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CASE REPORT Table of Contents  
Ahead of print publication
Factor XI deficiency case reports on congenital and acquired Hemophilia C - A case report


1 Department of Haematology and Clinical Pathology, Apollo Hospitals, Chennai, Tamil Nadu, India
2 Department of Clinical Haematology, Apollo Hospitals, Chennai, Tamil Nadu, India

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Date of Submission26-Jul-2022
Date of Decision03-Sep-2022
Date of Acceptance19-Oct-2022
Date of Web Publication18-Nov-2022
 

  Abstract 


Introduction: Factor XI deficiency or hemophilia C is a very rare coagulation factor deficiency, with a global incidence of 1 in 1 million. Although it is an under-recognized entity, it can cause significant bleeding, resulting in life-threatening complications. Materials and Methods: Coagulation parameters were analyzed using a Sysmex CS-2400 coagulation analyzer. Factor XI levels were detected using Factor XI deficient plasma from Siemens. Activated Partial Thromboplastin Time (APTT) testing was performed using Actin FSL from Siemens. Results: Here, we report the two cases of Factor XI deficiency, one genetic and the other a very rare acquired deficiency due to sepsis, detected during the workup of an isolated APTT prolongation. Conclusion: Factor XI deficiency is a rare bleeding disorder that presents as prolonged isolated APTT. Careful clinical evaluation and complete coagulation workup are necessary for the efficient management of patients, which can prevent life-threatening events.

Keywords: Acquired hemophilia, factor inhibitors, Factor XI deficiency, hemophilia c


How to cite this URL:
Soni M, Muralikrishnan S, Sundaram S. Factor XI deficiency case reports on congenital and acquired Hemophilia C - A case report. Apollo Med [Epub ahead of print] [cited 2022 Nov 28]. Available from: https://apollomedicine.org/preprintarticle.asp?id=361526





  Introduction Top


Factor XI plays a pivotal role in the intrinsic pathway of coagulation. It aids in thrombin generation, coagulation cascade propagation, and down-regulation of fibrinolysis.[1] The role of factor XI in inflammation and malignancies is an ongoing area of research with a potential impact on thromboprophylaxis and sepsis.[2],[3]

Deficiency of Factor XI, also known as hemophilia C, is a rare bleeding disorder with a global incidence of 1/1 million.[2],[4] It can be genetic, inherited as an autosomal recessive disease, or rarely acquired due to inhibitors. Most of these inhibitors are antibodies, which partially or completely neutralize the clotting factor.[3]

Spontaneous bleeding in an isolated factor XI deficiency is not very common, and the patient may remain asymptomatic for years, suddenly presenting with unexplained bleeding or elevated activated partial thromboplastin time (APTT).[5] In most patients, bleeding episodes occur after surgery, dental procedures, or trauma.[2]

An APTT mixing study after incubating patient plasma with pooled normal plasma differentiates genetic factor deficiency from acquired factor deficiency due to inhibitors.

Here, the authors present the two cases of Factor XI deficiency, one inherited and the other acquired, illustrating the importance of a complete coagulation workup for an elevated coagulation screening test. The first case is from an obstetric setup, and to the best of our knowledge, it is the second case of Factor XI deficiency in pregnant women reported in the literature from India (the first one being from North India at AIIMS, New Delhi, in the year 2013).[5]

The second case is of an acquired Factor XI deficiency (acquired haemophilia C), probably secondary to sepsis. Acquired haemophilia C is very rare, with no data published on its incidence. To the best of our knowledge, this is the first reported case.


  Materials and Methods Top


The coagulation parameters were analyzed using the Sysmex CS-2400 coagulation analyzer. Factor XI levels were detected using Factor XI deficient plasma from Siemens. APTT testing was performed using Actin FSLfrom Siemens.


  Case Presentation Top


Case 1

A 29-year-old pregnant female (G2P1 L1) presented for delivery to the gynecology outpatient department. She had delivered her first child by cesarean section 4 years back. She had undergone an appendicectomy approximately 10 years ago. There was no history of bleeding or bruising since her childhood or following these surgeries. Her preoperative workup revealed mildly elevated APTT of 34 s (normal: 24–32 s). Later, mixing studies with 1:1 pooled normal plasma was done which indicated the absence of any immediate-acting or delayed-acting inhibitor [Table 1].
Table 1: Mixing studies Case 1

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Further workup revealed normal Factor VIII, IX, XII, and VWF activities, but Factor XI activity was 50.7% (normal: 70%–120%). The patient was diagnosed with a congenital mild Factor XI deficiency, and fresh-frozen plasma was reserved in case it was required during surgery. The patient underwent elective cesarean section without requiring any blood products, and post-operative recovery was uneventful.

Mixing studies with 1:1 pooled normal plasma indicated the absence of any immediate-acting or delayed-acting inhibitor.

Case 2

An elderly 80-year-old female presented in the emergency department in septic shock with a history of high fever and swelling of the right lower limb. She was diagnosed with right leg cellulitis. Wound debridement and plantar fasciotomy were planned. The patient had undergone a right hemicolectomy for a carcinoma colon 3 years back and a hernia surgery before the hemicolectomy. Both surgeries had been uneventful, with no abnormal bleeding.

Preoperative investigations were abnormal [Table 2] with an isolated elevated APTT of 47 secs (average 24–32 s). Later, mixing studies with 1:1 pooled normal plasma was done which indicated the presence of a delayed-acting or time-dependent inhibitor [Table 3]. Factor assays revealed normal Factor VIII, factor IX, XII, and VWF activities, but Factor XI activity was 50.3% (normal: 70%–120%). The lupus anticoagulant was negative. A diagnosis of acquired Hemophilia C, probably secondary to sepsis, was made. The patient was started on antibiotics and other supportive care. The surgical procedure was performed, reserving fresh frozen plasma. The patient withstood the surgical procedure well and did not require any blood products. With improvement in her clinical condition and sepsis, her APTT also improved. The value of APTT at the time of discharge was 36 s.
Table 2: Preoperative laboratory investigations of Case 2

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Table 3: Mixing studies Case 2

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Mixing studies with 1:1 pooled normal plasma indicated the presence of a delayed-acting or time-dependent inhibitor.

The patient came for skin grafting after 1 month. Her APTT and Factor XI levels were found to be normal at 32 s and 133.5%, respectively, indicating the presence of transient inhibitors, due to sepsis, during her first presentation to the hospital.


  Discussion Top


Factor XI deficiency is classified as mild (40%–70%), moderate (20%–40%), and severe (<20%).[6],[7] The severity of bleeding in FXI deficiency is neither related to the levels nor the genotype.[2],[5]

The clinical presentation in Factor XI deficiency is grossly variable; risk assessment for bleeding in such cases is challenging, so the decision on prophylactic management is tough.[8] Further studies describing the management of pregnancy in Factor XI deficiencies are very few, limiting the availability of evidence-based guidelines.[8]

In Case 1, detecting factor XI deficiency was crucial as the patient was planned for a caesarean section. AlThough there was no known significant history of previous bleeding, this particular episode might have resulted in severe postpartum hemorrhage, putting the patient in a life-threatening situation. A thorough investigation of a mildly elevated APTT aided in detecting factor XI deficiency, and blood products were reserved to handle any event of abnormal bleeding during the surgical procedure.

In Case 2, the acquired factor XI deficiency can be attributed either to sepsis or secondary to carcinoma, as the patient had a history of colonic adenocarcinoma. Improvements in APTT levels with improvement in the clinical condition during admission and normal levels of APTT and Factor XI on her second hospital visit indicate sepsis being a cause of acquired hemophilia.

Sepsis is a systemic inflammatory response and a potent activator of thrombosis.[9] It activates Factor XI via the activation of Factor XII by the negatively charged bacterium and by increased tissue factor-initiated coagulation.[9],[10] Factor XI deficiency has been reported in children with meningococcal shock.[11] Similarly, factor XI levels were detected to be significantly lower among septicemia patients.[9] Usually, the cause of factor deficiency in sepsis is the activation and consumption of factors. However, in our case, the mechanism was possibly the development of a transient inhibitor against Factor XI, as indicated by mixing studies, resulting in factor XI deficiency. This mechanism does not find mentioned in the literature. Inhibitors against clotting factors generally occur in patients with severe congenital factor deficiencies who have undergone multiple replacement therapies.[12] Acquired factor Inhibitors in the absence of congenital deficiencies are very rare. Inhibitors against Factor XI have been reported anecdotally in the literature, primarily associated with autoimmune disorders, SARS-CO-V and certain malignancies.[12] To our knowledge, transient acquired Factor XI deficiency secondary to sepsis is probably the first case reported.

Extensive workup is required to accurately diagnose these rare cases. The significance of mixing studies could not be undermined. If mixing research had not been taken up for the patients, the presence of an inhibitor, and hence, acquired hemophilia would have been missed.


  Conclusion Top


Factor XI deficiency is a rare bleeding disorder that presents as prolonged isolated APTT. Careful clinical evaluation and complete coagulation workup are necessary for the efficient management of patients, which can prevent life-threatening events.

It is equally important to state that the publication of such cases should take place, enabling the formulation of treatment and investigation protocols.

Conflicts of interest

There are no conflicts of interest.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Funding

Nil.

Authors contribution

  • Dr. Mamta Soni: Diagnosing the case, conception of the idea, submission, and final approval of the version to be published
  • Dr. Srikanth Muralikrishnan: Critical review of the article
  • Dr. Supraja Sundaram: Conception of the idea and drafting of the article.




 
  References Top

1.
Preis M, Hirsch J, Kotler A, Zoabi A, Stein N, Rennert G, et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017;129:1210-5.  Back to cited text no. 1
    
2.
Jayakrishnan T, Shah D, Mewawalla P. Hemophilia C: A case report with updates on diagnosis and management of a rare bleeding disorder. J Hematol 2019;8:144-7.  Back to cited text no. 2
    
3.
Kyriakou DS, Alexandrakis MG, Passam FH, Foundouli K, Matalliotakis E, Koutroubakis IE, et al. Acquired inhibitors to coagulation factors in patients with gastrointestinal diseases. Eur J Gastroenterol Hepatol 2002;14:1383-7.  Back to cited text no. 3
    
4.
Asselta R, Paraboschi EM, Rimoldi V, Menegatti M, Peyvandi F, Salomon O, et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood 2017;130:e1-6.  Back to cited text no. 4
    
5.
Bhoi D, Sreekumar E J, Anand RK, Baidya DK, Chhabra A. Anaesthesia management of caesarean section patients with severe factor XI deficiency. J Obstet Anaesth Crit Care 2013;3:37-9.  Back to cited text no. 5
  [Full text]  
6.
Mandal S, Gami S, Shah S. A case report on an extremely rare disease: Factor XI deficiency. Cureus 2020;12:e10746.  Back to cited text no. 6
    
7.
Cetin G, Karatoprak C, Kiskac M, Zorlu M, Rezvani A, Cikrikcioglu MA. Factor XI deficiency diagnosed following use of adalimumab. Indian J Pharmacol 2014;46:553-4.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Gerber GF, Klute KA, Chapin J, Bussel J, DeSancho MT. Peri and postpartum management of patients with factor XI deficiency. Clin Appl Thromb Hemost 2019;25:1076029619880262.  Back to cited text no. 8
    
9.
Mor-Cohen R, Zucker M, Grissom C, Brown SM, Seligsohn U, Campbell RA, et al. The reduced form of coagulation factor XI is associated with illness severity and coagulopathy in critically-ill septic patients. J Thromb Thrombolysis 2019;47:186-91.  Back to cited text no. 9
    
10.
Bane CE Jr., Ivanov I, Matafonov A, Boyd KL, Cheng Q, Sherwood ER, et al. Factor XI deficiency alters the cytokine response and activation of contact proteases during Polymicrobial sepsis in mice. PLoS One 2016;11:e0152968.  Back to cited text no. 10
    
11.
Wuillemin WA, Fijnvandraat K, Derkx BH, Peters M, Vreede W, ten Cate H, et al. Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock. Thromb Haemost 1995;74:1436-41.  Back to cited text no. 11
    
12.
Andreani G, Uscello L, Montaruli B, Briozzo A, Vitale F, Tricarico M, et al. Acquired factor XI deficiency during SARS-CoV-2 infection: Not only thrombosis. TH Open 2020;4:e233-5.  Back to cited text no. 12
    

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Correspondence Address:
Mamta Soni,
Department of Haematology and Clinical Pathology, Apollo Hospitals, 21 Greams Lane, Off Greams Road, Chennai - 600 031, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_108_22




 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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    -  Soni M
    -  Muralikrishnan S
    -  Sundaram S


Abstract
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