Article, Emergency Medicine

Anaphylaxis-induced hyperfibrinogenolysis and the risk of Kounis syndrome: the dual action of tryptase

and also other related variables to mortality to get the adjusted odds ratios for all the independent variables.

Cenker Eken MD Department of Emergency Medicine Akdeniz University Medical Faculty

Antalya, Turkey E-mail address: [email protected]



  1. Lin GM, Li YH, Han CL. Letter for Killip classification and glucose level in patients with acute myocardial infarction. Am J Emerg Med 2011;29(4):462.
  2. Cheng HH. The authors respond. Am J Emerg Med 2011;29(4):462-3.
  3. Cheng HH, Yen PC. Killip classification and glucose level in patients with acute myocardial infarction. Am J Emerg Med 2010;28(8):853-6.

Anaphylaxis-induced hyperfibrinogenolysis and the risk of Kounis syndrome: the dual action of tryptase?

To the Editor,

In the very interesting report published in the Am J Emerg Med [1], a young lady had anaphylaxis after a wasp sting, and despite abnormalities in coagulation cascade with markedly increased prothrombin time and activated partial thrombo- plastin, neither bleeding nor Hepatic dysfunction was observed. The patient was discharged after treatment of anaphylaxis without administration of fresh-frozen plasma or antifibrino- lytics such as Tranexamic acid because the Coagulation abnormalities were normalized spontaneously, and bleeding diathesis or thrombosis was absent. The authors thought that this unique case provides an interesting area of discussion.

Although biomarkers of Myocardial necrosis and electro- cardiographic changes were not given and allergic workup was not performed, tryptase levels were significantly elevated (initial level 200 ug/L). Therefore, in this patient, an abortive episode of type I variant of Kounis syndrome [2] cannot be excluded. The patient was treated with intravenous epinephrine. Indeed, epinephrine is the primary drug for anaphylaxis, but commercially available preparations of epinephrine contain sodium metabisulfite as a preservative, which is known to induce Allergic reactions [3]. For this reason, currently, sulfide-free epinephrine preparations are available [4]. Insect stings can induce Kounis syndrome, which combines cardiac events with conditions associated with mast cell activation, involving interrelated and inter-

acting inflammatory cells and including allergic or hyper- sensitivity and anaphylactic or anaphylactoid insults.

Platelet activation and the ensuing coagulation cascade occur via stimulation of some known receptors on the platelet surface such as receptors for adenosine diphosphate, thromboxane, thrombin, serotonin, epinephrine, and some less-known receptors, which are associated with mast cell activation, such as receptors for histamine, high- and low- affinity immunoglobulin E receptors (FCe RI and FCe RII) and receptors for platelet-activating factor [5]. During activation, platelets change shape from discoid to spiculated form and release granules that contain proinflammatory (platelet factor 4, CD154 platelet-derived growth factor), prothrombotic (factor V, factor XI, platelet-activating inhib- itor-1), adhesive (thrombospondin, fibrinogen, P selectin, von Willebrand factor), and aggregatory mediators (serotonin, Ca2+, Mg2+, ATP, ADP) [6]. However, mast cell mediators are also associated with fibrinogenolysis. For example, tryp- tase can degrade fibrinogen [7] and can activate prourokinase [8]. Chymase can inactivate thrombin [9]. Moreover, mast cells are a unique and important source of heparin, which does not exhibit fibrinolytic activity but prevents coagulation by acting as a cofactor of antithrombin III. However, heparin has been described as a potent cofactor of tryptase and of tissue-type plasminogen activator [10,11]. Recent data pro- vide evidence that human tissue mast cells themselves are another important source of tissue plasminogen activator [12]. It is difficult to explain why anaphylaxis can be associated with either thrombotic or fibrinogenolytic events. Perhaps, mast cell clonality could explain this action, both thrombotic

[2] and fibrinogenolytic [1], on the coagulation cascade

? Conflict of interest: None declared.

Table 1 Tryptase dual action

Thrombotic action [2] Fibrinolytic action [1]

1. Activates the zymogen 1. Cleaves the ? and especially forms of metalloproteinases ? chain of fibrinogen, which such as interstitial regulate the removal of the collagenase, gelatinase, and thrombin cleavAge SIte and the stromelysin and can promote critical polymerization site,

plaque disruption or rupture

  1. Degrades the pericellular matrix components fibronectin and vitronectin and neuropeptides, such as vasoactive intestinal peptide and calcitonin gene-related peptide
  2. Activates neighboring cells by cleaving and activating

resulting in inhibition of clot formation

2. Degrades procoagulant proteins, which prevent fibrin deposition

3. Activates the single-chain urinary plasminogen activator

protease-activated receptor-2 (or prourokinase) and converts and thrombin receptors plasminogen into plasmin,

which degrades fibrinogen and other coagulation factors

4. Degrades high-density lipoprotein

(Table 1). Indeed, activating mutations were recently found in c-kit, which codes for KIT, the receptor for stem cell factor, which is essential for mast cell development, proliferation, survival, adhesion, and homing [13]. We postulate that these events result in hyperresponsive mast cell phenotype with increased release of mast cell tryptase and other Inflammatory mediators that are able to induce Kounis syndrome and differentiate mast cell content. This could also explain why few patients develop chest pain with/or electrocardiographic changes during allergic, hyper- sensitivity, anaphylactic, or anaphylactoid episodes. We believe that further studies are necessary to clarify the important role of mast cells in endogenous thrombolysis and coagulation cascade. We agree with the authors that, in any case of anaphylaxis, coagulation assessment should always be performed.

Nicholas G. Kounis MD, PhD Grigorios Tsigkas MD George Almpanis MD Sophia N. Kouni BSc, MSc George N. Kounis MD, MSc Andreas Mazarakis MD, PhD Department of Cardiology

University of Patras Medical School

Patras, Greece E-mail address: [email protected]



  1. Lombardini C, Helia RE, Boehlen F, Merlani P. “Heparinization” and hyperfibrinogenolysis by wasp sting. Am J Emerg Med 2009;27(1176): e1-3.
  2. Kounis NG. Kounis syndrome (Allergic angina and allergic myocardial infarction: a natural paradigm? Int J Cardiol 2006;110:7-14.
  3. Soulat JM, Bouju P, Oxeda C, Amiot JF. Anaphylactoid shock due to metabisulfites during caesarean section under peridural anesthesia. Cah Anesthesiol 1991;39:257-9.
  4. Ameratunga R, Webster M, Patel H. Unstable angina following anaphylaxis. Postgrad Med J 2008;84:659-61.
  5. Hasegawa S, Pawankar R, Suzuki K, Nakahata T, Furukawa S, Okumura K, et al. Functional expression of the high affinity receptor for IgE (FcepsilonRI) in human platelets and its intracellular expression in human megakaryocytes. Blood 1999;93:2543-51.
  6. Mehta SR, Yusuf S. Short- and long-term oral Antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention. J Am Coll Cardiol 2003;41(4 Suppl S):79S-88S.
  7. Schwartz LB, Badford TR, Littman BH, Wintroub BU. The fibrinogenolytic activity of purified tryptase from human lung mast cells. J Immunol 1985;135:2762-7.
  8. Stack MS, Johnson DA. Human mast cell tryptase activates single chain urinary- type plasminogen activator (pro-urokinase). J Biol Chem 1994;269:9416-9.
  9. Pejler G, Karlstrom A. Thrombin is inactivated by mast cell secretory granule chymase. J Biol Chem 1993;268:11817-22.
  10. Sakai K, Ren S, Schwartz LB. A novel heparin-dependent processing pathway for human tryptase. Autocatalysis followed by activation with dipeptidyl peptidase I. J Clin Invest 1996;97:895-6.
  11. Stein PL, van-Zonneveld AJ, Pannekoek H, Strickland S. Structural domains of human tissue type plasminogen activator that confer stimulation by heparin. J Biol Chem 1989;264:15441-4.
  12. Sillaber C, Baghestanian M, Bevec D, Willheim M, Agis H, Kapiotis S, et al. The mast cell as site of tissue type plasminogen activator production and fibrinolysis. J Immunol 1999;162:1032-41.
  13. Metcalfe DD, Schwartz LB. Assessing anaphylactic risk? Consider mast cell clonality. J Allergy Clin Immunol 2009;123:687-8.

Acute appendicitis: emergency medicine physician and surgeon clinical judgment vs Abdominal computed tomography scan

To the Editor,

We read, with great interest, the article by Jo et al [1], “The accuracy of emergency medicine and surgical residents in the diagnosis of acute appendicitis,” which states that, in patients with Right lower quadrant abdominal pain who have already been evaluated by an emergency medicine resident, consultation evaluation by a surgical resident does not appear to improve clinical diagnostic accuracy, and routine performance of computed tomography (CT) before Surgical consultation should be considered for these patients [1]. Although we agree with the authors that CT scanning is a useful option for detection or ruling out of acute appendicitis, in patients who have typical findings in history and physical examination, routine CT is not a necessary option, and early consultation with surgical resident will reduce the preoper- ative time and also avoids the patient from radiation exposure and cost of unnecessary CT scan. Indeed, we want to emphasize that even the best imaging modalities can never replace the clinical judgment of an experienced surgeon or emergency medicine physician.

Hamed Ghoddusi Johari MD Trauma Research Center General Surgery Department

Shiraz University of Medical Science

Shiraz, Iran E-mail address: [email protected]

Gholam Reza Mohseni MD

Anesthesiology Department Kermanshah University of Medical Science, Iran

Shima Eskandari MD

Trauma Research Center Shiraz University of Medical Sciences

Shiraz, Iran


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