Table 1.

Summary of Reports of ICI Induced Hemophilia A and Their Management

Author, Year	Characteristics	ICI and Time Since Initiation	Presentation	Coagulation Studies	Disease Status and Follow-Up	Treatment	Response
Delyon 20113	44M Metastatic melanoma	Ipilimumab 2 mo	Macroscopic hematuria Hemorrhagic bladder metastases	APTT 102 s FVIII < 1% FVIIIi 26 BU/mL	NR Died 2 mo later	Acute bleeding: rFVIIa 7 mg QID, activated prothrombin complex Inhibitor suppression: prednisone	Treatment response. Bleeding controlled, but recurrent.
Kato 20185	68M Metastatic lung squamous cell carcinoma	Nivolumab 17 mo	Melena Gastric ulcer secondary to NSAID Hemorrhagic shock	APTT 71s FVIII 3% FVIIIi 15 BU/mL	Continued disease response	Acute bleeding: rFVIIa Inhibitor suppression: prednisone 1 mg/kg, cyclophosphamide 15 mg/kg	Hemorrhage despite initial FVIII response to prednisone. Controlled with rFVIIa and immunosuppression.
Gozokan 20194	76M Metastatic lung squamous cell carcinoma	Nivolumab 6 wk	Extensive bruising and hematuria	APTT 93s FVIII <1% FVIIIi 31 BU/mL	Disease response maintained further 10 mo until censor	Acute bleeding: rpFVIII 100 U/kg, then activated prothrombin concentrate (1000 U/kg daily) until FVIIIi resolved Inhibitor suppression: steroids, four doses of weekly rituximab 375 mg/m2	Clinical response, however persistent FVIIIi and prolonged APTT persisted for two weeks after discharge. Resolution of bruising, undetectable FVIIIi, and normal FVIII after 4 mo.
Kramer 20215	71M NR	Pembrolizumab 128 wk	NR	NR	NR	Acute bleeding: rFVIIa, FEIBA Inhibitor suppression: corticosteroids, rituximab	Resolved after 29 d. Pembrolizumab was continued. Further details not reported.
Present case	57M Metastatic lung squamous cell carcinoma	Atezolizumab 16 mo	Asymptomatic anemia Extensive bruising and hemarthrosis	APTT 78 s FVIII 4% FVIIIi 14.6 BU/mL	Continued disease response for further 3 mo until censor	Acute bleeding: rFVIIa 42 mg Inhibitor suppression: prednisolone 100 mg, four doses of weekly rituximab 100 mg	Progressive haematoma and haemarthrosis despite initial factor response. Clinical improvement after rFVIIa. Weaned to prednisone 10 mg. No further bleeding events. Not rechallenged.

APTT, activated prothrombin time; BU, Bethesda Units; FEIBA, factor eight bypassing agent; FVIII, factor VIII; FVIIIi, factor VIII inhibitor; ICI, immune checkpoint inhibitor; NR, not reported; NSAID, nonsteroidal anti-inflammatory drug; QID, four times daily; rpFVIII, recombinant porcine factor VIII; rVIIa, recombinant activated factor VII.