PROS1 is a vitamin K-dependent plasma protein that plays a pivotal role in anticoagulants. It inhibits blood clotting by activating protein C(APC) and tissue factor pathway inhibitor(TFPI) serving as a cofactor. It also directs inhibition of prothrombin complex(FXa/FVA) production of thrombin. Starting from the N-terminal, RROS1 contains a vitamin K-dependent domain, named “Gla domain”, is sensitive to thrombin. Then, there are four consecutive epidermal growth factor(EGF) like domains with high-affinity calcium-binding ability. In the C-terminal, PROS1 has a homologous plasma sex hormone-binding globulin(SHBG) which has two Laminin G-like structures(LG1, LG2).In PROS1, the SHBG-like domain is used to interact with C4BPA[14, 15].
LG1(Amino acids 299-475)and LG2(amino acids 484-666) are arranged continuously like a V-shape. It may be adverse to protein stability in some cases.So they all have disulfide bonds between subunits to stabilize LG pairs . Cys448,475 in PROS1 LG1subunit and Cys639,666 in LG2 subunit are the key amino acids to form disulfide bonds.
Some disulfide bonds between domains or subunits are indispensable for the effective secretion of proteins. Free cysteine thiol groups can prolong the residence time of proteins in the endoplasmic reticulum. Pros1 Tyr444Cys is located near the key samino acids and the PROS1 secretion is greatly affected. In another report, pros1 Arg474Cys reduced the secretion of protein S by 8-fold, which was due to the impaired secretion and intracellular degradation. Many results suggest that the mutation in the SHBG-like domain, especially in LG2, does not affect the mRNA transcription and PROS1 synthesis but the protein secretion[20-23].In summary, the mutation of pros1 Gly638Cys introduces a new sulfhydryl group which impairs PROS1 secretion by affecting the disulfide bonds.
We collected the case information which mutated in the PROS1 LG2 subunit (Table 3). According to this table, we can find that the average onset age is 34.8 years old, the minimum age is 16 years old and the maximum age is 69 years old. About 76.92% of the patient are 21-50 years old when they experience primary VTE. Female (f): male (m) = 11:20. Most of the initial symptoms were DVT, followed by PE. DVT is particularly common in male patients, but less in females. Females have a considerable part of PE. PROS1 related test results vary greatly among individuals and lack follow-up test results. Only misuk Ji  provided FPS test results at multiple time points in patients with mesenteric venous thrombosis after total colectomy (Table 4). Therefore, we may need a more standardized standard or a more stable and accurate detection scheme.
The risk factors of cerebral venous thrombosis include dehydration, coagulation disorder, low intracranial pressure, etc [25, 26]. Arteriovenous malformation and head trauma are special factors that increase the risk of intracranial venous thrombosis.This patient has pros1 Gly638Cys that is considered as its etiology. In addition, the patient’s chromosome 3q26.32, q26.33 repeat amplified area include PIK3CA, which can lead to venous malformation. It may be the another pathogeny for ICoVT.
The most common symptoms of ICoVT are headache (71%), epilepsy (58%) and focal neurological dysfunction (62%). In imaging, about 84% of patients showed brain parenchymal lesions,46% of them were presented hemorrhagic lesions,37% of them would be local edema .The suggestive sign of intracranial venous thrombosis is called "spinal cord sign" in CT and "high-intensity venous sign and Dot sign” in MRI .In this paper,we can see them in MRI(Figure 2). Moreover, MRV may not give a clear suggestion due to the size and anatomical variation of cortical veins. At this time, GRE sequences are needed for auxiliary diagnosis . About half of the patients have a low apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance (DWI), who is more likely to have parenchymal sequelae. Although magnetic SWI is the most sensitive in diagnosing ICoVT, the changes of SWI and echo gradient may exist several years after the onset, so that we cannot distinguish whether the thrombus new or old. If there is no better choice, DSA can be used to exclude other vascular diseases, such as arteriovenous malformations and fistulas .
In terms of treatment, the existing research results suggest that individuals with hereditary thrombotic tendency have an increased risk of primary VTE. It can be seen from the table that many patients will have recurrent thrombosis within 10 years. At this time, we should pay attention to the choice of drugs. The efficacy and safety of patients using direct oral anticoagulants (DOACs) (such as dabigatran, rivaroxaban and apixaban) are similar to LMWH and vitamin K antagonist (VKA). The recurrence rate, massive bleeding rate and mortality of VTE in patients using DOACs in non-recommended dose or regimen are significantly higher , Therefore, taking DOACs correctly is an important part of effective treatment.
This case report and literature review provides information for us to understand the functional information of PROS1. When come to unexplained isolated cortical venous thrombosis, we need to consider the possibility of PROS1 gene mutation. We summarized the characteristics of cases with PROS1 LG2 subunit mutation which may does not affect the mRNA transcription and PROS1 synthesis but the protein secretion.