Acquired Hemophilia Associated with Rheumatic Diseases: A Case-Based Systematic Review

Figures & data

Figure 1 (A): The patient’s right buttock and left thigh was obviously enlarged. There was ecchymosis over left thigh (above). The ecchymosis disappeared after 3 months (below). (B): T2 weighted imaging of magnetic resonance imaging showed occupying lesion (probably hematoma, see white arrows) deep under the right gluteus maximus, and the signal of muscles and other soft tissues around the pelvis and femur increased widely.

Table 1 14 Cases of Acquired Hemophilia Associated with Rheumatic Diseases

Reference	Age/Sex	Race	Chief Complaint	Tests	Basic RDs	Treatment	Prognosis
Braunert et al^Citation3	76y/M	Caucasion	Hematoma	FVIII activity 1.2%; FVIII inhibitor 31.7 BU	Polymyalgia rheumatica	No improvement with aPCC, oral PED (1 mg/kg daily) and CTX (1.5mg/kg daily) after 2 weeks. Improvement with IV Rit at 375 mg/m2 weekly for four weeks.	No relapse within 6 months follow-up.
Arthanari et al^Citation4	78y/F	Caucasion	Spontaneous subcutaneous bleeding	APTT 56s; FVIII inhibitor 22 BU; FVIII activity 3%; RF+, ANA+	RA	CTX 100mg daily, Transfusion of aPCC	Died less than 2 months after diagnosis due to mass bleeding and multiorgan failure.
Rezaieyazdi et al^Citation5	37y/F	UK	Fatigue, malaise, abdominal pain, haematuria, large ecchymotic area on the left flank and leukopenia	HBG 12.5g/dl; PLT 180×10^3/µL; WBC 3×10^3/µL; APTT 95s; FVIII activity 3.9%; FVIII inhibitors>200 BU; ANA+, anti-Sm+, anti small nuclear RNP+, anti-dsDNA+; proteinuria 2350mg per 24h	SLE	Fresh frozen plasma infusion (10mL/kg), IV mPSN pulse 1000mg/day for 3 days, continued with 60mg PSN per day, IV pulse CTX	APTT, FVIII activity, and FVIII inhibitors became normal after 4 weeks. No relapse during the 1.5-year follow-up.
Drobiecki et al^Citation6	48y/F	Caucasion	Diffuse bruising of the forearms, the trunk and right breast	HGB 80g/l, PLT 444*10^9/l; APTT 112s; FVIII activity 5.48%; FVIII inhibitor 29.9 BU	RA	rFVIIa, PED 60mg/day, and CTX 100mg/day	FVIII activity 29%, APTT 50.6s after 6 weeks. Experiences several relapses after discontinuation of CTX. Success with Rit 375mg/m^2/week for four doses.
Sebastian et al^Citation7	25y/F	Caucasion	Multiple areas of ecchymoses on the upper and lower extremities, an episode of hemoptysis and increasing dyspnea	APTT 100s; Leukopenia 2.51×10^3/µL; HGB 7.2g/dl, PLT 210×10^3/µL; ANA1: 320+, SS-A+, Ro52+, ACA-; FVIII activity <5%; FVIII inhibitor 614.4 IU/mL	SLE	Oral mPSN 20 mg/day, chloroquine 250 mg/day and CsA 200 mg/day	Partially remission. Experienced a relapse due to pregnancy, and recieved remission with rfVIIa, PED 1 mg/kg and CsA 250 mg/day. No relapse during the 5-year follow-up with chloroquine 250 mg/ day, CsA 200 mg/day and mPSN in a maintenance dose.
Cui et al^Citation8	42y/M	Asia	Gradually enlarged subcutaneous hematoma on the right scapula, sporadic skin ecchymosis, and painful swelling for 2 months	APTT 121.9s; FVIII activity 1%; FIX activity 4%; FVIII and FIX inhibitors levels were 30 and 15 BU; Proteinuria was 4.5 g per 24 hours; ANA 1:160+, anti-dsDNA 1:160+, anti-SSA+, anti-SSB+	SLE	Failed to respond to aPCC and PED 60 mg/day for 6 weeks. Weekly Rit at 375 mg/m2 for four consecutive weeks	Achieved partially remission with no haemorrhagic manifestations during the 1-year follow-up. Experienced relapse of both nephritis and AH after 1 year and 4 months, and died of progressive renal failure, severe pneumonia and intra-abdominal bleeding.
Khodamoradi et al^Citation9	55y	UK	Hematoma and hematuria	Prolonged APTT, normal PT and platelet, low FVIII, high FVIII inhibitor	SLE	GC, FEIBA and Rit	Recovered.
Hashimoto et al^Citation10	61y/F	Asia	Extensive subcutaneous bleeding	UK	RA	Failure with GC and CTX, success with tocilizumab	UK
Mo et al^Citation11	87y/F	Asia	Diffuse ecchymoses, melena, vaginal bleeding	HBG 5.7 mg/d; APTT>150s; FVIII level <1%; FVIII inhibitor 27.6 BU; ANA 1:160+, anti-SSA+; CT showed deep venous thrombosis	Undifferentiated connective tissue disease	GC and HCQ, an inferior vena cava catheter was placed	Achieved remission after 3 months.
Yang et al^Citation12	53y/M	Asia	Arthralgia and ecchymotic skin lesions after arthrocentesis of knee joint	APTT 92.2 s; FVIII activity 1%; FVIII inhibitors 60.0 BU	SLE	IV pulse mPSN 500 mg/d, IV CTX, plasma and aPCC infusion	Achieved remission with no relapse.
Ghozlani et al^Citation13	66y/M	UK	Spontaneous ecchymotic patches and hemarthrosis	APTT 49s; FVIII inhibitors 19 BU/mL; RF and CCP positive	RA	IV mPSN 240 mg for 3 days followed up with MTX 20mg/week and PED 7.5 mg/day; Rit 1g/2 weeks for 2 times; rFVIIa infusion	After 6 months, FVIII was 75% and the RA was in remission.
Wei et al^Citation14	40y/F	Asia	Oral cavity and nose mucosal bleeding, joint hemarthrosis	HGB 49g/l, PLT 31*10^9/l; APTT 107.4s; FVIII inhibitor positive; Platelet associated antibody IgG positive	ITP	IVIG 2g/kg; PED 1mg/kg/day; IV CTX 2 mg/kg/day. After failure, Rit at 375mg/m2/week was added	After 4 weeks of Rit, APTT, FVIII activity, and FVIII inhibitors became normal. No relapse during 3-year follow-up.
Zaidi et al^Citation15	20y/F	Saudi	Sudden onset swelling of the right hand	APTT 102.9s; FVIII activity 0.02%; FVIII inhibitor 22.4BU; ACA and anti-β2GPI antibody were very high; ANA+, anti-dsDNA+	SLE APS	rFVIIa, PSN 1 mg/kg and HCQ. As the patient’s APTT was still prolonged 2 weeks later with mild bleeding, she was started on Rit at 375 mg/m2 weekly for 4 weeks	APTT, FVIII levels, and FVIII inhibitors became normal after two weeks of initiating Rit. No relapse during the 2-year follow-up.
Shen et al^Citation16	51y/F	Asia	Fatigue, hematuria and ecchymoses for 1 week	HGB 55g/l, PLT 37*10^9/l; APTT 65.7s; FVIII activity 1.4%; FVIII inhibitor 8.5BU; ANA+, SSA+	SLE	Transfusion of rFVIIa, IV mPSN 80mg daily, IV CTX 200 mg weekly, plasmapheresis	Achieved remission after 1 month. No relapse during the 1-year follow-up.

Figure 2 PRISMA Flow Diagram. PubMed Searching Strategy: (“acquired hemophilia” OR “secondary hemophilia”) AND (“connective tissue disease” OR “rheumatic diseases” OR “rheumatoid arthritis” OR “systemic lupus erythematosus”) AND (“2010/01/01”[Date - Publication]: “2021/12/31”[Date - Publication]) AND English[Language] EMBASE Searching Strategy: (“acquired hemophilia”: ab,ti OR “secondary hemophilia”: ab,ti) AND (“connective tissue disease”: ab,ti OR ‘rheumatic diseases’: ab,ti OR ‘rheumatoid arthritis’: ab,ti OR “systemic lupus erythematosus”: ab,ti) AND English: la AND (2010: py OR 2011: py OR 2012: py OR 2013: py OR 2014: py OR 2015: py OR 2016: py OR 2017: py OR 2018: py OR 2019: py OR 2020: py OR 2021: py).

Figure 3 Diagnosis and treatment flow chart of rheumatic diseases associated acquired hemophilia. *FVIII inhibitors are most common in AH, and FIX inhibitors are extraordinarily rare.

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