Development of autoantibodies against coagulation factors is an uncommon bleeding disorder associated with cancer, autoimmune conditions, pregnancy, or no apparent disease. Spontaneous FVIII inhibitors are the most frequently encountered; those against FXI have been only anecdotally reported. We report a case of acquired FXI inhibitor presenting as fatal intracranial spontaneous bleeding in an elderly patient with history of cancer and previous transfusions. Few cases of acquired FXI inhibitor have been reported in association with connective tissue disease, cancer, or surgery. Bleeding includes mucocutaneous bleeding, postsurgical hemorrhage, or life-threatening events. Treatment consists of arresting the bleeding and inhibitor eradication. High degree of suspicion is essential to promptly diagnose and treat this uncommon condition.
Immune-mediated development of autoantibodies against coagulation factors in patients without congenital deficiency is a rare but potentially life-threatening bleeding disorder [
Here we report a case of acquired FXI inhibitors presenting as spontaneous intracranial bleeding in an elderly patient with history of cancer and briefly review current literature on clinical characteristics and management strategies of this uncommon condition.
A 90-year-old man presented with decreased level of consciousness and generalised tonic-clonic seizure. He had a history of mild cognitive impairment, myocardial infarction, recurrent syncope, and resected colorectal and bladder cancer two years before, with postsurgical transfusion of six units of packed red blood cells. He did not have hypertension or diabetes and did not smoke. There was no family history of bleeding disorders or altered coagulation tests. His medications included low-dose aspirin, amiodarone, and a statin.
The patient had been in his usual state until 24 hours before this presentation, when worsening confusion, inability to walk, and lethargy developed. There was no recent head trauma. On examination, he was afebrile and unresponsive to deep painful stimuli, with mid-dilated fix pupils and periodic breathing. The arterial blood pressure was 170/100 mmHg, the pulse 60 beats per minute, and the oxygen saturation 97% while he was breathing ambient air. During examination he had a generalized convulsive seizure.
The blood levels of glucose, creatinine, alanine aminotransferase, total bilirubin, sodium, potassium, calcium, and lactic acid were normal. Serum protein electrophoresis showed polyclonal hypergammaglobulinemia without a monoclonal component. The coagulation tests revealed prolonged activated partial thromboplastin time (aPTT: 51 sec, reference range 22–34 sec). Other test results are shown in Table
Laboratory data.
Variable | 18 months before | Admission | Reference range |
---|---|---|---|
Hematocrit, % | 38.1 | 28.2 | 39.0–50.0 |
Hemoglobin, g/dL | 12.4 | 9.2 | 13.2–17.0 |
platelet count, ×109/L | 435 | 200 | 150–400 |
PT, % | 93 | 75 | 70–110 |
INR | 1.06 | 1.18 | |
aPTT, sec | 25 | 51 | 22–34 |
Fibrinogen, mg/dL | — | 710 | 200–420 |
FVIII, % | — | 263 | 70–150 |
FIX, % | — | 95 | 70–150 |
FXI, % | — | 31 | 70–150 |
Lupus anticoagulant | — | absent | absent |
Total protein, g/dL | 5.1 | 6.3 | 6.1–8.1 |
Serum protein electrophoresis | |||
Albumin, % | — | 36.6 | 55.8–66.1 |
alpha1, % | — | 6.7 | 2.9–4.9 |
alpha2, % | — | 11.5 | 7.1–14.8 |
beta1, % | — | 6.6 | 4.7–7.2 |
beta2, % | — | 7.2 | 3.2–6.5 |
gamma, % | — | 31.4 | 11.1–18.8 |
Computed tomography of the brain, performed without the administration of contrast material, showed bilateral subdural hematoma with signs of recent bleeding (Figure
Axial nonenhanced cranial CT scan performed on admission, showing bilateral subdural hematoma with signs of recent bleeding.
Intravenous mannitol was administered and additional blood samples were obtained for further coagulation studies. Despite this treatment, clinical conditions did not improve and the patients died few hours after admission. No hemostatic therapy was administered. Laboratory tests showed (a) prolonged aPTT which could not be corrected by mixing with normal plasma, (b) absence of lupus anticoagulant, and (c) reduced FXI activity (31%, reference range 70–150) due to a low-titer FXI inhibitor (
Acquired hemophilia should be suspected in presence of unexpected bleeding and a prolonged aPTT [
Acquired FVIII inhibitor is the most common autoantibody affecting the clotting cascade, with AHA estimated incidence of 1 to 4 per million/year [
Here we reported a case of acquired inhibitor-related FXI deficiency with fatal intracranial spontaneous bleeding in a patient with advanced age and history of cancer.
FXI inhibitors have been mostly reported in subjects with congenital FXI deficiency after plasma exposure and in presence of specific FXI mutations [
Acquired FXI inhibitors in patients without congenital FXI deficiency have been associated with systemic lupus erythematosus (SLE) [
Bleeding symptoms of acquired FXI deficiency are poorly related to residual FXI activity [
Standard first-line treatment for AHA consists of bypassing agents (activated prothrombin complex concentrates (aPCC) or recombinant activated FVII (rFVIIa)) to control bleeding and steroids with or without cyclophosphamide to eradicate inhibitors [
A limitation of current report is that family members were not directly tested for factor XI deficiency; in fact, despite the normality of routine coagulation tests, the possibility of an undiagnosed inherited FXI deficiency could not be definitely excluded [
In conclusion, acquired factor FXI inhibitors formation is a rare event, which needs to be promptly recognized and managed. There is a polymorphic range of hemorrhagic symptoms and underlining diseases. High degree of suspicion is essential to detect this condition. The optimal hemostatic and eradication therapy should be individualized according to the bleeding severity and the associated disorders.
The authors declare that there is no conflict of interests regarding the publication of this paper.