Johansson et al. (1978) studied a family in which thromboembolic disease was associated with impaired capacity for release of fibrinolytic activity from the vessel wall. In 4 generations of a family, 22 persons had a history of deep ... Johansson et al. (1978) studied a family in which thromboembolic disease was associated with impaired capacity for release of fibrinolytic activity from the vessel wall. In 4 generations of a family, 22 persons had a history of deep venous thrombosis. After venous occlusion and/or infusion of a vasopressin derivate, release of fibrinolytic activity from vessel wall was defective. However, the fibrinolytic activator activity was normal in all cases. The pattern of inheritance was autosomal dominant. Male-to-male transmission was observed. Jorgensen et al. (1982) studied 6 members of a family with a tendency to thrombosis and defective fibrinolysis. After stimulation of tissue plasminogen activator (PLAT; 173370) release from the vessel wall by local venous occlusion or by submaximal physical exertion, they had a lower plasminogen activator activity in blood than did healthy controls. Five of the 6 suffered from recurrent venous thrombosis. Inheritance was autosomal dominant; male-to-male transmission was observed. However, the pedigree showed venous thrombosis beginning at age 17 in 2 brothers, both of whose parents had venous thrombosis and plasminogen activator deficiency. Each parent had a father with venous thromboses beginning at age 18 and demonstrated deficiency of plasminogen activator, and a sister with plasminogen deficiency but no thromboses. The father of the 2 brothers had a sister who died of 'pneumonia' at age 21; the authors suggested that this may have been pulmonary embolus. Stead et al. (1983) demonstrated defective release of vascular plasminogen activator in a family in which venous thrombosis, pulmonary emboli, and mesenteric vein thrombosis were documented in 5 males of 2 generations. Onset was as early as 14 years of age. In this family, affected persons also showed significantly elevated levels of factor VIII (F8; 300841)/von Willebrand factor (VWF; 613160). Physical conditioning enhances plasminogen activator release; 2 of the affected persons engaged in active exercise programs. Heavy smoking also increases PLAT release; none smoked. The elevation of factor VIII was thought not to represent a factor in the thrombophilia, but perhaps to indicate a second manifestation of endothelial cell dysfunction. Stead et al. (1983) suggested that a defect in PLAT release might also take the form of increased release; in this case, activator would become rapidly depleted from the vessel walls since the vessel has only a limited capacity to synthesize activator and stores are easily exhausted. - Hyperfibrinolysis due to Increased tPA Release Booth et al. (1983) reported a patient with a life-long bleeding disorder characterized by hemorrhage occurring after surgery, injury, or dental extraction, and finally by spontaneous intracerebral bleeding. There were no abnormalities of platelet function or plasma coagulation, but grossly enhanced overall fibrinolytic activity was present. Laboratory studies indicated that the enhanced fibrinolysis was due to consistently increased levels of tPA. Aznar et al. (1984) reported a man with a history of excessive bleeding after minor trauma and dental extractions. The patient, 3 of his children, and 1 grandchild showed in vitro increased red cell fallout from the blood clot and increased tissue plasminogen activator activity. Only the proband had bleeding. Aznar et al. (1984) noted the similarities to the patient reported by Booth et al. (1983).
Among 51 healthy males, Jern et al. (1999) found that a 311-bp Alu insertion/deletion (I/D) polymorphism in intron 8 of the PLAT gene was significantly associated with the vascular release rate of tPA as assessed by a forearm ... Among 51 healthy males, Jern et al. (1999) found that a 311-bp Alu insertion/deletion (I/D) polymorphism in intron 8 of the PLAT gene was significantly associated with the vascular release rate of tPA as assessed by a forearm venous occlusion test. Individuals homozygous for the insertion had significantly increased net local release rates than those who were either heterozygous or homozygous for the deletion. The genotypic association was not reflected in circulating steady state plasma levels of tPA, which is a poor marker of local secretion. In a follow-up study to that of Jern et al. (1999), Ladenvall et al. (2000) postulated that the I/D polymorphism in the PLAT gene was unlikely to have a direct effect on tPA expression, but rather was in linkage disequilibrium with a putative functional variant. In the same group of 51 males, Ladenvall et al. (2000) identified several SNPs in the PLAT gene that were in linkage disequilibrium with the I/D polymorphism and were associated with tPA release. In particular, a -7351T-C transition within an enhancer site of the PLAT gene showed the strongest association with tPA release (p = 0.008). Individuals homozygous for the C allele had more than twice the release rates compared to CT heterozygotes or TT homozygotes. The SNP was not associated with steady state plasma levels of tPA, only with the rate of local release after a forearm occlusion test. In vitro functional expression studies showed that the transcription factor SP1 (189906) bound strongly to the -7351C allele, but weakly to the T allele. These findings were consistent with the observation of higher tPA release rates in those with the C allele, which may reflect increased gene expression. Sartori et al. (2003) evaluated 82 patients with a previous thrombotic event or a suspected thrombotic state. Forty of these patients were found to have reduced tPA release, whereas the remaining 42 patients had increased plasminogen activator inhibitor-1 (PAI1; 173360), resulting in decreased functional tPA and a hypofibrinolytic state. There was no difference in the frequencies of PLAT I/D genotype between patients and 50 controls. The tPA antigen increase after venous occlusion was significantly higher in controls and in patients with increased PAI carrying the I allele compared to the D allele. Sartori et al. (2003) concluded that there may be a genetic modulation of tPA-regulated secretion. Ladenvall et al. (2003) screened 240 Swedish individuals without cardiovascular disease for 8 SNPs and an Alu insertion polymorphism at the PLAT locus, as well as for a polymorphism (173360.0002) in PAI1 promoter. None of these was found to be a strong predictor of plasma tPA levels.