Protein C, protein S, and antithrombin are key regulatory proteins in the coagulation cascade. Protein C is a vitamin K-dependent serine protease that is expressed in the endothelial cells and is activated when thrombin binds to thrombomodulin. The activated Protein C (APC) in turns inactivates factors Va and VIIa inhibiting thrombosis. As such, Protein C controls the generation of prothrombin. In addition, Protein C inhibits plasminogen activator inhibitor-1 (PAI-1). Protein C abnormalities are the result of a deficient quantity (type 1) or deficient function (type 2) [5, 6].

Primary protein C deficiency is an autosomal dominant disorder that is present in about 0.2 % of the general population [7]. Homozygous protein C deficiency is not compatible with life and usually manifests as neonatal purpura fulminans [8]. The heterozygous form is associated with recurrent thrombosis, relatively younger persons, and most of the thromboembolic events emanate from the venous system …. The majority of patients with primary protein C deficiency present with thrombotic events before age 45 years. Secondary causes of protein C deficiency include liver disease, disseminated intravascular coagulation (DIC) in severe infections, acute respiratory distress syndrome, and administration of L asparaginase or methotrexate [6].

Protein S is a glycoprotein that is also vitamin K-dependent. Its function is that of a catalyst or cofactor for the APC. Protein S (PS) in the circulation is present as a free form that is biologically active and bound to C4b complement protein. Primary protein S deficiency occurs as type I characterized by low free PS levels and normal PS bound levels; type IIa has low levels of both free and bound PS; and type IIb has normal levels of both free and bound PS, but functionally deficient PS. Either the quantitative or qualitative/functional deficiency forms can result in thrombosis. The inherited form of PS deficiency is transmitted as an autosomal dominant trait and the homozygous form results in death. The heterozygous form behaves similarly to the protein c deficiency producing primarily venous thromboembolic events. Case control studies and an extensive review found no association to ischemic stroke [9]. Acquired cases of PS deficiency have also been described associated with pregnancy, infection, DIC, oral contraceptives, HIV infection, and nephrotic syndrome among other disease states [6, 10–15]. It is worth noting that during pregnancy the C4b binding protein increases resulting in a lower amount of free PS levels normally therefore altering the range of reference making the diagnosis of PS deficiency more challenging during pregnancy. Under these circumstances is recommended to retest no less than 6 weeks postpartum [10, 16].

The prevalence of protein C or protein S deficiencies in patients with venous thrombosis is low at 2–10 %, in fact prior to 2000 there were no prevalent protein C or S deficiencies reported [5, 9]. Case series initially brought attention to these deficiencies in the thrombin pathway however an extensive review of the literature that included six case-control studies of cases of ischemic stroke found that cases and controls had similar rates of protein deficiencies (0–21 % vs 0–20 % respectively) and therefore no causal association [10].

A single point mutation in the factor V gene (factor V R506Q) results in activated protein C (APC) resistance, Factor V Leiden (FVL) mutation, and explains 90–95 % of cases of APC resistance and is the most common genetic risk factor for thrombosis [17–19]. The prevalence of the heterozygous form of FVL mutation varies among different ethnic groups and races. The higher prevalence is among whites at 5.3 % while among Hispanics is 2.2 %, Native Americans 1.3 %, African Americans 1.2 %, and Asian Americans 0.5 % [17]. The relative risk for thrombotic events among homozygous is 80 as compared to heterozygous in whom the relative risk is only 7 [18]. The thromboembolic events are venous. Since the mutation is not fully penetrant, only about 5–10 % of heterozygous patients will develop venous thromboembolism [18]. In a large review of 16 case control studies of FVL mutation or prothrombin mutation, the authors the authors did find an association between the mutation and ischemic stroke in 14 of those studies [9].

The gene variant G20210A is a point mutation in the prothrombin (PT) gene that leads to high prothrombin levels. The mutation has a 7 % prevalence among whites and is very uncommon among other racial and ethnic groups [20]. Homozygous patients have higher risk of venous thromboembolism. Acquired AT deficiency is associated with liver disease, DIC, oral contraceptives, sepsis, among others. This mutation has no conclusive association with ischemic stroke [6, 20, 21].

Antithrombin (AT) is a glycoprotein that is not a vitamin K-dependent. AT inhibits serine proteases and lyses thrombin and factor Xa. This disorder is autosomal dominant and its prevalence in the general population is 1 in 2,000–5,000 [22]. The most frequent gene mutation is A384S which is seen among whites [23, 24] and it presents with venous thromboembolism.

APS is an autoimmune disorder that has been positively associated with venous and arterial thromboembolism. It characteristically presents with deep venous thrombosis or arterial thrombosis (typically ischemic stroke), thrombocytopenia and in women with recurrent spontaneous miscarriages usually before the tenth week of pregnancy [3, 25]. Current diagnostic criteria are in Table 17.2.

Antiphospholipid antibodies (aPL) include lupus anticoagulant (LA) and anticardiolipin antibodies (aCL). aPL are a group of polyclonal antibodies directed against several phospholipids including cardiolipin, phosphatidylcholine, and phosphatidyl serine [26–29]. There is a group of aPL that are associated with infections and are not pathogenic and a second type that binds to phospholipid-binding proteins, such as the β2 glycoprotein I or prothrombin, which are bound to injured endothelial cells [26, 30]. Usually patients with underlying autoimmune disease such as systemic lupus erythematous (SLE) with aCL are at particular high risk of thromboembolic complications [26, 30]. The risk of thromboembolic events varies with the type of immunoglobulin isotype (higher with IgG and IgM as compared with IgA), titer and specificity (higher with aCL antiphosphaditylethanolamine or antiphosphatidylserine) [26, 30].

The prevalence of aPL has been reported in as many as 10–30 % of unselected patients with stroke and 4–46 % of young stroke patients as compared with 2–12 % of controls [2, 31, 32]. The prevalence of aPL among SLE patients is 40 % [33]. The presence of aPL has been positively associated as an independent risk factor for stroke [31, 34]. While the presence of aPL does not reliably predict recurrent ischemic strokes, a systematic review and meta-analysis showed higher odds for recurrence for those older than 50 years as compared to all ages (5.8 vs 2.5). It is worth noting that the titers of aPL can fluctuate and therefore positive results should be confirmed with repeat testing several weeks later [34].

From the clinical standpoint, patients with ischemic stroke suspected of having APS may present with a history of DVT, thrombocytopenia, and miscarriages, and they can also present with: