Activated protein C resistance

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Activated protein C resistance (APCR)
Protein C anticoagulant.jpg
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
Specialty Hematology

Activated protein C resistance (APCR) is a hypercoagulability (an increased tendency of the blood to clot) characterized by a lack of a response to activated protein C (APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of venous thrombosis (blood clots in veins), which resulting in medical conditions such as deep vein thrombosis (usually in the leg) and pulmonary embolism (in the lung, which can cause death). [1] The most common cause of hereditary APC resistance is factor V Leiden mutation.

Contents

Presentation

Associated conditions

An estimated 64 percent of patients with venous thromboembolism may have APC resistance. [2] [ needs update ]

Genetics

The disorder can be acquired or inherited, the hereditary form having an autosomal dominant inheritance pattern. [3]

Pathophysiology

APC (with protein S as a cofactor) degrades Factor Va and Factor VIIIa. APC 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. [4] The best known and most common hereditary form is Factor V Leiden, which is responsible for more than 95% of cases. [5] Other genetic causes include Factor V Cambridge (VThr306) and the factor V HR2 haplotype (A4070G mutation). [5] [6] Acquired forms of APC resistance occur in the presence of elevated Factor VIII concentrations.[ citation needed ] Antiphospholipid antibodies, [5] pregnancy, and certain forms of estrogen therapy, such as ethinylestradiol-containing birth control pills, have been found to produce acquired APC resistance. [7] [8] [9] [10] [11] [12] [13] [14] [ excessive citations ]

Diagnosis

APC resistance can be evaluated using an APC resistance test. [15] There are two types of APC resistance tests with different properties: the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test. [9] [10] [11] [16]

Treatment

Asymptomatic individuals with APC resistance (e.g., heterozygous factor V Leiden) are not normally treated unless additional risk factors for thrombosis are also present. [17] An example is surgery, in which perioperative short-term anticoagulation may be used. [17] However, people with homozygous factor V Leiden, and people with heterozygous factor V Leiden who have an additional thrombophilic condition (e.g., antithrombin deficiency, protein C deficiency, or protein S deficiency), should be considered for lifelong oral anticoagulation therapy. [17] People with APC resistance and initial DVT are treated with a standard anticoagulant regimen, for instance intravenous heparin therapy followed by oral anticoagulation. [17]

Related Research Articles

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

Factor V Leiden is a variant of human factor V, which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoagulant protein that normally inhibits the pro-clotting activity of factor V, is not able to bind normally to factor V, leading to a hypercoagulable state, i.e., an increased tendency for the patient to form abnormal and potentially harmful blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans. It is named after the Dutch city of Leiden, where it was first identified in 1994 by Rogier Maria Bertina under the direction of Pieter Hendrick Reitsma. Despite the increased risk of venous thromboembolisms, people with one copy of this gene have not been found to have shorter lives than the general population.

<span class="mw-page-title-main">Deep vein thrombosis</span> Formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms. The most common life-threatening concern with DVT is the potential for a clot to embolize, travel as an embolus through the right side of the heart, and become lodged in a pulmonary artery that supplies blood to the lungs. This is called a pulmonary embolism (PE). DVT and PE comprise the cardiovascular disease of venous thromboembolism (VTE). About two-thirds of VTE manifests as DVT only, with one-third manifesting as PE with or without DVT. The most frequent long-term DVT complication is post-thrombotic syndrome, which can cause pain, swelling, a sensation of heaviness, itching, and in severe cases, ulcers. Recurrent VTE occurs in about 30% of those in the ten years following an initial VTE.

<span class="mw-page-title-main">Partial thromboplastin time</span> Test for coagulation of blood

The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time, is a blood test that characterizes coagulation of the blood. A historical name for this measure is the kaolin-cephalin clotting time (KCCT), reflecting kaolin and cephalin as materials historically used in the test. Apart from detecting abnormalities in blood clotting, partial thromboplastin time is also used to monitor the treatment effect of heparin, a widely prescribed drug that reduces blood's tendency to clot.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

The prothrombinase complex consists of the serine protease, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, to thrombin (Factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can Factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

Sticky platelet syndrome is a term used by some to describe a disorder of platelet function. It was first described by Mammen in 1983. It is inherited in an autosomal dominant pattern. It has not been associated with a specific gene, and it is not recognized as an entity in OMIM.

Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. Two copies increases the risk to up to 20 in 1,000 per year. Most people never develop a blood clot in their lifetimes.

<span class="mw-page-title-main">Nomegestrol acetate/estradiol</span> Combination drug

Nomegestrol acetate/estradiol (NOMAC-E2), sold under the brand names Naemis and Zoely among others, is a fixed-dose combination medication of nomegestrol acetate, a progestogen, and estradiol, an estrogen, which is used in menopausal hormone therapy and as a birth control pill to prevent pregnancy in women. It is taken by mouth.

Drospirenone/estetrol, sold under the brand name Nextstellis among others, is a fixed-dose combination medication containing drospirenone, a progestin, and estetrol, an estrogen, which is used as a combined birth control pill for the prevention of pregnancy in women. It is taken by mouth.

Thrombin–antithrombin complex (TAT) is a protein complex of thrombin and antithrombin. It is a marker of net activation of coagulation.

Prothrombin fragment 1+2 (F1+2), also written as prothrombin fragment 1.2 (F1.2), is a polypeptide fragment of prothrombin generated by the in vivo cleavage of prothrombin into thrombin by the enzyme prothrombinase. It is released from the N-terminus of prothrombin. F1+2 is a marker of thrombin generation and hence of coagulation activation. It is considered the best marker of in vivo thrombin generation.

The calibrated automated thrombogram is a thrombin generation assay (TGA) and global coagulation assay (GCA) which can be used as a coagulation test to assess thrombotic risk. It is the most widely used TGA. The CAT is a semi-automated test performed in a 96-well plate and requires specialized technologists to be performed. As a result, it has seen low implementation in routine laboratories and has been more limited to research settings. Lack of standardization with the CAT has also led to difficulties in study-to-study comparisons in research. However, efforts have recently been made towards standardization of the assay. An example of a specific commercial CAT is the Thrombinoscope by Thrombinoscope BV.

A thrombin generation assay (TGA) or thrombin generation test (TGT) is a global coagulation assay (GCA) and type of coagulation test which can be used to assess coagulation and thrombotic risk. It is based on the potential of a plasma to generate thrombin over time, following activation of coagulation via addition of phospholipids, tissue factor, and calcium. The results of the TGA can be output as a thrombogram or thrombin generation curve using computer software with calculation of thrombogram parameters.

The activated protein C resistance (APCR) test is a coagulation test used in the evaluation and diagnosis of activated protein C (APC) resistance, a form of hypercoagulability. Hereditary APC resistance is usually caused by the factor V Leiden mutation, whereas acquired APC resistance has been linked to antiphospholipid antibodies, pregnancy, and estrogen therapy. APC resistance can be measured using either an activated partial thromboplastin time (aPTT)-based test or an endogenous thrombin potential (ETP)-based test.

<span class="mw-page-title-main">Fibrinopeptide</span> Chemical compound

The fibrinopeptides, fibrinopeptide A (FpA) and fibrinopeptide B (FpB), are peptides which are located in the central region of the fibrous glycoprotein fibrinogen and are cleaved by the enzyme thrombin to convert fibrinogen into covalently-linked fibrin monomers. The N-terminal FpA is cleaved from the Aα chains of fibrinogen and FpB from the Bβ chains of fibrinogen, with FpA released before FpB. Subsequent to their formation, fibrin monomers are converted to cross-linked fibrin polymers by the action of thrombin-activated factor XIII, and these fibrin polymers form the backbone of a thrombus. Hence, the fibrinopeptides are sensitive markers of fibrinogenesis, thrombin activity, and coagulation.

Plasmin-α2-antiplasmin complex (PAP) is a 1:1 irreversibly formed inactive complex of the enzyme plasmin and its inhibitor α2-antiplasmin. It is a marker of the activity of the fibrinolytic system and a marker of net activation of fibrinolysis.

The ST Genesia is a fully automated commercial analyzer system for performing thrombin generation assays (TGAs) and hence for coagulation testing. It was developed by Diagnostica Stago and was introduced by the company in 2018.

Fibrin monomers are monomers of fibrin which are formed by the cleavage of fibrinogen by thrombin. Levels of fibrin monomers in can be measured using blood tests and can serve as a marker of in vivo fibrinogenesis and coagulation activation. They may be useful in the evaluation hypercoagulability.

Coagulation activation markers are biomarkers of net activation of coagulation and fibrinolysis. Examples include prothrombin fragment 1+2 (F1+2), thrombin–antithrombin complex (TAT), fibrinopeptide A (FpA), fibrin monomers (FMs), plasmin-α2-antiplasmin complex (PAP), activated protein C–protein C inhibitor (APC-PCI), and D-dimer (DD). These compounds are markers of thrombin generation, fibrin generation, and fibrinolysis. Coagulation activation markers, particularly D-dimer, are useful in the diagnosis of acute venous thromboembolism. They may also be useful in the assessment of hypercoagulability and venous thromboembolism risk.

References

  1. ↑ Dahlbäck B (2003). "The discovery of activated protein C resistance". J. Thromb. Haemost. 1 (1): 3–9. doi: 10.1046/j.1538-7836.2003.00016.x . PMID   12871530. S2CID   2147784.
  2. ↑ Sheppard DR (2000). "Activated protein C resistance: the most common risk factor for venous thromboembolism". J Am Board Fam Pract. 13 (2): 111–5. doi: 10.3122/15572625-13-2-111 . PMID   10764192. S2CID   20016675.
  3. ↑ Koster T, Rosendaal FR, De Ronde H, Briët E, Vandenbroucke JP, Bertina RM (December 1993). "Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study". Lancet. 342 (8886–8887): 1503–6. doi:10.1016/S0140-6736(05)80081-9. ISSN   0140-6736. PMID   7902898. S2CID   54283312.
  4. ↑ Nicolaes GA, Dahlbäck B (2003). "Congenital and acquired activated protein C resistance". Semin Vasc Med. 3 (1): 33–46. doi:10.1055/s-2003-38331. PMID   15199491.
  5. 1 2 3 Kujovich JL (January 2011). "Factor V Leiden thrombophilia". Genet Med. 13 (1): 1–16. doi: 10.1097/GIM.0b013e3181faa0f2 . PMID   21116184. S2CID   220861191.
  6. ↑ Hotoleanu, Cristina (2016). "Genetic Risk Factors in Venous Thromboembolism". Advances in Experimental Medicine and Biology. Vol. 906. Springer International Publishing. pp. 253–272. doi:10.1007/5584_2016_120. eISSN   2214-8019. ISBN   978-3-319-22107-6. ISSN   0065-2598. PMID   27638626.
  7. ↑ Tchaikovski SN, Rosing J (July 2010). "Mechanisms of estrogen-induced venous thromboembolism". Thromb Res. 126 (1): 5–11. doi:10.1016/j.thromres.2010.01.045. PMID   20163835.
  8. ↑ Hemelaar M, van der Mooren MJ, Rad M, Kluft C, Kenemans P (September 2008). "Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review". Fertil Steril. 90 (3): 642–72. doi: 10.1016/j.fertnstert.2007.07.1298 . PMID   17923128.
  9. 1 2 Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J (2021). "Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk". Front Endocrinol (Lausanne). 12: 769187. doi: 10.3389/fendo.2021.769187 . PMC   8697849 . PMID   34956081.
  10. 1 2 Douxfils J, Morimont L, Bouvy C (November 2020). "Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk". Semin Thromb Hemost. 46 (8): 872–886. doi:10.1055/s-0040-1714140. PMID   33080636. S2CID   224821517.
  11. 1 2 Reda S, Morimont L, Douxfils J, Rühl H (August 2020). "Can We Measure the Individual Prothrombotic or Prohemorrhagic Tendency by Global Coagulation Tests?". Hamostaseologie. 40 (3): 364–378. doi: 10.1055/a-1153-5824 . PMID   32726831. S2CID   220878363.
  12. ↑ Clark P (February 2003). "Changes of hemostasis variables during pregnancy". Semin Vasc Med. 3 (1): 13–24. doi:10.1055/s-2003-38329. PMID   15199489.
  13. ↑ Asscheman H, T'Sjoen G, Lemaire A, Mas M, Meriggiola MC, Mueller A, Kuhn A, Dhejne C, Morel-Journel N, Gooren LJ (September 2014). "Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review". Andrologia. 46 (7): 791–5. doi: 10.1111/and.12150 . hdl:11585/413984. PMID   23944849. S2CID   5363824.
  14. ↑ Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J (December 2003). "Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people". J Clin Endocrinol Metab. 88 (12): 5723–9. doi: 10.1210/jc.2003-030520 . PMID   14671159.
  15. ↑ Amiral J, Vissac AM, Seghatchian J (December 2017). "Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay". Transfus Apher Sci. 56 (6): 906–913. doi:10.1016/j.transci.2017.11.021. PMID   29162399.
  16. ↑ de Visser MC, van Hylckama Vlieg A, Tans G, Rosing J, Dahm AE, Sandset PM, Rosendaal FR, Bertina RM (July 2005). "Determinants of the APTT- and ETP-based APC sensitivity tests". J Thromb Haemost. 3 (7): 1488–94. doi:10.1111/j.1538-7836.2005.01430.x. hdl: 1887/5044 . PMID   15978106. S2CID   23567724.
  17. 1 2 3 4 Nichols WL, Heit JA (September 1996). "Activated protein C resistance and thrombosis". Mayo Clin Proc. 71 (9): 897–8. doi:10.4065/71.9.897. PMID   8790269.
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