Correlation Between Factor VIII and C-Reactive Protein
Factor VIII levels and C-reactive protein (CRP) show a statistically significant correlation, but elevated Factor VIII levels in patients with venous thrombosis are NOT primarily caused by acute phase reactions—the thrombotic risk from high Factor VIII persists independently of CRP elevation. 1
Evidence for the Relationship
Primary Research Findings
The Leiden Thrombophilia Study definitively addressed this question by measuring CRP as a sensitive marker of acute phase reactions in 474 thrombosis patients and 474 matched controls. 1
Key findings include:
- Mean and median CRP levels were higher in thrombosis patients than controls, suggesting inflammation was present in some patients 1
- CRP did affect both Factor VIII and fibrinogen levels in patients and controls alike 1
- However, after statistical adjustment for CRP effects, high Factor VIII:C levels (>150 IU/dL) still increased thrombosis risk 6-fold, virtually identical to the risk before CRP correction 1
- This demonstrates that although systemic inflammation may be present in some patients, elevated Factor VIII:C levels were generally not caused by acute phase reactions 1
Clinical Implications
Factor VIII behaves differently from typical acute phase reactants:
- While CRP and Factor VIII show correlation, the relationship is not causal in most cases 1
- Factor VIII levels >150 IU/dL are present in 25% of patients with first venous thrombosis and confer 5- to 6-fold increased thrombotic risk independent of inflammation 1
- The persistence of thrombotic risk after CRP adjustment supports a causal relationship between constitutively elevated Factor VIII and venous thrombosis 1
Mechanism of Elevation
The source of elevated Factor VIII appears to be increased synthesis rather than acute phase response:
- Factor VIII activity (FVIII:C) and Factor VIII antigen (FVIII:Ag) are highly correlated (p = 0.003), confirming true increases in Factor VIII protein rather than circulating activated forms 2
- In a thrombophilia screening study, elevated FVIII:C (>1.5 IU/mL) was the single most common abnormality, detected in 25.4% of 260 patients with unexplained thromboembolism 2
- Only 4 of 46 patients with elevated Factor VIII had clear acute phase reactions, and neither FVIII:C nor FVIII:Ag showed significant correlation with fibrinogen, ESR, or CRP by nonparametric analysis 2
- The elevation appears constitutive in many cases, potentially representing an abnormal or exaggerated response to inflammatory stimuli in others 2
Clinical Context in Inflammatory States
In critically ill patients with hyperinflammation:
- Elevated fibrinogen and Factor VIII can create heparin resistance, requiring unfractionated heparin doses exceeding 35,000 units/day to achieve therapeutic range 3
- Hyperfibrinogenemia antagonizes heparin's anticoagulant effects through binding to heparin-binding proteins 3
- In COVID-19 patients specifically, elevated acute phase reactants including CRP create this heparin resistance phenomenon 3
Important Caveats
Do not dismiss elevated Factor VIII as merely an acute phase reaction:
- The correlation with CRP exists but does not explain the majority of Factor VIII elevation in thrombotic patients 1
- Supraphysiological Factor VIII levels are an established independent risk factor for venous thromboembolism 4
- Patient stress, recent exercise, pregnancy, or inflammatory illness can falsely elevate Factor VIII and von Willebrand factor levels, potentially masking mild deficiencies 5
In hemophilia populations, the relationship differs:
- Clot waveform analysis parameters can reflect clinical severity in hemophilia A patients independent of standard Factor VIII:C measurements 6
- Trace amounts of Factor VIII may mediate higher coagulation acceleration in some severe hemophilia A patients, though factors other than Factor VIII:C alone may influence clotting kinetics 6