Activated protein C resistance
(Redirected from APC resistance)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2];Associate Editor(s)-in-Chief: Mohsen Basiri M.D.
Synonyms and Keywords: APC Resistance;
Overview
Activated protein C (APC) resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII. This hemostatic disorder may be caused by either acquired, inherited, or a combination of both conditions. The factor V Leiden (FVL) mutation is the best known hereditary form accounts for more than 95 percent of cases of hereditary APC resistance, and acquired forms occur in the presence of elevated Factor VIII concentrations or conditions like hormone replacement therapy and pregnancy. These conditions contribute to the increased risk of hypercoagulable state and thrombosis.[1] It has been estimated that up to 64% of patients with venous thromboembolism might have activated protein C resistance.[2]
Historical Perspective
- In the late 1980s, Dr. Dahlbäck a Swedish physician discovered activated protein C resistance associated with hypercoagulable condition.[3]
- 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.[4]
Classification
There is no established system for the classification of activated protein C resistance, however according to etiologic causes may be classified into inherited (primary), acquired (secondary), or a combination of both conditions.
Pathophysiology
- Protein C is a vitamin K-dependent zymogen synthesized in the liver. Inactivated form of protein C is activated when it binds to thrombin, and the endothelial proteoglycan thrombomodulin.
- Activated protein C (APC) functions an important role in regulating anticoagulation, and maintaining the permeability of blood vessel walls with negative feedback loop. Activated protein C anticoagulant activity operated by proteolytically inactivating proteins Factor Va and Factor VIIIa which are required for factor X activation and thrombin generation.
- Protein C and S are natural anticoagulants which inhbit thrombin formation. Dysregulation in activated protein C (APC) can occur as either defects in the protein C or S molecule (Protein C and S deficiency) or as resistance to APC activity.[5]
- Activated protein C resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII.
- The most common cause of activated protein C resistance is Factor V Leiden, which is a polymorphism of Factor V that is resistant to APC inactivation.[5]
- In addition to the FVL mutation, a number of conditions which cause activated protein C resistance have been identified and are included: increased factor VIII, increased estrogen levels, antiphospholipid antibodies, and a variety of solid tumors and hematologic malignancies.
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
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) | |
| Protein S deficiency | Pregnancy | |
| Antiphospholipid syndrome (APLS) or lupus anticoagulant | ||
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 Activated Protein C Resistance from Other Diseases
Activated protein C resistance must be differentiated from other diseases that cause recurrent thrombosis including deep venous thrombosis, pulmonary embolism or thrombosis at multiple sites, or unusual locations including in cerebral, hepatic, portal, mesenteric, and renal veins; in settings of family history of thrombosis, especially at an early age (< 45 years) such as:[6][5][7][8]
- Antithrombin III deficiency
- Protein C deficiency
- Protein S deficiency
- Prothrombin gene mutation
- Disseminated intravascular coagulation (DIC)
Epidemiology and Demographics
- The prevalence of factor V Leiden mutation as the main cause of activated protein C resistance is approximately 5% between the general population and up to 18% in individuals with venous thromboembolism.[9][10]
- Higher prevalence of the FVL mutation (12 to 14 percent) are reported in parts of Greece, Sweden, and Lebanon.[11]
Risk Factors
Common risk factors in the development of acquired activated protein C resistance include:
Common risk factors for the development of inherited activated protein C resistance are a family history of thrombosis at an early age or a family history of inherited thrombophilia.
Common genetic risk factors in the development of inherited activated protein C resistance is mutation in Factor V Leiden and Prothrombin G20210A.[6][5][12]
Screening
- According to the American Society of Hematology, screening for inherited thrombophilias is not recommended in adult patients with venous thrombosis in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility.[13]
- According to the American Society of Hematology, British Committee for Standards in Hematology, and the British Society for Hematology, screening for inherited thrombophilias may be useful in the following situations:[12] [14]
- Asymptomatic screening: First degree relatives of patients with homozygosity for Factor V Leiden, antithrombin deficiency, Protein C or Protein S deficiency and anticipated hormone therapy or pregnancy
- Symptomatic screening- patients with acute thrombus
- Refer to thrombophilia laboratory findings for more information on specific screening tests
Natural History, Complications, and Prognosis
Natural History
- If left untreated, the annual incidence of incident thrombosis in asymptomatic patients with Factor V Leiden and Prothrombin G20210A is low (<0.06%).[15] The risk is approximately equivalent to treatment with oral contraceptives.
- In patients on oral anticoagulant therapy for venous thromboembolism, the annual incidence of significant bleeds is approximately 2-3%.[16]
- Inherited thrombophilia from Factor V Leiden and Prothrombin G20210A did not predict for recurrent thrombosis.[17][18]
- In untreated patients with protein C, protein S, and antithrombin deficiencies, there is an increased risk for recurrent thrombosis.[17][19]
- Oral contraceptives, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with thrombophilia.[20]
- Certain high risk thrombophilias require indefinite anticoagulation.
Complications
- The primary complication of thrombophilia is the development of blood clots.
- Common complications of thrombophilia include deep vein thrombosis and pulmonary embolism.
The risk of future thrombosis in patients with activated protein C resistance:
| Thrombophilic state | Thrombotic risk[15] |
|---|---|
| Trauma/General surgery | Modest |
| Age > 60 | Modest |
| Immobilization | Modest |
| Pregnancy | Modest |
| Hormone therapies | Modest |
| Factor V Leiden heterozygosity | Modest |
| Prothrombin mutation | Modest |
| Homocysteinemia | Modest |
| Increased factor VIII levels | Modest |
| Increased factor IX levels | Modest |
| Increased factor XI levels | Modest |
| Protein C and S deficiency | Intermediate |
| Dysfibrogenemia | Intermediate |
| Malignancy | High |
| APLS/Lupus anticoagulant | High |
| Myeloproliferative disorders/hyperviscosity | High |
| PNH | High |
| Orthopedic surgery | High |
| Antithrombin deficiency | High |
| Factor V Leiden homozygosity | High |
The effect of concurrent hormone exposure on incident thrombosis and thrombotic risk in patients with activated protein C resistance:
| Thrombophilic state | Annual Incidence (%) | Relative Risk |
|---|---|---|
| Normal | 0.008 | 1 |
| Factor V Leiden heterozygous | 0.06 | 3-10 |
| Factor V Leiden homozygous | 0.5-1 | 80 |
| Prothrombin G20210A | 0.02 | 1-5 |
| Oral contraceptive (OCP) | 0.03 | 4 |
| OCP and factor V leiden heterozygous | 0.3 | 35 |
| OCP and factor V leiden homozygous | 100 | |
| OCP and prothrombin G20210A | 16 | |
| OCP and protein C/S, or antithrombin III deficiency | 9.7 | |
| Pregnancy | 7 | |
| Pregnancy and factor V leiden heterozygous | 35 | |
| Cancer | 5 | |
| History of venous thrombosis | 50 |
Data were extracted from multiple sources.[15][20][21]
Prognosis
- The prognosis depends on the underlying activated protein C resistance as each form has a different associated thrombotic risk. Patients who develop multiple or atypical clots, arterial thrombosis, or life-threatening thrombosis have worse prognosis.
- Thrombophilias generally associated with worse prognosis include:
- Certain thrombophilic conditions are high risk and require consideration for lifelong anticoagulation. In these cases, expert consultation is recommended.
| Possible indications for lifelong/prophylactic anticoagulation |
|---|
| Antiphospholipid syndrome |
| Paroxysmal nocturnal hemoglobinuria |
| Recurrent thrombosis regardless of underlying thrombophilia |
| History of life-threatening thrombosis or atypical locations |
| Malignancy with history of thrombosis |
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.[22][6][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:[5][6][23]
- 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
- The second generation for activated protein C resistance (APCR) assay, uses the ratio of aPTT with activated protein C (APC) and aPTT without APC. This functional assay is acceptably sensitive and specific for factor V Leiden, with significant differentiating between normal population and factor V Leiden heterozygous or homozygous patients.[24]
- The normal reference range is ratio greater than 2.1. This range for heterozygous individuals with factor V Leiden is 1.5 -1.8, and for homozygous patients is less than 1.5.
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[25]
- 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[25]
- Low molecular weight heparin (LMWH) is recommended for anticoagulation for the following acquired thrombophilias:
- Post-surgery prophylaxis[28][29][30]
- 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[31]
- DOACs may be considered as agents for extended thromboprophylaxis after total hip replacement and total knee replacement.
- Pregnancy and postpartum[26]
- 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[27]
- Post-surgery prophylaxis[28][29][30]
- 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.[32][33]
- 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.[32][33]
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.[34]
Primary Prevention
Thromboprophylaxis with anticoagulation may be recommended for primary prevention of acute thrombosis in high risk acquired and inherited thrombophilias.[23][6][5][28][29][30]
Secondary Prevention
Thromboprophylaxis with anticoagulation may be recommended for secondary prevention of acute thrombosis in high risk acquired and inherited thrombophilias:[25][23][6][5][28][29][30]
- 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
- ↑ Elisabetta Castoldi, Jeroen M. Brugge, Gerry A. F. Nicolaes, Domenico Girelli, Guido Tans & Jan Rosing (2004). "Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations". Blood. 103 (11): 4173–4179. doi:10.1182/blood-2003-10-3578. PMID 14976057. Unknown parameter
|month=ignored (help) - ↑ D. R. Sheppard (2000). "Activated protein C resistance: the most common risk factor for venous thromboembolism". The Journal of the American Board of Family Practice. 13 (2): 111–115. PMID 10764192. Unknown parameter
|month=ignored (help) - ↑ 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) - ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 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 6.3 6.4 6.5 Cohoon KP, Heit JA (2014). "Inherited and secondary thrombophilia". Circulation. 129 (2): 254–7. doi:10.1161/CIRCULATIONAHA.113.001943. PMC 3979345. PMID 24421360.
- ↑ P. M. Mannucci, R. Asselta, S. Duga, I. Guella, M. Spreafico, L. Lotta, P. A. Merlini, F. Peyvandi, S. Kathiresan & D. Ardissino (2010). "The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease". Journal of thrombosis and haemostasis : JTH. 8 (10): 2116–2121. doi:10.1111/j.1538-7836.2010.03982.x. PMID 20626623. Unknown parameter
|month=ignored (help) - ↑ A. Venugopal (2014). "Disseminated intravascular coagulation". Indian journal of anaesthesia. 58 (5): 603–608. doi:10.4103/0019-5049.144666. PMID 25535423. Unknown parameter
|month=ignored (help) - ↑ D. C. Rees, M. Cox & J. B. Clegg (1995). "World distribution of factor V Leiden". Lancet (London, England). 346 (8983): 1133–1134. PMID 7475606. Unknown parameter
|month=ignored (help) - ↑ P. M. Ridker, J. P. Miletich, C. H. Hennekens & J. E. Buring (1997). "Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening". JAMA. 277 (16): 1305–1307. PMID 9109469. Unknown parameter
|month=ignored (help) - ↑ A. Taher, I. Khalil, A. Shamseddine, F. El-Ahdab & A. Bazarbachi (2001). "High prevalence of Factor V Leiden mutation among healthy individuals and patients with deep venous thrombosis in Lebanon: is the eastern Mediterranean region the area of origin of this mutation?". Thrombosis and haemostasis. 86 (2): 723–724. PMID 11522037. Unknown parameter
|month=ignored (help) - ↑ 12.0 12.1 Middeldorp S (2011). "Evidence-based approach to thrombophilia testing". J Thromb Thrombolysis. 31 (3): 275–81. doi:10.1007/s11239-011-0572-y. PMC 3056012. PMID 21340752.
- ↑ Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A; et al. (2013). "The ASH Choosing Wisely®campaign: five hematologic tests and treatments to question". Hematology Am Soc Hematol Educ Program. 2013: 9–14. doi:10.1182/asheducation-2013.1.9. PMID 24319155.
- ↑ Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M; et al. (2016). "Guidance for the evaluation and treatment of hereditary and acquired thrombophilia". J Thromb Thrombolysis. 41 (1): 154–64. doi:10.1007/s11239-015-1316-1. PMC 4715840. PMID 26780744.
- ↑ 15.0 15.1 15.2 Bates SM, Ginsberg JS (2004). "Clinical practice. Treatment of deep-vein thrombosis". N Engl J Med. 351 (3): 268–77. doi:10.1056/NEJMcp031676. PMID 15254285.
- ↑ Linkins LA, Choi PT, Douketis JD (2003). "Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis". Ann Intern Med. 139 (11): 893–900. PMID 14644891.
- ↑ 17.0 17.1 Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR (2005). "Thrombophilia, clinical factors, and recurrent venous thrombotic events". JAMA. 293 (19): 2352–61. doi:10.1001/jama.293.19.2352. PMID 15900005. Review in: Evid Based Med. 2006 Apr;11(2):59
- ↑ Baglin T, Luddington R, Brown K, Baglin C (2003). "Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study". Lancet. 362 (9383): 523–6. doi:10.1016/S0140-6736(03)14111-6. PMID 12932383.
- ↑ De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A; et al. (2006). "The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S." Haematologica. 91 (5): 695–8. PMID 16670075.
- ↑ 20.0 20.1 Dalen JE (2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am J Med. 121 (6): 458–63. doi:10.1016/j.amjmed.2007.10.042. PMID 18501222.
- ↑ Bauer KA (2001). "The thrombophilias: well-defined risk factors with uncertain therapeutic implications". Ann Intern Med. 135 (5): 367–73. PMID 11529700.
- ↑ DeLoughery TG. Hemostasis and Thrombosis: Springer International Publishing; 2014.
- ↑ 23.0 23.1 23.2 DeLoughery TG. Hemostasis and Thrombosis: Springer International Publishing; 2014.
- ↑ J. I. Jorquera, J. M. Montoro, M. A. Fernandez, J. A. Aznar & J. Aznar (1994). "Modified test for activated protein C resistance". Lancet (London, England). 344 (8930): 1162–1163. PMID 7864945. Unknown parameter
|month=ignored (help) - ↑ 25.0 25.1 25.2 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.
- ↑ 26.0 26.1 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.
- ↑ 27.0 27.1 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
- ↑ 28.0 28.1 28.2 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.
- ↑ 29.0 29.1 29.2 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.
- ↑ 30.0 30.1 30.2 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