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
Suspicion of activated protein C resistance being the cause for any thrombotic event should be considered in a member of a thrombophilic family or in an individual with venous thromboembolism (VTE), especially VTE at a young age (eg, <50 years), VTE in an unusual location (eg, portal vein, cerebral vein), or recurrent VTE.
This disease can be diagnosed by watching the aPTT (the time it takes for blood to clot) as activated protein C is added. With a normal patient, adding aPC increases the APTT. In patients with factor V Leiden, adding aPC will barely affect the time it takes for blood to clot.
functional coagulation test for aPC resistance using "second generation" aPC resistance assays.
approximately 95% of cases is due to the Factor V Leiden [FVL] mutation –There is also a simple genetic test that can be done for this disorder. The mutation (a 1691G→A substitution) removes a cleavage site of the restriction endonuclease MnlI, so simple PCR, treatment with MnlI, and then DNA electrophoresis will give a quick diagnosis.
The FVL mutation can be detected directly by analyzing genomic DNA from peripheral blood cells. Since only a single mutation is involved, this testing is straightforward and relatively inexpensive to perform.
History and Symptoms
A positive family history of thrombosis and individual recurrent thrombosis history is suggestive of inherited thrombophilias. Thrombophilia screening may be beneficial in these scenarios.[3][4][5] A positive history of the following is suggestive of inherited thrombophilias:
- Family history of thrombosis, especially at an early age (< 45 years)
- Unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis)
- Recurrent thrombosis including deep venous thrombosis, pulmonary embolus, or superficial venous thrombosis
- Thrombosis at multiple sites, or unusual locations including in cerebral, hepatic, portal, mesenteric, and renal veins
- Thrombosis in arteries with the absence of arterial disease
- History of fetal loss
- History of warfarin skin necrosis
Physical Examination
Physical examination of patients with thrombophilia is usually remarkable for:[6][4][5]
- Signs of deep venous thrombosis, pulmonary thrombosis, renal vein thrombosis, cerebral vein thrombosis, superficial vein thrombosis, or arterial thrombosis
- Portal hypertension, which can be a sign of portal vein thrombosis
- Warfarin skin necrosis
- Livedo reticularis
Laboratory Findings
Imaging Findings
- There are no x-ray findings associated with thrombophilia. X-ray may be helpful in the diagnosis of thrombosis.
- Ultrasongraphy may be diagnostic of acute deep vein thrombosis, and is associated with the diagnosis of thrombophilia.
- Chest CTA is the imaging modality of choice for the diagnosis of pulmonary embolism
- CT scans may also be helpful to diagnose deep vein thrombosis, renal vein thrombosis, and cerebral venous thrombosis
- There are no magnetic resonance imaging (MRI) findings associated with thrombophilias. MR angiography may be diagnostic of pulmonary embolism, deep vein thrombosis, or cerebral venous thrombosis.
- Ventilation/perfusion scan may be diagnostic of acute pulmonary embolism, and may be helpful in the diagnosis of thrombophilia.
Treatment
Medical Therapy
Activated protein C resistance is a description for a condition which can be caused by either acquired, inherited, or a combination of both conditions etiologies. Most individuals with activated protein C resistance are asymptomatic. Up to 30% of patients who present with deep vein thrombosis (DVT) or pulmonary embolism (PE) have this condition.The initial treatment of venous thromboembolism (VTE) in individuals with activated protein C resistance is the same as that of the general population, with anticoagulation unless there is a contraindication. The mainstay of therapy for thrombophilia is anticoagulation with either warfarin, low molecular weight heparin, direct Xa inhibitors, or direct thrombin inhibitors. Treatment should be tailored to the individual patient. The risks and benefits, required monitoring, and costs associated with each form of anticoagulation should be discussed with the patient prior to initiation of therapy. All patients on anticoagulation should be monitored for bleeding.
- The 2016 guidelines from the American College of Chest Physicians (ACCP) recommend that patients with provoked venous thrombosis from reversible risk factors should receive 3-6 months of anticoagulation[7]
- Response to anticoagulation can be monitored clinically, with repeat ultrasongraphy for deep vein thrombosis or measuring D-dimer levels after treatment
- The 2016 guidelines from the ACCP recommend that direct oral anticoagulants (DOACs), including direct Xa inhibitors and direct thrombin inhibitors, be used for long term treatment of most patients[7]
- Low molecular weight heparin (LMWH) is recommended for anticoagulation for the following acquired thrombophilias:
- Post-surgery prophylaxis[10][11][12]
- The duration of anticoagulation after surgery is variable. Most clinical trials have evaluated anticoagulation for 10-35 days
- General recommendations for thrombophrophylaxis is 7-10 days for standard risk patients and 10-35 days for higher risk patients as described in the algorithims below and for patients undergoing abdominal and pelvic surgeries for gynecologic malginancies[13]
- DOACs may be considered as agents for extended thromboprophylaxis after total hip replacement and total knee replacement.
- Pregnancy and postpartum[8]
- Patients who develop acute thrombosis during pregnancy should be anticoagulated for the remainder of the their pregnancy and 6 weeks postpartum for a minimum of 3 months
- A similar duration of anticoagulation is recommended for patients with high risk thrombophilias as described in the algorithims below
- Malignancy[9]
- Post-surgery prophylaxis[10][11][12]
- Alternative agents include Warfarin and Fondaparinux
- Warfarin is the agent of choice for prophylactic anticoagulation in patients with nephrotic syndrome, as there are no studies evaluating DOACs and LMWH for this clinical indication. Refer to the treatment algorithim below. It is important to note that the recommendations for prophylactic anticoagulation in patients with nephrotic syndrome are not based on expert consensus guidelines.[14][15]
- Lee et al created an online tool to assist in evaluating the benefits and risks of prophylactic anticoagulation in patients with membranous nephropathy.
- Warfarin is the agent of choice for prophylactic anticoagulation in patients with nephrotic syndrome, as there are no studies evaluating DOACs and LMWH for this clinical indication. Refer to the treatment algorithim below. It is important to note that the recommendations for prophylactic anticoagulation in patients with nephrotic syndrome are not based on expert consensus guidelines.[14][15]
Surgery
Surgery is not required for treatment for thrombophilia. IVC filter placement may be indicated if the patient has contraindications to or complications from anticoagulation, recurrent thrombosis on anticoagulation, or failure to achieve therapeutic anticoagulation levels.[16]
Primary Prevention
Thromboprophylaxis with anticoagulation may be recommended for primary prevention of acute thrombosis in high risk acquired and inherited thrombophilias.[6][4][5][10][11][12]
Secondary Prevention
Thromboprophylaxis with anticoagulation may be recommended for secondary prevention of acute thrombosis in high risk acquired and inherited thrombophilias:[7][6][4][5][10][11][12]
- Antiphospholipid syndrome
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Eculizumab is a monocolonal antibody used for treatment of PNH
- Recurrent thrombosis
- Unprovoked thrombus
- History of life threatening thrombus or thrombosis in atypical locations
- Multiple inherited thrombophilias
- Malignancy with history of thrombosis
- Concerning family history
- Male sex
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) - ↑ DeLoughery TG. Hemostasis and Thrombosis: Springer International Publishing; 2014.
- ↑ 4.0 4.1 4.2 4.3 Cohoon KP, Heit JA (2014). "Inherited and secondary thrombophilia". Circulation. 129 (2): 254–7. doi:10.1161/CIRCULATIONAHA.113.001943. PMC 3979345. PMID 24421360.
- ↑ 5.0 5.1 5.2 5.3 Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis". N Engl J Med. 344 (16): 1222–31. doi:10.1056/NEJM200104193441607. PMID 11309638.
- ↑ 6.0 6.1 6.2 DeLoughery TG. Hemostasis and Thrombosis: Springer International Publishing; 2014.
- ↑ 7.0 7.1 7.2 Streiff MB, Agnelli G, Connors JM, Crowther M, Eichinger S, Lopes R; et al. (2016). "Guidance for the treatment of deep vein thrombosis and pulmonary embolism". J Thromb Thrombolysis. 41 (1): 32–67. doi:10.1007/s11239-015-1317-0. PMC 4715858. PMID 26780738.
- ↑ 8.0 8.1 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO; et al. (2012). "VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e691S–736S. doi:10.1378/chest.11-2300. PMC 3278054. PMID 22315276.
- ↑ 9.0 9.1 Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M; et al. (2003). "Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer". N Engl J Med. 349 (2): 146–53. doi:10.1056/NEJMoa025313. PMID 12853587. Review in: ACP J Club. 2004 Jan-Feb;140(1):10 Review in: J Fam Pract. 2003 Nov;52(11):843-4
- ↑ 10.0 10.1 10.2 Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S; et al. (2012). "Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e278S–325S. doi:10.1378/chest.11-2404. PMC 3278063. PMID 22315265.
- ↑ 11.0 11.1 11.2 Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani A; et al. (2002). "Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer". N Engl J Med. 346 (13): 975–80. doi:10.1056/NEJMoa012385. PMID 11919306.
- ↑ 12.0 12.1 12.2 Agnelli G (2004). "Prevention of venous thromboembolism in surgical patients". Circulation. 110 (24 Suppl 1): IV4–12. doi:10.1161/01.CIR.0000150639.98514.6c. PMID 15598646.
- ↑ Muntz J (2010). "Duration of deep vein thrombosis prophylaxis in the surgical patient and its relation to quality issues". Am J Surg. 200 (3): 413–21. doi:10.1016/j.amjsurg.2009.05.045. PMID 20409525.
- ↑ Glassock RJ (2007). "Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum". J Am Soc Nephrol. 18 (8): 2221–5. doi:10.1681/ASN.2006111300. PMID 17599972.
- ↑ Lee T, Biddle AK, Lionaki S, Derebail VK, Barbour SJ, Tannous S; et al. (2014). "Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy". Kidney Int. 85 (6): 1412–20. doi:10.1038/ki.2013.476. PMC 4040154. PMID 24336031.
- ↑ Inferior Vena Cava Filters. Medscape (2015). URL Accessed on July 17, 2016
- 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