesion to granulocytes, they can facilitate granulocyte recruitment into body tissues. They also secrete mediators including chemokines and lipids, which are released upon platelet activation. All of these contribute to symptomatic asthma exacerbations. Specific to AERD, patients with the condition have high numbers of platelet-adherent granulocytes in their nasal polyp tissue, which contributes to the overproduction of cysteinyl leukotrienes.

Whether or not the circulating platelets implicated in AERD possess an intrinsic defect is still unknown. In vitro stimulation studies have shown platelets from AERD patients released nearly twice as much ATP when activated with platelet-activating factor than those from healthy controls did. The platelets also released significantly increased levels of TXB2, which was not seen in the controls. Differences in biochemistry seem possible, suggesting trials examining targeted anti-platelet therapeutics may be appropriate. Studies have also suggested therapies aimed at reducing numbers of platelet-leukocyte aggregates, T-prostanoid receptor blockade, and P2Y12 receptor antagonism all may be of use, and relevant clinical trials are in their early stages.

1 comment:

  1. I recently read that INF-gamma, which is highly express in AERD, induces IgE receptor expression on human platelets. Could this play a key role in AERD?
    - Steve Bigelsen MD