Mechanism

Both protein C and protein S are vitamin K–dependent plasma proteins, which play important roles in the human protein C anticoagulation pathway. Protein C is activated on the endothelial cell surface by the thrombin-thrombomodulin complex, generated during vessel injury to form the serine protease activated protein C (APC). On the other hand, protein S functions as a cofactor for protein C, so that the APC activity is increased 10-fold in the presence of protein S. Once APC is generated, it binds as a complex with its cofactor protein S, which can inactivate clotting factors (F) Va and FVIIIa. As a result the pathway can effectively regulate further thrombin formation and thrombosis.

Classification

Protein C deficiency or protein S deficiency may be acquired or hereditary. The hereditary form can be categorized as heterozygous, homozygous, and compound heterozygous. Phenotypically, 2 types of protein C deficiency have been described: type 1 whereby both the antigenic levels and functional activities are reduced, and type 2 whereby protein C activity levels are reduced to a greater extent than antigenic levels.

Homozygous (or compound heterozygous) deficiencies of protein C and protein S are rare conditions, and usually present as life-threatening disorders on the first few days of life. Homozygous protein C deficiency affects approximately 1 in 400,000 to 1 in 1 million live births. The first clinical manifestation is usually purpura fulminans, associated with laboratory evidence of disseminated intravascular coagulation (DIC). In some cases, massive major vessel thrombosis (renal vein, vena cava) can be the presenting features. By contrast, heterozygous protein C and protein S deficiencies rarely present in the neonatal period.

Epidemiology

In a Canadian registry of 171 children (including neonates) with VTE, the prevalence of protein C deficiency and protein S deficiency was 0.6% and 1.2%, respectively, which was considered to be low, not considerably different from the general population. The most significant etiologic factors for neonatal thrombosis are the presence of an intravascular catheter and/or other medical conditions. By contrast, the pathophysiology of neonatal CSVT and perinatal AIS are considered more complex and multifactorial, and include maternal disorders, placental problems, and perinatal and neonatal risk factors. However, meta-analysis of studies on CSVT and AIS in neonates and children indicates that genetic thrombophilia serves as an important risk factor for stroke. The calculated odds ratio (OR) for protein C deficiency and protein S deficiency were 8.76 (95% confidence interval [CI] 4.53–16.96) and 3.20 (95% CI 1.22–8.40), respectively.

Diagnosis

The diagnosis of homozygous (or compound heterozygous) deficiency can be confirmed by the findings of undetectable activity (<1% or <0.01 U/mL) on measuring the functional protein C (or protein S) activity, with heterozygous activity levels demonstrated in both parents. Heterozygous anticoagulant protein-deficiency states are difficult to diagnose in the acute stage of neonatal thrombosis, for 2 reasons. First, because of developmental hemostasis, all anticoagulant protein levels are physiologically lower (mean value for all <50%) in normal healthy term or preterm infants, in comparison with adult levels, until 6 months of age. Second, acquired deficiency states are common because of underlying medical conditions or consumption of coagulation proteins at the time of an acute thrombotic event. Therefore, for neonates suspected of having heterozygous protein C or protein S deficiencies, functional protein C (or protein S) assays must be repeated at 6 months of age or later to accurately confirm the diagnosis.

Acute treatment

For patients with neonatal purpura fulminans, assays of protein C and protein S levels must be drawn before the initiation of treatment. However, treatment should not be delayed while awaiting the results. Exogenous replacement of the deficient naturally occurring anticoagulant proteins forms the basis of treatment for this condition. Heparin and fibrinolytic agents are not effective treatments for this complex situation.

Fresh frozen plasma (FFP), given at a dose of 10 to 20 mL/kg every 12 hours, has proved to be successful for the management of patients with homozygous protein C deficiency or protein S deficiency. More frequent dosing may be required for protein C deficiency because protein C has a short plasma half-life, approximately 6 to 16 hours. However, the frequency of dosing is limited by the risk of hypervolemia and hypertension, and limited venous access. Protein C concentrate (Ceprotin; Baxter Healthcare Corp, Deerfield, IL) is another option. A starting dose of 100 U/kg, followed by 50 U/kg every 6 hours, is usually sufficient. Subsequent dosing with FFP or protein C concentrate depends on the patient’s response. The dose is titrated to achieve a trough level of protein C activity of 50 IU/dL. For homozygous protein S deficiency there is no currently available protein S concentrate; however, the same dose of FFP can be started at the acute stage. As protein S has a longer half-life of approximately 36 hours, the frequency of treatment can be titrated to achieve a trough level of free protein S of 30 IU/dL. The replacement therapy should be continued until purpuric lesions have resolved (typically 6–8 weeks) and the neonate has transitioned to anticoagulation therapy.

Long-term management

Neonates with homozygous/compound heterozygous protein C or protein S deficiency require life-long anticoagulation therapy to prevent thrombosis. Options for long-term treatment include low molecular weight heparin (target anti-FXa concentration of 0.5–1.0 U/mL), protein C supplementation, oral warfarin therapy, or a combination of all these therapies. Recent studies reported subcutaneous administration of protein C concentrate with a dose of 250 U/kg every third day provides protective levels of protein C (>25 IU/dL) and can be considered as an alternative.

Mechanism

Antithrombin (AT) is a glycoprotein of the family of serine protease inhibitors, and is synthesized in the liver. AT circulates in the blood in a quiescent form, slowly reacts with and irreversibly inhibits its primary targets thrombin and FXa, as well as secondary targets including FIXa, FXIa, FXIIa, and FVIIa. At the site of injury, thrombin is bound to thrombomodulin on the endothelial surface. The neutralization of thrombin is enhanced by the interaction with the thrombin-thrombomodulin complex. The inactive thrombin and AT then dissociates from thrombomodulin and is cleared rapidly in the liver. The removal of thrombin also prevents further activation of protein C.

Classification

Similarly to protein C/S deficiencies, AT deficiency can be acquired or inherited. Type I AT deficiency is characterized by parallel reductions of both antigen and activity levels, whereas type II deficiency covers all types of inherited dysfunctional AT variants, resulting in decreased functional activity. Among the group of dysfunctional AT, AT deficiencies may involve the reactive site (type II RS), the heparin-binding site (type II HBS), or both (“pleiotropic effect”; type II PE). Homozygous AT deficiency type I is most likely not compatible with life, and only patients with homozygous type II deficiency have been reported, of whom the majority are type II HBS. This AT variant was identified as a result of G2759T mutation, a Leu-Phe change at codon 99 (Antithrombin Budapest 3). Several other mutations of AT with heparin-binding defects were also reported, including 47 Arg-Cys, 47 Arg-His, and 41 Pro-Leu. Acquired low AT levels and dysfunctional AT have been reported in neonates with respiratory distress syndrome and in other sick premature infants.

Epidemiology

From the Canadian registry of VTE in children and neonates, none of the patients (out of 171) were found to have AT deficiency. This fact is in keeping with the notion that the most significant etiologic factor for neonatal thrombosis is still the presence of an intravascular catheter and/or other medical conditions. By contrast, for stroke, including both AIS and CSVT, meta-analysis indicated that inherited thrombophilia contributed significantly as risk factors, and the OR for AT deficiency was 7.06 (95% CI 2.44–22.42).

Diagnosis

As a result of developmental hemostasis, functional AT levels are normally reduced in healthy term neonates, and more so in premature infants. Therefore, establishing the diagnosis of AT deficiency in the neonatal period is especially challenging. The diagnosis of homozygous AT type II HBS deficiency in the neonatal period may require even more attention and suspicion. The presentation of heparin resistance and thrombosis suggests a type II HBS AT deficiency. The routine chromogenic AT assays may miss the diagnosis of AT type II HBS variant. These assays commonly recommend a preincubation time varying from 90 seconds to 5 minutes with the heparin-containing buffer and the patient’s plasma. The AT type II HBS variant binds to heparin slowly and, therefore, their anti-FIIa and anti-FXa activity will be low in the assay with a short incubation time, but significantly higher (or close to the normal range) in the assay with a longer incubation time. Thus, in patients suspected of inherited thrombophilia based on family history, or in the presence of heparin resistance, a 2-step AT assay measuring anti-FIIa activity with a short incubation time (10–30 seconds) and normal incubation time (>90 seconds) is recommended. Nevertheless, because AT activity is normally low in neonates, the 2-step assays could still yield nearly normal results in suspected cases in this age group. Molecular analysis of the AT gene will be particularly helpful in making the diagnosis of homozygous AT type II HBS deficiency in these situations.

Treatment

Neonates with suspected homozygous AT deficiency may present with arterial or venous thrombosis, as well as stroke. In the absence of medical risk factors and family history of thrombosis, thrombophilia screening (including AT assay) should be performed before the commencement of anticoagulation therapy. Cases with AT type II HBS deficiency typically also present with heparin resistance, in which case, despite increasing the heparin doses, the activated partial thromboplastin time (aPTT) will remain subtherapeutic. Again, this should alert the physician to the possibility of a type II HBS AT deficiency. The AT anti-FIIa activity (with short incubation time) will typically be less than 50% of normal. Formerly, human plasma-derived AT concentrate was used for patients with acquired or hereditary AT deficiency. Recombinant AT concentrate is now licensed in the United States, approved by Food and Drug Administration in 2009. Calculation of initial loading dose should be individualized, based on the actual level of AT activity, using the formula: IU/infused intravenously over 24 hours = (100 − baseline AT activity level (in % of normal)/2.3) × body weight (kg). The target level should be 80% to 120% of normal (30 minutes postinfusion), and the dose should be increased or decreased if the AT level is below 80% or above 120% of normal, respectively. Repeated AT level should be measured at 30 minutes and 4 hours after any rate change to confirm AT level is within the target range. As there are not currently any pediatric safety and efficacy studies published, this dosing recommendation is based on adult studies. Hence, clinicians should take extra precautions if considering the usage of recombinant AT concentrate. Frequent monitoring of bleeding symptoms, as well as close monitoring of AT activity, aPTT, and adjustment of the heparin dosage are required. For all patients with confirmed homozygous AT deficiency, long-term anticoagulation therapy is indicated. The advice of a pediatric hematologist should be sought to help manage these patients.

Mechanisms

Factor V Leiden (FVL) is characterized by a point mutation in the FV gene with a single amino-acid substitution (arginine 506 to glutamine at the APC cleavage site). The thrombin activation of FVL to Va is normal, whereas APC is not able to cleave FVa Leiden variant, leading to an excess of activated FVL and, hence, a hypercoagulable state.

Genetics and epidemiology

Inheritance of FVL is autosomal dominant. Approximately 4% of Caucasians are heterozygous for the gene defect. Meta-analysis of studies on inherited thrombophilia and pediatric VTE have shown that FVL is significantly associated with first VTE in all pediatric age groups (neonates/infants/older children), with the summary OR of 3.56 (95% CI 2.57–4.93). This figure is concordant with data from adult studies, in which FV mutation increases the risk of a first episode of VTE by 3- to 7-fold. Regarding the risk of pediatric AIS and CSVT, a meta-analysis demonstrated the calculated OR for FVL is 3.26 (95% CI 2.59–4.1).

Mechanisms

Prothrombin (FII G20210A) variant is characterized by a single G to A nucleotide substitution at position 20,210 in the prothrombin gene. FVa bound in the prothrombin-FVa complex is normally resistant to APC inactivation. This prothrombin mutation is associated with an increase in production of plasma prothrombin. An elevated plasma prothrombin level increases the half-life of FVa in the circulation by protecting it from APC cleavage, leading to a hypercoagulable state.

Genetics and epidemiology

Inheritance of prothrombin mutation is autosomal dominant. The prevalence of this mutation in Caucasians is approximately 2%. Meta-analysis demonstrated that the OR for FII G20210A and onset of VTE in pediatric age group is 2.63 (95% CI 1.61–4.29), and the OR for recurrent VTE in children is 2.15 (95% CI 1.12–4.1). These data concur with those from adult studies in which FII mutation increases the risk of first VTE by 2- to 3-fold.

Mechanisms

Hyperhomocysteinemia has been identified as an independent risk factor for VTE, CSVT, and AIS. The mechanisms appear to be related to the effect of high levels of homocysteine on vessel walls by inducing endothelial injury and dysfunction, with associated decreased thrombomodulin activity. The thermolabile homozygous methylenetetrahydrofolate reductase (MTHFR) C677T (alanine 677 to valine) genotype has half of the catalytic activity of the normal MTHFR enzyme, and can result in mild hyperhomocysteinemia. However, in individuals with adequate folate levels, the effect of the genetic defect will be canceled out and plasma homocysteine levels will remain normal. Therefore, not everyone with the MTHFR C677T genotype will develop high homocysteine levels and be prone to develop VTE or stroke.

Epidemiology

The MTHFR C677T genotype is present in up to 10% of the healthy population. In children with a first-episode stroke, homozygosity of MTHFR C677T mutation has been shown to be an independent risk factor. However, because homocysteine levels were not always studied, the potential associated risk could not be accurately determined.

Mechanisms

A plasma lipoprotein(a) (Lp(a)) level higher than 30 mg/mL is considered to be elevated. The plasminogen gene on chromosome 6 is linked closely to the structurally similar apolipoprotein(a) gene. The gene product associates with a low-density lipoprotein to form Lp(a). Owing to molecular mimicry, Lp(a) competes with plasminogen for the binding domain on the endothelial cell surface. A hypercoagulable state results from the decreased activity of plasminogen on the endothelial cell surface.

Epidemiology

Elevated Lp(a) was found to be present in 7% to 10.3% of the normal population. The OR of elevated Lp(a) associated with a first VTE onset in children was 4.49 (95% CI 3.26–6.18); however, no significant association with recurrent VTE was found for elevated Lp(a). From another meta-analysis, the calculated OR associated with first AIS/CSVT onset in children was 6.27 (95% CI 4.52–8.69).

Mechanism

Both protein C and protein S are vitamin K–dependent plasma proteins, which play important roles in the human protein C anticoagulation pathway. Protein C is activated on the endothelial cell surface by the thrombin-thrombomodulin complex, generated during vessel injury to form the serine protease activated protein C (APC). On the other hand, protein S functions as a cofactor for protein C, so that the APC activity is increased 10-fold in the presence of protein S. Once APC is generated, it binds as a complex with its cofactor protein S, which can inactivate clotting factors (F) Va and FVIIIa. As a result the pathway can effectively regulate further thrombin formation and thrombosis.

Classification

Protein C deficiency or protein S deficiency may be acquired or hereditary. The hereditary form can be categorized as heterozygous, homozygous, and compound heterozygous. Phenotypically, 2 types of protein C deficiency have been described: type 1 whereby both the antigenic levels and functional activities are reduced, and type 2 whereby protein C activity levels are reduced to a greater extent than antigenic levels.

Homozygous (or compound heterozygous) deficiencies of protein C and protein S are rare conditions, and usually present as life-threatening disorders on the first few days of life. Homozygous protein C deficiency affects approximately 1 in 400,000 to 1 in 1 million live births. The first clinical manifestation is usually purpura fulminans, associated with laboratory evidence of disseminated intravascular coagulation (DIC). In some cases, massive major vessel thrombosis (renal vein, vena cava) can be the presenting features. By contrast, heterozygous protein C and protein S deficiencies rarely present in the neonatal period.

Epidemiology

In a Canadian registry of 171 children (including neonates) with VTE, the prevalence of protein C deficiency and protein S deficiency was 0.6% and 1.2%, respectively, which was considered to be low, not considerably different from the general population. The most significant etiologic factors for neonatal thrombosis are the presence of an intravascular catheter and/or other medical conditions. By contrast, the pathophysiology of neonatal CSVT and perinatal AIS are considered more complex and multifactorial, and include maternal disorders, placental problems, and perinatal and neonatal risk factors. However, meta-analysis of studies on CSVT and AIS in neonates and children indicates that genetic thrombophilia serves as an important risk factor for stroke. The calculated odds ratio (OR) for protein C deficiency and protein S deficiency were 8.76 (95% confidence interval [CI] 4.53–16.96) and 3.20 (95% CI 1.22–8.40), respectively.

Diagnosis

The diagnosis of homozygous (or compound heterozygous) deficiency can be confirmed by the findings of undetectable activity (<1% or <0.01 U/mL) on measuring the functional protein C (or protein S) activity, with heterozygous activity levels demonstrated in both parents. Heterozygous anticoagulant protein-deficiency states are difficult to diagnose in the acute stage of neonatal thrombosis, for 2 reasons. First, because of developmental hemostasis, all anticoagulant protein levels are physiologically lower (mean value for all <50%) in normal healthy term or preterm infants, in comparison with adult levels, until 6 months of age. Second, acquired deficiency states are common because of underlying medical conditions or consumption of coagulation proteins at the time of an acute thrombotic event. Therefore, for neonates suspected of having heterozygous protein C or protein S deficiencies, functional protein C (or protein S) assays must be repeated at 6 months of age or later to accurately confirm the diagnosis.

Acute treatment

For patients with neonatal purpura fulminans, assays of protein C and protein S levels must be drawn before the initiation of treatment. However, treatment should not be delayed while awaiting the results. Exogenous replacement of the deficient naturally occurring anticoagulant proteins forms the basis of treatment for this condition. Heparin and fibrinolytic agents are not effective treatments for this complex situation.

Fresh frozen plasma (FFP), given at a dose of 10 to 20 mL/kg every 12 hours, has proved to be successful for the management of patients with homozygous protein C deficiency or protein S deficiency. More frequent dosing may be required for protein C deficiency because protein C has a short plasma half-life, approximately 6 to 16 hours. However, the frequency of dosing is limited by the risk of hypervolemia and hypertension, and limited venous access. Protein C concentrate (Ceprotin; Baxter Healthcare Corp, Deerfield, IL) is another option. A starting dose of 100 U/kg, followed by 50 U/kg every 6 hours, is usually sufficient. Subsequent dosing with FFP or protein C concentrate depends on the patient’s response. The dose is titrated to achieve a trough level of protein C activity of 50 IU/dL. For homozygous protein S deficiency there is no currently available protein S concentrate; however, the same dose of FFP can be started at the acute stage. As protein S has a longer half-life of approximately 36 hours, the frequency of treatment can be titrated to achieve a trough level of free protein S of 30 IU/dL. The replacement therapy should be continued until purpuric lesions have resolved (typically 6–8 weeks) and the neonate has transitioned to anticoagulation therapy.

Long-term management

Neonates with homozygous/compound heterozygous protein C or protein S deficiency require life-long anticoagulation therapy to prevent thrombosis. Options for long-term treatment include low molecular weight heparin (target anti-FXa concentration of 0.5–1.0 U/mL), protein C supplementation, oral warfarin therapy, or a combination of all these therapies. Recent studies reported subcutaneous administration of protein C concentrate with a dose of 250 U/kg every third day provides protective levels of protein C (>25 IU/dL) and can be considered as an alternative.

Mechanism

Antithrombin (AT) is a glycoprotein of the family of serine protease inhibitors, and is synthesized in the liver. AT circulates in the blood in a quiescent form, slowly reacts with and irreversibly inhibits its primary targets thrombin and FXa, as well as secondary targets including FIXa, FXIa, FXIIa, and FVIIa. At the site of injury, thrombin is bound to thrombomodulin on the endothelial surface. The neutralization of thrombin is enhanced by the interaction with the thrombin-thrombomodulin complex. The inactive thrombin and AT then dissociates from thrombomodulin and is cleared rapidly in the liver. The removal of thrombin also prevents further activation of protein C.

Classification

Similarly to protein C/S deficiencies, AT deficiency can be acquired or inherited. Type I AT deficiency is characterized by parallel reductions of both antigen and activity levels, whereas type II deficiency covers all types of inherited dysfunctional AT variants, resulting in decreased functional activity. Among the group of dysfunctional AT, AT deficiencies may involve the reactive site (type II RS), the heparin-binding site (type II HBS), or both (“pleiotropic effect”; type II PE). Homozygous AT deficiency type I is most likely not compatible with life, and only patients with homozygous type II deficiency have been reported, of whom the majority are type II HBS. This AT variant was identified as a result of G2759T mutation, a Leu-Phe change at codon 99 (Antithrombin Budapest 3). Several other mutations of AT with heparin-binding defects were also reported, including 47 Arg-Cys, 47 Arg-His, and 41 Pro-Leu. Acquired low AT levels and dysfunctional AT have been reported in neonates with respiratory distress syndrome and in other sick premature infants.

Epidemiology

From the Canadian registry of VTE in children and neonates, none of the patients (out of 171) were found to have AT deficiency. This fact is in keeping with the notion that the most significant etiologic factor for neonatal thrombosis is still the presence of an intravascular catheter and/or other medical conditions. By contrast, for stroke, including both AIS and CSVT, meta-analysis indicated that inherited thrombophilia contributed significantly as risk factors, and the OR for AT deficiency was 7.06 (95% CI 2.44–22.42).

Diagnosis

As a result of developmental hemostasis, functional AT levels are normally reduced in healthy term neonates, and more so in premature infants. Therefore, establishing the diagnosis of AT deficiency in the neonatal period is especially challenging. The diagnosis of homozygous AT type II HBS deficiency in the neonatal period may require even more attention and suspicion. The presentation of heparin resistance and thrombosis suggests a type II HBS AT deficiency. The routine chromogenic AT assays may miss the diagnosis of AT type II HBS variant. These assays commonly recommend a preincubation time varying from 90 seconds to 5 minutes with the heparin-containing buffer and the patient’s plasma. The AT type II HBS variant binds to heparin slowly and, therefore, their anti-FIIa and anti-FXa activity will be low in the assay with a short incubation time, but significantly higher (or close to the normal range) in the assay with a longer incubation time. Thus, in patients suspected of inherited thrombophilia based on family history, or in the presence of heparin resistance, a 2-step AT assay measuring anti-FIIa activity with a short incubation time (10–30 seconds) and normal incubation time (>90 seconds) is recommended. Nevertheless, because AT activity is normally low in neonates, the 2-step assays could still yield nearly normal results in suspected cases in this age group. Molecular analysis of the AT gene will be particularly helpful in making the diagnosis of homozygous AT type II HBS deficiency in these situations.

Treatment

Neonates with suspected homozygous AT deficiency may present with arterial or venous thrombosis, as well as stroke. In the absence of medical risk factors and family history of thrombosis, thrombophilia screening (including AT assay) should be performed before the commencement of anticoagulation therapy. Cases with AT type II HBS deficiency typically also present with heparin resistance, in which case, despite increasing the heparin doses, the activated partial thromboplastin time (aPTT) will remain subtherapeutic. Again, this should alert the physician to the possibility of a type II HBS AT deficiency. The AT anti-FIIa activity (with short incubation time) will typically be less than 50% of normal. Formerly, human plasma-derived AT concentrate was used for patients with acquired or hereditary AT deficiency. Recombinant AT concentrate is now licensed in the United States, approved by Food and Drug Administration in 2009. Calculation of initial loading dose should be individualized, based on the actual level of AT activity, using the formula: IU/infused intravenously over 24 hours = (100 − baseline AT activity level (in % of normal)/2.3) × body weight (kg). The target level should be 80% to 120% of normal (30 minutes postinfusion), and the dose should be increased or decreased if the AT level is below 80% or above 120% of normal, respectively. Repeated AT level should be measured at 30 minutes and 4 hours after any rate change to confirm AT level is within the target range. As there are not currently any pediatric safety and efficacy studies published, this dosing recommendation is based on adult studies. Hence, clinicians should take extra precautions if considering the usage of recombinant AT concentrate. Frequent monitoring of bleeding symptoms, as well as close monitoring of AT activity, aPTT, and adjustment of the heparin dosage are required. For all patients with confirmed homozygous AT deficiency, long-term anticoagulation therapy is indicated. The advice of a pediatric hematologist should be sought to help manage these patients.

Mechanisms

Factor V Leiden (FVL) is characterized by a point mutation in the FV gene with a single amino-acid substitution (arginine 506 to glutamine at the APC cleavage site). The thrombin activation of FVL to Va is normal, whereas APC is not able to cleave FVa Leiden variant, leading to an excess of activated FVL and, hence, a hypercoagulable state.

Genetics and epidemiology

Inheritance of FVL is autosomal dominant. Approximately 4% of Caucasians are heterozygous for the gene defect. Meta-analysis of studies on inherited thrombophilia and pediatric VTE have shown that FVL is significantly associated with first VTE in all pediatric age groups (neonates/infants/older children), with the summary OR of 3.56 (95% CI 2.57–4.93). This figure is concordant with data from adult studies, in which FV mutation increases the risk of a first episode of VTE by 3- to 7-fold. Regarding the risk of pediatric AIS and CSVT, a meta-analysis demonstrated the calculated OR for FVL is 3.26 (95% CI 2.59–4.1).

Mechanisms

Prothrombin (FII G20210A) variant is characterized by a single G to A nucleotide substitution at position 20,210 in the prothrombin gene. FVa bound in the prothrombin-FVa complex is normally resistant to APC inactivation. This prothrombin mutation is associated with an increase in production of plasma prothrombin. An elevated plasma prothrombin level increases the half-life of FVa in the circulation by protecting it from APC cleavage, leading to a hypercoagulable state.

Genetics and epidemiology

Inheritance of prothrombin mutation is autosomal dominant. The prevalence of this mutation in Caucasians is approximately 2%. Meta-analysis demonstrated that the OR for FII G20210A and onset of VTE in pediatric age group is 2.63 (95% CI 1.61–4.29), and the OR for recurrent VTE in children is 2.15 (95% CI 1.12–4.1). These data concur with those from adult studies in which FII mutation increases the risk of first VTE by 2- to 3-fold.

Mechanisms

Hyperhomocysteinemia has been identified as an independent risk factor for VTE, CSVT, and AIS. The mechanisms appear to be related to the effect of high levels of homocysteine on vessel walls by inducing endothelial injury and dysfunction, with associated decreased thrombomodulin activity. The thermolabile homozygous methylenetetrahydrofolate reductase (MTHFR) C677T (alanine 677 to valine) genotype has half of the catalytic activity of the normal MTHFR enzyme, and can result in mild hyperhomocysteinemia. However, in individuals with adequate folate levels, the effect of the genetic defect will be canceled out and plasma homocysteine levels will remain normal. Therefore, not everyone with the MTHFR C677T genotype will develop high homocysteine levels and be prone to develop VTE or stroke.

Epidemiology

The MTHFR C677T genotype is present in up to 10% of the healthy population. In children with a first-episode stroke, homozygosity of MTHFR C677T mutation has been shown to be an independent risk factor. However, because homocysteine levels were not always studied, the potential associated risk could not be accurately determined.

Mechanisms

A plasma lipoprotein(a) (Lp(a)) level higher than 30 mg/mL is considered to be elevated. The plasminogen gene on chromosome 6 is linked closely to the structurally similar apolipoprotein(a) gene. The gene product associates with a low-density lipoprotein to form Lp(a). Owing to molecular mimicry, Lp(a) competes with plasminogen for the binding domain on the endothelial cell surface. A hypercoagulable state results from the decreased activity of plasminogen on the endothelial cell surface.

Epidemiology

Elevated Lp(a) was found to be present in 7% to 10.3% of the normal population. The OR of elevated Lp(a) associated with a first VTE onset in children was 4.49 (95% CI 3.26–6.18); however, no significant association with recurrent VTE was found for elevated Lp(a). From another meta-analysis, the calculated OR associated with first AIS/CSVT onset in children was 6.27 (95% CI 4.52–8.69).