Activated protein C resistance
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Activated protein C resistance is a hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). This results in an increased risk of venous thrombosis.
Activated protein C (with protein S as a cofactor) degrades Factor Va and Factor VIIIa. Activated protein C resistance is the inability of protein C to cleave Factor Va and/or Factor VIIIa, which allows for longer duration of thrombin generation and may lead to a hypercoagulable state. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations.
It has been estimated that up to 64% of patients with venous thromboembolism might have activated protein C resistance.
Figure: The Protein C Anticoagulant Pathway: Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface. As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C. Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa. This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury. T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein S
Historical Perspective
- in the late 1980s, Dr. Dahlbäck a Swedish physician discovered activated protein C resistance associated with hypercoagulable condition.[1]
- In 1993, Dr. Rogier Bertina and his colleagues identified that activated protein C (APC) resistance was primarily due to a mutation in the factor V gene (guanine to adenine substitution at nucleotide 1691, G1691A) resulting in the Factor V Leiden molecule.[2]
Classification
Pathophysiology
Causes
Activated protein C resistance may be caused by either inherited (primary), acquired(secondary), or a combination of both conditions.:
- Inherited
- Acquired
- Mixed/Unknown
| Activated Protein C Resistance | ||
|---|---|---|
| Inherited (Primary) | Acquired (Secondary) | Mixed |
| Factor V Leiden mutation | Estrogen | |
| Hormone replacement therapy | ||
| Factor V Cambridge | Pregnancy | Increased Factor VIII levels |
| Factor V Nara | proteinuria | Increased Factor XI levels |
| Factor V Liverpool | elevated body mass | Increased Factor IX levels |
| Factor V Bonn | Myeloproliferative disorders (polycythemia vera, essential thrombocythemia, hyperviscosity) | |
| Pregnancy | ||
| Antiphospholipid syndrome (APLS) or lupus anticoagulant | ||
| Protein S deficiency | ||
Activated protein C resistance may be caused by either acquired, inherited, or a combination of both conditions. Common inherited causes of activated protein C resistance include:
- Factor V Leiden mutation: Factor V is a procoagulant which upon activation promotes the formation of thrombin. In 1994, Bertina and colleagues identified a single nucleotide polymorphism (guanine to adenine substitution in nucleotide 1691), which rendered factor V resistant to proteolytic inactivation by activated protein C (APC).
- Protein S deficiency
- Increased factor VIII: Increased levels of coagulation factor VIII can be associated with inflammatory disorders and pregnancy.
- Estrogens: Increased estrogen levels during the use of oral contraceptives, hormone replacement therapy , and pregnancy
- Antiphospholipid antibodies
- Cancer: Certain solid tumors and advanced hematologic malignancies can cause aPC resistanceare
Differentiating [Disease] from Other Diseases
Epidemiology and Demographics
- The prevalence of factor V Leiden mutation as the main cause of activated protein C resistance is approximately 5% between general population and up to 18% in individuals with venous thromboembolism.
- Higher prevalence of the FVL mutation (12 to 14 percent) are reported in parts of Greece, Sweden, and Lebanon.
Risk Factors
Screening
There is insufficient evidence to recommend routine screening for [disease/malignancy] in unselected population-based.
Natural History, Complications, and Prognosis
Natural History
Complications
Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
References
- ↑ B. Dahlback (2003). "The discovery of activated protein C resistance". Journal of thrombosis and haemostasis : JTH. 1 (1): 3–9. PMID 12871530. Unknown parameter
|month=ignored (help) - ↑ R. M. Bertina, B. P. Koeleman, T. Koster, F. R. Rosendaal, R. J. Dirven, H. de Ronde, P. A. van der Velden & P. H. Reitsma (1994). "Mutation in blood coagulation factor V associated with resistance to activated protein C". Nature. 369 (6475): 64–67. doi:10.1038/369064a0. PMID 8164741. Unknown parameter
|month=ignored (help)
- Nicolaes GA, Dahlback B (2003). "Congenital and acquired activated protein C resistance". Semin Vasc Med. 3 (1): 33–46. PMID 15199491
- Dahlback B (2003). "The discovery of activated protein C resistance". J Thromb Haemost. 1 (1): 3–9. PMID 12871530
- Sheppard DR (2000). "Activated protein C resistance: the most common risk factor for venous thromboembolism". J Am Board Fam Pract. 13 (2): 111–5. PMID 10764192