Acquired haemophilia A associated to autoimmune thyroiditis and pangastritis

Abstract

Acquired haemophilia A is a rare condition defined by the presence of coagulation inhibitors, which are autoantibodies directed against factor VIII that interfere with its activity. We report a case of a 69-year-old woman that presented with knee haemarthrosis followed by spontaneous retroperitoneal haematoma. On coagulation studies, she presented normal prothrombin time with prolonged activated partial thromboplastin time non-correcting on mixture test, low titers of factor VIII and was detected factor VIII inhibitor that led to diagnosis of acquired haemophilia A. She was managed with supportive measures to control haemorrhage and immunosuppressive therapy to eradicate inhibitors, initially with corticosteroids, with partial transitory response, after which she developed new spontaneous haematomas. Rituximab was started at that time, with a good outcome. The additional aetiological study identified autoimmune thyroiditis and autoimmune pangastritis, an association rarely described in literature.

Background

Acquired haemophilia is an autoimmune disease that results from the development of autoantibodies to coagulation factors. Acquired factor VIII deficiency or acquired haemophilia A is defined by the presence of factor VIII autoantibodies and is the most common of the acquired haemophilias albeit extremely rare. Autoantibodies in acquired haemophilia A are mainly of IgG class and do not bind to complement.^{1 2} Most common presentation is abnormal or spontaneous haemorrhage, and the most prevalent haemorrhage is from the skin, mucous, soft tissues and muscle.¹

Case presentation

We present the case of a 69-year-old woman with a history of hypothyroidism and hypertension, without personal or family history of bleeding disorders. Her medication was levothyroxine and perindopril. She denied taking new drugs or recent travel.

She came to emergency department (ED) after a minor left knee trauma where fracture was excluded, and she was medicated with non-steroidal anti-inflammatory drugs. After 7 days she complained with pain and knee oedema, returning to the ED. After clinical evaluation a local drainage of haematic fluid was done, and it was initiated an antibiotic therapy with flucloxacillin.

Twenty-two days after the first ED evaluation, she returned with a painful ecchymosis extending from lower left abdomen to proximal two-thirds of the left thigh. At observation she was haemodynamically stable, with pallor, there was a palpable painful mass in left lower quadrant of the abdomen with around 8 cm of diameter and the previous described ecchymosis.

Investigations

Initial laboratory results (table 1) showed acute anaemia with haemoglobin of 71g/L (previous 138g/L), normal protrombin time (PT), prolonged activated partial thromboplastin time (aPTT, 56 s), without correction on mixture test.

Table 1.

Laboratory results on admission

Parameters (units)	Value	Normal range
Haemoglobin (g/L)	71	120–160
Medium globular volume (fL)	103	80–100
Medium globular haemoglobin (pg)	33	26–34
Haematocrit (%)	22.1	36–46
Leukocytes (x109 /L)	10.50	4.0–10.0
Platelets (x109 /L)	621	150–400
Prothrombin time (s)	10.4	10.6–13.5
Activated partial thromboplastin time (s)	56.0	21.4–31.2
Creatinine (umol/L)	57.46	44.2-80
Urea (mg/dL)	33	17–49
Total bilirubin (mg/dL)	0.64	<1.20
Aminotransferase aspartate (IU/L)	19	<32
Aminotransferase alanine (IU/L)	25	14–59
Potassium (mmol/L)	3.5	3.5–5.1
Sodium (mmol/L)	139	135–145
C reactive protein (mg/dL)	8.77	<0.50

An abdominal CT was requested and revealed a large retroperitoneal haematoma with no cleavage plan with psoas and iliac muscles (figure 1) and two splenic haemangiomas.

Figure 1.

CT scan revealing a large retroperitoneal haematoma (circle).

A low factor VIII (<0.4%) was found, and the diagnosis of acquired haemophilia A was confirmed with the result of a positive factor VIII inhibitor.

Treatment

She was started on treatment with methylprednisolone 1 g daily for 3 days followed by prednisolone 1 mg/kg/day and activated prothrombin complex concentrate 50 units/kg 12/12 hours. From the complementary study, we highlight no evidence of neoplasm with a full-body CT and abdominal MRI which only revealed splenic haemangiomas without haemorrhage and a normal colonoscopy.

The lab results led us to identify an hyperproliferative anaemia with increased reticulocytes count (11%) which was compatible with the active haemorrhage scenario. Further characterisation excluded iron deficiency (serum iron 61 µg/dL, ferritin 389 µg/L) but showed low levels of cyanocobalamin (85 ng/L) and folic acid (3.1 ng/L). Thyroid function tests revealed a hyperthyroidism (thyroid-stimulating hormone 12.54 mg/dL and free thyroxin 9.0 pmol/L).

The upper endoscopy showed a pangastritis with biopsies suggestive of autoimmune gastritis. The full autoimmune panel revealed positive antithyroglobulin (>500 IU/mL), antiperoxidase (1075 UI/mL) and antiparietal cells. An autoimmune thyroiditis and gastritis were assumed as aetiology of acquired haemophilia A.

During treatment with prednisolone there was only a partial improvement of aPTT while some minor ecchymosis appeared. After almost 2 months since admission, she complained of a new onset of abdominal pain. A new abdominal CT revealed an important reduction of the previous haematoma, with appearance of a new retroperitoneal haematoma on the right side, confirming the need of a more intensive immunosuppressive treatment. It was admitted an incomplete response to corticoids and rituximab was initiated (375 mg/m², 4 weeks), maintaining aPTT and factor VIII in normal range with a negative factor VIII inhibitor, allowing to stop the activated prothrombin complex, without recurrence of any haemorrhagic episodes.

Outcome and follow-up

The patient was discharged clinically stabilised for an internal medicine and immunotherapy consultation. Azathioprine was initiated as maintenance therapy, and prednisolone was slowly tapered and stopped. The follow-up included regular appointments, laboratory analysis, imagological and endoscopic examinations with no evidence of malignancy. She never had recurrence of major haemorrhagic complications, and she is stabilised after 4 years of follow-up.

Discussion

Acquired haemophilia A is a rare disease, with an incidence of 0.2–1.48 cases/million/year, and has a biphasic age distribution with the first peak from 20 to 30 years old and the second after 60 years old. This disease can be associated with many conditions, the most common being malignancy, autoimmune disorders (eg, rheumatoid arthritis and systemic lupus erythematosus), post partum and drugs (eg, penicillin, sulphonamides and phenytoin). Nevertheless, around 50% are idiopathic. In the presented case, the autoimmune thyroiditis and pangastritis were linked with the acquired haemophilia.^1–3 Only autoimmune thyroiditis is scarcely associated to acquired haemophilia A.^{4 5} There is not any case in the literature that linked acquired haemophilia A, autoimmune thyroiditis and pangastritis.

For diagnosis, in addition to clinical features, the prolonged aPTT with normal prothrombin time (PT) should rise suspicion for the presence of an acquired inhibitor. This diagnosis is supported with persistent aPTT prolongation after a mixing test. Next we can add a source of phospholipid and if the aPTT corrects, it indicates the presence of antiphospholipid antibodies; if the aPTT remains prolonged, the Bethesda assay should be performed to confirm the diagnosis and quantify the antibody titre.^4–9

After establishing the diagnosis, it is important to iniciate the treatment as soon as possible. On the one hand, it is critical to control bleeding with supportive measures, with the most recent recommendations suggesting the use as first-line therapy of recombinant activated factor VII and activated prothrombin concentrate complex, functioning as a bypass to the missing factor in the coagulation cascade. In alternative human factor VIII, concentrates or desmopressin can be used, based on availability, cost and ability to monitor. On the other hand, despite the severity of the haemorrhage, treatment to reduce or eliminate the inhibitors by using immunosuppressive drugs should be initiated as the haemorrhagic risk persists until the inhibitor eradication. Due to the lack of evidence in this rare disease, it is difficult to make recommendations on the best therapy to use. The recommendation of 2020 includes the use of glucocorticoids in all patients and the combination therapy (with cyclophosphamide or rituximab) depending on prognostic markers or in non-responding patients. Red blood cells transfusion should be used as needed until necessary.^{2 7–12} The inhibitor titers should drop slowly, so the advice is to check them and the aPTT just every 2 or 4 weeks once immunosuppressive treatment has been started.¹³

In terms of prognosis, mortality rate is estimated between 8% and 20%. Aside of bleeding, sepsis is another important cause of mortality, mostly due to the multiple immunosuppressive treatments that are used to eliminate the inhibitor. Achieving complete remission is linked to a better survival, but relapse rate after proper treatment and remission is estimated at about 20%. There are some case reports of spontaneous recovery without treatment, with an average duration of 14–31 months until inhibitor disappearance. When associated with underlying conditions, the control of that condition is determinant for treatment and for preventing relapses.^{1 13}

The case presented is of a patient with a manifestation of major haemorrhage with no previous known pathology, who was diagnosed with acquired haemophilia A. Prolongation of aPTT was the initial clue with low factor VIII assay and identification of factor VIII inhibitors confirming this hypothesis. From the study performed, it was possible to identify pangastritis and thyroiditis simultaneously with this diagnosis. Treatment with corticoid monotherapy was inefficient, and it was possible to eradicate inhibitors after combination therapy with rituximab.

Learning points.

• Acquired haemophilia A is a rare condition defined by the presence of coagulation inhibitors to factor VIII.

• The main aim of the treatment is to treat and prevent bleeding complications and to eradicate the inhibitor. The immunosuppressive treatment is the gold standard.

• It is important to rule out all the known causes: autoimmune disease, cancer or drugs.

• This case reports an association between haemophilia A and autoimmune thyroiditis and autoimmune pangastritis.

• More studies are needed to have better knowledge of these entities.

Ethics statements

Patient consent for publication

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