| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q34 | [Protein Z deficiency] | 614024 | 3 | PROZ | 176895 |
A number sign (#) is used with this entry because of evidence that protein Z deficiency is caused by heterozygous mutation in the PROZ gene (176895) on chromosome 13q34.
Protein Z serves as a cofactor for the downregulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI; 605271). Evidence also suggests that protein Z may promote the assembly of thrombin with phospholipid surfaces, thus enhancing coagulation. There is a wide variation of protein Z levels in human plasma, and studies have reported conflicting results of the clinical consequences of protein Z deficiency in humans. Most studies have reported an association between decreased protein Z levels and thrombosis, including stroke, venous thrombosis, and obstetric complications, although early reports suggested an association between protein Z deficiency and bleeding tendency (Kemkes-Matthes and Matthes, 1995). Overall, a role for protein Z in the pathogenesis of hemostatic disorders in humans is controversial and remains unclear (review by Broze, 2001 and Vasse, 2008).
Protein Z deficiency has been shown to exacerbate the thrombotic phenotype in patients with thrombophilia due to factor V Leiden (see 188055).
Reports of Bleeding Tendency
Kemkes-Matthes and Matthes (1995) examined 36 patients with bleeding tendency of unknown origin who were not under oral anticoagulant treatment and had normal liver synthesis function. The mean protein Z levels of patients with bleeding tendency was significantly diminished (52%) in comparison with the healthy control group. In 21 of the patients, they found lower protein Z levels than in the lowest protein Z level of the control group. Kemkes-Matthes and Matthes (1995) concluded that protein Z deficiency is a new type of bleeding tendency that cannot be detected by routine coagulation tests and could be the cause for the 'capillary fragility syndrome.' The latter disorder is characterized by positive Rumpel Leed tests and normal routine coagulation tests. At the time of this study, protein Z was believed to associate with and help localize thrombin at the phospholipid surface at sites of injury. However, it was later found that the main role of protein Z is to inhibit the coagulation cascade prior to the formation of the prothrombinase complex (Vasse, 2008).
In contrast to the study of Kemkes-Matthes and Matthes (1995), Gamba et al. (1998) found no difference in plasma levels of protein Z between healthy controls and 15 adult patients with mild to moderate bleeding tendencies of unknown origin. These authors concluded that protein Z deficiency did not play a pathogenetic role in the bleeding tendency of their patients, and noted that the clinical impact of protein Z on hemostasis remained obscure.
Ravi et al. (1998) found a wide range of protein Z levels in healthy men and women, although women tended to have lower levels. None of 48 patients with a suspected bleeding disorder had a protein Z level below the normal range, but protein Z levels were significantly lower in the group of male patients with a bleeding history as compared to healthy men. The data indicated that low-normal protein Z levels are not associated with a bleeding tendency. However, the study did not rule out the possibility that a low protein Z level may be a weak cofactor associated with an increased bleeding tendency, and did not indicate whether decreased or absent protein Z may result in a hemorrhagic diathesis.
Reports of Increased Thrombosis
Vasse et al. (2001) analyzed plasma protein Z levels in 56 patients with deep venous thrombosis (DVT), 169 patients with ischemic stroke, and 88 controls. There was no significant difference in mean protein Z concentrations between the deep venous thrombosis group and the controls, and 5% of individuals in both groups had protein Z deficiency. In patients with ischemic stroke, however, protein Z levels were lower than the normal range, and 33 of these patients (20%) had protein Z deficiency.
In a study of 450 women with unexplained fetal loss and 200 controls, Gris et al. (2002) found an association between decreased plasma protein Z levels and early fetal demise (odds ratio (OR) of 6.7, p less than 0.003). Gris et al. (2002) postulated that protein Z deficiency may induce an enhanced risk of severe placental insufficiency soon after the connection of maternal and fetal circulations.
Santacroce et al. (2006) found similar protein Z levels in 197 patients with deep vein thrombosis and healthy controls. However, the incidence of protein Z levels below the 5.0 or 2.5% ranges was higher in patients (10.2% and 8.7%, respectively) than in controls (4.1 and 2.0%, respectively), yielding an odds ratio of 2.7 and 4.6, respectively, for the risk of DVT in individuals with low protein Z levels. The authors concluded that very low levels of protein Z may be associated with an increased risk of DVT.
In a metaanalysis involving 28 case-control studies including 4,218 patients with thrombotic diseases and 4,778 controls, Sofi et al. (2010) found that low protein Z levels were associated with an increased risk of thrombosis (OR of 2.90, p less than 0.00001). By subgroup analysis, significant associations were found between low protein Z levels and arterial vascular diseases (OR of 2.67, p = 0.0002), pregnancy complications (OR of 4.17, p less than 0.00001), and venous thromboembolic diseases (OR of 2.18, p = 0.01). These results were consistent with a role for protein Z deficiency in various thrombotic diseases, including arterial thrombosis, pregnancy complications, and venous thromboembolism.
Rice et al. (2001) found no association between polymorphisms in the PROZ gene and risk for deep venous thrombosis among 564 patients with DVT and 492 controls.
Souri et al. (2004) reported a patient with thrombophilia due to factor V Leiden (see 188055) who had had 3 DVT events and 1 spontaneous miscarriage and who also had low levels of plasma protein Z to about 15% of normal. In addition to a heterozygous F5 mutation (612309.0001), she had a heterozygous mutation in the PROZ gene (E30Q; 176895.0001) that resulted in decreased release of protein Z from synthesizing cells. The patient was also heterozygous for a 79G-A polymorphism in intron 6 of the PROZ gene, which had also been associated with lowered protein Z levels. The findings suggested that PROZ deficiency enhances the thrombotic phenotype in those with factor V Leiden.
Among 42 control individuals, Lichy et al. (2004) found that the A allele of the intron F 79G-A polymorphism (rs17882561) was significantly associated with lower plasma protein Z levels (p = 0.0032). The frequency of the A allele of this SNP was significantly lower in 200 patients with onset of cerebral ischemia before age 50 years compared to controls (15.7% compared to 24.4%, OR of 0.58), suggesting that the A allele is a protective genetic marker. The study suggested that high levels of protein Z may represent a prothrombotic condition. Lichy et al. (2004) stated that their findings were consistent with a role of protein Z as an enhancer of thrombin activity, but noted that the results of their study were contradictory to those of other studies, such as Vasse et al. (2001).
Yin et al. (2000) found that Proz-null mice had a normal phenotype with no increase of bleeding or thrombosis. However, Proz deficiency dramatically increased the severity of the prothrombotic phenotype of factor V Leiden (see 612309) mice. These results suggested that PROZ plays a physiologically important role in the regulation of coagulation in certain circumstances.
Broze, G. J., Jr. Protein Z-dependent regulation of coagulation. Thromb. Haemost. 86: 8-13, 2001. [PubMed: 11487045]
Gamba, G., Bertolino, G., Montani, N., Spedini, P., Balduini, C. L. Bleeding tendency of unknown origin and protein Z levels. Thromb. Res. 90: 291-295, 1998. [PubMed: 9700859] [Full Text: https://doi.org/10.1016/s0049-3848(98)00036-x]
Gris, J.-C., Quere, I., Dechaud, H., Mercier, E., Pincon, C., Hoffet, M., Vasse, M., Mares, P. High frequency of protein Z deficiency in patients with unexplained early fetal loss. Blood 99: 2606-2608, 2002. [PubMed: 11895801] [Full Text: https://doi.org/10.1182/blood.v99.7.2606]
Kemkes-Matthes, B., Matthes, K. J. Protein Z deficiency: a new cause of bleeding tendency. Thromb. Res. 79: 49-55, 1995. [PubMed: 7495103] [Full Text: https://doi.org/10.1016/0049-3848(95)00089-a]
Lichy, C., Kropp, S., Dong-Si, T., Genius, J., Dolan, T., Hampe, T., Stoll, F., Reuner, K., Grond-Ginsbach, C., Grau, A. A common polymorphism of the protein Z gene is associated with protein Z plasma levels and with risk of cerebral ischemia in the young. Stroke 35: 40-45, 2004. [PubMed: 14671240] [Full Text: https://doi.org/10.1161/01.STR.0000106909.75418.E4]
Ravi, S., Mauron, T., Lammle, B., Wuillemin, W. A. Protein Z in healthy human individuals and in patients with a bleeding tendency. Brit. J. Haemat. 102: 1219-1223, 1998. [PubMed: 9753048] [Full Text: https://doi.org/10.1046/j.1365-2141.1998.00908.x]
Rice, G. I., Futers, S., Grant, P. J. Identification of novel polymorphisms within the protein Z gene, haplotype distribution and linkage analysis. (Letter) Thromb. Haemost. 85: 1123-1124, 2001. [PubMed: 11434699]
Santacroce, R., Sarno, M., Cappucci, F., Sessa, F., Colaizzo, D., Brancaccio, V., Grandone, E., Margaglione, M. Low protein Z levels and risk of occurrence of deep vein thrombosis. J. Thromb. Haemost. 4: 2417-2422, 2006. [PubMed: 16938126] [Full Text: https://doi.org/10.1111/j.1538-7836.2006.02186.x]
Sofi, F., Cesari, F., Abbate, R., Gensini, G. F., Broze, G., Jr., Fedi, S. A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis. Thromb. Haemost. 103: 749-756, 2010. [PubMed: 20076855] [Full Text: https://doi.org/10.1160/TH09-09-0645]
Souri, M., Koseki-Kuno, S., Iwata, H., Kemkes-Matthes, B., Ichinose, A. A naturally occurring E30Q mutation in the Gla domain of protein Z causes its impaired secretion and subsequent deficiency. Blood 105: 3149-3154, 2004. [PubMed: 15626740] [Full Text: https://doi.org/10.1182/blood-2004-06-2250]
Vasse, M., Guegan-Massardier, E., Borg, J.-Y., Woimant, F., Soria, C. Frequency of protein Z deficiency in patients with ischaemic stroke. (Letter) Lancet 357: 933-934, 2001. [PubMed: 11289354] [Full Text: https://doi.org/10.1016/S0140-6736(00)04218-5]
Vasse, M. Protein Z, a protein seeking a pathology. Thromb. Haemost. 100: 548-556, 2008. [PubMed: 18841275]
Yin, Z.-F., Huang, Z.-F., Cui, J., Fiehler, R., Lasky, N., Ginsburg, D., Broze, G. J., Jr. Prothrombotic phenotype of protein Z deficiency. Proc. Nat. Acad. Sci. 97: 6734-6738, 2000. [PubMed: 10829076] [Full Text: https://doi.org/10.1073/pnas.120081897]