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Table of Contents

Hypercoagulable States

Reviewed
December 15, 2003

Steven R.
Deitcher, MD

Steven R. Deitcher, MD

Department of
Hematology and
Medical Oncology

Marcelo P. V.
Gomes, MD

Marcelo P. V. Gomes, MD

Department of
Hematology and
Medical Oncology

Print Chapter

Copyright 2003
The Cleveland Clinic Foundation

  
DEFINITION

 

Chapter Outline

Definition

Etiology

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Outcomes

References

National Guidelines

American
Cancer Society Guidelines for the Early Detection of Cancer
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

The concept of a "state of hypercoagulability" dates back to 1854, when German pathologist Rudolph Virchow postulated that thrombosis resulted from, and in turn precipitated, three interrelated factors:1 (1) "decreased blood flow" (venous stasis); (2) "inflammation of or near the blood vessels" (vascular endothelial injury); and (3) "intrinsic alterations in the nature of the blood itself." These "blood changes" alluded to in "Virchow's triad" have become what are contemporarily known as "hypercoagulable states," or "thrombophilias."

Hypercoagulable states can be defined as a group of inherited or acquired conditions that are associated with a predisposition to venous thrombosis (including upper- and lower-extremity deep venous thrombosis with or without pulmonary embolism, cerebral vein thrombosis, and intra-abdominal venous thromboses); arterial thrombosis (including myocardial infarction, stroke, acute limb ischemia, and splanchnic ischemia); or both. Venous thromboembolic disease is the most common clinical manifestation resulting from hypercoagulable states. Although most inherited conditions appear to increase solely the risk of venous thromboembolic events (VTEs), some of the acquired conditions have been associated with both VTEs and arterial thrombosis. These include cancer, myeloproliferative syndromes, antiphospholipid antibodies (APA), hyperhomocysteinemia, and heparin-induced thrombocytopenia.

Most hypercoagulable states alter the blood itself whereas others affect the vasculature directly. Although patients with hypercoagulable states are at greater risk for developing a thrombotic event than those without such disorders, not all persons with a well-defined hypercoagulable state will develop an overt thrombosis and not all persons with thrombosis have an identifiable hypercoagulable state. In fact, in 2003, testing for an inherited hypercoagulable state is likely to uncover an abnormality in more than 60% of patients presenting with idiopathic (ie, spontaneous or unprovoked) VTEs (Figure 1).2 Although the remaining 30% to 40% will have unremarkable test results, this does not imply a true absence of a hypercoagulable state. Some of these individuals may have an acquired condition such as cancer or APA, others may have a disorder or defect that has not yet been discovered or characterized. This can be illustrated by the fact that, before 1993 (before the discoveries of factor V Leiden and the prothrombin G20210A mutation), an inherited predisposition to hypercoagulability was identified in only 15% to 20% of patients presenting with idiopathic VTEs.2

This chapter will focus on the most common hypercoagulable states and their association with VTEs. Readers are referred to recent reviews on the association between hypercoagulable states and arterial thrombosis.3,4 Specific derangements that will be reviewed in this chapter include activated protein C resistance, factor V Leiden, prothrombin G20210A mutation, deficiencies of natural anticoagulants (antithrombin, protein C, and protein S), APA, and hyperhomocysteinemia. Although it is beyond the scope of this chapter to review the association between cancer and thrombosis or to discuss issues pertaining to cancer screening following VTEs, malignant diseases are likely the most common acquired hypercoagulable state. At a minimum, appropriate age- and gender-specific cancer screening must be considered after VTEs, particularly in older individuals and in young patients with idiopathic VTEs but without laboratory evidence for a hypercoagulable state. Guidelines for the early detection of cancer have been recently updated by the American Cancer Society.5
ETIOLOGY

Hypercoagulable states can be inherited, acquired, or both. Activated protein C (APC) resistance secondary to factor V Leiden, prothrombin G20210A mutation, and deficiencies of natural anticoagulants are examples of inherited conditions, whereas APA are an acquired set of disorders. Hyperhomocysteinemia can be precipitated by both genetic defects and acquired medical conditions, including vitamin deficiency states.

Factor V Leiden, or factor V G1691A, is a single-point mutation in the gene that codes for coagulation factor V.2 It involves a G (guanine)-to-A (adenine) substitution at nucleotide 1691 (G1691A) in exon 10, which predicts the replacement of arginine at amino acid residue 506 by glutamine (Arg506Gln).6 The mutation, transmitted through autosomal dominant inheritance, renders factor V resistant to inactivation by APC (a natural anticoagulant protein).2 Factor V Leiden accounts for 92% of cases of APC resistance (APC-R), with the remaining 8% of cases resulting from pregnancy, oral contraceptive use, cancer, selected APA, and other factor V point mutations.2 Therefore, the terms "factor V Leiden" and "APC-R" should not be considered synonymous; in fact, APC-R is an independent risk factor for VTEs even in the absence of factor V Leiden.2 It is estimated that the mutation arose in a single Caucasian ancestor some 21,000 to 34,000 years ago, well after the evolutionary separation of non-Africans from Africans (≈100,000 years ago) and of Caucasoid (white non-africans) from Mongoloid (Asians) subpopulations
(≈60,000 years ago).7

Prothrombin G20210A is a single-point mutation (G-to-A substitution at nucleotide 20210) in the 3′ untranslated region of the prothrombin (coagulation factor II) gene.2 This autosomal dominant mutation appears to result in elevated concentrations of plasma prothrombin. Like factor V Leiden, the prothrombin G20210A mutation arose in a single common Caucasian founder, and probably also occurred after the evolutionary divergences of subpopulations.8

Over 100 different mutations have been detected in the genes that code for each of the natural anticoagulant proteins (protein C, protein S, and antithrombin), resulting in quantitative (type I) or qualitative (type II) deficiencies.9 Both antithrombin and protein S deficiencies have an autosomal dominant pattern of inheritance.10,11 Protein C deficiency was believed to be inherited in an autosomal dominant pattern with incomplete penetrance. Recent studies have suggested that protein C deficiency is an autosomal recessive disorder and that coinheritance of another defect (particularly factor V Leiden) results in a high degree of penetrance that appears as dominant inheritance in double-heterozygous carriers.12,13

APA consist of two major subgroups: the lupus anticoagulants and the anticardiolipin antibodies. Lupus anticoagulants are detected by their ability to prolong phospholipid-dependent coagulation tests in vitro (such as the activated partial thromboplastin time and dilute Russell viper venom time). Anticardiolipin antibodies are detected by enzyme-linked immunosorbent assay (ELISA).14 APA that occur in association with autoimmune disorders such as systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and mixed connective tissue disease, as well as in the setting of cancer, are considered "secondary."15 APA detected in individuals without any obvious underlying autoimmune or malignant diseases are called "primary."15 APA have also been reported in conjunction with idiopathic autoimmune hemolytic anemia; malaria; syphilis; Q fever; infections by mycobacteria, Pneumocystis carinii, cytomegalovirus, and human immunodeficiency virus (HIV); and after exposure to drugs such as neuroleptics, quinidine, and procainamide.14,16

The metabolism of the amino acid homocysteine consists of a vitamin B6-dependent transsulfuration pathway involving the enzyme cystathionine β-synthase (CBS), and of a folate- and vitamin B12-dependent remethylation pathway involving the enzymes methylenetetrahydrofolate reductase (MTHFR) and methionine synthase 17,18 (Figure 2). Inherited severe hyperhomocysteinemia (plasma level >100 µmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR or CBS deficiencies and, more rarely, from inherited errors of cobalamin (vitamin B12) metabolism.19 Inherited mild to moderate hyperhomocysteinemia (plasma level between 15 and 100 µmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the C677T gene polymorphism, which is the most common mutation in the gene that codes for the MTHFR enzyme.18,19 This single-point mutation (C677T) in the coding region for the MTHFR binding site (exon 4) is autosomal recessive, leads to the substitution of a valine for an alanine, and results in a thermolabile variant of the MTHFR (tlMTHFR).18 Acquired hyperhomocysteinemia in the absence of any mutation or polymorphism may be caused by folate deficiency, vitamins B6 and B12 deficiencies, renal failure, diabetes mellitus, hypothyroidism, carcinoma, pernicious anemia, inflammatory bowel disease, and methotrexate, theophylline, or phenytoin therapy.17,18

Individuals who are heterozygous for the tlMTHFR variant have normal plasma homocysteine levels, whereas homozygous carriers may have mild to moderate fasting hyperhomocysteinemia in the setting of concomitant folate deficiency.17,19 However, homozygosity for the tlMTHFR in the absence of hyperhomocysteinemia does not appear to be associated with increased risk of VTEs, and the majority of patients with hyperhomocysteinemia do not have the tlMTHFR polymorphism.19 Excess homocysteine in the plasma is the risk factor and target of therapeutic intervention, not the C677T mutation.
PREVALENCE

The prevalence of hypercoagulable states depends on the ethnicity and clinical history of the studied population. Prevalence is lowest in the general population, greater in individuals with a single VTE, and greatest in those with recurrent VTEs or from known thrombophilic families20 (Table 1).

APC-R due to factor V Leiden is the most common inherited predisposition to hypercoagulability in Caucasian populations of northern European background.2 Factor V Leiden follows a geographic and an ethnic distribution: it occurs most frequently in northern and western Europe (the highest prevalence of 15% has been reported in Sweden), but high prevalences are also found in Cyprus (13%), Turkey (9%) and the Middle East (5.4%).21 The mutation is also found in Caucasians from eastern Europe and South America (prevalences of 2% to 4%), but is rare in the Asian and African continents as well as in ethnic groups from Asian descent, such as Inuit Eskimos, Amerindians, Australian Aboriginals, and Polynesians.21 In the United States, factor V Leiden is most commonly seen in Caucasians (6%), with lower prevalences in Hispanics (2.2%), African and Native Americans (1.2%), and Asian Americans (0.45%).22

The prothrombin G20210A mutation is the second most common inherited predisposition to hypercoagulability, occurring more frequently in Caucasians of southern European background. In fact, the 3% prevalence in southern Europe is almost twice the prevalence observed in northern Europe.23 Similar to factor V Leiden, the prothrombin G20210A mutation is also found in the Middle East and Indian regions, but is virtually absent in individuals of African and eastern Asian backgrounds.23 These distributions provide support to the estimate that both mutations (factor V Leiden and prothrombin G20210A) originated relatively recently in the European founding population, after the evolutionary divergences of subpopulations.

The deficiencies of natural anticoagulants are rare in the general population, and combined are found in less than 15% of all individuals with a single VTE (Table 1; Figure 1). The prevalence of APA (an acquired set of disorders) is significantly higher among patients with autoimmune disorders than in healthy individuals from the general population. In patients with systemic lupus erythematosus, the reported average prevalences for lupus anticoagulants and anticardiolipin antibodies are 34% and 44%, respectively.15

PATHOPHYSIOLOGY

Appreciation of the mechanisms by which hypercoagulable states lead to pathologic thrombosis requires an understanding of normal hemostasis, which comprises two equally important processes: primary hemostasis and secondary hemostasis. While described as separate events, both primary and secondary hemostasis occur concurrently at a site of vascular injury.

Primary hemostasis consists of three events that lead to the formation of a platelet "plug," namely, platelet adhesion, platelet activation, and platelet aggregation. Platelets adhere to the vascular subendothelium by attaching to subendothelial von Willebrand factor molecules exposed at a site of vascular injury. Once adherent, platelets are activated by a number of agonists (including thrombin, collagen, epinephrine, and thromboxane A2) and are stimulated to release their alpha- and dense-granule contents, which further promote platelet recruitment, activation, and aggregation. After additional platelets are recruited, they are linked by fibrinogen through the surface glycoprotein IIb/IIIa receptors to form the platelet plug.

Secondary hemostasis consists of a series of sequential reactions ("coagulation cascade") in which inactive protease zymogens are converted to active serine proteases, ultimately resulting in the production of thrombin and covalently cross-linked fibrin (Figure 3). In response to vascular injury, the in vivo coagulation cascade is triggered by the exposure of tissue factor. Tissue factor not only complexes with trace amounts of activated factor VII (present in the circulation of normal individuals) but also activates factor VII to factor VIIa. The complex formed by factor VIIa and tissue factor then activates factors IX and X, leading to the formation of small amounts of thrombin. However, this pathway is rapidly downregulated by tissue factor pathway inhibitor. Nevertheless, potent positive feedback by thrombin itself results in activation of factor XI to factor XIa, which can activate factor IX, hence perpetuating the production of thrombin and, subsequently, of a fibrin "clot." Thrombin also promotes ongoing thrombosis by activation of factor VIII, factor V, and factor XIII. Factor VIIIa functions as a cofactor during the activation of factor X to Xa (catalyzed by factor IXa). Factor Va functions as a cofactor during the activation of prothrombin to thrombin (catalyzed by factor Xa). The end-result of these sequential reactions is the conversion of fibrinogen to fibrin monomers. Factor XIIIa cross-links fibrin to promote a stabilized platelet plug (Figure 3).

The natural anticoagulants function to confine thrombus formation to the site of vascular injury and to limit thrombus size. While promoting ongoing coagulation by a number of positive feedbacks, thrombin also provides an important negative feedback to limit thrombus formation by binding to thrombomodulin on endothelial cells. The complex thrombin:thrombomodulin then converts protein C to APC. Antithrombin and protein C are the major natural anticoagulants, while protein S serves as a vital cofactor for APC-mediated inactivation of factors Va and VIIIa (Figure 3).

Vascular endothelial disruption triggers not only coagulation reactions but also the fibrinolytic pathways (Figure 4). Physiologic fibrinolysis is initiated by endothelial-cell-derived tissue plasminogen activator (tPA)-mediated conversion of plasminogen to plasmin. Plasmin can degrade both fibrinogen and fibrin, thus limiting the size of a thrombus and helping to clear a thrombus once the vascular injury has been repaired. The fibrinolytic pathways are regulated by the inhibitory proteins alpha-2 antiplasmin and plasminogen activator inhibitor-1.

Therefore, the human hemostatic system can be defined as consisting of multiple independent yet integrally related cellular and protein components that function to maintain blood fluidity under normal conditions and to promote localized, temporary thrombus formation at sites of vascular injury (Figure 5). The six major components of this hemostatic system are vascular endothelium, platelets, plasma coagulation proteins or "factors," natural anticoagulant proteins, fibrinolytic proteins, and antifibrinolytic proteins. In the presence of an intact endothelium, there is no "clot" formation taking place inside the blood vessels, even though a low, basal physiologic level of coagulation factor activation is occurring continuously. This highly regulated hemostatic system maintains a delicate balance between a prohemorrhagic state and a prothrombotic state. This balance is maintained by the concomitant actions of platelets, coagulation factors, and fibrinolytic inhibitors (on one side of the "hemostatic scale"), and of natural anticoagulants and fibrinolytic proteins (on the other side of the scale), as shown in Figure 6. Marked thrombocytosis, accentuated platelet aggregation, increased activity levels of coagulation factors, and excess plasma levels of fibrinolytic inhibitors may lead to pathologic thrombosis. Likewise, quantitative or qualitative deficiencies of a natural anticoagulant, coagulation factor resistance to inactivation by a natural anticoagulant (in the specific case of factor V Leiden), and a deficiency of a fibrinolytic protein may all be associated with a "state of hypercoagulability." Thus, it is not surprising that a multitude of "potential" hypercoagulable states has been described (Table 2).

The factor V Leiden mutation renders factors V and Va partially (but not completely) resistant to inactivation by APC.2,6 APC inactivates factor Va in an orderly and sequential series of cleavages, first at Arg506, and then at Arg306 and Arg679.6 This partial resistance is explained by the fact that cleavage of factor Va by APC at Arg306 continues to occur, although at a slower rate. In fact, factor V Arg506Gln (factor V Leiden) is inactivated 10 times slower than normal factor Va.24 This provides a pathophysiologic explanation for why factor V Leiden, although common, is a relatively weak risk factor for VTEs. Because factor Va functions as a cofactor in the conversion of prothrombin to thrombin, the mutation results in greater amounts of factor Va available for coagulation reactions, shifting the hemostatic balance toward greater thrombin generation.2,9

By unknown mechanisms, the prothrombin G20210A mutation results in elevated concentrations of plasma prothrombin, which is the immediate precursor of thrombin. The tendency to hypercoagulability is believed to be derived from the greater availability of prothrombin for conversion to thrombin.2

Antithrombin is the primary inhibitor of thrombin and the other serine proteases, factors XIIa, XIa, Xa, and IXa. Deficiency of antithrombin leads to enhanced thrombin formation. Complete deficiency of antithrombin likely leads to unfettered thrombin formation and hypercoagulability to a degree that it is fatal in utero. Protein C, in its activated form (APC), controls the formation of thrombin in the presence of its cofactor, free protein S. Thus, in the setting of protein C or protein S deficiency, thrombin formation is also enhanced, leading to hypercoagulability.9 Type I deficiencies of natural anticoagulants are characterized by low antigen and activity (functional) levels of the deficient natural anticoagulant, whereas type II defects are characterized by normal (total) antigen levels but low activity (dysfunctional molecules).6,10,11 Under normal conditions, protein S exists in plasma in two forms: bound to C4b-binding protein (60% of total) and free (40% of total). Because only free protein S has cofactor activity, a type III protein S has been described, consisting of low activity and free antigen levels but with normal total antigen level.6,11 This type III protein S deficiency may result from excess C4b-binding protein or free protein S inhibitory and clearing antibodies.25

The exact mechanisms by which APA cause thrombosis are unknown. Some of the proposed mechanisms include acquired APC-R; stimulation of platelet adhesion, activation, and aggregation; upregulation of the tissue factor pathway; enhanced expression of cell adhesion molecules; and reduction of the free protein S level by inducing protein S binding to C4b-binding protein.14,16 One described mechanism for APA-associated fetal loss involves the presence of trophoblast-reactive antibodies that disrupt the annexin V shield on trophoblast cell membranes, thus enhancing thromboxane A2 production and leading to placental insufficiency.14

The pathophysiology of thrombosis in hyperhomocysteinemia is also unclear. Proposed mechanisms include direct endothelial injury, increased tissue factor activity, inhibition of protein C activation, increased platelet activation and aggregation, suppression of thrombomodulin expression, and impaired fibrinolysis by inhibition of tPA binding to its endothelial cell receptor.17,18
SIGNS AND SYMPTOMS

There are no specific signs or symptoms associated with hypercoagulable states. The finding of livedo reticularis upon examination of the skin has been frequently associated with the presence of APA, but a true causality has not been established. The most common clinical manifestation of an underlying hypercoagulable state is lower-extremity deep venous thrombosis with or without pulmonary embolism. Because the clinical signs and symptoms associated with deep venous thrombosis and pulmonary embolism are insensitive and nonspecific, objective diagnostic confirmation by the use of an imaging method, such as contrast venography and duplex ultrasound, is mandatory (see "Signs and Symptoms" and "Diagnosis" sections in Venous Thromboembolism chapter). Other less common or unusual clinical presentations of venous thrombosis appear to occur more commonly, but not exclusively, in certain hypercoagulable states, as depicted in Table 3.

The risk of a first VTE varies, depending on the hypercoagulable state being considered 2,14,19,20 (Table 4). This risk is usually expressed as relative risk. Although the relative risk is useful in comparing the VTE rates between a patient population with a given disorder and normal controls, the absolute risk is the best measure to assess the importance of a given risk factor for an individual patient.2 This is particularly important considering the fact that the baseline risk of thrombosis for both women and men increases exponentially with age.20

DIAGNOSIS

Laboratory testing for hypercoagulable states can uncover an inherited abnormality in more than 60% of patients presenting with a first VTE (Figure 1). However, testing is costly, it rarely influences acute VTE management, and its results are frequently misinterpreted, which may lead to a non-evidence-based use of antithrombotic drugs and inappropriate justification of "lifelong" therapy. More important, a focus exclusively on hypercoagulable state testing may undermine the performance of age- and gender-specific cancer screening in patients with idiopathic VTEs. In the absence of validated guidelines, testing for hypercoagulable states should be performed only in selected patients, and only if the results will significantly affect management.

Who Should Be Tested?
Selected testing should be considered mainly in the following circumstances:

  • Idiopathic (ie, spontaneous) VTE
  • VTE at young age (<45 years old)
  • Recurrent VTE
  • VTE in unusual sites (see Table 3)
  • VTE in the setting of a strong family history of VTE
  • Recurrent pregnancy loss (>3 consecutive first-trimester pregnancy losses without an intercurrent term pregnancy).

Testing should be strongly considered in patients who present with two or more of the above-listed criteria. It may also be considered in selected asymptomatic individuals, particularly women relatives of patients with known inherited hypercoagulability, provided that the results will affect their decision to begin oral contraceptive pill (OCP) use or hormone replacement therapy (HRT).

Why Should a Patient Be Tested?
Testing should be performed if the results will affect management by guiding:

  • Duration of anticoagulation therapy
  • Choice of anticoagulant agent
  • Intensity of anticoagulation therapy
  • Therapeutic monitoring strategies
  • Family screening
  • Family planning
  • Choice of concomitant medications

The issue of OCP use and HRT in the setting of an inherited hypercoagulable state remains a matter of intense debate. Both groups of medications are associated with a two- to sixfold increased relative risk of a VTE in women without hypercoagulable states.26 Based on data from the Leiden Thrombophilia Study,27 the risk of a VTE is increased sevenfold in heterozygous carriers of factor V Leiden. The relative risk of VTEs is increased exponentially in women taking an OCP who are carriers of factor V Leiden (35-fold) and prothrombin G 20210A (16-fold).28,29 The VTE risk appears even higher in women homozygous for factor V Leiden, and an absolute risk of VTEs of 4% per year has been reported in women who are taking an OCP and carry a natural anticoagulant deficiency.30,31 OCP users who carry the prothrombin G20210A mutation also have a 150-fold increased risk of cerebral vein thrombosis.32

It is not currently recommended that all asymptomatic women be screened prior to initiation of such therapies, mainly because it is not cost effective.33 It is clear, however, that the combination of factor V Leiden with OCP use leads to an exponential increase in the relative risk of VTEs, even though the absolute risk still remains fairly low (Table 5). Thus, in asymptomatic women with a family history of VTEs, selected testing may be considered if the results of testing will affect a woman's decision to proceed with OCP use. It is generally recommended that OCP use be avoided in the setting of objectively and properly confirmed antithrombin, protein C, and protein S deficiency states because of the high annual rates of VTEs reported in this group of women.31,33 However, current evidence does not allow that such a firm recommendation be made regarding OCP use in a woman with factor V Leiden or even prothrombin G20210A mutation heterozygosity. This is because OCPs remain the most effective form of prescribed contraception, and the increased risk of VTEs associated with the presence of factor V Leiden or prothrombin G20210A heterozygosity needs to be balanced against the possibility of unwanted pregnancy with its attendant 9- to 15-fold increased risk of VTEs in this same population.34

The relative risk of VTEs is also further increased (by 15-fold) in women on HRT who are heterozygous for factor V Leiden. The epidemiologic importance of this increased risk lies in the fact that women on HRT belong to an older group than those on OCP, with a baseline risk of VTEs between 1 per 1,000 and 1 per 100 persons (instead of 1 per 10,000 persons) per year.26 Thus, it is likely that the impact of a 15-fold increased risk of VTEs is more significant in women within this age group, and it is possible that the benefits of HRT may not outweigh the risk of VTEs.

What Tests Should Be Performed?
Testing for hypercoagulable states is best performed in stages. Highest-yield assays (screening tests) should be performed first and, if positive, should be followed by appropriate confirmatory tests (Table 6). If screening test results are negative and sufficient suspicion exists, less common disorders can be tested for. Specific testing for factor V Leiden is not necessary if the test result for APC-R is negative.2 Prothrombin G20210A mutation detection by polymerase chain reaction is preferred over prothrombin activity level quantification because the latter does not sufficiently differentiate carriers from noncarriers of the mutation.2 Activity assays for antithrombin, protein C, and protein S are preferred at first, because they will be abnormal in both type I (quantitative) and type II (qualitative) deficiencies.35 If activity assays are normal, there is no benefit to pursuing antigenic testing. Factor VIII activity testing should also be considered, especially in patients suspected of having protein S deficiency. Both factor VIII activity >250% and APC-R can interfere with some available protein S activity assays.36

The International Society on Thrombosis and Haemostasis Guidelines for APA testing suggest performance of two distinct lupus anticoagulant assays, in addition to anticardiolipin antibody testing by ELISA.37 If either clot-endpoint lupus anticoagulant assay (either the activated partial thromboplastin time- aPTT- or the dilute Russel viper venom time- dRVVT) is abnormal, the assay should be repeated with a phospholipid or platelet neutralization step to increase its specificity. We do not recommend genotyping for the tlMTHFR polymorphism because hyperhomocysteinemia from any cause is the risk factor for thrombosis, not the presence of the tlMTHFR polymorphism.19 Total plasma homocysteine should be obtained in a fasting state.17,19

When Should Tests Be Performed?
Ideally, testing should be performed in the outpatient setting at least 4 to 6 weeks after any acute thrombotic event. This is because acute illness states, including VTEs, can cause elevations of a number of acute-phase reactants, including factor VIII, C4b-binding protein, fibrinogen, and IgM anticardiolipin antibodies, all of which may interfere with testing and often lead to false-positive diagnoses. Heparins (unfractionated and low-molecular-weight) can interfere with antithrombin activity and with lupus anticoagulant assays, and warfarin predictably lowers protein C and S activity levels.35 Low activity levels of natural anticoagulants also occur as a result of liver disease, because protein C, protein S, and antithrombin are all synthesized in the liver.10,11,35 Antithrombin activity level may be reduced in nephrotic syndrome and active colitis, and protein S activity may also be reduced in the setting of HIV infection.35

TREATMENT

There are no specific therapies to reverse most hypercoagulable states. Recombinant factor concentrates of antithrombin and APC exist and may be useful in select situations beyond the scope of this review. Gene transfer to correct a particular genetic defect is theoretically feasible but likely cost prohibitive at this time. Attempts to eliminate APA by plasmapheresis or immunosuppressive therapy have not been very successful.

Hyperhomocysteinemia is treatable, and plasma homocysteine levels can be lowered in many individuals by folic acid or other B-complex vitamin supplementation.3 It is not known whether normalization of plasma homocysteine levels reverses the hypercoagulability completely.

Initiation of oral anticoagulation for primary VTE prophylaxis in asymptomatic carriers of any hypercoagulable state has not been advised, mainly because the annual absolute risk of idiopathic VTE is either low or not high enough to be favorably balanced against the annual risk of oral anticoagulation-related major and fatal hemorrhage.38 However, because most VTEs (50% to 70%) in patients with a predisposition to hypercoagulability occur following a situational risk factor, such as major or orthopedic surgery, aggressive VTE prophylaxis should be prescribed to asymptomatic carriers of hypercoagulable states during high-risk situations.2,38

The presence of a hypercoagulable state should not affect acute VTE treatment (ie, initial anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin followed by oral anticoagulation with warfarin) in most patients, except for those with a lupus anticoagulant. Because these antibodies can prolong the activated partial thromboplastin time, monitoring of unfractionated heparin therapy in this scenario should be performed by heparin assay (protamine titration or anti-factor Xa activity assay). If such assays are not immediately available, the use of weight-based, subcutaneous low-molecular-weight heparin should be considered instead of unfractionated heparin, because the former compounds do not require monitoring. Moreover, 26.8% to 53% of all patients with a lupus anticoagulant have an abnormal, prolonged baseline prothrombin time, and in many of these patients the international normalized ratio is not an adequate tool for monitoring warfarin therapy. In this situation, monitoring by chromogenic factor X activity assay is recommended.39

Many physicians justify hypercoagulable state testing because, if an abnormality is found, prescription of long-term oral anticoagulation is believed to be more appropriate than the recommended 3- to 6-month course. However, it must be emphasized that there currently are no data from prospective, randomized controlled trials specifically designed to address the optimal duration of anticoagulation therapy in patients with specific hypercoagulable states. Thus, any decisions regarding the ideal duration of therapy must take into account the estimates of VTE recurrence for a given disorder, the nature of the index VTE, and the risk of bleeding associated with prolonged oral anticoagulation. The Sixth American College of Chest Physicians (ACCP) Guidelines to Antithrombotic Therapy do not recommend continuation of anticoagulation therapy beyond 3 to 6 months after a situational VTE in patients with heterozygous factor V Leiden or the prothrombin G20210A mutation, and suggest that such therapy should last "1 year to lifetime" only in individuals with active cancer, persistently elevated anticardiolipin antibodies, and antithrombin deficiency40 (see Table 4 in the Venous Thromboembolism chapter). Based on available data, it is also reasonable to consider long-term anticoagulation therapy for patients with conditions known to be associated with increased rates of VTE recurrence. These include individuals with documented persistent lupus anticoagulants, homozygous factor V Leiden, and maybe patients with a deficiency of protein C or protein S, or with double heterozygosity for factor V Leiden and the prothrombin G20210A mutation. However, the simple fact that a condition increases the risk of VTE recurrence should not be viewed as a mandatory indication for long-term or "lifelong" therapy. This is because most recurrent VTEs tend to occur within the first 1 to 3 years following the index VTE, with the annual rate of recurrence declining thereafter. Conversely, the risk of oral anticoagulation-related major bleeding increases with aging. Therefore, the balance between the benefits of long-term oral anticoagulation (in preventing recurrent VTEs) and the bleeding risk associated with this therapy (particularly of major and fatal hemorrhage) is likely to evolve over time, with risks outweighing benefits as the patients age.

OUTCOMES

The outcomes of patients with hypercoagulable states are dependent upon the rates of VTE recurrence associated with the different disorders. There currently are no data to suggest reduced survival in patients who carry an inherited predisposition to hypercoagulability.

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REFERENCES
  1. Kitchens CS. Concept of hypercoagulability: a review of its development, clinical application, and recent progress. Semin Thromb Hemost. 1985;11:293-315.

  2. Deitcher SR, Caiola E, Jaffer A. Demystifying two common genetic predispositions to venous thrombosis. Cleve Clin J Med. 2000;67:825-826, 829, 833-836.

  3. Deitcher SR, Carman TL, Sheikh MA, Gomes M. Hypercoagulable syndromes: evaluation and management strategies for acute limb ischemia. Semin Vasc Surg. 2001;14:74-85.

  4. Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease. Thromb Haemost. 2001;85:584-595.

  5. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, 2003. CA Cancer J Clin. 2003;53:27-43.

  6. Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 1. Thromb Haemost. 1996;76:651-662.

  7. Zivelin A, Griffin JH, Xu X, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood. 1997;89:397-402.

  8. Zivelin A, Rosenberg N, Faier S, et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood. 1998;92:1119-1124.

  9. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

  10. Van Boven HH, Lane DA. Antithrombin and its inherited deficiency states. Semin Hematol. 1997;34:188-204.

  11. Aiach M, Borgel D, Gaussem P, Emmerich J, Alhenc-Gelas M, Gandrille S. Protein C and protein S deficiencies. Semin Hematol. 1997;34:205-216.

  12. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. 1987;317:991-996.

  13. Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood. 1994;84:1031-1035.

  14. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346:752-763.

  15. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med. 1990;112:682-698.

  16. Shapiro SS. The lupus anticoagulant/ antiphospholipid syndrome. Annu Rev Med. 1996;47:533-553.

  17. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-1050.

  18. Guba SC, Fonseca V, Fink LM. Hyperhomocysteinemia and thrombosis. Semin Thromb Hemost. 1999;25:291-309.

  19. De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost. 2000;26:305-311.

  20. Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol. 1997;34:171-187.

  21. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical indications. Semin Thromb Hemost. 1998;24:367-379.

  22. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997;277:1305-1307.

  23. Rosendaal FR, Doggen CJM, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79:706-708.

  24. Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V. Blood. 1995;85:3405-3411.

  25. Deitcher SR, Erban JK, Limentani SA. Acquired free protein S deficiency associated with multiple myeloma. Am J Hematol. 1996;51:319-323.

  26. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol. 2002;22:201-210.

  27. Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993;342:1503-1506.

  28. Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453-1457.

  29. Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol. 1999;19:700-703.

  30. Rintelen C, Mannhalter C, Ireland H, et al. Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol. 1996;93:487-490.

  31. Pabinger I, Schneider B, for the GTH Study Group on Natural Inhibitors. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. Thromb Haemost. 1994;71:548-552.

  32. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338:1793-1797.

  33. Vandenbroucke JP, Rosing J, Bloemenkamp KWM, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001;344:1527-1535.

  34. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342:374-380.

  35. Van Cott M, Laposata M. Laboratory evaluation of hypercoagulable states. Hematol Oncol Clin North Am. 1998;12:1141-1166.

  36. Deitcher SR, Volner JS, Kottke-Marchant K. Activated protein C resistance (APC-R) and elevated factor VIII (FVIII) activity associated interference in functional protein S assays. Blood. 1998;92(suppl 1):357b.

  37. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995;74:1185-1190.

  38. Kearon C, Crowther M, Hirsh J. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med. 2000;51:169-185.

  39. Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997;127:177-185.

  40. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119:176S-193S.

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