D-dimer

Last updated

D-dimer (or D dimer) is a dimer that is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein joined by a cross-link, hence forming a protein dimer. [1]

Contents

D-dimer concentration may be determined by a blood test to help diagnose thrombosis. [2] Since its introduction in the 1990s, it has become an important test performed in people with suspected thrombotic disorders, such as venous thromboembolism. [2] [3] While a negative result practically rules out thrombosis, a positive result can indicate thrombosis but does not exclude other potential causes. [3] Its main use, therefore, is to exclude thromboembolic disease where the probability is low. [1] [2]

D-dimer levels are used as a predictive biomarker for the blood disorder disseminated intravascular coagulation and in the coagulation disorders associated with COVID-19 infection. [1] [3] A four-fold increase in the protein is an indicator of poor prognosis in people hospitalized with COVID-19. [1] [3] [4]

Principles

D-dimer formation. Shown are fibrinogen, with its one E domain and two D domains, acted upon in cascade, by the following enzymes: Thrombin, to create a mesh of fibrin protofibrils; Factor XIII to crosslink the fibrin mesh (linking protofibril D domains), the scaffold for clot formation; Plasmin, whose action in fibrinolysis produces fibrin degradation products (FDPs), the smallest of which are D-dimers, protein fragments with one E and two crosslinked D domains from an original fibrinogen. D-dimer.png
D-dimer formation. Shown are fibrinogen , with its one E domain and two D domains, acted upon in cascade, by the following enzymes: Thrombin , to create a mesh of fibrin protofibrils; Factor XIII to crosslink the fibrin mesh (linking protofibril D domains), the scaffold for clot formation; Plasmin , whose action in fibrinolysis produces fibrin degradation products (FDPs), the smallest of which are D-dimers, protein fragments with one E and two crosslinked D domains from an original fibrinogen.

Coagulation, the formation of a blood clot or thrombus, occurs when the proteins of the coagulation cascade are activated, either by contact with a damaged blood vessel wall and exposure to collagen in the tissue space (intrinsic pathway) or by activation of factor VII by tissue activating factors (extrinsic pathway). Both pathways lead to the generation of thrombin, an enzyme that turns the soluble blood protein fibrinogen into fibrin, which aggregates into protofibrils. Another thrombin-generated enzyme, factor XIII, then crosslinks the fibrin protofibrils at the D fragment site, leading to the formation of an insoluble gel that serves as a scaffold for blood clot formation. [1]

The circulating enzyme plasmin, the main enzyme of fibrinolysis, cleaves the fibrin gel in a number of places. The resultant fragments, "high molecular weight polymers", are digested several times more by plasmin to lead to intermediate and then to small polymers (fibrin degradation products or FDPs). The cross-link between two D fragments remains intact, however, and these are exposed on the surface when the fibrin fragments are sufficiently digested. The structure of D-dimer is either a 180 kDa [6] or 195 kDa [7] molecule of two D domains, or a 340 kDa [7] molecule of two D domains and one E domain of the original fibrinogen molecule. [1] The half-life of D-dimer in blood is approximately 6 to 8 hours. [8]

D-dimers are not normally present in human blood plasma, except when the coagulation system has been activated, for instance, because of the presence of thrombosis or disseminated intravascular coagulation. The D-dimer assay depends on the binding of a monoclonal antibody to a particular epitope on the D-dimer fragment. Several detection kits are commercially available; all of them rely on a different monoclonal antibody against D-dimer. For some of these, the area of the D-dimer to which the antibody binds is known. The binding of the antibody is then measured quantitatively by one of various laboratory methods. [1]

Indications

D-dimer testing is of clinical use when there is a suspicion of deep venous thrombosis (DVTl), pulmonary embolism (PE) or disseminated intravascular coagulation (DIC). [1] [3]

For DVT and PE, there are possible various scoring systems that are used to determine the a priori clinical probability of these diseases; the best-known is the Wells score. [5]

In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This reduces the need for unnecessary tests in those who are high-probability. [11] Performing the D-dimer test first can avoid a significant proportion of imaging tests and is less invasive. Since the D-dimer can exclude the need for imaging, specialty professional organizations recommend that physicians use D-dimer testing as an initial diagnostic. [12] [13] [14] [15]

Interpretation

Reference ranges

The following are reference ranges for D-dimer: [16]

UnitsNonpregnant
adult		First trimester Second trimesterThird trimester
mg/L or μg/mL< 0.50.05 - 0.950.32 - 1.290.13 -1.7
μg/L or ng/mL< 50050 - 950320 - 1290130 - 1700
nmol/L< 2.70.3 - 5.21.8 - 7.10.7 - 9.3

D-dimer increases with age. It has therefore been suggested to use a cutoff equal to patient’s age in years × 10 μg/L (or x 0.056 nmol/L) for patients aged over 50 years for the suspicion of venous thromboembolism (VTE), as it decreases the false positive rate without substantially increasing the false negative rate. [17] [18]

An alternative measurement of D-dimer is in fibrinogen equivalent units (FEU). The molecular weight of the fibrinogen molecule is about twice the size of the D-dimer molecule, and therefore 1.0 mcg/mL FEU is equivalent to 0.5 mcg/mL of d-dimer. [19]

Thrombotic disease

Various kits have a 93 to 95% sensitivity (true positive rate). For hospitalized patients, one study found the specificity to be about 50% (related to false positive rate) in the diagnosis of thrombotic disease. [20]

In interpretation of the D-dimer, for patients over age 50, a value of (patient's age) × 10 μg/L may be abnormal. [23] [24]

History

D-dimer was originally identified, described and named in the 1970s (Fibrinolysis, Dr P J Gaffney) and found its diagnostic application in the 1990s. [1] [5]

Related Research Articles

<span class="mw-page-title-main">Thrombosis</span> Medical condition caused by blood clots

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Thrombus</span> Blood clot

A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through a healthy blood vessel in the circulatory system.

<span class="mw-page-title-main">Pulmonary embolism</span> Blockage of an artery in the lungs

Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathing in, and coughing up blood. Symptoms of a blood clot in the leg may also be present, such as a red, warm, swollen, and painful leg. Signs of a PE include low blood oxygen levels, rapid breathing, rapid heart rate, and sometimes a mild fever. Severe cases can lead to passing out, abnormally low blood pressure, obstructive shock, and sudden death.

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

Venous thrombosis is the 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).

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Disseminated intravascular coagulation</span> Medical condition where blood clots block small blood vessels

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

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. It is an autosomal dominant genetic disorder with incomplete penetrance.

<span class="mw-page-title-main">Fibrinogen</span> Soluble protein complex in blood plasma and involved in clot formation

Fibrinogen is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

<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.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and, in the treatment of venous thromboembolism, and the treatment of myocardial infarction.

<span class="mw-page-title-main">Thromboembolism</span> Obstruction of a blood vessel by a clot

Thromboembolism is a condition in which a blood clot (thrombus) breaks off from its original site and travels through the bloodstream to obstruct a blood vessel, causing tissue ischemia and organ damage. Thromboembolism can affect both the venous and arterial systems, with different clinical manifestations and management strategies.

<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.

An embolus, is described as a free-floating mass, located inside blood vessels that can travel from one site in the blood stream to another. An embolus can be made up of solid, liquid, or gas. Once these masses get "stuck" in a different blood vessel, it is then known as an "embolism." An embolism can cause ischemia—damage to an organ from lack of oxygen. A paradoxical embolism is a specific type of embolism in which the embolus travels from the right side of the heart to the left side of the heart and lodges itself in a blood vessel known as an artery. Thus, it is termed "paradoxical" because the embolus lands in an artery, rather than a vein.

Antithrombin III deficiency is a deficiency of antithrombin III. This deficiency may be inherited or acquired. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism, and repetitive intrauterine fetal death (IUFD). Hereditary antithrombin deficiency results in a state of increased coagulation which may lead to venous thrombosis. Inheritance is usually autosomal dominant, though a few recessive cases have been noted. The disorder was first described by Egeberg in 1965. The causes of acquired antithrombin deficiency are easier to find than the hereditary deficiency.

<span class="mw-page-title-main">Superficial thrombophlebitis</span> Medical condition

Superficial thrombophlebitis is a thrombosis and inflammation of superficial veins presenting as a painful induration (thickening) with erythema, often in a linear or branching configuration with a cordlike appearance.

<span class="mw-page-title-main">Thrombosis prevention</span> Medical treatment

Thrombosis prevention or thromboprophylaxis is medical treatment to prevent the development of thrombosis in those considered at risk for developing thrombosis. Some people are at a higher risk for the formation of blood clots than others, such as those with cancer undergoing a surgical procedure. Prevention measures or interventions are usually begun after surgery as the associated immobility will increase a person's risk.

<span class="mw-page-title-main">Ultrasonography of deep vein thrombosis</span>

Ultrasonography in suspected deep vein thrombosis focuses primarily on the femoral vein and the popliteal vein, because thrombi in these veins are associated with the greatest risk of harmful pulmonary embolism.

Henri Bounameaux is a known clinical faculty and Professor of Medicine (hon), specialized in internal and vascular medicine (angiology), and general medicine.

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. 1 2 3 4 5 6 7 8 9 10 Asakura, Hidesaku; Ogawa, Haruhiko (2020). "COVID-19-associated coagulopathy and disseminated intravascular coagulation". International Journal of Hematology. 113 (1): 45–57. doi:10.1007/s12185-020-03029-y. ISSN   0925-5710. PMC   7648664 . PMID   33161508.
  2. 1 2 3 Khan, Faizan; Tritschler, Tobias; Kahn, Susan R; Rodger, Marc A (2021). "Venous thromboembolism". The Lancet. 398 (10294): 64–77. doi:10.1016/s0140-6736(20)32658-1. ISSN   0140-6736. PMID   33984268. S2CID   234497047.
  3. 1 2 3 4 5 Ponti, G; Maccaferri, M; Ruini, C; Tomasi, A; Ozben, T (2020). "Biomarkers associated with COVID-19 disease progression". Critical Reviews in Clinical Laboratory Sciences. 57 (6): 389–399. doi:10.1080/10408363.2020.1770685. ISSN   1040-8363. PMC   7284147 . PMID   32503382.
  4. ↑ Velavan, Thirumalaisamy P.; Meyer, Christian G. (25 April 2020). "Mild versus severe COVID-19: laboratory markers". International Journal of Infectious Diseases. 95: 304–307. doi: 10.1016/j.ijid.2020.04.061 . PMC   7194601 . PMID   32344011 . Retrieved 25 April 2020.
  5. 1 2 3 4 Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. (September 2003). "Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis". The New England Journal of Medicine. 349 (13): 1227–35. doi: 10.1056/NEJMoa023153 . PMID   14507948.
  6. ↑ Kogan AE, Mukharyamova KS, Bereznikova AV, Filatov VL, Koshkina EV, Bloshchitsyna MN, Katrukha AG (July 2016). "Monoclonal antibodies with equal specificity to D-dimer and high-molecular-weight fibrin degradation products". Blood Coagulation & Fibrinolysis. 27 (5): 542–50. doi:10.1097/MBC.0000000000000453. PMC   4935535 . PMID   26656897.
  7. 1 2 Olson JD, Cunningham MT, Higgins RA, Eby CS, Brandt JT (August 2013). "D-dimer: simple test, tough problems". Archives of Pathology & Laboratory Medicine. 137 (8): 1030–8. doi:10.5858/arpa.2012-0296-CP. PMID   23899057.
  8. ↑ Lippi G, Cervellin G, Franchini M, Favaloro EJ (November 2010). "Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future". J Thromb Thrombolysis. 30 (4): 459–71. doi:10.1007/s11239-010-0460-x. PMID   20213258. S2CID   23806848.
  9. ↑ American College of Chest Physicians; American Thoracic Society (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation , American College of Chest Physicians and American Thoracic Society, retrieved 6 January 2013.
  10. ↑ Crawford F, Andras A, Welch K, Sheares K, Keeling D, Chappell FM (August 2016). Cochrane Vascular Group (ed.). "D-dimer test for excluding the diagnosis of pulmonary embolism". The Cochrane Database of Systematic Reviews. 2016 (8): CD010864. doi:10.1002/14651858.CD010864.pub2. PMC   6457638 . PMID   27494075.
  11. ↑ Rathbun SW, Whitsett TL, Vesely SK, Raskob GE (March 2004). "Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings". Chest. 125 (3): 851–5. doi:10.1378/chest.125.3.851. PMC   1215466 . PMID   15006941.
  12. ↑ American College of Physicians, "Five Things Physicians and Patients Should Question" (PDF), Choosing Wisely, presented by ABIM Foundation, American College of Physicians, archived from the original (PDF) on June 24, 2012, retrieved August 14, 2012
  13. ↑ Fesmire FM, Brown MD, Espinosa JA, Shih RD, Silvers SM, Wolf SJ, Decker WW (June 2011). "Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism". Annals of Emergency Medicine. 57 (6): 628–652.e75. doi: 10.1016/j.annemergmed.2011.01.020 . PMID   21621092.
  14. ↑ Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, et al. (September 2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". European Heart Journal. 29 (18): 2276–315. doi: 10.1093/eurheartj/ehn310 . PMID   18757870.
  15. ↑ Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, et al. (2007). "Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians". Annals of Family Medicine. 5 (1): 57–62. doi:10.1370/afm.667. PMC   1783928 . PMID   17261865.
  16. ↑ Reference Values During Pregnancy at perinatology.com. Retrieved October 2014.
  17. ↑ Urban K, Kirley K, Stevermer JJ (March 2014). "PURLs: It's time to use an age-based approach to D-dimer". The Journal of Family Practice. 63 (3): 155–8. PMC   4042909 . PMID   24701602.
  18. ↑ Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD (November 2015). "Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians". Annals of Internal Medicine. 163 (9): 701–11. doi: 10.7326/M14-1772 . PMID   26414967.
  19. ↑ "Clinical Education Center". Quest Diagnostics. Document FAQS.149 Version: 3 effective 07/23/2019 to present
  20. ↑ Schrecengost JE, LeGallo RD, Boyd JC, Moons KG, Gonias SL, Rose CE, Bruns DE (September 2003). "Comparison of diagnostic accuracies in outpatients and hospitalized patients of D-dimer testing for the evaluation of suspected pulmonary embolism". Clinical Chemistry. 49 (9): 1483–90. doi: 10.1373/49.9.1483 . PMID   12928229.
  21. ↑ Kabrhel C, Mark Courtney D, Camargo CA, Plewa MC, Nordenholz KE, Moore CL, et al. (June 2010). "Factors associated with positive D-dimer results in patients evaluated for pulmonary embolism". Academic Emergency Medicine. 17 (6): 589–97. doi:10.1111/j.1553-2712.2010.00765.x. PMC   3538031 . PMID   20624138.
  22. ↑ Baglin T, Keeling D, Kitchen S (November 2012). "Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: guidance from the British Committee for Standards in Haematology". British Journal of Haematology. 159 (4): 427–9. doi: 10.1111/bjh.12052 . PMID   22970737.
  23. ↑ van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T, et al. (January 2012). "The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded". Thrombosis and Haemostasis. 107 (1): 167–71. doi:10.1160/TH11-08-0587. PMID   22072293. S2CID   4832019.
  24. ↑ Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A, et al. (March 2010). "Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts". BMJ. 340: c1475. doi:10.1136/bmj.c1475. PMC   2847688 . PMID   20354012.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.