Sticky platelet syndrome: history and future perspectives.

The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait, characterized by increased in vitro platelet aggregation after low concentrations of adenosine diphosphate and/or epinephrine. Its clinical manifestation includes arterial thrombosis, pregnancy complications (fetal growth retardation and fetal loss), and less often venous thromboembolism. SPS was considered to be a rare thrombophilic disorder, but it can be found relatively often as a cause of unexplained thrombosis, particularly among patients with arterial thrombosis such as stroke. The syndrome was recognized as a distinct disorder in 1983 by Holiday and further characterized in the 1980s and 1990s, with Mammen and Bick providing the key findings. Although recognized for more than 30 years, significant issues, namely the syndrome's etiology, inheritance, and epidemiology, remain unclear. The aim of the first part of this review is to summarize the previous 35 years of the research into, and to provide a brief historical account of, SPS. The history section is focused particularly on the work of two most prominent investigators: Eberhard F. Mammen and Rodger L. Bick. The second part summarizes the present understanding of the syndrome and outlines unresolved issues and the trends in which the future research is likely to continue.

Anticoagulant factor V: factors affecting the integration of novel scientific discoveries into the broader framework.

Since its initial discovery in the 1940s, factor V has long been viewed as an important procoagulant protein in the coagulation cascade. However, in the later part of the 20th century, two different scientists proposed novel anticoagulant roles for factor V. Philip Majerus proposed the first anticoagulant function for factor V in 1983, yet ultimately it was not widely accepted by the broader scientific community. In contrast, Björn Dahlbäck proposed a different anticoagulant role for factor V in 1994. While this role was initially contested, it was ultimately accepted and integrated into the scientific framework. In this paper, I present a detailed historical account of these two anticoagulant discoveries and propose three key reasons why Dahlbäck's anticoagulant role for factor V was accepted whereas Majerus' proposed role was largely overlooked. Perhaps most importantly, Dahlbäck's proposed anticoagulant role was of great clinical interest because the discovery involved the study of an important subset of patients with thrombophilia. Soon after Dahlbäck's 1994 work, this patient population was shown to possess the factor V Leiden mutation. Also key in the ultimate acceptance of the second proposed anticoagulant role was the persistence of the scientist who made the discovery and the interest in and ability of others to replicate and reinforce this work. This analysis of two different yet similar discoveries sheds light on factors that play an important role in how new discoveries are incorporated into the existing scientific framework.

El componente genético de las alteraciones de la coagulación y de la trombosis / The genetic component of disorders of coagulation and thrombosis

La trombosis tiene un papel crucial en la patogenia del infarto agudo de miocardio, los accidentes cerebrovasculares y la tromboembolia venosa y es el principal factor de su desenlace fatal. Estas enfermedades, cada una de las cuales tiene una incidencia anual de 1-3/1.000 individuos adultos, constituyen una de las primeras causas de mortalidad y morbilidad en la sociedad occidental. En consecuencia, a su diagnóstico, su tratamiento y su prevención se dedican grandes esfuerzos asistenciales y económicos. La trombosis es un buen ejemplo de enfermedad compleja, donde la acción de múltiples genes y su interacción con factores ambientales determinarán en cada individuo el grado de susceptibilidad a padecer la enfermedad. Está bien establecido que variantes genéticas en los genes que codifican para factores o inhibidores de la coagulación son importantes factores de riesgo tromboembólico; sin embargo, en el 50% de los pacientes con trombofilia hereditaria no se identifica ninguna de estas alteraciones. Por consiguiente, el gran reto en la actualidad es la identificación de nuevos factores genéticos de riesgo trombótico (AU)

Thrombosis plays a crucial role in the pathogenesis of acute myocardial infarction, stroke and venous thrombosis, and is the principle factor responsible for a subsequent fatal outcome. These conditions, each of which has an annual incidence of 1 to 3 per 1000 adults, are some the principle causes of morbidity and mortality in developed countries. Consequently, considerable financial and health-care resources are being devoted to their diagnosis, treatment and prevention. Thrombosis is a good example of a complex disease, in which each individual’s susceptibility to the disease is determined by the actions of numerous genes and their interactions with environmental factors. It has been established that genetic variations in the genes that code for coagulation factors or inhibitors are important risk factors for thromboembolism. However, 50% of patients with inherited thrombophilia do not have any of these genetic variations. Consequently, the major challenge today is to identify new genetic risk factors for thrombosis (AU)

Venous thrombosis: the history of knowledge.

Venous thrombosis is a frequent disease. It is surprising, therefore, that no case truly compatible with a diagnosis of venous thrombosis was apparently reported in the antiquity. There is no case that could be reasonably attributed to a venous thrombus in the writings of Hippocrates, Galenus, Celius Aurelianus, Ibn an-Nafiz, Avicenna and others. Venous thrombosis is not among the many diseases mentioned in the Bible. The term "leucophlegmasia", first used by Hippocrates and then by Celius Aurelianus, refers to cases of bilateral leg edema, most likely due to conditions such as heart failure, liver cirrhosis and renal insufficiency. Nothing compatible with a diagnosis of venous thrombosis can be found in pieces of art from ancient Egypt, Greece, Rome, Persia and South America. While in these sources there are sometimes representations of varicose veins and ulcers, unilateral leg edema or other pictures compatible with venous thrombosis are not featured. The first well documented case of venous thrombosis is depicted in a beautifully illustrated manuscript written in the 13th century and currently preserved in Paris at the Bibliothèque Nationale (MS Fr 2829, Folio 87). The manuscript describes the case of a young man from Normandy named Raoul who at the age of twenty developed unilateral edema in the right ankle that subsequently extended up to the thigh, with no obvious symptoms in the contralateral leg. Raoul was advised to visit the tomb of Saint Louis who was buried in the church of Saint Denis, where the patient spent several days confessing his sins and praying the saint. Afterwards he chose to collect the dust accumulating below the stone that covered the tomb and to apply it on the fistulae and ulcers of his foot. The openings stopped running and were filled with flesh. He was first obliged to use crutches but subsequently he could walk with a cane, to be eventually able to dispose of all devices, even though his foot throbbed a little. Raoul was cured as described above in the year 1271 and was still alive and well in 1282. Not only this is the first case of venous thrombosis, the young age of the patients leads us to suspect that Raoul had a thrombophilic condition.

Evidence of a founder effect for the protein C gene 3363 inserted C mutation in thrombophilic pedigrees of French origin.

We have previously reported that the 3363 inserted (Ins) C mutation in exon 6 of the protein C gene was present in four unrelated French patients and in four French Canadian families with type I protein C deficiency as well as in a large Vermont protein C deficient kindred of French Canadian origin. The present study was designed to investigate the likelihood of the existence of a founder effect for this mutation in protein C deficient individuals of French origin living in France, Quebec and Vermont. In order to demonstrate a possible founder effect for the 3363 InsC mutation, we have previously constructed a high-resolution genetic map to locate several highly polymorphic markers close to the protein C locus. Thereafter, the markers D2S347, D2S2339, D2S383, D2S2271 and D2S2215 were genotyped in 117 heterozygotes from France (n = 7), Quebec (n = 36) or Vermont (n = 74). The allelic frequency distribution of these five markers was also determined in fifty control French Canadian subjects and thirty-two unaffected members of the Vermont kindred with normal protein C levels and compared with their frequency in our cohort of heterozygotes. Our data suggest that patients from Quebec and Vermont carry a common haplotype at the protein C locus. Moreover, in order to study the evolutionary history of the 3363 InsC mutation, we traced back the ascending genealogy of one proband in each of the families with this mutation. These results showed that the 3363 InsC mutation was most probably introduced in North America by a couple of French settlers who established themselves in 1669 on Isle d'Orleans located near Quebec City. All heterozygotes for the 3363 InsC mutation living in North America are related to these founders within 10 generations. Thus, these families afford a unique opportunity to evaluate the role of the protein C system in thrombophilia due to the high degree of linkage disequilibrium at the protein C gene, which in essence holds that variable more constant than in a more heterogeneous population.

[Olav Egeberg--hereditary antithrombin deficiency and thrombophilia]. / Olav Egeberg--arvelig antitrombinmangel og trombofili.

In 1965 Olav Egeberg (1916-77) presented the first report that linked a defined, hereditary defect in the control of blood coagulation to thrombotic disease. Having examined a family in which several members had sustained venous thrombosis, he demonstrated that antithrombin activity was clearly subnormal in the affected members. Heparin cofactor activity was also subnormal in these persons. This supported the hypothesis that the two activities might reside in a single protein. The condition was inherited as an autosomal dominant trait. Egeberg's publication initiated thrombophilia as a rewarding research area, and also as an important clinical discipline.