Complement Blockade with C1 Esterase Inhibitor in Refractory Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired thrombocytopenia due to autoantibody-mediated destruction of platelets. Multiple therapies targeting antibody production, the reticuloendothelial system and platelet production are used to treat ITP, including glucocorticoids, intravenous immune globulin (IVIG), Rituximab, splenectomy and thrombopoietin-receptor agonists. The response to therapy is heterogeneous, supporting the concept that multiple mechanisms are ultimately responsible for thrombocytopenia.

In vitro complement fixation assays have shown that serum obtained from 50% of patients with ITP is able to fix complement to the platelet surface. Autoantibodies to platelet surface antigens GPIIb/IIIa and/or GPIb/IX have also been shown to activate complement via the classical pathway. We suspect that complement fixation/activation plays an important role in platelet destruction in ITP. Proposed mechanisms include C3b deposition on the platelet surface leading to opsonization, direct damage to platelets by C5b-9, and a role for complement in the imbalance in T-cell regulator/effector activity. T-cell activity has been proposed to stimulate B-cell production of autoantibodies against platelet surface antigens.

C1 esterase inhibitor (C1INH) is a member of the serine protease inhibitor family and interacts with C1 esterase to block activation of the classical pathway of complement activation. Case reports have demonstrated that C1INH can prevent C3-mediated lysis of PNH erythrocytes (DeZern 2014) and attenuate hemolysis in a patient with DAT C3d positive autoimmune hemolytic anemia (Wouters 2013). Based on these data, we hypothesized 1) complement activation/deposition may play an important role in persistent thrombocytopenia in refractory ITP, and 2) blockade of the classical pathway with C1INH may lead to prolonged platelet survival.

Two female patients with a history of autoimmune disease (systemic lupus erythematosus (SLE) and Sjogren's) and primary refractory ITP [steroids, IVIG, Rituximab, and Romiplostim (23-38 days)] were treated with C1INH, Berinert 20 units/kg. Within 8 hours of first C1INH dose, platelet count improved significantly in both patients. Given the rapid increase in platelet count, each patient received two additional doses of C1INH. Both patients demonstrated a continued increase in platelet count with no further C1NH therapy. In patient 1, platelet count normalized on day 63 and remains normal without additional therapy 194 days post C1INH treatment. In patient 2, platelet count has risen to 568K 14 days after C1INH administration.

These cases clinically illustrate a thought provoking relationship between antigen/antibody complexes, complement activation, and platelet destruction in ITP. We suspect a potential biphasic response to C1INH therapy. We hypothesize immediate inhibition of the classical pathway and subsequent decrease of C3b deposition on platelet surface may be responsible for the acute rise in platelet count, while a reset of T-cell regulatory/effector function via complement blockade may be accountable for the longevity of platelet count increase and normalization seen in our patients.

Refractory ITP may involve antibody-mediated complement activation via the classical pathway. The destruction of platelets may be driven by C3b-mediated phagocytosis and/or by C5b-9-mediated membrane damage, as well as by modulation of the immune system and T regulator cell function. In our patients, the commercially available C1INH, Berinert, was well-tolerated and platelet count improvement was noted almost immediately after administration and has appeared to be sustained. Future studies evaluating treatments that target inhibition of the complement pathway may be an effective alternative or adjunctive therapy for refractory immune thrombocytopenia.

Platelet Counts	Baseline	Diagnosis	Prior to 1st C1NH dose	8 hours post 1st C1NH dose	Prior to 2nd C1NH dose	8 hours post 2nd C1NH dose	Prior to 3rd C1NH dose	Post 3rd C1NH dose	7 days post 1st C1NH dose	10 days post 1st C1NH dose	14 days post 1st  C1INH dose
Patient 1 62yo F H/O SLE	160 K/UL	0 K/UL	2 K/UL	12 K/UL	5 K/UL	9 K/UL	15 K/UL	30 K/UL	38 K/UL	105/UL	139K/UL
Patient 2 47yo F H/O Sjogren's	Unknown	1 K/UL	4K/UL	8K/UL	9 K/UL	18 K/UL	18 K/UL	25 K/UL	122 K/UL	469 K/UL	568 K/UL