Autoimmunity And Factor Xi Deficiency: Case Report and Brief Review

Factor 11 deficiency is associated with bleeding diathesis and is a rare disease in hematology. It was first described in the 1950s. Although it is rare in society, it is more common in the Jewish population. There is no correlation between factor level and bleeding. It presents with hemostasis disorder. Some cases may not even be diagnosed due to the generally mild bleeding clinic. In this study, a patient who was first diagnosed with FXI deficiency at the age of 48 was presented. The patient, who also received thyroxine treatment due to hypothyroidism, also received his first diagnosis of type 1 diabetes mellitus (DM) 10 months before the diagnosis of factor deficiency. The presentation was planned because he was diagnosed with Type 1 DM and FXI deficiency at a middle age and there were no similar cases in the English literature. The patient's accessible relatives (mother and son) were also examined.

Historically, FXI deficiency was first described by Rosenthal and his colleagues in 1953 after bleeding during dental treatment [1]. It is inherited in an autosomal recessive manner [2]. Although its prevalence in society was stated to be 1/1,000,000 in the last two decades, it was stated in a publication in 2023 that it could be in the range of 1-55.9/1,000,000 [3]. Although different figures are given for prevalence, it is more common in Jews [4]. FXI, one of the coagulation factors, is involved in the contact pathway in the coagulation cascade. In its deficiency, bleeding diathesis is expected. However, the detected factor level is insufficient to predict bleeding [5].  Even in severe FXI deficiency, major bleeding is generally not expected. Unlike hemophilia A (factor VIII deficiency) and hemophilia B (factorIX deficiency), intra-articular and intramuscular bleeding are not typical findings. Skin bruising and nosebleeds are common presentations [1].

In October 2022, a 48-year-old female patient was admitted to our hematology outpatient clinic due to skin bruises that may occur after minor trauma. In the medical history of the patient, who did not use herbal medicine or non-steroidal anti-inflammatory drugs, it was determined that he had been receiving thyroxine treatment since 2020. In addition, in January 2022, it was seen that he was diagnosed with type 1DM for the first time and received intensive insulin (quadruple insulin) treatment. In laboratory tests, complete blood count, transaminases, renal function tests, and hemoglobin A1C levels under insulin treatment were within the normal range. Islet cell antibody (ICA) in January 2022 examinations for thyroid and pancreas: positive, antiglutamic acid decarboxylase (GAD) antibody: 101.9 IU/ml (normal: 0-17 IU/ml), anti-insulin antibody: 59.2 IU/ ml (normal: 0-20 IU/ml), c-peptide level: 0.067 ng/ml (normal: 0.9-7.1 ng/ml), antithroglobulin grater than 1000 IU/ml (normal: 0-4.5 IU/ml), antiperoxidase was grater than 1300U/ml (normal: 0-57 U/ml). No atypical findings were found in the peripheral blood smear. In the patient whose prothrombin time was within the normal range for coagulation, activated partial thromboplastin time (APTT): 86.9 s (normal: 22.8-31.9), and the control APTT value was 80 s. The patient's APTT value for previous years could not be reached. However, it was learned that she did not receive any plasma products during the birth 16 years ago and subsequent tooth extraction procedures. No major bleeding or thrombotic events were observed in him or his first-degree relative. There was no pathological value in lupus anticoagulant, antiphospholipid, anticardiolipin, and anti beta2 glycoprotein tests.  Due to the APTT length, the FXI level measured after the mixing test was less than 0.9% (normal: 70-120%). In genetic (targeted next-generation sequence analysis) testing, c.151 A grater than C homozygous mutation for FXI was detected(figure-1). The patient, who did not receive any replacement therapy until the age of 48 (including birth and dental procedures), is still being monitored in the hematology outpatient clinic.

Figure1

When considered in terms of diabetes mellitus (DM), it has been stated that FXI levels increase in both type 1 DM and type 2 DM [6]. In this case, FXI due to genetic defect was found to be less than 0.9%. The patient's 16-year-old son was examined even though he had no complaints of active coagulation disorder. PTZ: 13.2, INR: 1.1, APTT: 39.8 seconds. APTT check was 40.1 s. Factor levels checked for prolonged APTT were FXI: 25.5% (normal: 70-120%), factorial: 81.4% (normal: 70-150%), factor VIII inhibitor: <0>

Figure 2:The patient's mother was also examined for coagulation. PTZ, APTT, factor XI levels were found to be within normal range.

The coagulation cascade activates FXII prekallikrein, which is activated by negative electrical charge in the intrinsic (contact) pathway. Kallikrein also further activates FXII with a feedback effect. Activated FXII activates FXI. Activated FXI activates FIX. Active FIX enters the common path by activating FX together with FVIII [5]. On the common path, FX activates FII together with FV. Activated FII also converts fibrinogen (F1) into fibrin. In this process, while FXI does not play a major role in the initiation of coagulation, it plays an important role in the maintenance of coagulation [4]. In the extrinsic pathway, which is the other pathway of coagulation, tissue factor (TF: FIII) released after trauma combines with FVIIa and enters the common pathway via FX [5].

The gene that synthesizes FXI, which is in the intrinsic pathway, is located on the long arm of chromosome 4 (4q35) and weighs 23 kb [7]. While the genetic transmission of FXI deficiency is mostly autosomal recessive, it has been shown to be autosomal dominant [3, 7]. Due to autosomal transmission, men and women are at equal risk. However, when patient data in the studies are evaluated, female dominance attracts attention [8].  Nearly 200 mutations have been identified so far on chromosome 4 for deficiency at the factor level [1, 9, 10]. Further examination is also recommended for first-degree relatives of cases with a genetic predisposition [7]. While the general opinion for FXI deficiency in the society is 1/1,000,000, heterozygosity can reach 8-9% and homozygosity or compound heterozygosity can reach 0.2% in Ashkenazi and Iraqi Jews [7]. Two genetic forms explain more than 90% of abnormal alleles in the Jewish population. Type 2: Glu 117 Stop and Type3: Phe 283 Leu [7]. While FXI was less than 1% in the type 2 group, the FXI level was found to be approximately 10% in type 3. On the other hand, a study in 2023 focused on the change in prevalence. According to this study, while the prevalence range is given as 0-5/1,000,000 in the majority of countries outside the European continent, it is stated that it is more than 5/1,000,000 in European countries. Moreover, rates are given as 55.5/1,000,000 for Ireland and 55.9/1,000,000 for the United Kingdom. With the number of cases per 1,000,000 among other high prevalence countries; They are listed as Canada (14.3), Venezuela (14.1), Australia (12.7), Tunisia (10.1), Singapore (9.0) [3].

The liver plays a leading role in the synthesis of FXI. Although different figures are given, the normal range for FXI is 50-150% (50-150U/dl), while the range of 20-60% is defined as mild deficiency, and less than 20% is defined as severe deficiency. FXI level is detected as 30-60 u/dl in heterozygous cases and less than 20 U/dl in homozygous or compound heterozygous cases [1]. Consanguineous marriages have been noted for factor XI deficiency [3]. In its deficiency (especially in case of FXI less than 30%), prolongation of APTT is expected. Although the normality of APTT excludes severe FXI deficiency, it cannot exclude the partial deficiency (FX 20-60%) group [7]. In a study of 20 patients, APTT was found to be normal in 25% of the patients [11]. On the other hand, there is no linear relationship between factor level and bleeding diathesis in the clinic [1]. Although mild bleeding is generally observed, this is not a rule. It may occur in the form of skin bruising, menorrhagia, epistaxis, and bleeding after tooth extraction [1]. Often there is no need for replacement. Postpartum hemorrhage was detected in only 20% of affected women [2]. Due to the mild bleeding pattern, some patients with FXI deficiency may not even be diagnosed. The authors' opinion about FXI is that it is diagnosed less than it should be [3]. This may be effective in prevalence differences between countries.

When the literature was scanned for comorbidities accompanying FXI deficiency, one publication reported FXI inhibitor development in a 32-week pregnancy with systemic lupus erythematosus (SLE) [12], another study reported FXI inhibitor development in a plasma cell leukemia case [13], another study reported juvenile rheumatoid arthritis, The combination of SLE and FXI deficiency [14] has been presented. In this presented case, homozygous FXI deficiency is notable for hypothyroidism (autoantibodies positive) starting at the age of 44 and type 1DM (autoantibodies positive) starting at the age of 47. Routine prophylactic dosing for activities of daily living is not recommended in FXI deficiency. The gold standard in treatment is the patient's bleeding history. It is important to personalize the treatment [7]. Antifibrinolytics are usually the first choice in bleeding control, and when necessary, fresh frozen plasma (FFP), exogenous FXI concentrate, recombinant activated FVII in case of FXI inhibitors, and fibrin glue products are among the treatment options [15, 16]. Plasma exchange accompanied by fresh frozen plasma was also used as a treatment option in a pregnancy with acquired FXI deficiency [17]. Antifibrinolytic options are tranexamic acid and epsilon aminocaproic acid [1]. The most commonly used option is fresh frozen plasma. The half-life of plasma-derived FXI is approximately 50 hours [7]. FFP or FXI concentrates can be given every 48-72 hours. In the study of Seligsohn et al., the target FXI level was recommended as 45 U/dl for 7 days for major surgery and 30 U/dl for 5 days for minor surgery [2]. Replacement is not routinely recommended for tooth extraction and skin biopsy [2]. 

Tranexamic acid, which is more frequently preferred than antifibrinolytics, can be used orally at a dose of 15-20 mg/kg three times a day [7]. For intravenous use, a dose of 10 microg/kg is recommended every 6-8 hours [7]. FFP is recommended at an average dose of 15-20 ml/kg [7]. FXI concentrate dose of 15-20U/kg increases FXI activity by an average of 30% [7]. A repeat dose may be required every 48-72 hours. The target level in FXI deficiency is approximately 30-45%. It is recommended not to exceed the level of 70% due to the risk of thrombosis [7]. In the presence of FXI inhibitor, if the inhibitor level is low, a higher dose of FXI or FFP is preferred, while in those with high inhibitor levels, recombinant activated FVII is an alternative option at a dose of 15-20 microg/kg and is used every 2-4 hours [2, 7, 18]. Anticoagulant and antiplatelet drugs should be avoided in FXI deficiency. However, if the patient needs to use these drugs for another reason, patients should be referred to hemophilia centers [7]. Factor deficiency is a risk and some complications may occur due to treatment agents. For example, there may be an allergic reaction due to the use of FFP, transfusion-related acute lung injury (TRALI), transfusion-related circulatory overload (TACO), and the risk of transmission of possible infectious agents [3]. Inhibitor development was observed in 1/3 of replacement-related cases [2]. However, inhibitor development has not been described in the group called partial deficiency (FXI level 20-60%) [7]. Thrombotic events may occur due to FXI and FVIIa[3]. A risk of thrombosis of up to 10% has been found due to the use of FXI [1, 2, 4]. On the other hand, a decrease in the frequency of ischemic stroke in cases with severe FXI deficiency has also been noted [5, 19]. However, it was not seen to be protective for acute myocardial infarction [2]. 

FXI deficiency, one of the bleeding disorders, is rare but generally causes mild bleeding. There is no correlation between bleeding and factor deficiency. Aggressive FXI use should be avoided due to the risk of inhibitory development and possible thrombosis. The relationship between FXI deficiency and immune system disorders is unknown, considering concomitant autoimmune diseases as in this case.