Factor XII (Hageman Factor) Deficiency: a rare harbinger of life threatening complications

Hageman factor (factor XII) has a key role in activation of intrinsic coagulation system gauged by activated partial thromboplastin time (aPPT). Hageman factor deficiency is more often an autosomal recessive condition, but an autosomal dominant inheritance is also reported. This condition in its own is not known to cause bleeding complications rather is associated with paradoxical fatal thromboembolic complications. Exact prevalence of this condition is not known, as under normal conditions they are asymptomatic. In literature, a prevalence of 2.3% has been reported in one study on 300 patients presenting with complications. Homozygous patients has non-detectable levels of factor XII, while heterozygous individuals has variable levels ranging from 20-60%. Hageman factor is a pro-coagulation protein initiating intrinsic pathway. Intrinsic pathway is activated either by direct contact with a negative charged surface or by proteolytic activation on the endothelial cells via prekallikerin/kallikerin system. Factor XII as an integral part of this system leads to factor XI activation resulting in production of thrombin orchestrated by intrinsic system. In addition, there is concomitant activation of complement components C3 and C5 via C1-estrase activation. Patients with this condition are known to have spontaneous thromboembolic complications although less common but are prone to life threatening complications under provocating circumstances. The aim of this case report is to study the relation of factor XII deficiency and isolated raised activated partial thromboplastin time (aPPT) and how it can be prevented. We are presenting a Saudi female patient, 29 years of age who presented to accident and emergency room (A&E room) of our hospital with sudden severe breathlessness and chest pain.


Introduction
Hageman factor (factor XII) deficiency is a congenital condition inherited in large majority as autosomal recessive condition. It belongs to the vast group of kinins [1,2]. Factor XII is important in initiating activation of intrinsic coagulation pathway. Surprisingly it is very rarely if at all associated with bleeding diathesis that too is very mild like epistaxis or skin abrasions. But contrary and confusingly factor XII deficiency is more often associated with thromboembolic complications which are sometimes life threatening [3,4]. The condition is often incidentally discovered during coagulation screening having isolated prolonged activated partial thromboplastin time (aPTT) or during an unexplained coagulopathy. Association of arterial and venous thromboembolic events has been debated in the literature leading to myocardial infarction and life-threatening pulmonary embolism [4,5]. A high index of suspicion is kept in individuals, known to have factor XII deficiency, presenting with thromboembolic events spontaneously or more so under provocation as in the subject patient.
Early diagnosis based on unexplained isolated prolonged PTT and prompt intervention with anticoagulation is lifesaving in acute myocardial infarction or massive or sub-massive pulmonary embolism [6].

Patient and observation
A Saudi female age 29, presented to accident and emergency room (A&E) of our hospital with sudden severe breathlessness and chest pain. She has been ambulant and asymptomatic, discharged recently from our hospital three weeks ago after an uneventful caesarean section delivery being primigravida.
History: she was in obvious respiratory distress, tachypneic and tachycardiac having desaturation at room air under resting conditions. Admitting diagnosis was pulmonary embolism until proved otherwise.
She has been ambulant and had no past history of significance being non-smoker, no history of taking any medications. She denied family history of any blood disorders. deficiency.

Discussion
In the intrinsic coagulation cascade, factor XII acts as an initiating step orchestrating enzymatic conversion of factor XI to activated factor Xia [7,8]. Although majority is autosomal recessive as a result of spontaneous mutation, but autosomal dominant inheritance is also reported in the literature. This initial step is followed by thrombin stabilization, release of bradykinin and local inflammatory reaction [9,10]. Causes of isolated elevated aPPT (activated partial thromboplastin time) include use of unfractionated-heparin, antiphospholipid syndrome, Von Willebrand varients, and deficiency of IX, XI, XII factors [11]. A mixing study and coagulation factor assay is contemplated to confirm the diagnosis. In vitro prolongation of aPPT may not represent increased risk of coagulopathy in vivo, because it is masked by other coagulation factors. Immunoassay is used directly to estimate the levels of factor XII [12]. No other coagulopathy was reported in this patient. The subject patient did not predate any symptoms related to factor XII deficiency, until her presentation with sudden chest pain and breathlessness due to sub-massive pulmonary embolism.  [15]. An acquired factor XII deficiency has been reported as well, in patients having liver transplants [16].

Classification of pulmonary embolism
Our patient did not report any pre-existing symptoms or history of any coagulopathy or acute event in the past. She was ambulant and asymptomatic being hospitalized and discharged, 3 weeks ago after an uneventful caesarian section as a primigravida. Diagnosed having sub-massive pulmonary embolism and respiratory failure associated with factor XII deficiency presentation with sudden breathlessness and chest pain. She was initially treated with low molecular weight heparin and subsequently replaced with oral warfarin.

Conclusion
An isolated prolonged aPTT in a patient having thromboembolic event, is a pointer to factor XII deficiency as a rare harbinger of life threatening complications as in our patient. Due to the rarity of factor XII deficiency, and variation in its clinical presentations, other possible causes under the clinical circumstances (provocating and nonprovocating) must be ruled out before definitely associating them with inherited coagulopathy. Transmission of autosomal recessive disorders, which put the pregnancy at risk, could be prevented by avoiding consanguineous marriages, necessitating counseling and education. Question remains whether such patients be offered