IBMIR is NOT Exclusively Caused by Bone Marrow-Derived MSCs
No, the instant blood-mediated inflammatory reaction (IBMIR) is not always or exclusively caused by bone marrow-derived stem cells—in fact, MSCs from adipose tissue (AT) and perinatal tissue (PT) express significantly higher levels of procoagulant tissue factor and trigger more severe IBMIR than bone marrow MSCs. 1
Tissue Source Determines TF Expression and IBMIR Severity
The critical finding from guideline-level evidence is that tissue factor expression and IBMIR triggering are fundamentally dependent on the tissue source from which MSCs are derived, not limited to bone marrow origin 1:
Hierarchy of Procoagulant Activity by Source:
- Bone marrow MSCs (BM-MSCs): Lowest TF expression, best hemocompatibility profile, with meta-analysis demonstrating safety 1
- Adipose tissue MSCs (AT-MSCs): Higher TF expression than BM-MSCs, reduced hemocompatibility, more consistently procoagulant across all populations examined 1, 2
- Perinatal tissue MSCs (PT-MSCs): Higher TF expression than BM-MSCs, reduced hemocompatibility, with substantial donor variation 1
The evidence demonstrates that compared to BM-MSCs, AT- and PT-derived products show higher TF expression and reduced hemocompatibility, with substantial donor variation and culture passage-dependent TF induction 1. This is not a minor difference—adipose-derived MSCs were found to be more consistently procoagulant than BM-MSCs, presenting a potential safety concern for systemic administration in coagulopathic patients 2.
Why This Matters Clinically
Safety Implications:
The diversification of MSC products over the past decade means that extrapolation about safety from first-generation BM-MSC products to newer AT- and PT-derived products is inappropriate 1. While BM-MSC infusion has been shown safe in meta-analysis 1, potentially lethal adverse events including thrombosis and embolization have been repeatedly reported with diverse new MSC products 1.
The Mechanism:
All MSC products can trigger IBMIR through TF-mediated activation of the extrinsic coagulation pathway 1. Blocking studies using TF antibodies, inactivated factor VIIa, and factor VII-deficient plasma demonstrated that a large share of procoagulant activity across various clinical MSC products could be attributed to triggering the extrinsic TF pathway 1.
Additional Confounding Factors Beyond Tissue Source
The procoagulant activity is not solely determined by tissue source. Multiple variables affect TF expression and IBMIR:
- Culture passage number: Extended culture increases prothrombotic properties 1, 3
- Cell dose: Higher doses significantly increase clot formation 4, 3
- Donor variation: Substantial variability exists between different cell populations 1, 2
- Culture conditions: Coculture with activated lymphocytes increases prothrombotic properties 3
- Cryopreservation status: Post-thaw functional impairment affects hemocompatibility 5
Critical Clinical Pitfall
The most dangerous assumption is that all MSC products behave like bone marrow MSCs. Umbilical cord and adipose tissue preparations show particularly strong procoagulant activity, sounding "an additional note of caution regarding uncritical systemic application of stromal cells, particularly from non-hematopoietic extravascular sources" 4.
Recommended Approach
All cellular therapies intended for intravascular delivery should undergo hemocompatibility screening before clinical application 1. This should include:
- Functional coagulation assays (thromboelastography, calibrated automated thrombogram) rather than TF expression alone 6, 4, 2
- TF/CD142 expression measurement by flow cytometry 4, 2
- Consideration of selecting TF-deficient subpopulations when using BM-MSCs 4
The evidence is unequivocal: tissue factor expression varies dramatically by MSC source, with adipose and perinatal tissues expressing higher levels than bone marrow, and this directly correlates with IBMIR severity and thrombotic risk 1.