Findings

=Discussion and Diagnosis=

**The research I conducted has supported coagulation factor XII to be the source of Hereditary Angioedema type III.** **Figure 1:** Haplotype analysis of chromosome 5 region specific for F12  in a French family diagnosed with HAE type III **The KEGG pathway: Complement and Coagulation Cascade (3)** This component became highly important to the research conducted in this study. F12 is a component of the Kallik rein-kinin system which result in the generation of bradykinin and kalladin peptides. Kinin peptides have been found to regulate many processes such as blood pressure, sodium hemostasis and inflammation. The Hageman Factor is initiated by activated platelets and secretion which is in turn responsible for activating prekallikrein. Coagulation factor XII has an effect on downstream kinins resulting in bradykinin. Bradykinin produces inflammation, prostaglandin biosynthesis and and nitric oxide biosynthesis. The effects of bradykinin are the expressed symptoms in a patient during an attack of HAEIII (3).
 * The BlastP search found F12 to be conserved in the superfamily Trypsin-like serine protease (Tryp_SPc) (2). Many structures such as those, are inactive precursor zymogens. This means that the enzyme will only become active when it is cleaved during proteolysis (2).
 * The genetic location for coagulation factor XII is located on chromosome 5: 5q33-qter reverse strand.
 * The phylogenetic tree of F12 and it's isoforms show that there are divergences in the sequences. Hageman factor and isoforms b-d are structurally more similar, were as precursor 2 and isoform A are less closely related.

The **haplotype analysis** performed by Dr. Cichon (et.al.) (Figure 1) confirmed linkage of the disease to the at 5q35.2-q35.3 locus. The markers used to identify putative disease-associated haplotype was present in all females and obligate carriers. From his studies, Cichon concluded that a mutation in p.Thr328Lys could be the genetic variant that causes the expression of F12 in females (5).

**Figure 2:** Diagnostic algorithm for the various types of Hereditary Angioedema ** Diagnosis of hereditary angioedema III (1): ** The key factor in establishing the diagnosis is a positive family history. For women, the age at which symptoms first appear is important in diagnosis as levels of estrogens may be assessed and proper treatment can be administered. The 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema created a set of standards and protocol in designating the various forms of HAE (1). **﻿** **Establishing a diagnosis of hereditary angioedema III (1)****:** Refer to Figure 2 for Diagnostic algorithm (1).
 * Recurrent angioedema (without urticaria), recurrent episodes of abdominal pain and vomiting, laryngeal edema, positive family history
 * C4, C1-INH protein normal
 * Confirm C4, C1-INH normal during attack
 * Consider angioedema types other than HAE-C1-INH (Types I and II)
 * Diagnosis is HAE Type III


 * Short-term Prophylaxis for HAEIII:**
 * Most proposed treatments for HAE have not been trialed in pregnancy
 * In pregnant women diagnosed with HAEIII, a pasteurized plasma derivative C1INH (pdC1INH) should be given anecdotally(1)
 * 5 days before event, 2 days after(1)


 * Long-term Prophylaxis for HAEIII:**
 * recombinant human C1INH (rhC1INH), Rhucin
 * The latest approved medicine in treating Hereditary Angioedema is a drug called Rhucin (4).
 * Administered as an injection straight into the bloodstream, therefore it can be given in lower doses and have a quicker response (4).
 * Attenuated androgens have shown to be effective long-term when used in prepubertal patients (1).

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1. Bowen, T, & Bork, K. (2010). 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Proceedings of the Hereditary Angioedema- Management Consensus 2010, [] 10.1186/1710-1492-6-24.

2. Marchler-Bauer A et al. (2009), "CDD: specific functional annotation with the Conserved Domain Database.", Nucleic Acids Res.37(D)205-10. http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=153545

3. Caen, J., & Wu, Q. (2010). Hageman factor, platelets and polyphosphates: early history and recent connection. Journal of Thrombosis and Haemostasis, 8(8), Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20456750 doi: 10.1111/j.1538-7836.2010.03893.x.

4. Bauer, Scott (2010). The Facts: Down on the Pharm; Agricultural Research Service. Popular Science: []

5. Cichon, S., Martin, L., Hennies, H., & Nothen, M. (2006). Increased activity of coagulation factor XII (hageman factor) causes hereditary angioedema type III. The American Journal of Human Genetics, 79(6), Retrieved from@http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698720/?tool=pubmed