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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).
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.
Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.
Activated protein C resistance (APCR) is a hypercoagulability 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, which resulting in medical conditions such as deep vein thrombosis and pulmonary embolism. The most common cause of hereditary APC resistance is factor V Leiden mutation.
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.
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.
Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.
An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
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 Estrogen in Venous Thromboembolism Trial (EVTET) was a randomized controlled trial (RCT) of menopausal hormone therapy in 140 postmenopausal women with previous history of venous thromboembolism (VTE). It was a double-blind RCT of the estrogen, oral estradiol 2 mg/day, plus the progestogen, norethisterone acetate (NETA) (n=71) 1 mg/day versus placebo (n=69). The results of the trial were published in 2000 and 2001. The incidence of VTE was 10.7% in the hormone therapy group and 2.3% in the placebo group, with all events occurring within 261 days after study inclusion. The difference did not reach statistical significance in the sequential analysis, but was statistically significant if the sequential design was ignored. Markers of coagulation were likewise increased by hormone therapy. As a result of the high incidence of VTE in the treatment group, the trial was terminated prematurely. The researchers concluded on the basis of their findings that menopausal hormone therapy should not be used in women with a previous history of VTE.
The Menopause, Estrogen and Venous Events (MEVE) study was a retrospective observational study of menopausal hormone therapy and venous thromboembolism (VTE) in postmenopausal women with a previous history of VTE. It found that transdermal estradiol was not associated with increased risk of VTE whereas oral estrogens were associated with a large increase in risk. The mean dose of transdermal estradiol in the study was 50 μg/day, although data on dose were missing for around 50% of women. Similarly, a small study found that transdermal estradiol did not influence coagulation in women with prior VTE. These findings are similar to studies in menopausal women without prior history of VTE which have found that transdermal estradiol has minimal influence on coagulation and is not associated with increased risk of VTE at doses of up to 100 μg/day. Menopausal hormone therapy guidelines have cited the MEVE study and recommended use of transdermal estradiol over oral estrogens in women at high risk for VTE. However, randomized controlled trials (RCTs) are still needed to definitively confirm findings that transdermal estradiol is safer than oral estrogens in terms of VTE risk.
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.
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.
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 overall hemostatic potential (OHP) test is a global coagulation assay which can be used to measure coagulation. The OHP assay measures total fibrin generation in the presence of thrombin or tissue factor and tissue plasminogen activator (t-PA). It generates a fibrin time curve through the use of optical density measurement. This curve represents the balance between fibrin formation induced by thrombin or tissue factor and fibrinolysis induced by t-PA. The assay provides three parameters: overall coagulation potential (OCP), overall hemostatic potential (OHP), and overall fibrinolytic potential (OFP). OHP is the main parameter, while OCP and OFP are supplementary parameters to assess coagulation and fibrinolysis. One further parameter, clot lysis time (CLT), can also be determined. The OHP assay measures the integrated effect of procoagulant, anticoagulant, and fibrinolytic factors.
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.
Activated protein C–protein C inhibitor (APC-PCI) is a complex of activated protein C (APC) and protein C inhibitor (PCI). It has been measured in coagulation testing to evaluate coagulation, thrombosis, and other cardiovascular complications. It is a marker of thrombin generation and indicates hypercoagulability. The half-life of APC-PCI is either 40 minutes or 140 minutes.
References
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- ↑ Zwicker JI, Furie BC, Furie B (2007). "Cancer-associated thrombosis". Crit. Rev. Oncol. Hematol. 62 (2): 126–36. doi:10.1016/j.critrevonc.2007.01.001. PMID 17293122.
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- ↑ Hellgren M (April 2003). "Hemostasis during normal pregnancy and puerperium". Semin Thromb Hemost. 29 (2): 125–30. doi:10.1055/s-2003-38897. PMID 12709915.
- ↑ 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.
- ↑ Skouby, Sven O.; Sidelmann, Johannes J. (2 July 2020). "Menopausal Hormone Therapy (MHT) and Venous Thrombosis". Managing the Menopause. Cambridge University Press. pp. 223–233. doi:10.1017/9781108869102.023.
- ↑ Ockrim JL, Lalani EN, Kakkar AK, Abel PD (August 2005). "Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism". J Urol. 174 (2): 527–33, discussion 532–3. doi:10.1097/01.ju.0000165567.99142.1f. PMID 16006886.
- ↑ Kohli, M.; Alikhan, M. A.; Spencer, H. J.; Carter, G. (15 July 2004). "Phase I trial of intramuscular estradiol valerate (I/M-E) in hormone refractory prostate cancer". Journal of Clinical Oncology. 22 (14 suppl): 4726–4726. doi:10.1200/jco.2004.22.90140.4726. eISSN 1527-7755. ISSN 0732-183X.
- ↑ Kohli M (January 2006). "Phase II study of transdermal estradiol in androgen-independent prostate carcinoma". Cancer. 106 (1): 234–5, author reply 235. doi:10.1002/cncr.21528. PMID 16284988.