Timeline (Historical)
2020 – The American Factor V Leiden Association was formed in Tampa, FL to create more awareness of the disorder, provide an educational resource library, help establish comprehensive testing guidelines, and encourage more scientific research.
2018 – A consumer experience study showed that a majority of participants felt they benefited from knowing that they carried the Factor V Leiden gene mutation after getting their 23andMe test results. Most felt they benefited in becoming aware and felt they now had an increased risk perception of developing a venous thrombosis (VTE). Most of the participants shared the test results with family and/or their health care provider and many took action to reduce their risk after finding out.
2015 – Venous thromboembolism becomes the 3rd leading cause of cardiovascular death (behind myocardial infarction and stroke) and the leading cause of preventable hospital deaths.
2011 – Created in 1953 in Oxford, the thrombin generation test (TGT) was updated. The TGT is a functional test exploring coagulation in its entirety, thus constituting a modern exploration path of hemostasis.
2008 – A new class of anticoagulant drugs are introduced on the market alongside heparins and vitamin K antagonists called direct oral anticoagulants or DOACs.
2002 – Women’s Health Initiative (WHI) results in 2002 found that post-menopausal women taking combination (estrogen and progestin) hormone therapy for menopause symptoms had an increased risk for breast cancer, heart disease, stroke, blood clots, and urinary incontinence.
2001 – The World Health Organization (WHO) recognizes the association between thrombosis and air travel. The likelihood of developing deep vein thrombosis doubles after a flight of about four hours in patients with an increased risk.
1994 – Dr. Rogier Bertina and his team in Leiden, Netherlands discovered that the inherited resistance to activated protein C was associated with a missense mutation in the gene encoding coagulation factor v, which dramatically slowed the cleavage of the activated form of this cofactor by activated protein C. The mutation, called Factor V Leiden, leads to a gain of function of activated factor V, which in turn causes a hypercoagulable state.
1993 – Dr. Björn Dahlbäck discovered and proposed that activated protein C (APC) resistance is an inherited risk factor for venous thrombosis at Lund University in Sweden.
1991 – In 1991, the National Heart, Lung, and Blood Institute, part of National Institutes of Health (NIH), launched the Women’s Health Initiative (WHI) to understand better how cardiovascular disease, breast cancer, colorectal cancer, and osteoporosis affect post-menopausal women and to reduce the number of women who develop and die from these diseases. More than 160,000 post-menopausal women ages 50 to 79 participated in the 15-year study, making it one of the largest prevention studies involving women in the United States.
1983 – Philip Majerus proposes the first anticoagulant function for factor V, yet ultimately it was not widely accepted by the broader scientific community.
Early 1980s – Paul Owren’s findings in 1944 “spurred an unprecedented activity in the field”, and factor V has since been known to play a key role as a procoagulant protein in the coagulation cascade. By the early 1980s, there was a consensus model for how the clotting cascade worked. The activated form of factor V, termed factor Va, was known to play an important role in the coagulation cascade because it serves as a cofactor in the conversion of prothrombin to thrombin. The enzyme thrombin cleaves fibrinogen into fibrin, which binds to and crosslinks platelets, resulting in a platelet plug and clot formation. Patients who are missing factor V have serious bleeding disorders because they are unable to generate factor Va. To properly regulate the coagulation cascade so that clotting doesn’t continue out of control, factor Va can be inhibited by activated protein C (APC), thereby shutting down the cascade.
1980 – The D-Dimer measurement is proposed as the exclusion test for deep vein thrombosis and pulmonary embolism.
1970s – Discovery of two physiological inhibitors of coagulation, proteins C and S. The first, discovered by Jan Stenflo, was arbitrarily named Protein C because it was the third molecule he examined in his protocol. Protein S, identified by Richard DiScipio, was so named because it was discovered in Seattle.
1960s – Angiography / Scintigraphy – Pulmonary angiography and ventilation / perfusion scanning enters into clinical practice. Before the advent of these investigations, pulmonary embolism was mainly diagnosed after the patient’s death.
1967 – The first case-control study by the Royal College of General Practitioners, reported that users of oral contraceptives had a threefold increased risk of venous thrombosis compared with nonusers. Most of these studies indicated that the risk was immediate, in the early phases of use, and did not further increase with a longer duration of use.
1961 – The first case of thrombosis associated with hormone contraception (HC) occurred in 1961 when a nurse taking a high-dose estrogen oral contraceptive pill (OCP) developed a pulmonary embolism. Myocardial infarction and stroke were reported in OCP users during the following years and were associated with older women who smoke and use HC. These early reports seemed to suggest that the thrombotic potential of the OCP was related to its relatively high estrogen content of 50 µg or more. (Cleveland Clinic report)
1959 – The introduction of the hormonal contraceptive (HC) pill in 1959 was a major medical achievement that changed the way women could control reproduction and thereby achieve a greater life expectancy and better health status. HC remains the most popular form of reversible contraception worldwide. (Cleveland Clinic report)
1944 – In 1943, a young woman named Mary came to a hospital in Norway because of a bleeding episode. Mary had been healthy for the first few years of her life, but she had suffered a severe bleeding episode at the age of three that left her blind, initially in both eyes. She had many bleeding episodes in the subsequent years, but menstrual bleeding proved to be the most problematic for Mary. It was for this reason that she came to the hospital at the age of 29. Paul Owren, an assistant professor at the hospital, was responsible for her care, and after laborious effort, it was he who discovered that she had a deficiency in a clotting factor. At that time, the theory of blood coagulation included just four clotting factors, so Owren named Mary’s missing protein factor V, setting the precedent for the use of roman numerals in naming the blood coagulation factors. He published his work in Norway in 1944, but his results were not widely known until after the war, when he was able to publish in The Lancet.
1941 – First description of the effect of warfarin on the prothrombin time (PT) in humans by Butt, Allen, and Bollman.
1939 – First descriptions by Tage Astrup of a physiological anticoagulant protein, the effect of which is 2,000 more potent in the presence of heparin. It was successively name “Pro-antithrombin”, antithrombin III, and finally Antithrombin. However, its deficit is described in 1965 by Olav Egeberg.
1937 – The first valid treatment for thrombosis, heparin, is introduced in medical practice.
1935 – Development of the prothrombin time (PT) test by Dr. Armand Quick. This test is used to help detect and diagnose a bleeding disorder or excessive clotting disorder.
1931 – An American vet observes large numbers of deaths through bleeding in cattle that had eaten moldy sweet clover. The doctor Karl Link and collaborators identify the molecule responsible in the clover: dicoumarol, the antidote for which is vitamin K.
1926 – First description of von Willebrand disease by von Willebrand.
1916 – Jay McLean isolates and identifies molecules with anticoagulant properties from dog liver extract which he names Heparine. The anticoagulant isolated independently by Maurice Doyon in 1911 also proved to be heparin.
1915 – Use of citrate to anticoagulant blood for transfusion optimized by Lewisohn.
1905 – Dr. Paul Morawitz publishes his best known paper ‘Die Chemie der Blutgerinnung’ (The Chemistry of Blood Clotting). In this paper, Morawitz described four coagulation factors: fibrinogen, prothrombin, thrombokinase, and calcium. Morawitz was a pioneer in the study of coagulation, and his 1905 landmark paper is still regarded as a springboard for further study of the physiology of blood; He also pioneered blood transfusion, initially without the benefit of blood typing, and studied angina and the use of quinidine as an antiarrhythmic.
1901 – Discovery of blood groups, A, B, AB, and O by Landsteiner.
1888 – First description of the role of platelets in hemostasis and thrombosis by Bizzozero.
1868 – Virchow describes leukemia, thrombosis, and embolism.
1865 – Armand Trousseau theorized that cancer can induce venous thrombosis.
1856 – Rudolf Virchow defined the triad that can lead to vein thrombosis: venous stasis, vascular wall injury, and a hypercoagulability. These three features are now referred to as “Virchow’s Triad”.
1676 – The first detailed description of venous thrombosis was made in England by Richard Wiseman, Sergeant-Chirurgeon to King Charles II. He wrote about the wife of a pharmacist who, after a difficult delivery, developed swelling and pain of the right leg, extending from the knee to the hip, with no inflammation and discoloring of the skin. Wiseman surmised that thrombus formation was caused by a systemic alteration in circulating blood, thereby pioneering the concept of hyper-coagulability. He also he established a symptomatic treatment of thrombosis with the use of a lace stocking as a means of compression.
