Systematic review of the presentation of coagulation factor VIII inhibitors in rheumatic diseases: A potential cause of life-threatening hemorrhage.

Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]

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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit

Systematic review of the presentation of coagulation factor VIII inhibitors in rheumatic diseases: A potential cause of life-threatening hemorrhage Carolyn Riester O’Connor, MD Division of Rheumatology, Drexel University College of Medicine, 245 N. 15th St, Philadelphia, PA 19102

a r t i c l e in fo

Keywords: Activated partial thromboplastin time Autoimmune diseases Acquired hemophilia Blood coagulation factor inhibitors Lupus coagulation inhibitor

a b s t r a c t Objectives: To provide a comprehensive review regarding the clinical presentation of acquired factor VIII (FVIII) inhibitors, also known as “acquired hemophilia,” in patients with rheumatic diseases. Methods: A systematic MEDLINE search was conducted to identify English-language articles published from 1993 through January 10, 2012, providing details regarding the clinical presentation, laboratory evaluation, and management of a patient(s) with newly or previously diagnosed autoimmune disease coexistent with an acquired FVIII inhibitor. Results: In total, 49 patients fulfilled the criteria for inclusion in the review; the greatest percentage (24.5%) had systemic lupus erythematosus, followed by rheumatoid arthritis (16%). The majority (78%) presented with spontaneous mucocutaneous or muscular bleeding. Prolonged activated partial thromboplastin time (aPTT) was identified in all of the 45 patients for whom results were provided. Five patients presented with an asymptomatic prolonged aPTT, which was attributed to a lupus anticoagulant in two patients, only one of whom actually had a coexisting lupus anticoagulant. Invasive procedures led to serious bleeding in both of these patients, one of whom died as a result. The majority (59%) of patients experienced complete or partial remission of their inhibitors, most (96%) after systemic eradicative therapy. A total of three (6%) patients died as a direct result of FVIII inhibitors. Conclusions: Although acquired FVIII inhibitors are rare in patients with autoimmune diseases, prompt diagnosis is essential to avoid extensive bleeding, which could be life threatening. Treatment requires eradication of the factor inhibitors. Rheumatologists must be able to distinguish acquired FVIII inhibitors from lupus anticoagulants. & 2015 Elsevier Inc. All rights reserved.

Introduction The development of autoantibodies (or inhibitors) to a coagulation factor, most often factor VIII (FVIII), is a rare but potentially serious and likely under-recognized occurrence that affects patients with autoimmune disease, presumably because of underlying immune dysregulation and the resultant development of autoantibodies [1]. This phenomenon, commonly known as

Under the direction of the author, writing and editorial support was provided by Lara Primak, MD, of ETHOS Health Communications, Newtown, PA, with financial support from Novo Nordisk, Inc. No other aspect of the development of the manuscript was financially or otherwise supported by Novo Nordisk. Dr. O’Connor received no remuneration of any kind for the development of the manuscript. Carolyn Riester O’Connor, MD, reviewed the articles selected for inclusion in the manuscript; chose the topics to be included; developed an outline; drafted, reviewed, and revised the manuscript for intellectual content throughout the writing process; and approved the submitted version of the manuscript. E-mail address: [email protected] http://dx.doi.org/10.1016/j.semarthrit.2014.11.008 0049-0172/& 2015 Elsevier Inc. All rights reserved.

“acquired hemophilia” or “autoimmune hemophilia,” typically presents with new or recent-onset bleeding and may be recurrent. Therefore, early identification of this condition is critical so that targeted therapies to eliminate the inhibitor can be initiated. Bleeding due to acquired FVIII inhibitors may be severe and life threatening. Accordingly, urgent diagnosis and treatment is crucial. Given that autoimmune diseases are among the most common underlying conditions associated with acquired FVIII inhibitors, coagulation studies including activated partial thromboplastin time (aPTT) should be obtained in patients with autoimmune disease who present with excessive bruising or other bleeding symptoms. If aPTT is prolonged in isolation, acquired FVIII inhibitors should be suspected, and further evaluation for this condition should be urgently undertaken [2]. Occasionally, affected patients present with an asymptomatic isolated prolonged aPTT during routine or screening laboratory testing. Accordingly, it is important that the clinician managing patients with rheumatic disease be familiar with the diagnostic evaluation for a prolonged

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C.R. O’Connor / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]

aPTT. Ultimately, any patient with autoimmune disease who presents with a prolonged aPTT should undergo immediate testing to determine the underlying cause. This includes patients with a minimally prolonged aPTT accompanied by bleeding and those with significant prolongation who are asymptomatic. The initial clinical presentation may not provide the necessary clues to differentiate between a coagulation factor inhibitor (associated with bleeding) and a lupus anticoagulant (associated with thrombosis), both of which may prolong the aPTT [3]. Failure to consider acquired coagulation factor inhibitors in this setting may have profoundly catastrophic consequences, particularly when a procedure is performed in a patient with an undiagnosed inhibitor. The important process by which a FVIII inhibitor is distinguished from a lupus anticoagulant is reviewed in several articles [4–8]. In addition, the coexistence of both acquired FVIII inhibitors and lupus anticoagulants has been reported [5,7] and should be considered in every instance. The primary objective of this review is to describe the association of autoimmune disease with acquired FVIII inhibitors, namely the specific autoimmune conditions associated with these inhibitors and the clinical presentation and outcome of this disorder in patients with coexisting autoimmune conditions.

263 articles identified in MEDLINE search

Methods A systematic MEDLINE search was conducted to identify English-language articles published within the past 20 years (1993 through January 10, 2012) pertaining to coexisting acquired FVIII inhibitors and rheumatic disease, using each of the search terms “acquired hemophilia” and “factor VIII inhibitor” in combination with “autoimmune disease” (Supplemental Table S1). Articles were screened for relevance to the primary topic based on the title or, in cases where the title was ambiguous, on the abstract or article contents (Fig.). The criteria for excluding articles from analysis are summarized in the Figure. Articles (case reports/ series and correspondence) identified as relevant were examined and, if they provided sufficient details regarding the clinical presentation, laboratory evaluation, and management of a patient(s) with a previously or newly diagnosed autoimmune disease coexistent with an acquired FVIII inhibitor as ultimately determined by a measurable inhibitor titer, they were included in the current review. An additional pertinent case report [9] cowritten by the author, which was not retrieved in the MEDLINE searches, was also included. The information extracted from this article and those retrieved in the systematic searches consisted of

1 additional article identified through other source

203 articles screened (excluding duplicates)

Excluded: • Not specific to autoimmune disease (n = 58) • Associated underlying conditions other than autoimmune disease (n = 35) • Hematologic condition other than acquired FVIII inhibitors (n = 23) • Not specific to FVIII inhibitors (n = 10) • Unrelated to FVIII inhibitors or other bleeding disorder (n = 9) • Non-FVIII inhibitors (n = 3) • •

Letter to editor regarding prior article (n = 2) Insufficient detail regarding clinical presentation ( n = 1)

62 articles reviewed

Excluded: • Limited detail regarding clinical presentation ( n = 5) • Associated underlying conditions other than autoimmune disease (n = 10)

47 articles included in systematic review Fig. Flow diagram of systematic literature search. FVIII, factor VIII.


the following: (1) the specific autoimmune disorders associated with acquired FVIII inhibitors and (2) the range of clinical presentations, laboratory findings, eradicative treatments, and outcomes of FVIII inhibitors in this population.

Results A total of 49 patients with underlying autoimmune disease and acquired FVIII inhibitors were identified in a total of 47 articles (Table 1) [2,3,9–53]. A few series incorporating large numbers of patients with autoimmune disease [54–56] were excluded from the systematic review because they did not provide sufficient detail regarding clinical presentation and laboratory evaluation of individual patients. The majority [n ¼ 33 (67%)] of patients were female. Ages ranged from 9 to 92 years, with a median age of 61 years. Of the patients, 22 (45%) were under the age of 60 years. Systemic lupus erythematosus [n ¼ 12 (24.5%)], rheumatoid arthritis [n ¼ 8 (16%)], bullous pemphigoid/pemphigus [n ¼ 9 (18%)], and Sjögren syndrome [n ¼ 5 (10%)] were among the most prevalent concurrent autoimmune conditions identified in the selected literature. Systemic lupus erythematosus was quiescent at the time of presentation in three of the 12 patients with this underlying condition. Acquired FVIII inhibitors were also described in patients with organ-specific autoimmune diseases, namely of the thyroid. Overall, the vast majority (78%) of patients initially presented with spontaneous bleeding symptoms involving the skin, mucous membranes, or muscles. Bleeding after relatively minor procedures (ie, venipuncture, intramuscular injection, skin biopsy, dental extraction, placement of a peripherally inserted central catheter, and fine-needle aspiration of a breast lesion) was also described as a presenting symptom in nine cases. Previous bleeding symptoms were reported in six patients, as long as 8–15 months before presentation. Quantitative or qualitative aPTT results were provided for 45 of the 49 patients. In all cases, aPTT was noted to be prolonged. Of the 41 patients for whom actual aPTT values were provided, aPTT was 50 s or greater in 38 patients, with aPTT exceeding 60 s in the majority (n ¼ 32) of these patients. aPTT was less than 50 s in three patients, with the shortest aPTT being 42 s. Five patients included in the review presented with an asymptomatic prolonged aPTT (ie, without bleeding). One of those patients (the only one among the patients identified in the current review) had a coexisting lupus anticoagulant, which was initially identified as the cause of a prolonged aPTT found on hematologic evaluation prior to liver biopsy; a concomitant FVIII inhibitor was ultimately diagnosed after the patient developed severe bleeding following the procedure. In another case, an initially prolonged aPTT was initially attributed to a lupus anticoagulant in a patient with a mixed connective tissue disease (MCTD)/systemic lupus erythematosus overlap syndrome who developed fatal bleeding complications due to femoral artery laceration during attempted femoral venipuncture. In one patient, a prolonged PTT was identified approximately 2 months prior to presenting with bleeding symptoms. Concurrent FIX inhibitors were detected in two patients upon evaluation for FVIII inhibitors. Therapy to eradicate FVIII inhibitors is detailed in Table 1. Systemic therapies were used in 47 (96%) patients. Two patients with bullous pemphigoid were treated with topical corticosteroids only; in one of those patients, the inhibitor disappeared, and in the other, the inhibitor titer decreased while on topical therapy. Of those patients who received systemic therapies, all but one received corticosteroids, which were the sole agents used in six (13%) of those patients. Of additional concomitant therapies, cyclophosphamide [n ¼ 28 (60%)] was the most frequently used, followed by intravenous immunoglobulin G [IVIG; n ¼ 13 (28%)];

3

rituximab [n ¼ 6 (13%)]; cyclosporine, azathioprine, and plasmapheresis [n ¼ 5 (11%) each]; mycophenolate mofetil [n ¼ 2 (4%)]; and vincristine and mitoxantrone [n ¼ 1 (2%) each]. Use of both short- and long-term courses of IVIG and plasmapheresis was described (Table 1). The majority (59%) of patients exhibited evidence of complete or partial remission of their FVIII inhibitors (Table 1). Successful inhibitor eradication without interim recurrence of bleeding was specifically reported in 15 (31%) patients, including one of the patients who received topical corticosteroids only. Some of these patients required adjustments in eradicative therapy because of adverse events or biochemical evidence of a persistent inhibitor before their inhibitor was eventually eliminated. Other indicators of a treatment response (ie, reduced inhibitor titer, increased or normalized FVIII activity, normalizing clotting studies, or clinical improvement) were reported in 14 (28%) patients. Recurrent bleeding was reported in 11 (22%) patients. In 10 of those patients, a favorable treatment response was eventually achieved, although one continued to have a very high inhibitor titer. The remaining patient was reportedly nonadherent to treatment. Nine (18%) patients were reported to have died. In one case, death occurred after successful inhibitor eradication and was due to a gastrointestinal bleed that was not attributed to FVIII inhibitors. Death was seemingly unrelated to bleeding or FVIII inhibitors in an additional three cases: one due to respiratory complications from chronic obstructive pulmonary disease 46 days after presentation, and two from sudden heart failure after achieving partial remission of FVIII inhibitors. In another case, death occurred as a result of massive chest wall hemorrhage more than a year after presentation, following a protracted course characterized by recurrent bleeding and a persistently elevated inhibitor titer despite treatment with high-dose corticosteroids. Two patients died of multisystem organ failure despite eradication of their inhibitors and normalization of FVIII activity, but after having suffered serious bleeding events (massive intramuscular bleed with shock and gallbladder hematoma/rupture in one, and expanding sublingual hematoma with airway obstruction warranting intubation in the other). Another patient experienced massive hemorrhage from a femoral artery laceration acquired during a femoral venipuncture attempt, resulting in cardiac arrest, hypoxic– ischemic brain injury, and brain death. Finally, one individual suffered a thrombotic stroke that was attributed to hemostatic therapy; this patient eventually succumbed after ongoing bleeding and failure to regain consciousness.

Discussion Acquired FVIII inhibitors are rare in the general population, with the reported incidence ranging from one to four persons per one million population per year overall [57] and a higher annual incidence among older adults (6.0 per 1 million in those aged 65–85 years and 16.6 per 1 million in those aged 4 85 years) [58]. The majority of patients diagnosed with acquired FVIII inhibitors are over the age of 60 years [59]. There are a total of 899 individuals with acquired FVIII inhibitors reported in larger multinational registries [56,60,61] and series [54]. The median age of these groups at diagnosis ranges from 70 to 78 years. Distribution of FVIII inhibitors between the sexes is roughly equal except in younger age groups, due to pregnancy-related cases [56,59]. In the current review, patients were overall younger and predominately female; nearly half (45%) of patients were under the age of 60 years, and women outnumbered men approximately two to one. Presumably, this was due to the coexistence of autoimmune disease, which tends to present before the age of 50 years and affect women more often than men.

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Table 1 Spectrum of coexisting rheumatic diseases and clinical presentations associated with acquired factor VIII inhibitors Underlying rheumatic disease

Age Bleeding symptoms at (years)/ presentation sex

SLE

37/F

Eradicative therapy

Large flank ecchymosis and 95 hematuria (both spontaneous) Ecchymoses and swelling of 102.4 upper extremity at site of previous blood draws; Hgb ¼ 8.3 g/dL

4200

3.9

440

o7

40/F

Intramuscular hematoma with Hgb ¼ 6 g/dL

65.8

10

15

38/F

Multiple ecchymoses of the extremities and trunk

90.4

1320

0.1

69/F

Hemarthrosis

82

307

0

54/F

Subcutaneous and gingival hemorrhages; Hgb ¼ 8.4 g/dL on initial presentation

77.3

38.7

2

24/F

Uncontrollable bleeding after 116 tooth extraction requiring PRBC transfusion (Hgb ¼ 6.7 g/dL)

46.5

2.8

19/F

Sudden metrorrhagia; microcytic 54.6 anemia (Hgb ¼ 9.1 g/dL)

2.8

3

Prednisolone 60 mg/day and IV pulse Inhibitor eradicated with cyclophosphamide treatment Prednisone, cyclophosphamide, and weekly Treated for retroperitoneal rituximab hemorrhage within 1 week of hospital discharge; “slowly responded to immunosuppression” Tapering corticosteroids plus Clotting studies normalized on cyclophosphamide later replaced by immunosuppressive therapy mycophenolate mofetil Prednisolone 60 mg/day following IV pulse Inhibitor titer decreased/FVIII steroids (1 g/day); oral CsA 200 mg/day activity increased with treatment Daily prednisolone following IV pulse Inhibitor eradicated with steroids plus IV cyclophosphamide treatment 500 mg every 2 weeks, followed by monthly and quarterly Prednisolone 30 mg/day plus CsA 200 mg/ Died of multiple organ failure day despite eradication of inhibitor/normalized FVIII activity Inhibitor titer decreased/FVIII Tapering prednisolone (30 mg/day to 10 mg/day after 4 months); tapering activity increased with cyclophosphamide (100 mg/day to treatment 50 mg/day) for 4 months then azathioprine 50 mg/day Prednisolone 50 mg/day plus Inhibitor eradicated with plasmapheresis TIW initially, followed by treatment (after presentation tapering prednisolone and with lower limb and hip cyclophosphamide 2 mg/kg/day ecchymoses)

32/M

Severe epistaxis requiring PRBC transfusion; Hgb ¼ 7.8 g/dL

NRd

105

o1

45/F

Spontaneous soft tissue hemorrhages

66

2857

o1

42/F

Soft tissue and both traumatic ↑ and spontaneous hemarthroses

1000

NR

27/F

Menorrhagia, epistaxis, and subcutaneous hematomata

16

o 0.01e

42

Outcome

Comments

Source

Autoimmune hepatitis also present.

Rezaieyazdi et al. [44] Secondary ESRD on hemodialysis. Had been Phadke et al. [40] seen 4 days prior to presentation with left thigh swelling and elevated INR; warfarin withheld.

Autoimmune myelofibrosis also present, with a normal platelet count at presentation. Presented with prolonged aPTT of 89.9 s 2 months before bleeding symptoms manifested. FIX inhibitor also present; SLE in clinical remission at presentation.

SLE inactive at presentation. Eventually developed massive intramuscular bleeding with shock and a gallbladder hematoma/rupture. Previous bleeding symptoms including refractory epistaxis and widespread ecchymoses, reported 8–15 months prior to presentation; SLE quiescent at presentation. Presented 4 days prior with a similar episode requiring blood transfusion and estrogen administration; experienced recurrent bleeding (ecchymoses of the lower limbs and hips) 1 month after second episode of metrorrhagia. Prednisolone 20 mg/day plus Bleeding recurred from previous Spontaneous psoas bleed 6 months before cyclophosphamide (500 mg IV then venipuncture site; patient presentation. 150 mg/day PO) reportedly nonadherent with treatment initiated after presenting with severe epistaxis Thrombocytopenia also present. Plasmapheresis then pulse IV prednisolone Inhibitor titer decreased after for 3 days plus IV cyclophosphamide multiple adjustments in 750-mg dose; high-dose dexamethasone treatment (40 mg/day for 4 days every 28 days) trial; monthly plasmapheresis followed by IVIG (0.4 g/kg/day for 5 days) Prednisone and cyclophosphamide; Inhibitor titer decreased after Patient thought to have a forme fruste of monthly IVIG (0.4 g/kg/day for 5 days) adjustments in treatment SLE (did not meet the criteria for SLE following recurrent bleeding diagnosis). episodes Two courses IVIG (2 g/kg over 2–5 days), six Inhibitor eradicated and FVIII Bleeding symptoms developed while IV cyclophosphamide pulses (10 mg/kg), activity normalized after patient was on corticosteroids for and IV prednisolone (250 mg every 2–3 multiple adjustments in symptoms of autoimmune disease. weeks), then tapering CsA plus treatment prednisone 5–7.5 mg/day

Pillai et al. [41]

Akahoshi et al. [2] Porru et al. [42]

Onishi et al. [38]

Ishikawa et al. [27]

Trotta et al. [50]

Kazmi et al. [30]

Lafferty et al. [31]

Lafferty et al. [31]

Schulman et al. [46]


Initial inhibitor Initial titera,b factor activitya,c

45/M

Initial aPTT, sa

RA

61/F

Postprocedural bleeding, multiple 61.4 ecchymoses, and hematoma of the left upper extremity causing compartment syndrome after PICC insertion Bleeding into/from a bullous 115 lesion of the buccal mucosa and extensive ecchymoses on both the arms; microcytic anemia

2

7

Inhibitor titer decreased and IV pulses of prednisolone and History of long-standing RA unresponsive Oliveira et al. [37] FVIII activity normalized with mycophenolate mofetil initially, then to methotrexate, leflunomide, and TNF-α 2 treatment rituximab (375 mg/m ) monthly plus IV blockers. prednisolone

839

o1

71/M

Bleeding duodenal bulb ulcer 46 presenting with lightheadedness and confusion due to anemia (Hgb ¼ 6.6 g/dL)

NR

NR

72/M

Massive spontaneous flank hematoma and macroscopic hematuria; CBC normal

6

6

54/F

Purpura extending from the right 91.2 thigh to the abdomen; hematomata of the right quadriceps femoris and left iliopsoas muscles; Hgb ¼ 10.1 g/ dL Traumatic hemarthrosis and 71 subsequent recurrent epistaxis, subconjunctival hemorrhage, and excessive bruising

145.6

1.0

IV hydrocortisone (100 mg) plus Inhibitor eradicated with Bullous pemphigoid and vitiligo also cyclophosphamide (100 mg) initially, treatment; FVIII level present; bullous pemphigoid presented followed by PO prednisolone (30 mg/day, declined 3 months later but and diagnosed 4 months prior. with increase to 60 mg for relapse; responded to adjustments in cyclophosphamide withdrawn due to treatment neutropenia and sepsis) IV prednisolone 60 mg every 12 hours; Died Developed presumed hematoma extending cyclophosphamide 1 g on day 11 from the left hip to foot 3 days after presentation. On subsequent laboratory evaluation, aPTT of 108 s, FVIII activity o 1%, and FVIII inhibitor titer of 66 BU were recorded. Impaired consciousness and right hemiplegia were noted after repeat EGD on day 13 (for ongoing drop in Hgb despite hemostatic treatment); found to have left MCA infarct. Extraperitoneal bleeding noted in the pelvis on CT. Prednisone 25 mg/day; PO CsA added Inhibitor eradicated and FVIII 2 weeks later; pulse IV CsA for recurrent activity normalized with bleeding, followed by tapering ongoing treatment (following prednisone intensified treatment for interim recurrent bleeding) PO prednisolone (50 mg/day for 24 days Inhibitor eradicated with then 40 mg/day) and cyclophosphamide treatment (100 mg/day for 24 days then 50 mg/day)

17f

5

78/M

JIA

70/M

No bleeding sequelae or history of 85.1 bleeding after multiple prior surgeries

500g

NR

78/F

Large atraumatic hematoma of right upper extremity

NR

Detected

7

19/M

Persistent oozing from venipuncture sites and intramuscular hemorrhage of left lower extremity

↑

3h

5–9

Oral prednisolone 40 mg/day

Ashrani et al. [11]

Hall and Leahy [25]

Nishino et al. [36]

FVIII activity normalized with treatment

History of squamous cell carcinoma of the Jones et al. [28] lung; subsequently developed a large hematoma over his right chest wall and right iliopsoas region requiring PRBC transfusion after initial presentation (before normalization of FVIII activity). Prednisone and cyclophosphamide Experienced recurrent bleeding Referred for hematologic evaluation prior Ballard and episodes despite treatment, to liver biopsy and found to have Nyamuswa [3] with eventual normalization prolonged aPTT, which remained of coagulation assays prolonged in a mixing study (65.4 s at 0 h; 75.5 s at 1 h). Coexisting lupus anticoagulant initially identified as a cause of prolonged aPTT. Liver biopsy performed, during which severe bleeding developed. Additional testing revealed a FVIII inhibitor. IVIG 400 mg/kg/day for 5 days then PO FVIII activity increased with Had previously undergone numerous Struillou et al. cyclophosphamide (100 mg/day) starting treatment surgical procedures without bleeding [49] 15 days after IVIG dosing tendency. Unable to quantify inhibitor titer because the titration was “technically impossible.” Developed GI bleeding from duodenal ulcer shortly after presentation, with drop in Hgb from 14 g/dL to 8 g/dL. Low FVIII activity, with normal FIX and FXI De Inocencio activity noted on presentation; initially et al. [18] treated with FFP and cryoprecipitate. FVIII inhibitor diagnosed based on persistently abnormal FVIII activity and aPTT.

5

IV prednisolone (1 g) then PO prednisone Inhibitor eradicated/FVIII activity increased with 30 mg/day (for active JIA); PO treatment cyclophosphamide 100 mg/kg/day until discontinuation for adverse effects, then 2 pulse IV cyclophosphamide (500 mg/m ) every 2 weeks for 4 months


62/M

55

Patel et al. [39]

6

Table 1 (continued ) Age Bleeding symptoms at (years)/ presentation sex

Initial aPTT, sa


Eradicative therapy

Outcome

Bullous pemphigoid/ pemphigus

60/F

IV prednisolone (40 mg/day), Inhibitor eradicated/FVIII cyclophosphamide (800 mg monthly for activity normalized with 3 months), and IVIG 20 g/day for 5 days treatment No systemic immunosuppressive agents; Inhibitor eradicated/FVIII topical clobetasol for bullous pemphigoid activity normalized with treatment No systemic immunosuppressive agents; Inhibitor titer decreased/FVIII topical steroids for bullous pemphigoid activity increased with treatment; died 8 weeks later due to unrelated acute cardiac failure Single dose of cyclophosphamide (10 mg/ Bleeding stopped and inhibitor kg) and ongoing IV dexamethasone eradicated/FVIII activity normalized with treatment before death due to sepsis

100.6

NR

10.5

68/F

Postprocedural bleeding and tongue hematoma and progressive anemia No bleeding sequelae

50

1.4

6

81/F

Asymptomatic

4 180

7

2

84/F

Atraumatic sublingual hematoma 104 involving the neck and chin

29.4

o1

49/F

Presented with multiple episodes 80.5 147.8 of bleeding, including soft tissue and cutaneous hemorrhages, intramuscular hematoma following an IM injection, and upper GI bleeding; Hgb ¼ 8 g/dL Macroscopic hematuria, multiple 1.5 42 ecchymoses, and hematomata normal

1.4

Prednisone 30 mg/day for 2 weeks, then plasmapheresis (2000 mL exchange volume) plus PO cyclophosphamide 100 mg/day for persistent symptoms

0.1i

Corticosteroids 1 mg/kg

92/F

Ecchymosis

32

0.02e

68/M

Spontaneous subcutaneous 71.3 hematomata on the trunk and extremities of 3 weeks duration

7.5

9

45/M

Delayed bleeding from skin biopsy site, followed by hematuria and hematoma of the left arm

65.3

20f

3.4

Linear IgA bullous dermatosis

69/F

None apparent at presentation; noted to have low Hgb (8.8 g/ dL) and prolonged aPTT

63.3

NR

NR

Tapering prednisolone (50–5 mg/day)

Epidermolysis bullosa acquisita

44/M

Large ecchymoses of extremities 55.2 and trunk; Hgb ¼ 6.8 g/dL

392

NR

Pulsed IV cyclophosphamide (750 mg/m2) Decreased but elevated inhibitor plus PO prednisone (60 mg/day) initially; titer (89 BU) with treatment, cyclophosphamide replaced with PO CsA with periodic episodes of 100 mg BID due to persistence of FVIII ecchymoses not requiring deficiency additional treatment

68/M

NR

Inhibitor titer decreased/FVIII activity increased with treatment

Comments

Isolated prolonged aPTT (59 s) noted before Qiu et al. [43] skin biopsy to confirm diagnosis of bullous pemphigoid. Diagnosis made based on asymptomatic Caudron et al. prolonged aPTT at presentation with [14] bullous lesions. Had coexisting transitory severe FV Ryman et al. [45] deficiency without a detectable FV inhibitor that responded to topical corticosteroids as well. Diagnosed with bullous pemphigoid Gupta and 2 months prior. On aspirin and warfarin Mahipal [23] for atrial fibrillation. Hematoma rapidly progressive, leading to airway obstruction requiring intubation. Ultimately died from sepsis-related multisystem organ failure. Zhang et al. [53]

Inhibitor eradicated/FVIII Diagnosed with anti-laminin 5 pemphigoid activity normalized with 6 months prior to presentation. treatment PO prednisone 1 mg/kg daily; duration Partial remission with reported as 3–6 weeks (case series) treatment before death from sudden heart failure Tapering prednisone starting at 80 mg/day Inhibitor titer decreased/FVIII History of pemphigus of the pharyngeal activity increased with mucosa. Bleeding symptoms and treatment (laboratory results inhibitor resolved during an 8-week normalized) course of corticosteroids and had not recurred after 1.5 years of follow-up. Tapering dexamethasone (2.5 mg/day to Inhibitor titer and clinical 0.5 mg/day); plasma exchange initially symptoms improved with treatment Inhibitor titer decreased/FVIII activity increased with treatment

Source

Ly et al. [32]

Godreuil et al. [22] Halbertsma et al. [24]

Ishikawa et al. [26]

Initially presented for evaluation of diffuse Arakaki et al. [10] skin eruption consistent with linear IgA bullous dermatosis. Developed left hip pain and trouble walking; imaging studies revealed extensive hematoma interior to the left iliac bone. Laboratory testing revealed FVIII activity of 18% and FVIII inhibitor titer of 18.2 BU. Maize and Cohen [33]


Underlying rheumatic disease

Sjögren syndrome

58/F

Extensive spontaneous ecchymoses of the neck and upper extremities; normochromic, normocytic anemia (Hgb ¼ 10 g/dL)

64/M

108

287

NR

Extensive subcutaneous and 100 muscular hematomata; Hgb ¼ 10 g/dL

25

5

72/F

Scattered, large, spontaneous, subcutaneous hematomata; Hgb ¼ 5 g/dL

512

3

72/F

Decreased Hgb, severe abdominal 61 pain, and Grey Turner’s sign after fasciotomy for compartment syndrome of the left thigh

40

NR

57/F

Spontaneous hematomata of extremities and hematuria

↑

26.4

5

Tapering prednisone (25 mg/day initially) and azathioprine (100 mg/day initially)

Dermatomyositis 65/M

Gross hematuria a few weeks before presentation; large hematoma of left upper extremity after venipuncture

112.2

61

o1

Prednisone 1 mg/kg daily plus IVIG 2 g/kg Inhibitor eradicated/FVIII activity increased with 12 over 5 days; rituximab (375 mg/m2 weekly for total of 8 doses then every months treatment 3 months) added for persistent inhibitor

Diagnosed with dermatomyositis 6 months Ayoola et al. [12] before presentation. aPTT was normal 4 months prior to presentation. aPTT initially partially corrected (to 59 s) in a mixing study but increased to 87.8 s after 2-h incubation.

MCTD/SLE overlap syndrome

33/F

No bleeding symptoms

68

200j

1j

NA; was treated with corticosteroids for sequelae of underlying autoimmune disease

Presented for evaluation of a psychotic O’Connor et al. episode. Had presented with [9] spontaneous mucocutaneous ecchymoses and personality changes 6 weeks prior, resulting in increased corticosteroid dosing. This history was not available at presentation given the patient’s mental status. Developed severe bleeding after femoral artery laceration during attempted femoral venipuncture, subsequent cardiopulmonary arrest, and, ultimately, HIE.

ANCA þ vasculitis

48/M

Oral hemorrhage with buccal hematomata, progressive dysphagia, and staining of peritoneal dialysate

61.7

1.1

4

Prednisolone 1 mg/kg/day; rituximab Inhibitor titer undetectable with Vasculitis presented with acute renal Clatworthy and (1000 mg on 2 occasions 2 weeks apart) treatment after initial failure that did not resolve despite Jayne [15] added after FVIII levels dropped upon presentation; subsequently treatment; therefore, started on repeated attempts to wean prednisolone relapsed with attempts to peritoneal dialysis. Acquired inhibitor wean treatment. Died due to presented 5 years after vasculitis GI bleeding unrelated to FVIII diagnosed. Presented with melena and inhibitor hemodynamic instability several months after initial presentation; laboratory evaluation showed normal FVIII activity and no detectable inhibitor.

96

Inhibitor titer decreased/aPTT Normal FIX activity (62%) reported; had Vintimilla et al. shortened with treatment recurrent bleeding symptoms (easy [52] before recurrence of bleeding bruising) and prolonged aPTT (45.6 s) at symptoms 5 months after 5 months after first presentation. first presentation

Inhibitor eradicated/FVIII (and Cutaneous vasculitis and a coexisting FIX FIX) activity normalized with inhibitor also present. treatment

Inhibitor titer decreased/FVIII activity increased with treatment

Carmassi et al. [13]

Received PRBC transfusion for severe Vignes et al. [51] anemia in addition to treatments for FVIII inhibitor.

aPTT shortened but remained Hgb decreased from 14.6 g/dL Dachman et al. persistently prolonged preoperatively to 5.3 g/dL on POD 1 after [16] despite treatment; died 46 fasciotomy. Subsequent exploratory days after presentation due to laparotomy revealed no source of respiratory complications bleeding but an ongoing drop in Hgb and from COPD prolonged aPTT prompted diagnosis of FVIII inhibitor after lupus anticoagulant was ruled out. Inhibitor eradicated with Received PRBC transfusion due to Dannhäuser et al. treatment persistent bleeding. [17]

Developed evidence of brain death, resulting in discontinuation of life support


Tapering PO prednisone (starting at 100 mg/day) over 2 months; 4 weekly infusions of rituximab (375 mg/m2); repeat rituximab course for second bleeding episode 5 months later (prednisone withheld due to presence of avascular necrosis of the hip) Prednisone 1 mg/kg/day; IVIG (400 mg/kg/ day for 5 days) starting day 3 with periodic maintenance doses thereafter; azathioprine 150 mg/day added for laboratory-confirmed relapse 5 months later IVIG 2 g/kg plus steroids (IV prednisolone 1000 mg/day for 3 days followed by PO prednisone 1 mg/kg/day) initially; cyclophosphamide [two 750-mg IV pulses in 15 day followed by PO dosing 1 month later (150 mg/day)] added due to poor response to prior therapies IVIG and steroids

7

8

Table 1 (continued ) Age Bleeding symptoms at (years)/ presentation sex

PMR

69/F

PAN

70/F

Goodpasture syndrome

75/F

Hypothyroidism 64/M

Initial aPTT, sa


Eradicative therapy

Outcome

Major spontaneous thigh 106 hematoma; drop in Hgb from 14.9 g/dL to 12.4 g/dL Large hematoma after fine-needle 103 aspiration of a breast lump

27

o1

48

o 0.01k

Paraplegia from an intramedullary hematoma linked to a minor fall

NR

32

o 0.1e

PO prednisone 1 mg/kg daily; duration reported as 3–6 weeks (case series)

Massive hematomata of the extremities and trunk with anemia (Hgb 8.2 g/dL)

160

20

2.6

IVIG 400 mg/kg/day for 5 days; steroids (IV Eventual inhibitor eradication/ prednisolone 1 g/day for 3 days then PO FVIII activity normalization prednisone 1.5 mg/kg/day), and with treatment cyclophosphamide (1 g IV then 100 mg/ day PO)

Tapering methylprednisolone (64 mg/day Inhibitor eradication/FVIII initially); PO cyclophosphamide (100 mg/ activity increased with day initially) for 4 months treatment Prednisone and cyclophosphamide Recurrent bleeding after initially; latter replaced with unsuccessful eradicative azathioprine due to development of therapy; ultimately died of hemorrhagic cystitis; azathioprine massive chest wall discontinued due to development of hemorrhage drug-induced hepatitis; able to eventually wean prednisone after initial presentation; high-dose steroids attempted for relapse 3 years later Remission with treatment

Comments

Source

Temporal arteritis also present.

Gallant et al. [21]

Repeatedly presented with mostly muscle Snowden et al. and joint bleeding after initial [48] presentation. Bleeding diathesis did not respond to high-dose steroids; eradicative treatment options limited by prior adverse effects.

Godreuil et al. [22] Readmitted 1 month after initial Franchini et al. presentation with large hematoma of the [20] left thigh, anemia (Hgb 6.9 g/dL), aPTT 54 s, FVIII level 16 U/dL, and FVIII inhibitor titer 2 BU (which were improved from time of discharge from previous admission). Experienced a second distinct bleeding Meiklejohn and episode (of rectus sheath) on day 10 Watson [35] (unclear if any resolution of inhibitor by this point); autoimmune hemolytic anemia also developed after eradication of FVIII inhibitor.

72/F

Spontaneous ecchymoses of the 54 face, neck, and left arm with compartment syndrome; drop in Hgb from 11.4 g/dL to 8.1 g/ dL within first 6 hours of admission

9

6

Steroids (methylprednisolone 100 mg/day Inhibitor eradication with initially, then PO prednisolone 60 mg/ treatment after second day) and cyclophosphamide 150 mg/day; bleeding episode IVIG 1 g/kg for 2 days

Hashimoto’s thyroiditis

81/F

Compartment syndrome of the right leg; multiple large ecchymoses over the entire body

390–409

o 0.1

High-dose steroids and IVIG initially, then Inhibitor titer decreased/FVIII “intensive chemotherapy” with activity increased with cyclophosphamide, mitoxantrone, treatment vincristine, and methylprednisolone following plasmapheresis for 4 days; rituximab 400-mg weekly for 4 weeks initiated after plasmapheresis discontinued

Patient had “history of” Hashimoto’s Jy et al. [29] thyroiditis and fibromyalgia. Developed severe bradycardia (HR 35 bpm) due to myocardial bleeding, requiring implantation of a pacemaker. Developed postoperative chest wall bleeding.

Graves disease

48/F

Macroscopic hematuria and 51 hemoperitoneum after hysterectomy and ovariectomy

5.8

6

aPTT only partially corrected (32 s) after 1 h Marongiu et al. [34] of incubation with normal plasma. Additional workup for underlying causes at presentation revealed the presence of autoimmune hyperthyroidism.

61/F

Spontaneous hemorrhages of extremities

57

17

Steroids [methylprednisolone (80 mg/day Inhibitor titer decreased/FVIII to 60 mg/day) for 17 days then tapering activity normalized with PO prednisone]; cyclophosphamide treatment 200 mg/day for 21 days then 150 mg/day for 12 days, when discontinued due to leukopenia Prednisone 50 mg/day, cyclophosphamide Inhibitor eradicated/FVIII 100 mg/day, and IVIG 57 g activity increased with treatment

83

73

Concurrently developed FVIII inhibitor and Sievert et al. [47] mild hyperthyroidism 1 month after L-thyroxine was discontinued due to decreased TSH concentration; had been on long-standing L-thyroxine for treatment of Hashimoto’s thyroiditis.


Underlying rheumatic disease

Normal reference ranges varied. Results may not have been consistently reproducible across laboratories. All results reported in BU unless otherwise specified. c All results reported in percentage (%) of normal unless otherwise specified. d aPTT ratio of 2.91 (normal range: 0.85–1.16) was reported in lieu of aPTT. e Reported in units per milliliter (U/mL). f Reported in Oxford Inhibitor Titers (1 Oxford unit ffi 0.8 BU [108]). g FVIII inhibitor titer was obtained after patient underwent liver biopsy and bleeding sequelae developed. (In contrast, the reported aPTT was obtained prior to the procedure.) h Inhibitor titer obtained after persistently low FVIII activity and prolonged aPTT noted after administration of FFP and cryoprecipitate. i Reported in international units (IU). j Laboratory values from 36 h after admission. k Reported in IU/dL. b

a

ALPS, autoimmune lymphoproliferative syndrome; ANCA, antineutrophil cytoplasmic antibody; aPTT, activated partial thromboplastin time; BID, twice daily; bpm, beats per minute; BU, Bethesda units; CBC, complete blood count; COPD, chronic obstructive pulmonary disease; CsA, cyclosporine; CT, computed tomography; EGD, esophagogastroduodenoscopy; ESRD, end-stage renal disease; F, female; FVIII, factor VIII; FIX, factor IX; FXI, factor XI; FFP, fresh frozen plasma; GI, gastrointestinal; Hgb, hemoglobin; HIE, hypoxic–ischemic encephalopathy; HR, heart rate; IgA, immunoglobulin A; IM, intramuscular; IV, intravenous; IVIG, intravenous immunoglobulin; JIA, juvenile idiopathic arthritis; M, male; MCA, middle cerebral artery; MCTD, mixed connective tissue disease; NA, not applicable; NR, not reported; PICC, peripherally inserted central catheter; PMR, polymyalgia rheumatica; PO, per os (by mouth); POD, postoperative day; PRBC, packed red blood cell; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TIW, three times a week; TNF, tumor necrosis factor; TSH, thyroid stimulating hormone.

ALPS

9/F

Worsening of preexisting recurrent epistaxis

46.2

38

13

Prednisone 1 mg/kg; azathioprine added for continued episodes of epistaxis and low FVIII activity

Clinical improvement but persistently lower-thannormal FVIII activity despite treatment

Normal aPTT (25 s) recorded 1 year prior to presentation.

Fang et al. [19]


9

Comorbidities are common among patients with acquired FVIII inhibitors [59]. Table 2 summarizes a total of 10 published series [54–56,60–66] that were not included in the current systematic review because they did not meet the criteria for inclusion. Approximately half of all patients with acquired FVIII inhibitors in these series were found to have an underlying condition such as autoimmune disease, malignancy, or pregnancy [55,56,60,62,63]. Overall, coexisting autoimmune disease was the most common underlying condition [54–56,61–66]. In some of these series, the proportion of patients with autoimmune disease may have been underreported, because cutaneous conditions that are currently considered by some to be autoimmune diseases (eg, bullous pemphigoid, pemphigus) were categorized as “dermatologic” [54–56,62]. Rheumatoid arthritis was the most prevalent concurrent autoimmune condition reported in those series that specified underlying conditions [54–56,61,62,64] (Table 2). In contrast, in the current systematic review, rheumatoid arthritis was the second most common single autoimmune disease represented, with systemic lupus erythematosus being more common (16% vs 24.5%, respectively). Bullous pemphigoid/pemphigus accounted for an additional 18% of cases. Acquired FVIII inhibitors have also been described in patients with organ-specific autoimmune diseases, such as Graves disease, myasthenia gravis, multiple sclerosis, and autoimmune hemolytic anemia [20,35,67]. Five cases of underlying autoimmune thyroid disease were represented in the current review. Interestingly, the underlying autoimmune disease may be quiescent when acquired FVIII inhibitors are present [2,27,36,38,42], as was seen in three patients with systemic lupus erythematosus captured in the current analysis [27,38,42]. Overall, the most common coagulation factor against which inhibitors develop in the setting of rheumatic diseases is FVIII, the activated form of which serves as a cofactor in the factor IX (FIX)mediated activation of factor X, which further mediates conversion of prothrombin to thrombin in the final common pathway of the clotting cascade [4]. Though not the subject of this review, inhibitors to coagulation factors other than FVIII have also been reported in patients with autoimmune disease but occur less frequently and, in some cases (eg, factor XII [FXII] inhibitors), are asymptomatic. Inhibitors to prothrombin (ie, factor II) have been described in patients with systemic lupus erythematosus and have been associated with bleeding [68–70] and thrombotic [71] sequelae. FIX inhibitors have been described in the literature in three patients with autoimmune disease, all of whom presented with bleeding symptoms [13,42,72]. Two of these patients had FVIII inhibitors in parallel [13,42], one of whom presented with hemarthrosis [42], which, though common in the setting of congenital FVIII or FIX deficiency, occurs rarely in association with acquired inhibitors to FVIII or FIX. Inhibitors to factor XI (FXI) have also been described specifically in patients with systemic lupus erythematosus and rheumatoid arthritis, with a spectrum of presentation ranging from life-threatening hemorrhage to thrombosis [73,74]. FXII inhibitors have likewise been reported in patients with autoimmune disease and, in contrast to FVIII and FIX inhibitors, have been associated with thrombotic complications rather than with bleeding when symptomatic [75]. Specifically, a relatively high incidence of FXII inhibitors, in concert with low FXII levels, has been reported in patients with antiphospholipid syndrome (APS): in one series of 42 patients with APS, half were found to have antibodies to FXII [76]. This finding led to the conclusion that acquired FXII deficiency may contribute to the pathophysiology of APS in some patients [76]. Finally, inhibitors to factor XIII (FXIII) or its specific subunits have been described in six patients with systemic lupus erythematosus [77,78]. FXIII inhibitors typically present with severe, even life-threatening, spontaneous bleeding events, including intracranial bleeding, leading to significant mortality [78].

10

Table 2 Comparative frequency of specified coexisting underlying conditions in published series of patients with acquired factor VIII inhibitors Green and Lechner Morrison et al. [65], Kessler et al. [63], Bossi et al. [62], Collins et al. [54], Lak et al. [64], Scharf et al. [66], Knoebl et al. [56], Kessler et al. [61], Borg et al. [60], [55], (n ¼ 177) (n ¼ 65) (n ¼ 65) (n ¼ 34) (n ¼ 150) (n ¼ 34) (n ¼ 31) (n ¼ 501)a (n ¼ 166) (n ¼ 82)

Autoimmune SLE Rheumatoid arthritis Polymyalgia rheumatica Temporal arteritis Ulcerative colitis Dermatomyositis Myasthenia gravis Polymyositis Sjögren syndrome Autoimmune thyroiditis Sarcoidosis Multiple sclerosis Antiphospholipid syndrome Otherc

32 (18) 10 (5.6) 14 (7.9) NR 2 (NR) 1 (NR) 1 (NR) 1 (NR) 1 (NR) 1 (NR) NR NR NR NR 1 (NR)

11 (17) – – – – – – – – – – – – – –

11 (17) – – – – – – – – – – – – – –

4 1 2 – – – – – – 1 – – – – –

(NR) (NR) (NR)

Malignancy Postpartum Dermatologicd Respiratorye Drug reactionf

12 13 8 7 10

8 (12) 7 (11) 1 (2) NR 2 (3)

9 7 NR NR NR

5 3 2 3 1

(NR) (NR) (NR) (NR) (NR)

(6.7) (7.3) (4.5) (3.9) (5.6)

(14) (11) (2) (3)

(NR)

25 (16.66) 3 (2.00) 9 (6.00) 3 (2.00) NR NR NR NR NR NR NR NR NR NR 10 (6.66)

– – 5 (14.70) – – – – 1 (2.94) – – – – – – –

7 (NR) – – – – – – – – – – – – – –

58 (11.6) 5 (NR) 20 (NR) 11 (2.2)b NR NR NR NR NR 3 (NR) 4 (NR) NR NR 2 (NR) 27 (NR)

39 (27) 4 (NR) 10 (NR) NR NR NR NR NR NR NR NR NR NR NR NR

12 (15) NR 2 (NR) NR NR NR NR NR NR NR NR NR NR NR NR

22 (14.66) 3 (2.00) 5 (3.33) 0 0

2 10 0 3 1

2 (NR) 1 (NR) 0 9 (NR) 0

59 (11.8) 42 (8.4) 7 (1.4) NR 17 (3.4)

20 (15) 5 (3) 0 0 0

18 (NR) 6 (NR) 0 0 0

(5.88) (29.41) (8.82) (2.94)

NR, not reportedg; SLE, systemic lupus erythematosus. a

Some patients in this series had more than one underlying etiology. Polymyalgia rheumatica was reported as a separate underlying condition in this series and not as a subtype of autoimmune disease. “Other” connective tissue/autoimmune conditions were not specified in the reporting series and may have incorporated some of the individual autoimmune conditions listed in the table. d Specific dermatologic conditions included psoriasis, pemphigus, exfoliative dermatitis, erythema annularis centrifugum, and nonspecific dermatosis, where indicated. e Specific respiratory conditions included asthma, chronic obstructive pulmonary disease, sarcoid, and respiratory failure, where indicated. f Specific drugs included antibiotics (eg, penicillin derivatives and chloramphenicol), clopidogrel, nonsteroidal anti-inflammatory agents, interferon, and phenytoin, where indicated. g Categories for which both patient numbers and percentages were NR may have been included among “other” causes in the respective series. b c


Underlying condition, n (%)


The typical clinical presentation of acquired FVIII inhibitors is major bleeding, which may be severe enough to warrant transfusion of packed red blood cells (PRBCs). Specifically, in the current series, bleeding was associated with a reduced hemoglobin level in 21 (43%) patients. Moreover, mortality rates are relatively high among patients with acquired FVIII inhibitors. In a meta-analysis from 2009, of 32 studies comprising 359 patients with acquired hemophilia, the all-cause mortality rate was 21%, with a slightly higher mortality rate of 26% among patients with underlying autoimmune disease (n ¼ 38) [79]. The overall mortality rate was slightly higher (27.9%) in the more recent European Acquired Haemophilia (EACH2) Registry analysis incorporating a total of 501 patients [56]. Rebleeding is a common cause of death among patients with acquired hemophilia who are initially effectively treated [65,80]. Three (6%) of 49 patients in the current series presented with hemarthroses [28,31,42], in contrast to congenital FVIII deficiency (hemophilia A), in which hemarthroses are relatively common. Affected patients may present with an asymptomatic prolonged aPTT without bleeding [56,81], but this occurred infrequently [5 (10%) of 49 patients] in the current review [3,9,10,14,45]. A similar frequency was noted in the EACH2 registry [56], in which 10% of patients had a prolonged aPTT without bleeding at diagnosis. Bleeding may occur spontaneously or secondary to a seemingly trivial injury or minor invasive procedure, such as an intramuscular injection or placement of a venous catheter [59]. In approximately 25% of cases described in other literature, bleeding occurs in the setting of a surgical procedure, occasionally after a prolonged preoperative aPTT is overlooked or attributed to another cause [3,43,59], as occurred in one of the patients represented in the current review [3]. In more than 80% of patients, bleeding involves the skin, muscles, soft tissues (eg, retroperitoneal space), or mucous membranes (eg, epistaxis or gastrointestinal or genitourinary bleeding) [82]. Serious bleeding in the form of melena, hematuria, intracranial and retroperitoneal bleeding, or any bleeding requiring PRBC transfusion may also occur. Serious bleeding occurred at a rate of 66.5% across 13 published series comprising 505 patients with acquired FVIII inhibitors from all causes [59]. In the current review, serious spontaneous bleeding events were described in at least 13 patients and consisted of massive intramuscular bleeding with shock and a gallbladder hematoma/ rupture [38], myocardial bleeding with subsequent bradycardia [29], sublingual hematoma with airway compromise [23], gastrointestinal bleeding [11,49,53], hematuria [12,17,25,26,44], and both severe epistaxis [30] and subcutaneous bleeding [51] requiring blood transfusion. Serious posttraumatic or postprocedural bleeding events were described in an additional seven patients [3,9,16,22,27,34,37]. Though rare, spontaneous intracranial hemorrhage has also been reported as an initial manifestation of acquired FVIII inhibitors [83,84] but was not reported in the current series, although one patient presented with a posttraumatic intramedullary bleed resulting in paraplegia [22]. The lower incidence of serious bleeding (41%) in the current review relative to the cumulative incidence across previously published series (66.5%) may reflect inherent biases of the source literature. Such biases may include a tendency to report patients with good outcomes and those who were quickly diagnosed (ie, before the onset of more serious bleeding events), or a lack of sufficient detail indicating the severity of a bleeding event. On the other hand, selection bias may have contributed to overreporting of more serious or dramatic cases of FVIII inhibitors in patients with autoimmune disease, resulting in underrepresentation of patients with less dramatic presentations in the literature. In summary, the clinical presentation of acquired FVIII inhibitors in patients with autoimmune disease (Table 1) is similar to that in patients without underlying autoimmune disease, except

11

for the younger age at presentation. However, it is critical to note that the presence of a known rheumatologic disease may prove to be a confounding variable in making the diagnosis of a FVIII inhibitor. Namely, the laboratory hallmark of an acquired FVIII inhibitor (an isolated prolonged aPTT that does not correct in a mixing study combining equal volumes of patient plasma and normal plasma) may be assumed to signify the presence of a “lupus anticoagulant.” Lupus anticoagulants are associated with antibodies against protein–phospholipid complexes and β2 glycoprotein-I and result in a hypercoagulable state [4,85]. Therefore, the presence of bleeding in a patient with a prolonged aPTT that does not correct in a mixing study should prompt immediate investigation for a coagulation factor inhibitor [86]. A lupus anticoagulant may be differentiated from a coagulation factor inhibitor by demonstrating prolongation of the dilute Russell viper venom test, an additional phospholipid-based screening test to aPTT [4– 6,87]. Another test that may be used to confirm a lupus anticoagulant is the platelet neutralization procedure; the addition of platelets as a rich phospholipid source in this test results in correction of the aPTT [4–6,87,88]. Likewise, normalization of aPTT when a lupus anticoagulant-insensitive aPTT reagent of unique phospholipid content is used suggests the presence of a lupus anticoagulant; conversely, persistent prolongation of aPTT in this setting would suggest the presence of a coagulation factor inhibitor [86,89,90]. Acquired FVIII inhibitors are confirmed by the presence of low FVIII levels and a measurable inhibitor titer using the Bethesda assay [87]. Rarely, co-occurrence of coagulation factor inhibitors with a lupus anticoagulant has been described [3,5,7,91], including in a patient with underlying rheumatoid arthritis who was captured in the current literature review [3]. This case exemplified the possibility that a prolonged aPTT (particularly if asymptomatic) may be solely attributed to an existing lupus anticoagulant, with potentially catastrophic consequences if a coexisting inhibitor is present, especially if an invasive procedure is planned [3]. Because the presence of a lupus anticoagulant may affect laboratory estimation of multiple factor levels [41], clinicians may erroneously attribute the reduced activity of all affected coagulation factors to the lupus anticoagulant, when, in fact, the reduced activity of one of the coagulation factors may be the result of an acquired inhibitor. In such cases, the persistence of reduced levels of a single coagulation factor after serial plasma dilutions will reveal the presence of a coexisting inhibitor [91,92]. Ultimately, even when a lupus anticoagulant has been detected, individual coagulation factor assays should be performed in patients who are about to undergo an invasive procedure or who have a history or symptoms of bleeding to rule out the presence of a concurrent acquired coagulation factor inhibitor [92]. Likewise, patients who may not have yet presented with bleeding symptoms, for example, due to their young age, are candidates for follow-up factor assays [92]. In addition to the propensity for serious bleeding attributable to acquired FVIII inhibitors, delays in diagnosis may further contribute to morbidity and mortality [67]. In an analysis of 499 patients with acquired FVIII inhibitors from the aforementioned EACH2 registry, the average time to diagnosis after detection of a prolonged aPTT was 22 days [93]. This interval was longest in patients with underlying autoimmune disease (mean ¼ 36 days) [93]. A delay of more than 1 week between bleeding onset and definitive diagnosis occurred in approximately one-third of patients who presented with bleeding in this registry and was associated with a significant delay in initiation of treatment [56]. Because acquired FVIII inhibitor-related bleeding cannot be controlled using customary hemostatic treatments, delays in diagnosis may have catastrophic consequences. In one series, the majority of deaths were specifically attributed to a delayed diagnosis, in that all but one of the five total deaths occurred in

12


patients who underwent surgery before the diagnosis of acquired FVIII inhibitors was made [94]. In the current review, delayed diagnosis of an acquired FVIII inhibitor proved deleterious in two patients when invasive procedures were carried out in the presence of an undiagnosed bleeding disorder: one with rheumatoid arthritis, in whom an asymptomatic prolonged aPTT was initially attributed to a coexisting lupus anticoagulant [3] and another with a MCTD/systemic lupus erythematosus overlap syndrome, whose overt bleeding symptoms 6 weeks prior to presentation were not disclosed [9]. Even when the diagnosis of acquired FVIII inhibitors is ultimately correctly made, the timing of diagnosis may impact the success of therapy: among patients in the EACH2 registry who received treatment for bleeding episodes, a delay in time to treatment was the only parameter that significantly differed between responders (median ¼ 1.00 day) and nonresponders (median ¼ 4.00 days; P ¼ 0.0155) [95]. Of the nine patients represented in the current analysis who died [9,11,15,16,22,23,38,48], only three (or 6% of the total cohort) seemingly died as a direct result of FVIII inhibitors [9,11,48]. In one case, massive iatrogenic bleeding resulted in cardiac arrest and subsequent brain death [9]. In another, death was caused by recurrent bleeding in a patient who was refractory to treatment aimed at eradicating FVIII inhibitors [48]. In the third case, the patient died after failing to regain consciousness following a thrombotic stroke (which was attributed to hemostatic therapy with porcine FVIII) while experiencing ongoing bleeding [11]. In two additional patients, death occurred due to multisystem organ failure after eradication of FVIII inhibitors and normalization of FVIII activity [23,38]; while death was not directly attributable to FVIII inhibitors in those cases, it is possible that serious bleeding events (massive intramuscular bleeding with shock and gallbladder hematoma rupture in one [38] and airway hematoma requiring intubation in the other [23]) contributed to the outcome. Because of the complexities of diagnosing and treating acquired FVIII inhibitors and the rarity with which nonhematologists encounter this condition, consultation with a hematologist is mandatory to facilitate prompt and appropriate management [81]. The ultimate objective of treatment is eradication of the inhibitor. Because this goal is typically achieved over a matter of days or weeks rather than hours, additional immediate measures are indicated in patients who present with active bleeding or who require immediate invasive procedures. Though not a focus of the current review, the challenging management of acute bleeding due to acquired FVIII inhibitors deserves special mention. Although increasing FVIII levels by giving FVIII concentrates or desmopressin makes intuitive sense, this strategy is likely to be unsuccessful, because FVIII levels must be sufficiently boosted to overwhelm the inhibitor [1,81,96]. The inhibitor titer does not correlate with FVIII activity and thus cannot be reliably used to guide therapy [97,98]. Likewise, fresh frozen plasma and cryoprecipitate are unlikely to effect hemostasis because of the small amounts of FVIII contained in those products [99]. Instead, treatments that circumvent the role of FVIII altogether in the coagulation process, so-called bypassing agents, are recommended as a first-line treatment for control of active bleeding [81]. In an analysis of data from the EACH2 registry, the rate of bleeding control was significantly higher among patients who received a bypassing agent for first-line treatment (93.3%) compared with patients who received FVIII concentrates or desmopressin (68.3%; P ¼ 0.003), after matching for factors that may have influenced treatment choice (eg, FVIII level, inhibitor titer, and site and severity of bleeding) [95]. The two commercially available bypassing agents are recombinant activated FVII (NovoSevens; Novo Nordisk A/S, Bagsvaerd, Denmark [100]) and plasma-derived activated prothrombin complex concentrate [Factor Eight Inhibitor Bypassing Agent (FEIBAs); Baxter Healthcare

Corporation, Westlake Village, CA [101]]. These agents are also used to provide hemostatic coverage for surgery or other invasive procedures in patients with acquired FVIII inhibitors [102]. However, only rFVIIa is approved specifically for use in acquired hemophilia in the United States. In cases of severe hemorrhage associated with high inhibitor titers, rapid removal of the inhibitor by extracorporeal techniques, such as plasmapheresis or immunoadsorption, may be warranted [57,103]. Extracorporeal removal of inhibitor should be followed up by administration of FVIII concentrate. These procedures provide only temporary reduction or removal of inhibitor; therefore, they do not supplant long-term eradicative strategies [59]. However, repeated plasmapheresis may be used as part of the longer-term strategy for eradicating inhibitors along with immunosuppressive agents, as occurred in two patients described in the current review [31,50]. Concurrent with treatment of any active bleeding, eradication of the inhibitor is a crucial component of managing FVIII inhibitors. While spontaneous resolution occurs in up to one-third of patients, this outcome is primarily limited to those with postpartum, drug-induced, or low-titer inhibitors [82]. In contrast, patients with underlying autoimmune disease often have hightiter inhibitors that rarely resolve spontaneously [82]. That said, it is possible that the two patients treated solely with topical steroids in the current review [14,45] experienced spontaneous remissions, given the presumably minimal systemic effect of topically administered steroids. However, neither patient had experienced bleeding, and the patient who experienced complete remission had a very low inhibitor titer (1.4 BU/mL) [14], suggesting that low-titer inhibitors may be clinically insignificant. Immediately after the diagnosis is made, treatment to eradicate the inhibitor should be attempted [102,104]. Consensus recommendations suggest that initial therapy for patients diagnosed with acquired FVIII inhibitors should consist of corticosteroids alone or a combination of corticosteroids and cyclophosphamide [81]. An analysis of data from the EACH2 registry from 2012 showed that a combination of corticosteroids and cyclophosphamide produced a sustained and more rapid remission compared to corticosteroids alone [105]. This observation is consistent with Green’s and Lechner’s [55] earlier findings in 215 patients, which were published in 1981. Likewise, among patients in the UK Haemophilia Centre Doctors’ Organisation registry, median time to remission was 10 days shorter with a combination of corticosteroids and cytotoxics versus corticosteroids alone [54]. Furthermore, acquired FVIII inhibitors in patients with autoimmune disease rarely respond to corticosteroids alone [55]. In the current review, 23 (47%) patients received a combination of corticosteroids and cyclophosphamide for initial immunotherapy. Rituximab, a monoclonal antibody that targets CD20 þ B-cells, is a promising new agent for the eradication of acquired FVIII inhibitors and was used in six (13%) patients receiving systemic eradicative therapy in the current review [12,15,29,37,40,52]. The exact role of rituximab in the treatment of acquired FVIII inhibitors is yet to be determined [15,29,37,106,107]. Other options for inhibitor eradication include azathioprine, vincristine, and mycophenolate [102], all of which were used in small numbers of patients in the current review. Cyclosporine has also been successfully used for inhibitor eradication in patients with underlying autoimmune disease, including in patients described in the current review who were unresponsive to other therapies [2,33,46]. Cyclosporine is generally reserved for acquired FVIII inhibitors that are unresponsive to other treatments [81], given its potential toxicity and the need to monitor serum levels when it is used. Although not generally recommended for inhibitor eradication [102], IVIG was used for this purpose in 13 (28%) patients who received systemic eradicative therapy in the current


review [12,13,16,20,29,31,35,43,46,47,49,51]. In most (69%) cases, IVIG was used for a brief period, shortly after diagnosis. Ultimately, the choice of eradicative therapy may be influenced by such factors as the occurrence of or risk for adverse events and the underlying condition that led to acquired FVIII inhibitor development; for example, certain agents may have additional benefits in specific autoimmune diseases (eg, cyclophosphamide in systemic lupus erythematosus and rituximab in systemic lupus erythematosus and rheumatoid arthritis). Clearly, life-long follow-up is required in patients who develop FVIII inhibitors. Following initiation of eradicative therapy, patients should be closely monitored for recurrence of inhibitors [81], because the recurrence rate has been reported to be as high as 20% following complete remission [54]. In the current review, recurrent bleeding was reported after eradicative therapy in 22% of patients, the majority of whom responded favorably to adjustments in eradicative treatment.

Conclusion Although rare, acquired FVIII inhibitors clearly affect patients with autoimmune diseases and may be difficult to diagnose because of the existence of antiphospholipid antibodies in this population. Patients with autoimmune disease and FVIII inhibitors present with spontaneous mucocutaneous and muscular bleeding and an isolated prolonged aPTT. Diagnosis may be confounded by suspicion or coexistence of a lupus anticoagulant, especially in patients who present with a prolonged aPTT without bleeding symptoms. Failure to identify FVIII inhibitors in this setting may prove particularly catastrophic in patients undergoing invasive procedures in whom the existence of an inhibitor is unknown. Given the high mortality and morbidity of FVIII inhibitors, particularly when diagnosis is delayed, rheumatologists must maintain a high index of suspicion for this condition in their patients who present with bleeding symptoms or with an asymptomatic, isolated, prolonged aPTT, particularly if surgery or other invasive interventions are planned. It is recommended that all patients with rheumatic disease who present with a prolonged aPTT should undergo a complete laboratory evaluation to determine the cause of the prolongation, as previously described. Consultation with a hematologist may facilitate efficient diagnosis and proper management, particularly when an acquired FVIII inhibitor is suspected or confirmed.

Appendix A. Supporting Information Supplementary material cited in this article is available online at http://dx.doi.org/%2010.1016/j.semarthrit.2014.11.008.

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Male fertility potential alteration in rheumatic diseases: a systematic review.

Renal hemorrhage caused by acquired inhibitors to coagulation factors VIII and V in a hemodialysis patient.

Amino acid substitutions in the factor VIII coagulation protein that cause hemophilia A in man.

Cryotherapy in inflammatory rheumatic diseases: a systematic review.

Factor VIII inhibitors in haemophiliacs.

What are the effects of medication adherence interventions in rheumatic diseases: a systematic review.

Factor VIII inhibitor by-passing activity (FEIBA) in the management of patients with factor VIII inhibitors.

Infections as a cause of autoimmune rheumatic diseases.

Calprotectin in rheumatic diseases: a review.

Helical organization of blood coagulation factor VIII on lipid nanotubes.

Influence of ABO type on global coagulation assay results: effect of coagulation factor VIII.

Definition of the affinity of binding between human von Willebrand factor and coagulation factor VIII.

Murine coagulation factor VIII is synthesized in endothelial cells.

Factor VIII assay mimicking in vivo coagulation conditions.

Variable inactivation of human factor VIII from different sources by human factor VIII inhibitors.

Acquired Factor VIII Inhibitors: Three Cases.

Accelerated telomere shortening in rheumatic diseases: cause or consequence?

Human coagulation factor VIII domain-specific recombinant polypeptide expression.

Mice deficient in the anti-haemophilic coagulation factor VIII show increased von Willebrand factor plasma levels.

Editorial: Treatment of hemophilic children who have factor VIII inhibitors.

The impact of inflammatory rheumatic diseases on the presentation, severity, and outcome of acute coronary syndrome.

Management of factor VIII inhibitors: evolution and current status.

Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat.

Could retinoids be a potential treatment for rheumatic diseases?