A Case of Unexplained Cerebral Sinus Thrombosis in a 22-Year-Old Obese Caucasian Woman

Jansen N. Seheult, MB, BCh, BAO, MSc; Irina Chibisov, MD


Lab Med. 2016;47(3):223-240. 

In This Article



The fibrinolytic cascade is a complex system of serine proteases and their inhibitors, activators, and receptors, which act to regulate the activation of plasminogen to plasmin.[1] The final steps in the coagulation cascade lead to thrombus formation by conversion of fibrinogen to fibrin monomers and covalent cross-linking of fibrin strands to form cross-linked fibrin (Figure 1).[2]

Figure 1.

Activators and inhibitors of the fibrinolytic system. tPA indicates tissue plasminogen activator; uPA, urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1; TAFI, thrombin activatable fibrinolysis inhibitor; and FDPs, fibrin degradation products.

Plasminogen is a circulating plasma zymogen, which can be converted on cell surfaces or on the surface of a thrombus to active plasmin by the action of 2 activators, namely, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA).[1,3] Whereas tPA is mainly involved in the dissolution of a thrombus, the major role of uPA is in pericellular proteolysis during tissue remodeling.[4] The catalytic activity of tPA is greatly enhanced when it is complexed with plasminogen on lysine-binding sites of fibrin.[1] Plasmin is the major fibrinolytic protease, which degrades cross-linked fibrin and fibrinogen into soluble fibrin degradation products, D-dimers, and fibrinogen degradation products.[5] In this regard, fibrin is a product of the coagulation cascade and a substrate for the fibrinolytic cascade (Figure 1). On cleavage of fibrin, additional C-terminal lysine residues are exposed, which creates positive feedback for the activation of plasminogen.[1] A recent study by Hur et al[6] also showed that plasmin can cleave plasma- and platelet-derived Factor XIIIa (FXIIIa) during clot lysis, leading to its inactivation. These findings suggest that the fibrinolytic cascade can also have downstream effects on cross-linking of blood proteins.

Inhibitors of Fibrinolysis

Inhibitors of fibrinolysis can be divided into 3 main categories: plasmin inhibitors, plasminogen activator inhibitors, and attenuators.[1] The main inhibitors of plasmin are α2-antiplasmin, α2-macroglobulin and protease nexin, of which α2-antiplasmin is the most important. α2-antiplasmin is a serine protease inhibitor or serpin that binds in a 1:1 stoichiometric reaction with the active site serine of plasmin, forming an irreversible complex.[7] Both molecules subsequently lose their catalytic activity and are cleared from the circulation. Plasmin and α2-antiplasmin have half-lives of approximately 50 hours, and the plasma concentration of plasmin (0.2 mg/mL) is approximately twice that of α2-antiplasmin (0.07 mg/mL).[8]

The most important class of fibrinolysis inhibitors is the plasminogen activator inhibitors. In order of reaction-rate constants, these include PAI-1, PAI-2, protease nexin, and PAI-3.[9] The most ubiquitous plasminogen activator inhibitor is PAI-1.

Thrombin activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis attenuator, which is activated to TAFIa by thrombin/thrombomodulin and by plasmin.[10,11] TAFIa can cleave lysine residues from fibrin, thus decreasing the binding of plasminogen to fibrin and reducing the fibrinolysis-enhancing effect of these residues.[12]


PAI-1 is a 52-kDa single-chain, labile, glycoprotein serpin that is produced by endothelial cells, platelets, megakaryocytes, monocytes, macrophages, hepatocytes, and adipocytes.[13–17] PAI-1 is present at a concentration of 60 ng per mL in plasma—approximately 5 to 10 times higher than the concentration of tPA and 50 times higher than the concentration of uPA.[8] Platelet PAI-1 accounts for approximately half of circulating PAI-1 activity but is less active than plasma PAI-1.[18] PAI-1 is also an acute-phase reactant that likely results from increased hepatocyte production.[19] The plasma half-life of PAI-1 has been reported to be approximately 5 to 7 minutes,[8] and the active form of PAI-1 is stabilized in the circulation by noncovalent binding to the glycoprotein vitronectin.[20] Four different conformations of PAI-1 have been described, namely, the active form that reacts with plasminogen activator, a latent form that is nonreactive but can be converted to the active form, a substrate form that can be cleaved by plasminogen activators but is noninhibitory, and the inert form of PAI-1 generated by the cleavage of the reactive site.[21]

PAI-1 inhibits tPA (single-chain and 2-chain) and uPA (2-chain only) by forming a stable 1:1 complex that causes loss of activity.[22] Elevations in PAI-1 levels can lead to hypofibrinolysis. Increased plasma levels of PAI-1 have been associated with venous and arterial thrombosis.[23–25]

PAI-1 concentrations are higher in older patients, in men, in current/former smokers, in obese patients, in patients with evidence of proteinuria or a chronic inflammatory state (elevated C-reactive protein levels), and in patients with metabolic syndrome.[26] It is likely that the production of PAI-1 by adipose tissue, in particular by tissue from the omentum, could be an important contributor to the elevated plasma PAI-1 levels observed in patients with insulin resistance.[27]

The PAI-1 Gene and 4G/5G Polymorphism

The SERPINE1 gene (OMIM: 613329), alternatively referred to as the PAI-1 gene, is located on chromosome 7 and is 12 kb long, consisting of 9 exons and 8 introns. The transcription start point is located 142 nucleotides upstream from the start codon.[28] The most frequently described polymorphism in the PAI-1 gene is the 4G/5G single base pair insertion/deletion polymorphism (allele frequency, 0.53/0.47), which is located 675 bp upstream of the transcriptional start site (Figure 2).[29] The 5G polymorphism is more common and allows a transcriptional repressor to bind to the transcriptional activator, thus reducing messenger RNA (mRNA) transcription and PAI-1 levels. The 4G polymorphism causes inhibition of binding of the transcriptional repressor, allowing unopposed action of the transcriptional activator and elevated PAI-1 levels.[30,31]

Figure 2.

Structure of SERPINE1 gene (OMIM: 613329), which encodes for PAI-1 gene, showing the site of 4G/5G polymorphism 675 bp upstream of the transcriptional start site and the possible mechanism of transcriptional control.

The PAI-1 4G/4G polymorphism has been associated with an elevated risk of certain venous thromboembolic disorders. Sartori et al[32] found an association between the 4G/4G genotype and a greater risk of thrombosis in patients with symptomatic thrombophilia (odds ratio [OR], 2.85; 95% confidence interval [CI], 1.26–6.46) and in patients with idiopathic DVT (3.1; 1.26–7.59). Balta et al[33] found an association between the 4G/4G and the 4G/5G genotypes with an increased risk of internal organ thrombosis, especially portal-vein thrombosis. Seguí et al[34] studied 190 genetically unrelated patients with DVT and 152 healthy control individuals and found no significant difference in allele frequencies between the groups. The authors reported that in the DVT group, PAI-1 antigen levels were influenced by the 4G allele dosage, triglyceride levels, and BMI. The 4G/4G genotype has also been associated with pregnancy complications due to placental insufficiency[35,36] and with myocardial infarction.[37,38] In all of the aforementioned studies, the PAI-1 4G/4G genotype was associated with elevated PAI-1 activity and/or antigen levels.

The evidence for the association between PAI-1 4G/5G genotype and cerebral sinus thrombosis is conflicting. Although several case reports have highlighted a possible relationship between the 4G allele and cerebral sinus thrombosis,[39–41] case-control studies to date have failed to find a significant independent relationship.[33,42] One study that examined PAI-1 4G/5G genotypes in carriers of the Factor V Leiden (FVL) mutation found that the concurrence of FVL and homozygosity for the 4G allele lead to an increased risk for cerebral sinus thrombosis. This finding supports the assumption that in carriers of the FVL mutation, a further prothrombotic factor may be necessary for the development of a manifest thrombotic event.[43]