Clotting Proteins
Baseline Clotting Proteins — Antithrombin III, Protein C & Protein S
What it is
The coagulation cascade is a tightly regulated system of enzymatic amplification that produces fibrin clot in response to vascular injury. Three plasma proteins function as the principal natural anticoagulants that limit and eventually terminate clot formation once haemostasis has been achieved: Antithrombin III (AT-III) is a serine protease inhibitor produced by the liver that directly inhibits thrombin (the enzyme that converts fibrinogen to fibrin) and several other activated clotting factors including Factor Xa, IXa, XIa, and XIIa — its activity is dramatically accelerated by heparin, which is the pharmacological basis for heparin anticoagulation. Protein C is a vitamin K-dependent serine protease activated by the thrombin-thrombomodulin complex on vascular endothelium; activated Protein C (APC) inactivates Factors Va and VIIIa — the same factors targeted in the Factor V Leiden mechanism — by proteolytic cleavage, shutting down the amplification phase of coagulation. Protein S is a vitamin K-dependent cofactor required for APC to exert its anticoagulant function at physiological efficiency; it circulates both free (active cofactor) and bound to complement component C4b-binding protein. Inherited deficiency of any of these three proteins — whether quantitative (reduced production) or qualitative (dysfunctional protein at normal concentration) — produces a prothrombotic state similar in clinical consequence to Factor V Leiden, often compounding it when co-inherited.
Why we measure it
Inherited deficiencies of AT-III, Protein C, and Protein S each independently and substantially increase lifetime venous thromboembolism (VTE) risk. AT-III deficiency increases VTE risk approximately 5–50-fold (the highest single-factor inherited thrombophilia risk); Protein C deficiency increases risk approximately 7–10-fold; Protein S deficiency increases risk approximately 5–10-fold. Combined deficiencies — or deficiency in the context of Factor V Leiden — produce multiplicatively greater risk. These deficiencies are rarer than Factor V Leiden (each affecting approximately 0.1–0.5% of the general population) but more clinically penetrant — the probability of experiencing at least one VTE event in a lifetime is very high in AT-III-deficient individuals if the diagnosis is not made. Establishing baseline clotting protein levels at enrollment serves two functions. First, it identifies the minority of individuals who have inherited deficiency and require a fundamentally different approach to prothrombotic risk management — different contraceptive recommendations, more aggressive thromboprophylaxis for surgery and immobility, and family screening. Second, it establishes a personal baseline against which future results can be compared: acquired deficiency of Protein C and S (from vitamin K deficiency, liver disease, warfarin therapy, or DIC) can produce low levels that might otherwise be misattributed to inherited deficiency — the enrollment measurement clarifies which came first.
Why once at enrollment
Clotting protein levels are assessed once at enrollment. The genetic basis of inherited deficiency means the underlying susceptibility does not change. Protein C and Protein S are vitamin K-dependent and will be transiently low during warfarin therapy — testing should not be performed while anticoagulated. In the presence of acute thrombosis, AT-III and Protein S levels may be transiently reduced; the enrollment measurement in a healthy, anticoagulant-naive state provides the definitive baseline.
What movement means
AT-III, Protein C, and Protein S are each reported as a percentage of normal activity (functional assays) or as a ratio (antigen assays). Normal is defined as 70–130% of mean normal activity for most reference methods, though laboratory-specific ranges apply. Deficiency is classified as type I (low activity and low antigen — reduced production) or type II (low activity with normal antigen — dysfunctional protein).
Normal — All Three
AT-III: 80–130% · Protein C: 70–140% · Protein S (free): 65–140%
Normal baseline anticoagulant protein status. No inherited deficiency in these natural anticoagulants. Risk of VTE from thrombophilia in this panel is not elevated above population baseline. Factor V Leiden remains the most common inherited thrombophilia.
Standard laboratory reference ranges — vary by assay method
Borderline Low — Any Marker
Any marker 50–70% of normal
Borderline range — may reflect mild inherited deficiency, laboratory variation, or acquired causes (liver disease, vitamin K deficiency for Protein C and S). Repeat testing and specialist haematology assessment are appropriate before a diagnosis of inherited deficiency is established.
Middeldorp S, Clinical and Applied Thrombosis/Hemostasis, 2011
Deficient — Any Marker
< 50% of normal for AT-III · < 50% for Protein C or S
Likely inherited deficiency. Substantially elevated VTE risk, particularly in combination with other prothrombotic exposures (surgery, oral contraceptives, immobility, pregnancy). Specialist haematology review is essential. Family screening is recommended. Thromboprophylaxis in high-risk situations and careful contraceptive counselling are required.
Middeldorp S, Clinical and Applied Thrombosis/Hemostasis, 2011 — doi:10.1177/1076029611398286
In the protocol
References
- 1.
Middeldorp S. “Inherited Thrombophilia: A Double-Edged Sword.” Hematology — American Society of Hematology Education Program. 2016.
- 2.
Lane DA, Mannucci PM, Bauer KA, et al.. “Inherited Thrombophilia: Part 1.” Thrombosis and Haemostasis. 1996.
- 3.
Lipe B, Ornstein DL. “Deficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin.” Circulation. 2011.
- 4.
Rosendaal FR. “Venous Thrombosis: A Multicausal Disease.” The Lancet. 1999.