The goal of this clinical trial is to evaluate the efficacy and safety of sirolimus in patients with anti-phospholipid antibody-associated thrombocytopenia.

In the 6-month randomized, double-blind, placebo-controlled phase, participants will receive either sirolimus 1 mg once daily or matching placebo. Participants will be followed at 2 weeks, 1 month, 3 months, and 6 months after enrollment.

Participants who do not achieve the primary endpoint at 6 months may enter a 3-month open-label extension and receive sirolimus 1.5 mg once daily, with follow-up through month 9.

The main question is whether sirolimus improves the overall response rate at 6 months compared with placebo.

Primary outcome:

- Overall response rate at 6 months

Secondary outcomes:

• Overall response rate at 1 month and 3 months
• Complete response rate at 6 months
• Partial response rate at 6 months
• Change in anti-phospholipid antibody titers at 6 months
• Change in oral glucocorticoid dosage at 6 months

Exploratory outcomes:

• Proportion and reasons for early discontinuation during the double-blind phase
• Among participants who do not achieve the primary endpoint at 6 months and enter the open-label extension, overall response rate, complete response rate, partial response rate, and safety outcomes after 3 months of open-label treatment

Complete response: the platelet count is more than or equal to 100×10^9/L Partial response: If the platelet count is less than 100×10^9/L, it should be more than 2 times of the baseline count Overall response: both complete and partial response

Inclusion Criteria:

• persistent positive of antiphospholipid antibody (either lupus anticoagulant, anti-cardiolipin antibody, or anti-b2GP1 antibody, at least two times with 12 weeks apart)
• persistent thrombocytopenia (30-100×10^9/L, at least for 2 weeks)

Eligible concomitant treatment:

• prednisone or equivalent dose less than 10mg per day is allowed, and dose should be stable for more than 2 weeks
• hydroxychloroquine less than 400mg per day is allowed, and dose should be stable for more than 1 month
• anti-platelet and/or anti-coagulant therapy is allowed, and strength should be the stable for 1 week
• these following therapies should be discontinued for more than 5 half-lives before the enrollment, including thrombopoietin or thrombopoietin receptor antagonist, intravenous immunoglobulin, immunosuppressants, B cell inhibitors (Belimumab or Talitacicept) and B cell depletion therapy (Rituximab or Obinutuzumab).

Exclusion Criteria:

• fulling the criteria of other connective tissue disease other than antiphospholipid syndrome
• received oral/intravenous antibiotics within 2 weeks before the enrollment.
• new onset of thrombosis within 4 weeks before the enrollment.
• apparent bleeding tendency.
• life or organ threatening manifestations, includes but not limit to catastrophic antiphospholipid syndrome and thrombotic microangiopathy.
• liver and renal dysfunction: ALT or AST more than three times of upper limit of normal range; eGFR<40mL/min/1.73m^2
• hematocytopenia: WBC<3.0×10^9/L, Hb<100g/L.
• uncontrollable hyperlipidemia: low density lipoprotein cholesterol>3.1 mmol/L, triglycerides>2.3 mmol/L after lipid lowering therapy.
• current active infection
• women in pregnancy and postpartum period

The de-identified participant-level STAR data underlying this study are not publicly available because they contain sensitive clinical information and public release is not covered by the applicable participant consent and ethics approval. Access may be requested from Zhuoli Zhang (zhuoli.zhang@126.com). Requests will be evaluated on the basis of scientific merit, participant privacy, ethical and institutional requirements, and the availability of a suitable data-use agreement.