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C H A P T E R 140

HYPERCOAGULABLE STATES

Julia A. Anderson, Kerstin E. Hogg, and Jeffrey I. Weitz

Arterial and venous thromboses are common problems for all clini- category involves gain of function in procoagulant pathways. These
cians. Some patients with thrombosis have an underlying hyperco- disorders include factor V Leiden and the FIIG20210A mutation, as well
agulable state. These hypercoagulable states can be divided into three as increased levels of procoagulant proteins, such as factors VIII, IX,
categories: inherited disorders, acquired disorders, and those that are and XI. Each of these conditions will be briefly described.
mixed in origin.
Inherited hypercoagulable states, also known as thrombophilic
disorders, can be due to loss of function of natural anticoagulant Loss of Function of Endogenous Anticoagulants
pathways or gain of function in procoagulant pathways (Table 140.1).
Acquired hypercoagulable states represent a heterogeneous group of Antithrombin Deficiency
disorders in which the risk for thrombosis appears to be higher than
that in the general population. These include such diverse risk factors Antithrombin, a single-chain glycoprotein with a molecular weight
as a prior history of thrombosis, obesity, pregnancy, cancer and its of 52,000 Da, is a member of the serine proteinase inhibitor (serpin)
treatment, antiphospholipid antibody syndrome, drug-induced superfamily that was first described by Brinkhous in 1939. Anti-
thrombosis such as heparin-induced thrombocytopenia or thrombosis thrombin is synthesized in the liver and endothelial cells, and its gene
associated with chemotherapeutic agents, or myeloproliferative disor- (SERPINC1, previously known as AT3) is localized on the long arm
ders. The pathogenesis of thrombosis in these situations is largely of chromosome 1 (1q23–1q25). SERPINC1 is composed of 7 exons
unknown and, in many cases, is likely multifactorial in origin. Mixed and 7 introns and spans 16 kb.
disorders are those with both an inherited and an acquired compo- Antithrombin plays a critical role in regulating coagulation by
nent; one example is hyperhomocysteinemia. Although severe forming a 1 : 1 covalent complex with thrombin, factor Xa, and other
hyperhomocysteinemia and associated homocysteinuria are rare activated clotting factors. Once covalent complexes are generated,
genetic disorders, most cases of mild to moderate hyperhomocyste- they are cleared from the circulation via the liver. The rate of anti-
inemia result from acquired folate and/or vitamin B 12 deficiency thrombin interaction with its target proteases is accelerated by heparin
superimposed on common genetic mutations in biochemical path- by 1000-fold. Heparan sulfate proteoglycan, which coats the vascu-
ways involved in methionine metabolism. lature, is the physiologic counterpart of medicinal heparin.
Genetic hypercoagulable states and acquired risk factors combine Newborn infants have approximately 50% of normal adult anti-
to establish an intrinsic risk for thrombosis for each individual. This thrombin levels, and much lower levels are found in preterm infants
risk can be modified by extrinsic or environmental factors, such as because of liver immaturity; adult levels are attained at 6 months.
surgery, immobilization, or hormonal therapy, which also increase the Antithrombin deficiency can be inherited or acquired, and con-
risk for thrombosis. When the intrinsic and extrinsic forces exceed a genital deficiency of antithrombin was the first reported inherited
critical threshold, thrombosis occurs (Fig. 140.1). Appropriate risk factor for venous thromboembolism. Congenital antithrombin
thromboprophylaxis can prevent the thrombotic risk from exceeding deficiency is relatively rare, occurring in about 1 in 2000, and can
this critical threshold, but breakthrough thrombosis can still occur if be one of two types (Table 140.2), both of which are inherited in
procoagulant stimuli overwhelm protective mechanisms. an autosomal dominant fashion and affect both sexes equally. Type I
This chapter describes the inherited, acquired, and mixed hyper- deficiency, which represents the classic deficiency state, is the result
coagulable states, details their laboratory evaluation, and provides of reduced synthesis of biologically normal antithrombin. Heterozy-
practical advice for the management of these conditions. gotes with this condition have parallel reductions in antithrombin
antigen and activity with levels reduced to about 50% of normal. A
heterogeneous group of nonsense mutations, small deletions, inser-
INHERITED HYPERCOAGULABLE STATES tions, or single-base substitutions are the molecular cause of most
cases, although gene deletions can also be responsible. In total, more
Inherited disorders are found in up to half of patients who present than 113 mutations have been identified as causes of type I anti-
with venous thromboembolism before the age of 40, particularly thrombin deficiency. An antithrombin mutation database compiled
those whose event occurred either in the absence of well-recognized by members of the Plasma Coagulation Inhibitors Subcommittee of
risk factors, such as surgery or immobilization, or with minimal the Scientific and Standardization Committee of the International
provoking factors, such as minor trauma, long-distance flight, or Society on Thrombosis and Hemostasis summarizes the mutations
estrogens. Patients with inherited thrombophilic disorders often have and can be accessed on the Imperial College London website
a family history of thrombosis. Of greatest significance is a family (www.imperial.ac.uk/departmentofmedicine/research/experimental
history of sudden death due to pulmonary embolism or a history of -medicine/haematology/haemostasis-and-thrombosis/database/) or in
multiple family members requiring long-term anticoagulation therapy the human gene mutation database (www.hgmd.cf.ac.uk).
because of recurrent thrombosis. Patients who present with venous Type II antithrombin deficiencies are characterized by normal
thrombosis in unusual sites, such as the cerebral or mesenteric veins, levels of antithrombin with impaired functional activity due to the
those with recurrent thrombosis, and patients who develop skin presence of a variant protein. This condition is mainly caused by
necrosis upon initiation of warfarin therapy should also be suspected missense mutations that result in single amino acid substitutions. The
of having an inherited hypercoagulable state. clinical consequences of type II antithrombin deficiency depend on
From a pathophysiologic perspective, inherited hypercoagulable the location of the mutation, which may involve the reactive center
states fall into two categories. First are those associated with loss of loop or the heparin-binding domain. For example, some mutations
function of endogenous anticoagulant proteins. These include defi- in the reactive center loop of antithrombin slow its interaction with
ciencies of antithrombin, protein C, and protein S. The second target proteases and are characterized by reduced antithrombin

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