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Antithrombin Deficiency. AT is a serine protease inhibitor (SERPIN) of thrombin, kallikrein, and

factors Xa, IXa, VIIa, XIIa, and XIa (Table 6-2). It is synthesized in the liver and has a half-life of 2.8

days. AT deficiency, accounts for approximately 0.5% to 3% of episodes of VTE, the prevalence in the

population is 0.2%, and it carries a 20× increased risk for VTE when heterozygous

145–147 and may occur

at unusual sites such as mesenteric or cerebral veins. Arterial and graft thromboses have also been

described in AT deficiency.148,149 It is inherited in an autosomal dominant fashion most cases become

apparent by 50 years of age.150 Homozygous patients usually die in utero, whereas heterozygous

patients usually demonstrate AT levels <70% of normal. Acquired AT deficiency results from liver

disease, malignancy, sepsis, disseminated intravascular coagulation (DIC), malnutrition, and renal

disease.148 AT deficiency is divided into type I deficiency (quantitative) and type II deficiency

(qualitative).

Table 6-2 Severity and Frequency of VTE due to Hypercoagulable States

The diagnosis of AT deficiency is suspected in a patient who cannot be adequately anticoagulated with

heparin or who develops thrombosis while on heparin and is made by measuring AT antigen and

activity levels. However, patients should not have been exposed to heparin or related compounds for at

least 2 weeks as heparin decreases AT levels 30%.151 Conversely, warfarin increases AT levels.

For a patient with AT deficiency, anticoagulation with heparin requires the administration of fresh

frozen plasma (FFP) to provide AT, 2 units every 8 hours, decreasing to 1 unit every 12 hours, followed

by oral anticoagulation. A reasonable alternative includes anticoagulation with direct thrombin

inhibitors such as argatroban or bivalirudin.105 Aggressive prophylaxis against VTE is recommended

during the perioperative period, and usually lifelong anticoagulation therapy is required after a first

episode of significant VTE.

Protein C and S Deficiencies. Protein C and its cofactor protein S are both vitamin K–dependent

factors synthesized in the liver with half-lives of 4 to 6 hours and 12 to 14 hours, respectively. The

majority of cases of protein C or protein S deficiency are inherited as autosomal dominant. Patients

present with VTE, often between the ages of 15 and 30 years.152,153 Heterozygous protein C deficiency

is present in 1 in 200 to 500 individuals in the general population and in approximately 3% of

individuals with VTE.146 In a study of 10,000 healthy blood donors, protein C deficiency was noted in

1.45 per 1,000.154 Protein deficiency is divided into a type I deficiency (quantitative) and a type II

deficiency (qualitative).

Levels of protein C in those heterozygous deficient may overlap with lower limit normal levels. In

addition to VTE, cases of arterial thrombosis have also been reported.155 If present as a homozygous

state at birth, infants usually die from unrestricted clotting and fibrinolysis, a condition of extreme DIC

termed purpura fulminans. Patients heterozygous for protein C deficiency usually have antigenic protein

C levels less than 60% of normal.156,157 Acquired protein C deficiency occurs with liver failure, DIC, and

nephrotic syndrome.

Protein S is a cofactor to protein C in inactivating FVa and FVIIIa, and is regulated by complement

C4b-binding protein. Inheritance of protein S deficiency is in an autosomal dominant pattern.157,158

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Approximately 40% of protein S circulates in a free active form, with the remainder bound to C4bbinding protein. Free protein S is functionally active as an anticoagulant. Protein S levels increase with

age, and females have lower levels than males. The deficiency of protein S results in a clinical state

identical to protein C deficiency with a VTE rate 5% to 7%, an estimated 8.5× higher risk for the

development of VTE.159 The frequency of protein S deficiency ranges from 3% to 6% for those with

VTE. Levels of protein S are reduced in liver disease, nephrotic syndrome, inflammation, OCP use, in

pregnancy, and during breastfeeding. Nephrotic syndrome leads to a reduction in free protein S,160

whereas inflammatory states such as SLE can result in an elevation of C4b-binding protein, reducing

free protein S.

The diagnosis of protein C or S deficiency is made by measuring plasma protein C and S levels.34,161

For protein C, both antigen and activity are measured, whereas for protein S, only antigen is measured.

A condition also exists in which there is an abnormality in the function of protein C itself, resulting in a

decrease in protein C activity without a decline in antigenic protein C.153

Treatment consists of anticoagulation, initially with heparin, usually followed by lifelong oral

anticoagulation after a first thrombotic event. However, not all patients with low levels develop VTE.

Many heterozygous family members of homozygous protein C–deficient infants also are unaffected.33

Thus, the institution of anticoagulation therapy in patients should occur only following an episode of

thrombosis. However, aggressive anticoagulant prophylaxis during perioperative periods or high-risk

environmental situations is necessary for asymptomatic heterozygote carriers.

With the initiation of oral anticoagulation, blood may become transiently hypercoagulable as the

vitamin K–dependent factors with short half-lives are inhibited (factor VII, protein C) before the other

vitamin K–dependent factors (factors II, IX, and X).162 In someone already partially deficient in protein

C or S, the levels of these anticoagulant factors will diminish even further with the initiation of

warfarin. This results in temporary hypercoagulability, resulting in thrombosis in the microcirculation

and warfarin-induced skin necrosis.163 This leads to full-thickness skin loss, especially over fatty areas

such as the breasts, buttocks, and abdomen. This complication can be prevented by initiating warfarin

therapy under the protection of systemic heparin anticoagulation or a direct thrombin inhibitor.

Defects with Lower Risk for Thrombosis

Resistance to APC (Factor V Leiden). Resistance to APC has been reported to be present in 20% to

60% of cases of idiopathic VTE and is the most common underlying abnormality associated with VTE.

This disorder is present in 1% to 2% of the general population.164–166 In a study of 4,047 Americans, the

carrier frequency of this mutation was 5.3% for Whites, 2.2% for Hispanic Americans, 1.25% for Native

Americans, 1.2% for African Americans, and 0.45% for Asian Americans, with no gender differences.164

It confers a relatively low risk for thrombosis, however, and is more common in whites than in

nonwhite Americans.164

As a result of the substitution of a single amino acid, glutamine for arginine, at position 506 in the

protein for factor V, caused by a nucleotide substitution of guanine for adenine at 1,691 in factor V

gene, hypercoagulability is conferred by resistance to inactivation of factor Va by APC.167–169

Additionally, less VIIIa is interfered with, compounding the hypercoagulability. Factor V Leiden

accounts for 90% of APC-R.

Thrombotic manifestations are noted in those individuals both homozygous and heterozygous for this

mutation. The relative risk for VTE in patients heterozygous for factor V Leiden is 7-fold, whereas the

relative risk is 80-fold for those homozygous for factor V Leiden.165,168 In contrast to factor deficiency

states, persons homozygous for this mutation usually do not die in infancy. Additionally, thrombosis is

potentiated in the presence of additional acquired risk factors.168,170

Combined defects with other hypercoagulable states, such as protein C and S deficiency or

prothrombin G20210A, are not uncommon and increase the thrombotic risk.171,172 In addition to cases

of VTE, recurrent VTE is also more common in patients with this entity, with a relative risk 1.4-

fold.166,173 Although VTE predominates in patients with this syndrome, arterial thrombosis has also been

reported.174

The diagnosis of APC-R is made by a clot-based functional assay with the addition of APC (modified

aPTT). Additionally, genetic analysis should be performed to confirm heterozygosity versus

homozygosity, as treatment decisions may be different between the two states.

Treatment options for APC-R after VTE include anticoagulation, initially heparin or LMWH, followed

by oral anticoagulation. The long-term use of warfarin is controversial. No data exist to suggest that

long-term warfarin should be given after a first episode of VTE in a patient heterozygous for the

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mutation. The fact that APC-R is a relatively low risk for recurrent thrombosis (1.4-fold) suggests that

not all patients after their first episode of VTE need long-term anticoagulant treatment. Patients must be

evaluated in light of their overall risk for bleeding versus thrombosis.152

Prothrombin G20210A Polymorphism. Prothrombin (factor II), a vitamin K–dependent factor

synthesized in the liver, becomes thrombin when activated. A genetic polymorphism in the distal 3′

untranslated region of the gene for prothrombin, a transition from guanine to adenine at the 20210

nucleotide of the prothrombin gene, has been described in patients with VTE.175 This results in a normal

prothrombin but at increased levels.153,170,176 This polymorphism, confers an increased risk for VTE by

2.8-fold, and is associated with 4% to 6% of patients with VTE.152,177–180 Of patients with spontaneous

DVT, the incidence is 7% to 16%.181,182 This is the second most common cause for hypercoagulability in

Caucasians and its prevalence is 1% to 2% of Caucasians. The thrombosis risk is increased in pregnant

women,183 in women with early myocardial infarctions,179 and in synergy with factor V Leiden.170 Most

patients are heterozygous for this mutation, and whites are more often affected than those of Asian or

African descent.179 Genetic analysis is the marker for this abnormality.184

Patients who present with VTE should be treated according to current standards and akin to the

treatment for heterozygous factor V Leiden. Individuals with prothrombin G20210A who have recurrent

episodes of VTE should undergo lifelong anticoagulation, as should those patients with both

prothrombin G20210A and factor V Leiden.170

Hyperhomocysteinemia. Hyperhomocysteinemia has been a known risk factor for atherosclerosis and

vascular disease for more than 25 years, though a direct cause and effect relationship has not been

established.185–187 However, a recent meta-analysis suggests the risk of VTE to be 2.5-fold with elevated

homocysteine levels.187–192

Two enzyme deficiencies, N5, N10, methylenetetrahydrofolate reductase (MTHFR) or cystathionine

beta synthase, are responsible for elevated homocysteine levels.193 Although mutations in these

enzymes are not infrequent, the common polymorphism in MTHFR alone is not a factor in either the

elevation of plasma homocysteine or thrombosis.194 Acquired causes include advanced age, smoking,

coffee consumption, low dietary folate, and low vitamin B6 and B12

intake. Higher levels are also

associated with diabetes mellitus, cancer, hypothyroidism, lupus IBD, and medications such as

metformin, methotrexate, anticonvulsants, theophylline, and levodopa.195,196

Hyperhomocysteinemia has a frequency of 10% in patients with a first episode of VTE, and is a risk

factor for VTE in those younger than 40 years,189 in women,185 and for recurrent VTE in patients

between 20 and 70 years of age.186 The combination of hyperhomocysteinemia and factor V Leiden

results in an increased risk of venous and arterial thromboses.197 Elevated plasma homocysteine results

in abnormal endothelial function.198–202 Fasting homocysteine levels are determined from serum,

usually on two occasions. The test may also be performed after a methionine oral loading