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Genetic Risk Factors for Disseminated Intravascular Coagulation

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Introduction

Disseminated intravascular coagulation (DIC) is a life-threatening condition that occurs due to a severe imbalance of the coagulation system. DIC is characterized by the combined occurrence of activation of the extrinsic coagulation pathway and decreased activity of the protein C-protein S and antithrombin (AT) inhibitory pathways. Furthermore, the process may be accompanied by excessive fibrinolysis or inhibited fibrinolysis. Clinically, DIC becomes manifest in different ways. The most prominent feature is the formation of microthrombi through activation of coagulation. This may lead to the syndrome of purpura fulminans, which in particular occurs in children with infection-associated DIC. Depletion of coagulation proteins due to the extensive and ongoing activation of the coagulation system and excessive fibrinolysis may induce severe bleeding complications. Paradoxically, thrombosis and bleeding can even occur together. Ultimately, DIC may lead to organ failure, amputation or even death.

Sepsis is probably the most frequent cause of DIC.1 Other clinical conditions that can be complicated by the development of DIC are malignancy, adult respiratory distress syndrome, obstetric complications like abruptio placentae and amniotic fluid embolism, snake bites, transfusion reactions, trauma, microangiopathic disorders and postsurgical conditions. DIC does not always complicate these conditions. It is possible that certain risk factors may, therefore, contribute to the likelihood of DIC. Because DIC is characterized by severe disturbances of the coagulation cascade, inherited abnormalities of coagulation proteins are candidate risk factors.

DIC very rarely occurs spontaneously without an underlying illness. A notable exception is that children with homozygosity for PC or PS deficiency develop severe neonatal purpura fulminans due to complete absence of protein C or S and without an underlying illness.24 Heterozygosity for protein C and S deficiencies, therefore, are also candidate risk factors for DIC.

So far, relatively few studies investigated whether inherited coagulation abnormalities play a role as risk factors in the development of DIC. These studies were done in particular in meningococcal disease,58 a severe infection, often complicated by sepsis and DIC. More studies on the relationship between risk factors and DIC are necessary to answer the important question about whether patients at risk to develop DIC should be examined for genetic coagulation abnormalities. In addition, treatment strategies of DIC may be adjusted to an individual patient, depending on the presence of a risk factor.

Anticoagulant Pathways

DIC is characterized by a marked reduction of the anticoagulant activity in blood. Antithrombin (AT) and the protein C/S anticoagulation pathway are the major inhibitors of activation of coagulation. Impaired function of these natural regulating pathways of coagulation activation may contribute to increased fibrin formation in DIC. Genetic predisposition to decreased function of these inhibitory pathways may therefore increase the risk for the development of DIC.

Protein C Deficiencies

A key component in the down-regulation of blood coagulation is the protein C anticoagulant pathway. Protein C circulates in plasma as a vitamin K-dependent zymogen. The thrombin-thrombomodulin complex on endothelial cell membranes activate protein C to generate the anticoagulant-activated protein C (APC).9 Binding of protein C to the recently identified endothelial protein C receptor (EPCR) enhances the activation of protein C by the thrombin-thrombomodulin complex.10,11 APC degrades activated coagulation factors Va and VIIIa, attenuating their procoagulant activity towards factor X and prothrombin.12,13 For optimal anticoagulant activity, APC needs [Ca2] and has to form a complex with the cofactor protein S.14

DIC is associated with decreased protein C levels in the blood.15–17 This decrease of protein C, probably due to significant consumption, appears to determine the clinical outcome of DIC.17Low protein C levels in meningococcal disease have also been associated with fatal outcome.16 In an experiment with E. coli-induced septicaemia in baboons, inhibition of the protein C system with protein C antibodies resulted in DIC and fatal septic shock at 10 times lower doses of E. coli than in control animals. In the same study, administration of activated protein C prevented both tissue necrosis and DIC.18 Very recently a study was published of 1690 patients with sepsis, which were randomized for treatment with recombinant APC or placebo. The treatment group had a significantly reduced mortality compared to the placebo group.19 These observations underline the importance of the protein C pathway in the pathogenesis of DIC.

Homozygous or compound heterozygous mutations in the protein C gene are associated with either DIC or thrombophilia. Difference in phenotype depends on which mutation is involved (Table 1). Mice with a total deficiency of protein C due to targeted gene disruption at the protein C locus develop symptoms of DIC during the embryonic period, which lead to death at birth or death within 24 hours after birth.20 Humans homozygous for the protein C mutation resulting in a total absence of the protein usually develop purpura fulminans shortly after birth.2,3,21 This severe clinical picture is characterized by widespread thrombosis of capillaries and venules, with subsequent necrosis of affected tissues and accompanied by massive progressive bleeding into the skin in children that seem to be healthy at birth. Unless treated adequately, the syndrome is fatal.22 Marciniak et al3 reported two newborn infants with identified homozygosity for familial protein C deficiency which developed black and purpuric skin lesions within 12 hours after birth due to thrombosis with widespread necrosis. In both cases, purpura fulminans was diagnosed. Despite treatment with antibiotics, transfusions and anticoagulant therapy, the syndrome deteriorated with more skin lesions and the development of seizures due to brain infarctions. Both infants finally died after 25 and 32 days, respectively, after birth.

Table 1. Phenotypes of protein C and protein S mutations.

Table 1

Phenotypes of protein C and protein S mutations.

Inherited defects in the protein C system have been found to be the underlying risk factors in many cases of familial thrombophilia.23 Heterozygosity for protein C deficiency is associated with a 7-fold increased risk for thrombosis.24 So far, there are no controlled studies on the relationship between heterozygosity for protein C deficiency and development of DIC. The only report on heterozygous protein C deficiency and the development of DIC deals with a boy with a combined inherited properdin (a complement system deficiency) and protein C deficiency.25 He developed the unusual symptoms of extensive gangrene of the limbs and septic shock with DIC due to meningococcal infection. The prevalence of hereditary protein C deficiencies is rather high. Heterozygous protein C deficiency can be found with an estimated prevalence of 1 in 300,26 autosomal inherited homozygous protein C deficiency with an estimated prevalence of 1 in 500,000-750,000 births.27

It could be that heterozygous protein C deficiency in combination with a second genetic abnormality increases the risk for DIC in meningococcal infection. However, controlled studies are necessary to investigate this relationship.

Protein S Deficiencies

Protein S is a vitamin K-dependent glycoprotein that acts as a nonenzymatic cofactor of activated protein C (APC).28,29 Besides its importance in the APC-mediated inactivation of factors Va and VIIIa, protein S also directly inhibits factor Xa.30 Protein S circulates in plasma both free and bound to C4b-binding protein, a component of the complement system. Only free protein S has anticoagulant activity.

DIC is associated with transient deficiencies of protein S.31–33 Two papers report children with purpura fulminans and DIC probably due to a severe acquired protein S deficiency following an infection.32,33

Genetic mutation in the protein S gene occurs very rarely. So far, only two patients with severe homozygous or compound heterozygous PS deficiency are reported in the literature.34,35 These patients develop DIC shortly after birth. They have symptoms of purpura fulminans or massive venous thrombosis very similar to those with homozygous protein C deficiency.

There are no studies on the relationship between heterozygous protein S deficiency and the risk for DIC. There is only one report on the combination of heterozygous deficiency of Protein S and factor V Leiden in two unrelated children with purpura fulminans induced by DIC following infection.36Family studies show that heterozygosity for protein S does increase the risk for venous thrombosis in early adulthood.37–39 However this could not be confirmed in a large patient-control study.40

The prevalence of heterozygous protein S deficiency may be 1% to 2% in patients with deep venous thrombosis (DVT).24,41 The prevalence of heterozygous protein S deficiency in the general population is not known.

It could be that a combination of heterozygous deficiency of protein S with a second genetic risk factor increases the risk for DIC. Further studies will be required to define the importance of hereditary protein S deficiency in DIC.

Factor V Leiden

Another hereditary abnormality of the protein C pathway involves the laboratory finding of a poor response to activated protein C, so called APC resistance. In the large majority of individuals, APC resistance is caused by factor V Leiden mutation. This mutation limits the degradation of factor Va by activated protein C. It therefore interferes with the natural inhibition of coagulation by activated protein C, predisposing to thrombosis.

The factor V Leiden mutation is an established risk factor for venous thrombosis in a number of settings.42 To date, the mutation in factor V is the most frequent genetic risk factor for thrombosis.43 Whereas homozygous deficiencies of protein C and S are associated with purpura fulminans or massive venous thrombosis in the neonatal period, no cases of neonatal purpura fulminans or DIC associated with the homozygous state of factor V Leiden have been reported. A number of studies have reported combined deficiencies of factor V Leiden with protein C, protein S or antithrombin that were associated with a high risk of thrombosis, and an earlier age of onset.44–48 In one report of two children, compound heterozygosity for factor V Leiden and protein S deficiency resulted in purpura fulminans following an infection.36 Another study notes the occurrence of varicella purpura fulminans in association with heterozygosity for factor V Leiden and transient protein S deficiency.49 Resistance to activated protein C has also been reported in a patient with cutaneous necrosis.50 These scarce data suggest that factor V Leiden mutation combined with another coagulation deficiency may be associated with DIC.

The effect of factor V Leiden mutation on the severity of meningococcal disease has been investigated in two studies. The first study of two large cohorts of patients with meningococcal disease reported that survivors with heterozygosity for factor V Leiden were more likely than those without the mutation to require skin grafting, referral to a plastic surgeon, or amputation. However, the majority of those carrying the factor V Leiden were not affected by severe thrombotic complications.8 Contrary to these findings, Westendorp et al7 found no relationship between factor V Leiden mutation and outcome of meningococcal disease in a group of 50 patients. These data underline that the role for factor V Leiden in the development of DIC remains controversial.

Other Anticoagulants

Antithrombin (AT) plays a major role in the regulation of haemostasis by inhibiting thrombin, factors IXa, Xa, XIa and XIIa, kallikrein, and plasmin. A study of patients with DIC by Bick et al51 showed an almost universal decrease in AT in patients with severe acute DIC. Low levels of AT are associated with increased mortality in DIC.51 However, so far no relation between heterozygosity for AT and DIC has been found. Heterozygous AT deficiency, which associated with a five-fold increased risk for thrombosis, is found in 0.05% to 1.0 % of healthy individuals.52 Homozygous deficiencies for ATIII are not known to occur.

Thrombomodulin (TM) is a transmembrane glycoprotein expressed mainly by endothelial, but also several other cells. TM is a key component in the protein C anticoagulant pathway as a receptor for thrombin. Bound to TM, thrombin undergoes conformational change, which facilitates conversion by limited proteolysis of circulating protein C to activated protein C.53 The binding of thrombin to TM also inhibits its ability to activate platelets and to cleave fibrinogen.54,55 Thrombomodulin may be down regulated on the endothelial surface in DIC.56 The localization on the endothelial cell has hampered the studies on genetic alterations of the thrombomodulin protein. There is no evidence yet, that genetic differences in the thrombomodulin gene are a risk factor for DIC.

Tissue factor pathway inhibitor (TFPI), heparin cofactor II, b2 glycoprotein deficiency and the recently identified EPCR are also candidate risk factors for DIC. However, there are no reports on the relationship between mutations in the genes of these proteins and DIC.

Fibrinolysis

Paradoxically, DIC can be accompanied by either excessive fibrinolysis or inhibited fibrinolysis. Increased fibrinolysis contributes to the severe bleeding complications in DIC. The occurrence of inhibited fibrinolysis can play a role in impaired fibrin dissolution and formation of microthrombi in DIC. Genetic alterations in the fibrinolysis pathway or in the inhibitory pathways of fibrinolysis are therefore candidate risk factors of DIC.

Variation in Plasminogen-Activator-Inhibitor Gene

The serpin plasminogen activator inhibitor 1 (PAI1) is one of the main inhibitors of fibrinolysis. PAI1 inactivates tissue type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) through complex formation. Animal studies substantiated that increased circulating PAI1 levels are associated with a prothrombotic tendency,57 whereas inhibition of PAI1 has antithrombotic effects.58–60 DIC is characterized by increased levels of PAI1. Different studies show that high levels of PAI1 are predictive for unfavorable outcome in DIC associated with sepsis.5,6,61,62 Little is known about genetic alterations in PAI1 levels as a risk factor for thrombotic events. Although almost half of the deep vein thrombosis (DVT) patients have increased PAI1 levels, elevated PAI1 is not considered to be a risk factor for venous thrombosis.63

Two studies in children with meningococcal disease suggest that the 4G/4G genotype in the promoter region of the PAI1 gene, which is associated with higher concentrations of PAI1, predicts a poor outcome and development of septic shock and DIC.5,6 Hermans et al 5 studied 175 children with meningococcal disease. Patients with the 4G/4G genotype had significantly higher PAI1 levels and an increased risk of death compared to patients with 4G/5G or 5G/5G genotype. The other study of 50 children with meningococcal disease reported that patients whose relatives were carriers of the 4G/4G genotype had a six-fold higher risk of developing septic shock with DIC compared to other genotypes.6 These data suggest that a functional genetic polymorphism in the PAI1 gene may be related to outcome in meningococcal disease.

Other Variations in Fibrinolysis or Anti-Fibrinolysis

Variations in other proteins of fibrinolysis or anti-fibrinolysis are also candidate risk factors for DIC: plasminogen, tissue-type or urokinase plasminogen activator (tPA or uPA), and thrombin-activatable fibrinolysis inhibitor (TAFI). However, no studies have been carried out on the association of genetic mutations of these proteins and DIC.

Procoagulant Pathways

DIC is characterized by massive activation of the coagulation cascade resulting in generation and deposition of fibrin, which leads to formation of microvascular thrombi in various organs. Therefore, genetically determined elevated levels of a procoagulant factor may be a risk factor for DIC.

Fibrinogen

DIC is associated with increased formation of fibrin. One study has reported a 29-year-old pregnant women with a functionally abnormal fibrinogen variant who developed DIC after delivery. 64 In this patient, common causes of DIC such as abruptio placentae, sepsis, amniotic fluid embolus, preeclampsia or eclampsia, acute fatty liver of pregnancy, and haemolytic uraemic syndrome could be excluded.

More than 250 dysfibrinogenaemias have been described so far.65These hereditary coagulation disturbances do not seem to cause a major increase in the risk for deep venous thrombosis,66 and the question whether dysfibrinogenaemias are a risk factor for DIC needs to be answered in future studies.

Other Procoagulant Proteins

So far, there is no evidence yet that established procoagulant genetic alterations associated with an increased risk for deep venous thrombosis such as prothrombin G20210A and high factor VIII or factor XII are a risk factor for DIC.

Summary

DIC is a syndrome characterized by increased activation of intravascular coagulation and decreased activity of protein C protein S and AT inhibitory pathways. DIC may be accompanied by secondary fibrinolysis or inhibited fibrinolysis. The development of this severe imbalance of the coagulation system may become clinically apparent by extensive formation of microthrombi or severe bleeding complications. Paradoxically, thrombosis and bleeding can occur at the same time.

Inherited abnormalities of coagulation proteins that are essential for the pathophysiology of DIC, could contribute to the risk for DIC. Relatively few studies addressed this issue, in particular in meningococcal disease,58 which is often complicated by sepsis and DIC. Data from these studies suggest that inherited coagulation differences, PAI1 promoter polymorphisms5,6 and Factor V Leiden mutation,8 may effect the outcome in meningococcal disease. These data are very limited and controversial,7 however.

Heterozygous protein C and S deficiencies could also be candidate risk factors for DIC because of the known relationship between homozygosity for protein C and S and development of spontaneous DIC in neonates. So far, there are only case reports but no controlled studies on this subject.

It still remains a question whether genetic protein abnormalities contribute to the development of DIC. More studies are necessary to elucidate this subject. It may be that insight in the relationship between risk factors and DIC leads to adjustment of treatment to individual patients and, ultimately, to a better outcome of DIC.

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