Figure 1
CRP-driven aPTT artefact pathway from ACS-induced inflammation to iatrogenic haemorrhage. CRP correlates with Factor VIII/fibrinogen elevation (r = 0.74; p < 0.001), which shortens aPTT independently of heparin effect. The resulting dose escalation disproportionately concentrates UFH in the smaller intravascular compartments of low-weight patients. Mediation analysis demonstrated that 47.3% of the CRP→bleeding effect operates through this pathway. ACS, acute coronary syndromes; aPTT, activated partial thromboplastin time; CRP, C-reactive protein; UFH, unfractionated heparin.
Table 1
Baseline demographics and clinical characteristics by body weight stratum.
| Variable | Total (N = 1600) | <65 kg (n = 320) | 65–85 kg (n = 848) | >85 kg (n = 432) |
|---|---|---|---|---|
| Age (years), mean ± SD | 64.8 ± 11.2 | 67.1 ± 10.8 | 64.2 ± 11.0 | 63.8 ± 11.5 |
| Male sex, n (%) | 1080 (67.5) | 185 (57.8) | 585 (69.0) | 310 (71.7) |
| Body weight (kg), mean ± SD | 76.8 ± 14.5 | 59.2 ± 4.1 | 74.8 ± 5.5 | 93.4 ± 7.2 |
| Hypertension, n (%) | 1105 (69.1) | 224 (70.0) | 582 (68.6) | 299 (69.2) |
| Diabetes mellitus, n (%) | 604 (37.8) | 118 (36.8) | 318 (37.5) | 168 (38.8) |
| eGFR < 60 mL/min, n (%) | 336 (21.0) | 85 (26.5) | 170 (20.0) | 81 (18.7) |
| CRP >24 mg/L, n (%) | 410 (25.6) | 112 (35.0) | 218 (25.7) | 80 (18.5) |
| Haemoglobin (g/dL), mean ± SD | 13.2 ± 1.8 | 12.4 ± 1.6 | 13.3 ± 1.7 | 13.8 ± 1.9 |
| CRUSADE score, median (IQR) | 32 (22–44) | 38 (28–48) | 31 (22–43) | 28 (20–39) |
| STEMI, n (%) | 611 (38.2) | 118 (36.9) | 325 (38.3) | 168 (38.9) |
| NSTEMI, n (%) | 714 (44.6) | 140 (43.8) | 378 (44.6) | 196 (45.4) |
| Unstable angina, n (%) | 275 (17.2) | 62 (19.4) | 145 (17.1) | 68 (15.7) |
| Peak hs-TnT (ng/L), median (IQR) | 1842 (486–4710) | 2010 (520–4920) | 1810 (470–4680) | 1720 (450–4510) |
| Killip III–IV, n (%) | 118 (7.4) | 32 (10.0) | 58 (6.8) | 28 (6.5) |
| Cardiogenic shock, n (%) | 77 (4.8) | 18 (5.6) | 39 (4.6) | 20 (4.6) |
| Inpatient PCI, n (%) | 1091 (68.2) | 212 (66.3) | 583 (68.8) | 296 (68.5) |
| CABG, n (%) | 139 (8.7) | 26 (8.1) | 74 (8.7) | 39 (9.0) |
[i] CABG, coronary artery bypass grafting; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; hs-TnT, high-sensitivity troponin T; IQR, interquartile range; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-elevation myocardial infarction.
Table 2
Covariate balance diagnostics before and after IPTW.
| Covariate | Pre-IPTW SMD | Post-IPTW SMD | Balance |
|---|---|---|---|
| Age (years) | 0.284 | 0.041 | Yes |
| Sex (male) | 0.312 | 0.035 | Yes |
| Baseline eGFR | 0.221 | 0.052 | Yes |
| Diabetes mellitus | 0.115 | 0.028 | Yes |
| LVEF (%) | 0.188 | 0.061 | Yes |
| Baseline haemoglobin | 0.205 | 0.044 | Yes |
| CRP quartile | 0.267 | 0.053 | Yes |
| CRUSADE score | 0.243 | 0.047 | Yes |
Table 3
Pharmacodynamic metrics, dosing velocity and CRP distribution by body weight stratum.
| Pharmacodynamic variable | <65 kg (n = 320) | 65–85 kg (n = 848) | >85 kg (n = 432) | p-Value |
|---|---|---|---|---|
| Pseudo-resistance, n (%) | 130 (40.6%) | 368 (43.4%) | 187 (43.3%) | 0.72 |
| Total UFH/24 hr (units), mean ± SD | 33,200 ± 3800 | 34,800 ± 4200 | 36,100 ± 4600 | <0.01 |
| Peak dosing velocity (U/kg/hr) | 23.8 ± 3.2 | 19.4 ± 2.6 | 16.2 ± 2.1 | <0.001 |
| TTR (%) | 43.8 | 45.2 | 46.4 | 0.18 |
| Median CRP (mg/L) | 14.8 | 9.1 | 7.2 | <0.001 |
| CRP Q4 (> 24 mg/L), n (%) | 112 (35.0%) | 218 (25.7%) | 80 (18.5%) | <0.001 |
Figure 2
(A) Weight-adjusted UFH infusion rate by CRP quartile and body weight stratum, demonstrating that both higher CRP and lower body weight independently and synergistically drive the escalation of UFH infusion rates. (B) Major bleeding (BARC 3–5) incidence by CRP quartile, showing a dose–response relationship (p for trend <0.001). BARC, Bleeding Academic Research Consortium; CRP, C-reactive protein; UFH, unfractionated heparin.
Table 4
Five-day clinical outcomes by body weight stratum.
| End-point | Total (N = 1600) | <65 kg (n = 320) | 65–85 kg (n = 848) | >85 kg (n = 432) |
|---|---|---|---|---|
| Composite MACE-5 | 122 (7.6%) | 28 (8.8%) | 63 (7.4%) | 31 (7.1%) |
| Recurrent MI | 54 (3.4%) | 12 (3.8%) | 28 (3.3%) | 14 (3.2%) |
| All-cause mortality | 68 (4.3%) | 16 (5.0%) | 35 (4.1%) | 17 (3.9%) |
| BARC 3–5 bleeding | 109 (6.8%) | 36 (11.4%) | 53 (6.2%) | 12 (2.8%) |
Figure 3
(A) Five-day clinical outcomes by weight stratum, demonstrating stable MACE rates with a progressive increase in bleeding from high- to low-weight groups. (B) Observed vs CRUSADE-predicted bleeding rates, isolating the protocol-attributable excess risk (+4.5%) concentrated in the low-weight, pseudo-resistant subgroup. BARC, Bleeding Academic Research Consortium; MACE, major adverse cardiovascular events.
Figure 4
Multivariable mediation analysis diagram and results (Baron and Kenny framework, bootstrapped with 5000 replications). The indirect (a × b) pathway – running through aPTT artefact and dose escalation – mediated 47.3% of the total CRP→bleeding effect. aPTT, activated partial thromboplastin time; BARC, Bleeding Academic Research Consortium; CI, confidence interval; CRP, C-reactive protein.
Figure 5
CRUSADE-adjusted forest plot of independent predictors of BARC 3–5 bleeding. The interaction between CRP >24 mg/L and weight <65 kg (SHR 2.94) represents the synergistic effect of inflammation and low intravascular volume on protocol-attributable bleeding risk. aPTT, activated partial thromboplastin time; BARC, Bleeding Academic Research Consortium; CI, confidence interval; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; IPTW, inverse probability of treatment weighting; SHR, sub-distribution hazard ratio.
Table 5
CRUSADE-adjusted protocol-attributable excess bleeding risk.
| Subgroup | Observed (%) | CRUSADE-Predicted (%) | Excess risk (%) | p-Value |
|---|---|---|---|---|
| <65 kg, pseudo-resistant | 11.4 | 6.9 | +4.5 | <0.001 |
| <65 kg, non-resistant | 4.8 | 5.2 | −0.4 | 0.74 |
| 65–85 kg, all | 6.2 | 5.8 | +0.4 | 0.62 |
| >85 kg, all | 2.8 | 3.1 | −0.3 | 0.68 |
Table 6
CRUSADE-adjusted multivariable predictors of BARC 3–5 major bleeding (IPTW-balanced Fine-Gray sub-distribution hazard model)
| Variable | Adjusted SHR | 95% CI | p-Value |
|---|---|---|---|
| Age (per 10-year increase) | 1.22 | 1.08–1.38 | 0.002 |
| Baseline eGFR <60 mL/min | 1.62 | 1.28–2.05 | <0.001 |
| Baseline Hgb <10 g/dL | 1.74 | 1.38–2.20 | <0.001 |
| Diabetes mellitus | 1.28 | 0.98–1.68 | 0.068 |
| Low body weight (<65 kg) | 1.88 | 1.42–2.48 | <0.001 |
| High CRP (>24 mg/L) | 1.52 | 1.18–1.96 | 0.001 |
| aPTT-defined pseudo-resistance | 1.71 | 1.34–2.18 | <0.001 |
| Interaction: CRP >24 × weight <65 kg | 2.94 | 2.08–4.15 | <0.001 |
Table 7
Anatomical distribution and severity of BARC 3–5 bleeding events by body weight stratum
| Location | Total (n = 109) | <65 kg (n = 36) | 65–85 kg (n = 53) | >85 kg (n = 12) |
|---|---|---|---|---|
| Gastrointestinal | 48 (44.0%) | 18 (50.0%) | 23 (43.4%) | 4 (33.3%) |
| Vascular access | 24 (22.0%) | 7 (19.4%) | 14 (26.4%) | 3 (25.0%) |
| Retroperitoneal | 22 (20.2%) | 8 (22.2%) | 11 (20.8%) | 2 (16.7%) |
| Intracranial | 6 (5.5%) | 2 (5.6%) | 3 (5.7%) | 1 (8.3%) |
| GU/Other | 9 (8.3%) | 1 (2.8%) | 2 (3.7%) | 2 (16.7%) |
Figure 6
Stacked bar chart showing the anatomical distribution of BARC 3–5 bleeding events across weight strata. The higher proportion of gastrointestinal and retroperitoneal bleeding in the low-weight group is consistent with systemic over-anticoagulation. BARC, Bleeding Academic Research Consortium; GU, genitourinary.