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The IHTC pharmacy and healthcare professionals effectively coordinate ongoing care by proactively communicating with our patients to manage clotting factor needs, therapy compliance, and bleeding episodes.
Inherited Causes of Thrombosis
- Inherited Causes of Thrombosis
- Increased levels of natural procoagulants
- Decreased levels natural anticoagulants
- Abnormalities of Fibrinolysis
- Other Inherited Causes
Causes of Thrombosis
Venous thrombosis is related to three pathologic factors commonly known as “Virchow’s triad”. The components of Virchow’s triad include the following:
- vessel damage
- blood hypercoagulability
- blood stasis
Maintaining normal blood flow involves a delicate balance between the three main clotting processes; procoagulant, anticoagulant, and fibrinolytic systems. Over the past 30 years, our understanding of the mechanisms that lead to thrombosis and its resolution has significantly improved.
Procoagulant clotting proteins are critical in initiation and propagation of normal clot formation. Naturally occurring anticoagulant proteins are required to regulate clotting once it initiated. This clotting process confines the clot to the area of injury through down-regulation of the procoagulant system. Once a stable clot has formed and bleeding has been controlled, the fibrinolytic system removes the clot and restores normal vascular architecture. In thromboembolic diseases, the causes of thrombosis may be related to increased levels of procoagulants, decreased levels of natural anticoagulants, or defects in the fibrinolytic system. In addition, vessel abnormalities contribute to development of clots.
Inherited Causes of Thrombosis
Inherited causes of thrombosis are related to a genetically determined tendency for venous thromboembolism (VTE) that characteristically occurs at a young age defined as occurring before 40 or 45 years, with or without an apparent cause, and with a tendency to recur.
In 1964, deficiency of antithrombin III, a naturally occurring anticoagulant, was discovered as a cause of familial thrombophilia. For many years, antithrombin was the only known protein regulating clot formation. In the 1980s the protein C and protein S pathways were described and individuals with deficiencies of these proteins identified. Deficiencies of natural anticoagulants such as antithrombin, protein C, and protein S account for fewer than 15% of selected cases of juvenile and/or recurrent thrombosis, and fewer than 10% of unselected cases.
In 1993, it was observed that plasma samples of some members of a kindred with inherited thrombophilia without a deficiency of antithrombin, protein C or protein S were resistant to the anticoagulant action of activated protein C (APC). APC resistance has now been demonstrated to be the most common cause of inherited thrombophilia, accounting for 20% to 50% of cases.
In 1994, mild hyperhomocysteinemia was found in 19% of cases of juvenile venous thrombosis; family studies revealed that this abnormality was inherited. Inherited hyperhomocysteinemia may be caused by defects in several genes coding for enzymes involved in the metabolism of the amino acid homocysteine.
In 1996 an alteration in the prothrombin gene (P20210) that results in an increased expression of prothrombin was identified and linked to an increased risk of thrombosis. Age-related increases in coagulation proteins, specifically increased levels of factors VIII, IX and XI, have also been linked to an increased risk of VTE.
Table 1 provides a list of inherited causes of thrombosis.
|Table 1. Inherited Causes of Venous Thrombosis|
|Increased Levels of Procoagulants||Decreased Levels of Anticoagulants||Abnormal Fibrinolysis||Other Inherited Causes|
|Factor V Leiden mutation or activated protein C resistance*||Antithrombin||Plasminogen Deficiency||Paroxysmal Nocturnal Hemoglobinemia|
|Prothrombin 20210 mutation||Protein C||Decreased Levels of Tissue Plasminogen Activator (t-PA)|
|Hyper-homocysteinemia||Protein S||Increased Levels of Plasminogen Activator Inhibitor-1 (PAI-1)|
|FVIII, FIX, FXI, FVII, VWF||Thrombomodulin||Elevated Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)|
|Heparin Cofactor II|
|Tissue Factor Pathway Inhibitor (TFPI)|
|*The Factor V Leiden mutation does not result in increased FV levels but a resistance to the anticoagulant action of activated protein C.|
Increased Levels of Procoagulants
Factor V Leiden (Activated Protein C Resistance)
What Is Factor V Leiden Mutation?
The factor V Leiden mutation (FVL) was identified in 1993 and has since been found to be a leading cause of VTE among white populations. FVL, a single nucleotide point mutation (Arg506Gly) in the coagulation factor V (FV) gene, represents the most common genetic risk factor for VTE. This mutation produces an altered FV commonly known as “Leiden” protein, which is responsible for the development of thrombosis. The FVL mutation makes the FV coagulation resistant to down-regulation by activated protein C.
Population Frequency of Factor V Leiden (FVL)
The population frequency of FVL mutation is high. Heterozygous FVL mutation is found in 5% to 10% of white individuals and in up to 30% of patients with VTE. Thus FVL mutation is by far the most common inherited risk factor for VTE. Although conventionally FVL is referred to as a “mutation,” it is actually the most common single nucleotide polymorphism within the FV gene. It is very uncommon in African Americans, Hispanics and Asians.
Why Do Patients With Factor V Leiden Mutation Develop VTE?
FV is an important coagulation protein that is synthesized in the liver. Normal or wild type FV has a dual role in coagulation. On activation, it acts as a procoagulant, while on inactivation by activated protein C (APC), it acts as an anticoagulant.
As a procoagulant, activated FV (FVa) acts as a cofactor along with activated factor Xa (FXa) to generate thrombin. Thrombin generation is the key step in coagulation to form a fibrin clot, the end result of coagulation.
The anticoagulant function of Factor V is related to its role as a cofactor in the APC/protein S complex. This complex is responsible for inactivation of activated FVIII (FVIIIa). The latter coagulation protein plays an essential role in clot formation.
Normally FV circulates in the blood in an inactive form. Direct cleavage of FVa by APC at position 506 is required for the formation of the anticoagulant FV. In patients with the FVL mutation, a single nucleotide substitution inhibits APC-mediated cleavage of FVa. FV therefore cannot function as a cofactor for the APC/protein S complex in the degradation of FVIIIa. This phenomenon is known as “APC resistance.” As a result of APC resistance, the generation of FVIIIa remains unchecked, which in turn continues to amplify the coagulation pathway, leading to excess thrombin generation and pathologic thrombosis.
Risk of VTE Associated With FVL Mutation
- Risk of VTE in FVL homozygotes: FVL homozygotes have only the Leiden protein and an 80-fold increased risk of VTE compared to the general unaffected population.
- Risk of VTE in FVL heterozygotes: FVL heterozygotes are believed to produce about 50% of Leiden protein and have a 5- to 7-fold increased risk of VTE compared to the general population. It is important to underscore that Factor V Leiden by itself does not cause thrombosis in individuals who are heterozygous for this mutation; usually a precipitating event is required.
Most blood clots in a heterozygous individual occur in association with some external cause or “trigger.” In heterozygous women, the most common triggers are pregnancy, the use of birth control pills, and hormone replacement therapy after menopause. This is because the balance of coagulation is tipped towards clotting during pregnancy. Hormonal replacement and birth control pills mimic this condition. In one study from Europe, 60% of women who experienced clots during pregnancy were found to have the FV Leiden mutation. The risk of blood clots is actually highest 6 to 8 weeks after the birth of a baby. In heterozygous men with factor V Leiden, blood clots may occur after surgery or an injury, especially injuries to the leg. Not everyone with heterozygous factor V Leiden develops a blood clot. For some people with heterozygous factor V Leiden, there is no history of abnormal blood clotting in their parents, even if one of their parents has this gene.
Other Causes of APC Resistance
Other Mutations within Factor V gene
Beyond the factor V Leiden mutation, several other alterations in the FV gene also contribute to APC resistance. Individuals with the Factor V Cambridge mutation (Arg306 Thr)1 and the Factor V Hong Kong mutation (Arg306 Gly)2 have demonstrated mild APC resistance. A complex haplotype of the FV gene (FV HR2) recently has been reported. This haplotype has several polymorphisms that also contribute to APC resistance.3 Although FV HR2 contributes to APC resistance, this haplotype results in far less APC resistance then the Factor V Leiden mutation.
Acquired causes of APC resistance
Acquired causes of APC resistance include the hypercoagulable states associated with pregnancy, estrogen therapy, antiphospholipid antibody syndrome and widespread inflammation or endothelial activation due to any cause, such as sepsis syndrome or disseminated intravascular coagulation (DIC).
Prothrombin 20210 Mutation
A nucleotide change at position 20210 (Gly to Arg) of the prothrombin gene was found to be present in 1% of the normal control population versus 18% of patients with VTE. This allele was found to increase the risk of thrombosis almost threefold because it is associated with elevated levels of prothrombin (usually greater than 1.15 U/ml, a 25% increase compared to the normal range). This was the first strong evidence of a quantitative trait locus mutation in the prothrombin gene influencing prothrombin activity levels and hence an individual’s risk for thrombosis. Other associated thrombotic episodes linked to this mutation include coronary artery disease, especially in young women and people with stroke, venous thrombosis, mesenteric vein thrombosis, central retinal arterial thrombosis, or portal vein thrombosis.
Homocysteine is an amino acid derived from the intracellular conversion of methionine to cysteine. The prevalence of hyperhomocysteinemia is estimated to be 5% in the general population. Among persons with symptomatic coronary artery disease, the prevalence is estimated to be 13% to 47%.4 Mild to moderate hyperhomocysteinemia is an independent risk factor for stroke, myocardial infarction, peripheral arterial disease, and extracranial carotid artery stenosis. High plasma levels are associated with enzymatic defects or deficiencies of folate or vitamin B6, particularly in the elderly. Mild or moderate hyperhomocysteinemia has been associated with venous thrombosis in the young and recurrent venous thrombosis, and has been shown to have a high frequency (10%) in patients with first episodes of venous thrombosis. Several inherited or acquired conditions may lead to an increase in homocysteine levels that are categorized as severe (>100 umol/L), moderate (25-100 umol/L) and mild (16 to 24 umol/L).
Inherited causes of hyperhomocysteinemia include deficiency of cystathionine beta-synthase, an enzyme necessary for the conversion of homocysteine to cysteine. Both the homozygous and heterozygous forms of the deficiency are associated with an increased incidence of a thromboembolic event.5 In family studies of these individuals, there has been at least one first-degree relative with hyperhomocysteinemia. These data suggest that this disorder may be inherited.
Acquired causes of hyperhomocysteinemia include advanced age, tobacco use, coffee intake, low dietary folate intake, and low vitamin B intake. Higher homocysteine levels are also associated with diabetes mellitus, malignancies, hypothyroidism, lupus, inflammatory bowel disease, and certain medication use such as cholesterol-lowering agents, metformin, methotrexate, anticonvulsants, theophylline, and levodopa.5
Elevated Levels of Clotting Factors
Elevated levels of other procoagulants such as factors VIII, IX, XI, VII, fibrinogen, and Von Willebrand factor (VWF) are associated with an increased risk of thrombosis. Specifically, persistent elevation of FVIII has been shown to be associated with recurrence of VTE.6 Currently there are no specific recommendations to include analysis of these clotting factor levels in a thrombophilia evaluation.
Elevated Factor VIII
Factor VIII is coded for on the X chromosome. FVIII activity levels may vary widely due a variety of contributing factors including pregnancy, use of hormonal therapy, stress, exercise, or presence of an inflammatory state. FVIII is a known acute-phase reactant. It is often difficult to determine whether an elevated FVIII level is due to an acute event or precedes it. Elevated levels of FVIII defined as those greater than 1.5 IU/ml (150%) represent a constitutional and independent risk factor for VTE. An odds ratio of 4.8 was determined for the first DVT with sustained levels >150% compared to those with a level <100% in the Leiden Thrombophilia Study.6,7 Another study8 demonstrated that levels >175% may be found in 25% of unselected patients with symptomatic VTE and are a dose-dependent risk factor, with each increment of 10 IU/ml increasing the risk of VTE by 10%. For recurrent disease, this figure is 24%, meaning that elevated FVIII is an even stronger risk factor for recurrent VTE. The likelihood of recurrence of a thrombotic event at 2 years was found in another study to be 37% versus 5% among patients with a lowered FVIII level.9
Elevated Factor IX Levels
Factor IX is coded for on the X chromosome. With its cofactor, FVIII, FX is activated to FXa. Elevated levels of FIX may play a role in VTE. The Leiden Thrombophilia Study found that levels of FIX in the 90th percentile and higher increased the risk of VTE by 2- to3-fold.10
Elevated Factor XI Levels
Factor XI has procoagulant and antifibrinolytic roles in hemostasis in that it contributes to the formation of fibrin and protects fibrin, once formed, from degradation. Through feedback mechanisms, secondary thrombin generation, thrombin levels are increased. These increased levels are required not only for the formation of fibrin but also to prevent its dissolution. Excess thrombin activates thrombin-activatable fibrinolysis inhibitor (TAFI, also called procarboxypeptidase B or procarboxypeptidase U), which once activated inhibits fibrinolysis. TAFI removes the C-terminal lysine residues from fibrin which are essential for the binding and activation of plasminogen in subsequent fibrinolysis.
Elevated FXI levels, those greater than 90th percentile or 120%, have been associated with an age- and sex-adjusted increased odds ratio of 2.2 for development of DVT. There also appears to be a dose-response relationship between the FXI level and the risk of thrombosis.11 Elevated levels of FXI also have been associated with an increased risk of cardiovascular disease in women.12
Elevated Factor VII Levels
Significant associations between levels of FVII and an increased risk of coronary artery disease have been documented; however, FVII levels are not an independent risk factor after controlling for cholesterol, LDL-cholesterol, and triglycerides.13 Elevated FVIIa levels have been documented in retinal vein occlusion.14
Elevated Von Willebrand Factor Levels
Von Willebrand factor (VWF) is produced in endothelial cells and secreted into the circulation both constituently and through a release mechanism from storage sites within these cells. Events that cause endothelial damage or inflammation lead to increased VWF levels. FVIII circulates in conjunction with VWF and often the levels of these two clotting factors are concordant when stress, inflammatory states, or endothelial injury occur. Sustained elevations in FVIII levels lead to an increased risk of VTE; therefore it might be reasonable to assume that elevated VWF levels would also be associated with and contribute to an increased risk of VTE. Additionally, VWF plays an integral role in platelet adhesion to areas of damaged endothelium. Elevated VWF levels may have more than one pathogenic mechanism through which they contribute to VTE.
Decreased Levels of Natural Anticoagulants
Antithrombin is a naturally occurring anticoagulant that inactivates serine proteases such as thrombin, and clotting factors IXa, Xa, XIa, and XIIa. The inhibition of serine proteases by AT is greatly accelerated by heparin. Molecular defects in the antithrombin gene (locus 1q23-q25) may result in deficiencies or abnormal activity of antithrombin. Antithrombin deficiency is inherited as an autosomal dominant trait.
Patients with a deficiency of AT are at risk for both arterial and venous thrombosis. The frequency of symptomatic AT deficiency is estimated to be 1:2,000 to 1:5,000. Asymptomatic deficiency may occur as frequently as 1:600. In patients with a history of thrombotic disease, the incidence of AT deficiency ranges from 0.5% to 4.9%. Homozygous deficient patients have been described very rarely and only in individuals with defects in the heparin-binding site. These individuals have a severe thrombotic tendency that presents early in life and often involves arterial thrombotic disease.
Types of AT deficiency
AT deficiency is subcategorized into Type I and II.
- Type I deficiency or quantitative deficiency: These patients demonstrate a proportionate decrease in both the antigenic and activity level of the protein, most often a result of an unexpressed protein from the mutant allele. Homozygous Type I deficiency is lethal.
- Type II deficiency or qualitative deficiency: This deficiency is characterized by a decrease in the activity of the protein with a normal antigenic level, resulting from the production of an abnormally functioning protein from the mutant allele. Type II is further subclassified into two subtypes; those with abnormalities affecting the unfractionated heparin binding site and those that reduce the neutralizing capacity of antithrombin for thrombin activity in the absence of unfractionated heparin.
Normal adult levels of antithrombin are achieved around 6 months of age. Antithrombin levels are dependent on the patient’s age and other associated conditions. Several conditions can reduce AT levels. These conditions include liver dysfunction, consumptive coagulopathy, obstetric complications, pregnancy, renal disease, malignancies, malnutrition, GI dysfunction, use of oral contraceptives, and other medications. Use of coumarins may lead to increases in antithrombin levels. In affected heterozygotes, the levels of AT range between 40% and 70% of normal.
Protein C, a vitamin K dependent protein, is synthesized in the liver and contributes to the inactivation of FVIII. It is slowly activated by thrombin to activated protein C (APC). The activation is increased 20,000 fold when protein C complexes with thrombin bound to an endothelial receptor, thrombomodulin. APC inactivates membrane-bound FVa and FVIIIa, thereby down-regulating the coagulation pathway. Protein C deficiency is inherited as an autosomal dominant trait. Aside from its role in coagulation, APC also has anti-inflammatory and cytoprotective functions that are mediated through the endothelial protein C receptor and the protease-activated receptor-1 (PAR-1).
In studies, the frequency of protein C deficiency ranges from 1.4% to 8.6%. In a study of healthy subjects, the frequency of the deficiency was found to be 1:200 to 1:300, while a study of almost 10,000 blood donors found a frequency of 1:500 to 1:700.
Types of Protein C deficiency
Protein C deficiency is divided into two categories.
- Type I deficiency or quantitative deficiency: Levels of both protein C activity and antigen are proportionately decreased.
- Type II deficiency or qualitative deficiency: Characterized by a decrease in the activity of the protein with a normal antigenic level, resulting from the production of an abnormally functioning protein from the mutant allele.
Homozygous Protein C deficiency usually presents in the neonatal period with purpura fulminans and is associated with severe morbidity if not death unless identified and treated. Purpura fulminans in these patients results from microvascular thrombosis with cutaneous and subcutaneous ischemic necrosis. Laboratory testing reveals a severe deficiency (protein C levels of <1% of normal). Interestingly, homozygous deficiencies with very low levels of protein C, ranging from 5% to 20%, also have been identified and may not be associated with neonatal purpura fulminans, but are associated with a severe thrombotic tendency at an early age. These patients require lifelong anticoagulation to prevent recurrent thrombosis.
Warfarin-Induced Skin Necrosis (WISN)
Individuals with protein C deficiency can experience a potentially catastrophic complication of warfarin therapy, commonly known as warfarin induced skin necrosis (WISN). This complication arises as a consequence of the different half-lives of the vitamin K-dependent coagulation proteins, especially protein C. One day after initiation of usual doses of warfarin, protein C activity is reduced by approximately 50% as the half life of protein C is approximately 7 to 8 hours. Because of their longer half-lives, the levels of the other vitamin K-dependent clotting factors such as FII (~2-3 days), FIX (~24 hours), and FX (~2 days) decline more slowly. The relative reduction in protein C activity in the presence of more normal procoagulant proteins creates a transient hypercoagulable state. This effect may be more pronounced when large loading doses of warfarin are administered. Indeed, WISN typically occurs during the first few days of warfarin therapy. The skin lesions of WISN are distributed on the extremities, torso, breasts, and penis. They begin as erythematous macules and, if appropriate therapy is not initiated promptly, evolve to become purpuric and necrotic. Biopsies of skin tissue demonstrate ischemic necrosis of the cutaneous tissue with cutaneous vessel thrombosis and surrounding interstitial hemorrhage. To avoid this catastrophic complication, individuals with protein C deficiency are concurrently treated with other anticoagulants such as heparins until therapeutic anticoagulation is achieved through warfarin. Infusion of protein C concentrate or fresh frozen plasma may be used to increase protein C levels.
Protein C Levels
Protein C levels are dependent on patient age and other associated conditions, with adult levels being reached at late adolescence. Many medical conditions may result in reduced protein C levels, and include liver disease, disseminated intravascular coagulation (DIC), thrombosis, neonatal respiratory distress syndrome (RDS), preeclampsia, acquired purpura fulminans, systemic lupus erythematosus, ulcerative colitis, oral contraceptives, and oral anticoagulants.
Protein S, a vitamin K-dependent glycoprotein, is synthesized by the liver and acts as the principal cofactor to protein C. Protein S exists in the circulation in two forms in equilibrium with each other: a free form and a non-covalently bound form that is complexed to C4 binding protein. The C4 protein is a component of the complement pathway. Approximately 60% to 65% of total protein S in the circulation exists in the bound form and ~35% to 40% in the free form. Free protein S is the form involved in the activated protein C (APC) anticoagulant activity.
Relatively few mutations of the protein S gene have been identified largely due to technical difficulties related to the size of the gene and the presence of a pseudo gene. The majority of reported defects are point mutations. There are no data on the frequency of protein S deficiency in the general population, but the frequency is believed to be roughly the same as for protein C deficiency (1.4% to 7.5%). Extrapolation from cohorts of patients with thrombotic disease gives a frequency of 1:33,000, which is likely an underestimate.
Types of Protein S Deficiency
There are three subtypes of protein S deficiency.
- Type I deficiency: There is a proportional decrease in both the antigen and activity level.
- Type II deficiency: There is a decrease in the functional activity of the protein with a normal antigen level, both of the free and total protein S, resulting from the production of an abnormally functioning protein from the mutant allele.
- Type III deficiency: There is a normal level of total protein S antigen, but the free protein S is abnormally low.
Protein S deficiency is rare in the healthy population, with a frequency of approximately 1:700 based on extrapolations from a study of over 9,000 blood donors tested for protein C deficiency. When considering a selected group of patients with recurrent thrombosis or a family history of thrombosis, the frequency of protein S deficiency ranges from 3% to 6%. The frequency of homozygous deficiency has been estimated to be 1:160,000 to 1:360,000.
Protein S Levels
Adult levels of protein S levels are achieved at approximately 6 months to 1 year of age. Physiologic variations include a lower mean free protein S level in normal females compared to males, lower free protein S in pregnancy and women taking oral contraceptives, and lower free and total protein S in newborn infants. Many medical conditions may be associated with abnormal protein S levels including liver disease, DIC, thrombosis, herpetic infections, systemic lupus erythematosus, ulcerative colitis, and use of oral contraceptives and oral anticoagulants. Levels in heterozygotes are approximately 40% to70% of the normal level.
Similar to protein C deficiency, homozygous protein S deficiency has been reported, and these individuals characteristically present with neonatal purpura fulminans or within the first year of life. Purpura fulminans is characterized by small vessel thrombosis with cutaneous and subcutaneous necrosis.
Thrombomodulin is a transmembrane glycoprotein expressed on the endothelial cell surface. It acts as a receptor for thrombin and plays an important role in coagulation and fibrinolysis. Binding of thrombin to this high-affinity receptor alters its specificity toward several substrates. Thrombomodulin-bound thrombin initiates the protein C anticoagulant pathway by activating protein C. Defects in thrombomodulin result in enhanced coagulation. Thrombomodulin also activates thrombin-activated fibrinolysis inhibitor (TAFI), thereby affecting fibrinolysis. Small heterogeneous thrombomodulin fragments circulate in soluble form in plasma of healthy individuals. These soluble fragments retain their functional activity and can be measured in plasma. The concentration of soluble thrombomodulin in healthy subjects ranges from 2.2 to 4.8 ng/ml. Increased levels are seen in patients with DVT, PE, arterial thrombosis, cerebral infarction, retinal thrombosis, and DIC. The clinical relevance of soluble thrombomodulin levels in the management of VTE requires clarification. A patient with a documented history of recurrent thromboembolic disease at a young age and a positive family history has been identified in whom baseline levels of thrombomodulin soluble fragments were decreased, and a point mutation was identified in the thrombomodulin gene.
Heparin Cofactor II
Heparin cofactor II is a serine protease inhibitor in plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin.
Heparin cofactor II deficiency is classified into:
- Type I (quantitative): There is a decrease in both antigen and functional activity
- Type II (qualitative): There is a decrease in the functional activity of the protein with normal antigen levels.
Only a few cases of heparin cofactor II deficiency have been described. Further research is required to clarify the relevance of heparin cofactor II deficiency in the clinical setting.
Tissue Factor Pathway Inhibitor (TFPI)
Tissue factor pathway inhibitor regulates initiation of coagulation. TFPI inhibits the tissue factor:FVIIa:FXa complex that initiates the coagulation cascade. The majority of TFPI (60% – 80%) is bound to the vascular endothelium, with only 20% free in the blood. Recent evidence suggests that low levels of TFPI are a risk factor for VTE.15 Interestingly, polymorphisms have been found in the TFPI gene that result in elevated levels of TFPI in the circulation. One report suggested that these elevated levels “correct the balance” in patients with Factor V Leiden, and normalize their risk for a thrombotic event.16
Abnormalities of Fibrinolysis
Plasminogen is synthesized in the liver and is present in other cells and in extravascular space of most tissues, some of which may be capable of synthesis, such as the kidney. Plasminogen is converted to a proteolytic enzyme, plasmin, by plasminogen activators including tissue-plasminogen activator (tPA) and urokinase-plasminogen activator(uPA). The main action of plasmin is to break down fibrin through a series of proteolytic cleavages. Defective fibrinolysis has been associated with thrombovascular disease.
Types of Plasminogen Deficiency
There are two types of plasminogen deficiency:
- Type I (quantitative) deficiency or hypoplasminogenemia: There is a proportionate decrease in both antigen and activity levels.
- Type II (qualitative) deficiency or dysplasminogenemia: There is a decrease in the functional activity of the protein with normal antigen levels.
Plasminogen levels do not reach the normal adult range until late adolescence. Higher levels of plasminogen are found in women in the last trimester of pregnancy; newborns have levels approximately one-half compared to normal adults.
Homozygous deficiency of plasminogen is characterized clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous (‘wood-like’) conjunctivitis, with conjunctival irritation due to formation of pseudomembranes mostly on palpebral surfaces. These pseudomembranes progress to white, yellow-white, or red thick masses with a wood-like consistency that may replace normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after excision. Pseudomembranous lesions of other mucous membranes have been reported to occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children have been noted to have congenital occlusive hydrocephalus. Removal of the lesions is not curative and may exacerbate recurrence. The lesions are responsive to systemic plasminogen replacement or to local therapy in the eyes. The incidence of plasminogen deficiency is not well characterized and may be underestimated because ophthalmologists, dentists, obstetricians, gynecologists, and ENT physicians may see these patients and not refer them or recognize the local manifestation to be plasminogen deficiency.
Familial plasminogen deficiency appears to be an uncommon but recognized cause of inherited thrombophilia. The thrombotic complications of this deficiency are predominantly venous and include thrombophlebitis, PE, and stroke. It is interesting to note that in affected individuals, there have not been reports of thrombotic disease in association with pregnancy or oral contraceptive use, and even more intriguing is the report of normalization of plasminogen levels in a deficient patient during pregnancy or with use of oral hormonal therapy. This finding indicates that in heterozygotes, the normal allele may be able to increase plasminogen synthesis. Since homozygous patients infrequently develop thromboses, especially spontaneous events, the diagnosis of heterozygous plasminogen deficiency as a cause for a thrombotic event may be dismissed or overlooked.
Decreased Levels of Tissue Plasminogen Activator (tPA)
Tissue plasminogen activator (tPA) is synthesized by endothelial cells. When tPA is released, it converts plasminogen to plasmin. Theoretically, decreased release of tPA could lead to a hypercoagulable state due to decreased fibrinolysis.
Increased Levels of Plasminogen activator inhibitor 1 (PAI-1)
Plasminogen activator inhibitor 1 (PAI-1) functions as the primary inhibitor of plasminogen activator in plasma. Increased levels of PAI-1 could lead to excessive inhibition of tPA, leading to decreased activation of fibrinolysis and a thrombotic tendency. Increased PAI-1 levels have been shown in some cases to be an inheritable trait.
Elevated levels of thrombin-activatable fibrinolysis inhibitor (TAFI)
Thrombin-activatable fibrinolysis inhibitor (TAFI) facilitates inhibition of fibrinolysis by preventing plasminogen from binding to the fibrin clot. Elevated levels of TAFI would prevent the onset of normal fibrinolysis and therefore should theoretically predispose to a prothrombotic state. One report from the Leiden Thrombophilia Study suggests that high levels of TAFI may be a mild risk factor for a hypercoagulable state.17 However, these results require confirmation.
Other Inherited Causes Associated with Increased Risk of Thrombosis
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder of hematopoetic stem cells and is caused by a mutation in a somatic cell of the phosphatidylinositol glycan class A (PIG A) gene, located on the X chromosome. PNH is known to be associated with an increased risk of thrombosis. PNH results in the breakdown of red blood cells, the release of hemoglobin into the blood and subsequently in the urine. This release of hemoglobin can be observed as dark-colored urine most often in the morning, termed hemoglobinuria. This type of hemoglobinuria was called “nocturnal” as it was believed that hemolysis was triggered by acidosis during sleep and activated complement to hemolyze an unprotected and abnormal red blood cell membrane. This observation was later disproved. Hemolysis has been shown to occur throughout the day; concentration of urine that occurs through sleep results in the dramatic color change. Once considered to be an acquired hemolytic anemia, PNH has been reclassified as an inherited condition related to a hematopoietic stem cell mutation defect. In individuals with PNH, surface proteins are missing not only in the RBC membrane but also in all blood cells, including the platelet and white cells.18
This disorder usually presents in adulthood and is less common in childhood. In adults the most common presentation is hemolytic anemia with nocturnal exacerbations, while in children bone marrow failure is the most common presentation. Thrombosis may occur in 39% of adults and 31% of children with PNH. Venous thrombosis predominates with a predilection towards the hepatic veins (Budd-Chiari syndrome), but the portal veins, central nervous system, and peripheral venous system also may be involved. Increased circulating activated platelets have been implicated in thrombotic events due to PNH, but no consistent fibrinolytic or coagulation abnormality has been documented.
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- Williamson D, et al. Factor V Cambridge: a new mutation (Arg306–>Thr) associated with resistance to activated protein C. Blood. 1998;91:1140-1144.
- Chan W, et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood. 1998;91:1135-1139.
- Bernardi F, et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood. 1997;90:1552-1557.
- Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999;354:407-413.
- Schlesselman LS. Novel risk factors for atherosclerotic disease. MedscapeCME. Available at: http://cme.medscape.com/viewarticle/418378, Accessed March 17, 2010.
- Koster T, et al. Lancet. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. 1995;345:152-155.
- van der Meer FJ, et al. The Leiden Thrombophilia Study (LETS). Thromb Haemost.
- Kraaijenhagen R. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost. 2000;83:5-9.
- Kyrle P. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343:457-462.
- Van Hylckama Vlieg A, et al. High levels of factor IX increase the risk of venous thrombosis. Blood. 2000;95:3678-3682.
- Meijers J, et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000;342:696-701.
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