LMRJ Volume 2 Issue 3 54 | P a g e Unusual Presentation of Factor XII Deficiency with Bleeding: A Rare Case Report Faryal Qadir1, Ayisha Imran1, Nauman Aslam Malik1, Arshi Naz2, Tahir Shamsi2 1Department of Hematology, Chughtai Lab, Pakistan, 2National Institute of Blood Disease and Bone marrow Transplantation, Pakistan. Correspondence: Dr. Faryal Qadir Department of Hematology, Chughtai Lab, Lahore, Pakistan. Email: dr.faryalqadir@gmail.com LMRJ. 2020; 2(3) DOI: 10.38106/LMRJ. 2020.2.3-02. Abstract: Factor XII (FXII) is a coagulation protein involved in the initiation of coagulation via contact activation system. Congenital FXII deficiency is a rare, asymptomatic disorder, associated with an isolated prolonged activated partial thromboplastin time (APTT). FXII deficiency is not commonly associated with any bleeding symptom except for a few cases presenting with occasional minor bleeds, which does not require treatment. Instead, a few literature reports suggest an increased incidence of various thromboembolic events in these patients. We report a rare occurrence of FXII deficiency presenting with severe bleeding symptoms. Key words: Factor XII deficiency, contact activation system, thromboembolic events. Introduction Factor XII (FXII), also known as Hageman factor, is an 80 kDa plasma protein synthesized in liver. It is involved in coagulation of blood via contact activation as seen in the activated partial thromboplastin time (APTT). Activation of FXII occurs when the complex of FXII, factor XI (FXI), pre- kallikrein, and high molecular weight kininogen contact a negatively charged surface. FXII subsequently activates FXI and thus plays a role in fibrin clot formation. A rather more important role of FXII is the conversion of plasminogen to plasmin and initiation of fibrinolysis1. Congenital FXII deficiency is inherited as an autosomal recessive disorder with a very low incidence of approximately 1 in a million individuals.2 Rare cases with autosomal dominant pattern have also been reported.3 The gene for FXII is located on chromosome 5. FXII deficiency is usually asymptomatic and associated with prolongation of APTT.4 The condition is usually diagnosed incidentally e.g. during pre- operative coagulation work up. FXII deficiency is normally asymptomatic, however, a few patients with occasional minor bleeds have been previously reported.3 In contrast, this disorder has been associated with a significantly increased risk of thrombosis, due to impaired fibrinolytic system.4 Case report mailto:dr.faryalqadir@gmail.com LMRJ Volume 2 Issue 3 55 | P a g e Case Report A 17 years old female born to consanguineously married couple presented to us for diagnostic work up of a suspected bleeding disorder. She complained off and on right knee joint pain with associated swelling for the past two years. Her past history included several episodes of epistaxis, gum bleeding, per rectal bleeding, melena and spontaneous bruising since childhood. She was transfused multiple times with whole blood and plasma for the mentioned bleeding symptoms; the symptoms would resolve with the transfusions. Two years back, she underwent exploratory laparotomy and abdominal lavage due to primary peritonitis. In the process she was given multiple fresh frozen plasma (FFP) and whole blood transfusions. She also complained of menorrhagia since menarche. Her complete blood count showed haemoglobin: 12 g/dl, total leukocyte count: 5.8 x 109/l, platelet count: 196 x 109/l. Coagulation screen revealed a normal prothrombin time (PT) of 12 seconds, (reference range 10-13sec), bleeding time: 3 minutes (reference range 3-7 min) with a prolonged APTT: more than 120 sec (reference range 24-32sec). A 1:1 mixture of patient’s plasma and pooled normal plasma revealed complete correction of patient’s APTT, excluding the presence of any inhibitor. We further performed coagulation assays of factors VIII, IX, XI and XII, (performed on Sysmex CA 550) as these clotting factor deficiencies can cause a prolonged APTT. Our results revealed normal levels of factors VIII, IX and IX with absent FXII. Von Willebrand antigen (Sysmex CA 500) levels and ristocetin co-factor activity (Aggram Helena) were also within normal limits. As FXII deficiency is usually not associated with any bleeding symptoms we further performed fibrinogen assays (Sysmex CA 50), platelet aggregation studies (Aggram Helena) and factor XIII (FXIII) levels to rule out any concomitant pathology; all of these turned out to be normal. Work up for renal and autoimmune disorders was also done to exclude the possibility of acquired deficiency. Thus, she was diagnosed as a case of congenital FXII deficiency. Interestingly, no mutations in the factor XII gene were found on Snager’s sequencing. She was put on oral hormonal contraceptive for her menorrrhagia. FFPs were given at 10ml/kg to treat right knee joint haemarthrosis after which her symptoms were resolved. She was offered physiotherapy for further management. Discussion FXII deficiency is a blood disorder with a very low incidence. It may be congenital, in which case it is usually diagnosed incidentally by an isolated prolonged APTT during routine coagulation screen. Other related disorders associated with a prolonged APTT include deficiency of factors VIII, IX, XI, contact factors, Von Willebrands disease as well as a few inhibitors of coagulation including lupus anticoagulant and acquired inhibitors against various coagulation factors e.g factor VIII. However, FXII deficiency is usually not associated with any bleeding manifestations, in contrast to other clotting factor deficiencies e.g factor VIII, IX etc. Another acquired form of factor XII deficiency may be caused by inhibitors against FXII. This has been reported in patients with nephrotic syndrome and leukemia.5 Conversely, these patients have an increased risk of thromboembolic phenomenon due to impaired fibrinolysis in FXII deficiency. Various researchers have reported association of FXII deficiency with myocardial infarction, pulmonary embolism and other life threatening thrombotic episodes.6 LMRJ Volume 2 Issue 3 56 | P a g e Parameter Patient Value Reference Range Bleeding score 19* - First Line Coagulation Screening Bleeding time 3 min 3-7 min PT 12 sec 10-13 sec APTT More than 120 sec 24-32 sec Fibrinogen 213mg/dl 180-350 mg/dl Intrinsic Pathway Factor VIII 141% 50-150% Factor IX 91% 50-150% Factor XI 81% 50-150% Factor XII 0% 50-150% Associated Factors Factor XIII 76% 50-150% VWF Antigen 89% 50-200% Ricof 94% 50-200% Platelet disorders Normal platelet aggregation - Autoimmune Work Up Anti ds- DNA 1.68 U/ml <20 U/ml ANA <1:100 (negative) <1:100 Renal Work Up Urea 20 mg/dl 10-50 mg/dl Creatinine 1.1 mg/dl 0.7- 1.3 mg/dl Genetic Work up Snager’s sequencing No mutation detected Platelet Aggregometry Results Ristocetin: 80.9% Collagen : 80.7% ADP : 82% Few reports have also emphasized that female patients with Hageman factor deficiency might also be at a higher risk for recurrent pregnancy losses.7, 8 Therefore, once diagnosed, these patients should be followed up closely for any thrombotic events. In a study carried out on all the available members of Swiss families affected by factor XII deficiency, it was found that patients with homozygous FXII deficiency are more likely to develop thromboembolic disease whereas partial FXII deficiency is not usually associated with thrombosis.9 However, different subsequent studies have shown that these patients developed thrombosis due to other risk factors rather than factor XII deficiency.10,11 Recently, researchers are working on newer anticoagulants targeting factor XII.11 There were a few limitations in this case report. Antigen level of FXII could not be performed because of non-availability of required resources and the diagnosis had to be made solely based on FXII activity. Similarly, we were unable to rule out any concomitant deficiency of other contact factors e.g pre-kallikrein, high molecular weight kininogen etc. Conclusion FXII deficiency is a rare genetic blood disorder; usually not associated with any bleeding tendencies. Moreover, these patients also do not bleed following invasive procedures such as surgery and dental extraction. Thus, these patients routinely do not need any treatment or prophylactic measures. However, as reported in our case a few patients with FXII deficiency may present with bleeding symptoms and LMRJ Volume 2 Issue 3 57 | P a g e should be managed accordingly. A probable cause for these haemorrhagic incidents in our case might be the complete absence of FXII activity in the plasma. The purpose of this case report is to bring forth the rare occurrence of severe bleeding manifestations in patients with FXII deficiency. References 1. Thomas Renne, Alvin H. Schmaier, Katrin F. Nickel, Margareta Blomback and Coen Maas.In vivo roles of factor XII.Blood 2012,120:4296-4303 2. Colman RW.Factor XII deficiency.NORD Guide to Rare Disorders. Lippincott Williams and Wilkins.Philadelphia,PA.2003,3 82-383 3. Kumar R,Gupta A,Mathur P,Garg M.Factor XII deficiency- A rare coagulation disorder.Indian J Child Health.2016,3(4):349-350. 4. Rygal P,Kuc A.Perioperative management of cardiac surgery patients with factor XII deficiency-two case reports.Anaesthesiol Intensive Ther.2012,44(4):217-20. 5. Wang Y,Wang Z,Li H,Bi K,Zhu C.Essential thrombocytosis accompanied by coagulation factor XII deficiency.A case report.Int J Clin Exp Med. 2014,7(10):3725-9. 6. Arphan Azaad,M.,Zhang,Q.R. and Li,Y.P.Factor XII (Hageman Factor) Deficiency.A Very Rare Coagulation Disorder.Open Journal of Blood Diseases.2015,5,39-42. 7. Mariano ML,Yadira P,Ana A,Manuel L,Lopez Galvez JJ.Coagulation factor XII congenital deficiency in women with recurrent miscarriage.Int J Clin Med.2011,2(4):469-72. 8. A.Seval Ozgu-Erdinc,Cihan Togrul,Ayla Aktulay,Umran Buyukkagnici,Elif Gul Yapar Eyi ,Salim Erkaya. Factor XII (Hageman) Levels in Women with Recurrent Pregnancy Loss. Journal of Pregnancy 2014, Article ID : 459192. 9. Lammle B.,Wuillemin W.A.,Huber I.,Furlan M. Thromboembolism and bleeding tendency in congenital factor XII deficiency-A study on 74 subjects from 14 Swiss families.Thrombosis and Haemostasis.1991,65(2):117-21. 10. A.Girolami, M. Morello,B. Girolami,A.M. L ombardi,C. Bertolo.Myocardial Infarction and Arterial Thrombosis in Severe (Homozygous) FXII Deficiency: No Apparent Causative Relation. Clinical and Applied Thrombosis/Hemostasis.2005,11 (1):49 – 53. 11. Felicitas Muller, David Gailani, Thomas Renne.Factor XI and XII as antithrombotic targets. Curr Opin Hematol.2011,18(5): 349– 355.