Hypercoagulability: clinical assessment and treatment. (REVIEW ARTICLE).

ABSTRACT: This review emphasizes pathophysiology, clinical features, assessment, and therapy for hypercoagulability. Risk factors that further increase clotting include obesity, recent surgery, pregnancy, and cancer. Clinical examples of coagulation abnormalities may occur from single or multiple abnormalities and include both inherited and acquired defects. Laboratory testing undertaken at the time of acute thrombosis is often inaccurate or difficult to interpret. Individuals are best tested when they are not taking anticoagulants. Treatment of patients with either inherited or acquired abnormalities usually requires heparin compounds followed by warfarin, but the length of therapy has not yet been settled. Asymptomatic individuals with underlying hypercoagulability may not require treatment except in clot-promoting situations such as trauma, pregnancy, recent surgery, or use of venous access devices. The detection of one abnormality may no longer suffice because multiple defects can be found frequently. In patients with clotting and underlying risk factors, such as malignancy, pregnancy, estrogens, or surgery, an assessment for hypercoagulabitity should be considered.

MORE THAN A CENTURY AGO, Rudolph Virchow identified a triad of factors responsible for vascular thrombosis: vessel injury, alteration in blood flow, and changes in the coagulability of the blood. Precipitating or anatomic factors for thromboembolic disease, such as pregnancy, surgery, obesity, and malignancy, are examples of the first two factors described by Virchow. The delineation of the clinical entity of "hypercoagulability" was designed to identify a syndrome of abnormalities of the third factor of Virchow, coagulability of blood. Consequently, the traditional diagnosis of "hypercoagulability" was created for thromboembolic disease that occurred in the absence of precipitating or anatomic (noncoagulant) factors. Traditional hypercoagulability generally excluded patients who were 45 years of age or older or who had identifiable noncoagulant risk factors.

Only recently have a number of defects in coagulability of blood been identified with precision. Many examples of hypercoagulability can now be explained. However, it is known that patients with risk factors that are now primarily of the coagulation system may also have coexistent coagulation defects. Therefore, clinicians should no longer exclude patients from an assessment of hypercoagulability because of known or malignancy, pregnancy, or surgery. Also, it is also appreciated that more than one of the hypercoagulability defects can occur in an individual patient; consequently, discovery of one abnormal factor does not obviate the need to look for others. This review will summarize the clinical features, assessment, and treatment of abnormalities of the coagulation system and illustrate examples of multiple factors.

CAUSES OF HYPERCOAGULABILITY

The best clue for the presence of hypercoagulability is a positive family history. Clinical suspicions occur when patients are seen with unexpected venous thromboembolic disease, recurrent thrombosis, or thrombosis at unusual sites, such as the brain, portal vein, or hepatic vein. In addition, this entity should be considered in cases of unanticipated arterial occlusive disease of the central nervous system, extremities, mesenteric vessels, or cardiac tree.

The defects that are responsible for hypercoagulability can be divided into inherited defects and acquired forms. Table 1 also includes noncoagulant factors. Before 1993, the chance of discovering a coagulation abnormality in patients with "traditional" hypercoagulability was as low as 5% to 15%. (1,2) Since the descriptive details of the protein C pathway and activated protein C (APC) resistance have been identified, (3-5) the frequency of finding underlying causes of hypercoagulability has increased significantly. Defects of the other proteins in this pathway, such as protein C and protein S, are discovered as etiologic factors but with a lesser frequency. Table 2 estimates the gene frequency of inherited defects as well as the incidence of detection of inherited genetic abnormalities in subjects being evaluated for traditional hypercoagulability. (6) The frequency of these abnormalities may be skewed by the geographic origin of the population being analyzed.

PROTEIN C PATHWAY

The pathophysiologic mechanism of the protein C pathway proteins is shown in Figure 1. On the surface of endothelial cells, thrombin (#1) binds to a receptor known as thrombomodulin. The thrombin-thrombomodulin complex is the site for interaction of protein C (#2). Once bound to this complex, protein C becomes activated (APC) (#3) and inactivates or destroys activated factor V (factor Va) and activated factor VIII (not illustrated). Protein S (#4) serves as a cofactor in this process. Uninhibited factor Va and factor VIIIa actively propagate coagulation; in the presence of [Ca.sup.++] and Xa, factor Va converts prothrombin to thrombin (#5), and in turn, thrombin converts fibrinogen to fibrin. In addition, studies in vitro implicate a connection of the APC system to platelet and endothelial surfaces. Thus, abnormalities in the pathway of APC, protein C, protein S, or other proteins that affect the action of thrombin (antithrombin) can cause hypercoagulability.

ACTIVATED PROTEIN C RESISTANCE 

The pathophysiologic mechanism of resistance of APC is related to an inherited abnormality of factor V.(3) Investigations have identified a genetic point mutation on chromosome 1 that encodes glutamine at the 506 site rather than arginine (ARG 506 GLN). This modification is responsible for the production of an aberrant factor V that is resistant to the proteolytic destruction by APC. (7-9) Aberrant factor V was originally described in Leiden (Holland) and is more commonly referred to as factor V Leiden. When normal factor V is digested at the arginine 506 site, two other sites cooperate; 70% of the destruction of factor Va occurs at arginine 306, and 30% occurs at arginine 679. Protein S cooperatively acts upon arginine 306; therefore, even in the presence of factor V Leiden, there is a lesser degree of thrombosis when protein S is present. Conversely, when protein S deficiency coexists with factor V Leiden, thrombotic events are more prevalent. Except for other rare genetic abnormalities (factor V Hong Kong and factor V Cambridge, factor V Leiden is synonymous with the term APC resistance.

Recent haplotype analyses among Arabs, Jews, Austrians, and French suggest that the factor V Leiden defect originated approximately 21,000 to 35,000 years ago at the time of the separation of the African and non-African populations and the divergence of the caucasian from the Asian groups. (10) Therefore, the finding that 15% of the European population are carriers of factor V Leiden, (11,12) with rare appearances in Africans, Asians, and American Indians, is expected. Among heterozygotes, thrombosis occurs at a rate of 5 to 10 times that in the unaffected population; with homozygotes, thrombosis occurs 50 to 100 times more frequently. (3,5,13)

Pregnancy and oral contraceptives may further contribute to thromboembolic events seen with APC resistance. Venous thrombosis during pregnancy has been reported in as many as 60% of genetically APC affected individuals. (14) In addition, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) has been noted in two women with factor V Leiden. (15) To complicate investigations of coagulation abnormalities, normal women who are pregnant have decreased levels of APC. This fact raises the possibility of a noninherited etiologic relationship between pregnancy and thrombosis. (16-18) Furthermore, relative APC resistance is produced in women taking oral contraceptives, some of whom were already known to be factor V Leiden heterozygotes. (19) In adults, instances of arterio-sclerotic cardiovascular disease and factor V point mutations have been reported, (20,21) but a definitive relationship is not established as of yet.

The anticipated frequency of thrombosis in subjects with factor V Leiden is less than one would expect, given the high prevalence of the gene. The occurrence of other defects combined with factor V Leiden promotes increased thrombosis. Factor V Leiden coexists with protein C (22) and protein S deficiencies, prothrombin 20210A allele, (23) lupus anticoagulants and anti-phospholipid antibodies, (24) elevated levels of factor VII, (25,26) and inherited homocysteine abnormalities. (27, 28) Furthermore, patients with factor V Leiden who are prescribed oral contraceptive pills or who become pregnant are at a higher risk for thromboembolic disease.

PROTEIN C AND PROTEIN S DEFICIENCIES

Protein C and protein S are vitamin K-dependent factors that are synthesized in the liver. Protein C originates on chromosome 2 and protein S on chromosome 3. Deficiencies of these proteins have been considered autosomal dominant defects, though recent analyses suggest that the defects may be recessive but with a high frequency of concomitant defects of other coagulation proteins. Two types of protein defects cause protein C or protein S deficiency: deficiency of protein content (antigen) or the presence of dysfunctional protein. Protein S deficiency occurs at a slightly greater frequency than does protein C deficiency. Heterozygote protein C and protein S abnormalities cause hypercoagulability; in rare instances, homozygote protein C or homozygote protein S deficiency can result in a life-threatening coagulopathy of neonates (purpura fulminans). (29-32)

ANTITHROMBIN

In the final phase of clot formation, thrombin converts fibrinogen to fibrin. Antithrombin (formerly referred to as antithrombin III), named for its action on thrombin, also inhibits the serine proteases of IXa, Xa, XIa, and XIIa. (33) Antithrombin is inherited in autosomal dominant fashion with an estimated frequency of 1 in 2,000. (34) Deficiency of antithrombin may be caused by decreased levels or by dysfunctional protein. The "anticoagulant" action of heparin requires the presence of antithrombin; thus, a clinical clue to diagnosis of antithrombin deficiency may be anticoagulation refractoriness to heparin.

HYPERHOMOCYSTEINEMIA

Most of the relationship between hyperhomocysteinemia and arterial vascular disease and venous thromboembolic disease is epidemiologically based. Suggestive pathophysiologic mechanisms of the effect of homocysteine include increased peroxidation injury, proliferation of smooth vessel, promotion of monocytic chemotaxis, enhanced cytotoxicity and inflammation, promotion of clotting, inhibition of anticoagulation, direct effects on endothelial cells, and activation of platelet aggregation. (35-37)

The metabolic pathway of homocysteine is shown in Figure 2. Levels of homocysteine are closely related to B vitamins; the conversion of homocysteine to methionine in the remethylation pathway requires folic acid and B (12). The conversion of homocysteine to cystathionine and cysteine through transsulfation necessitates B (6). Therefore, lowered levels of B (12) or B (6) can be associated with elevated homocysteine concentrations. Folic acid deficiency or methylenetetrahydrofolate reductase (MTHFR) deficiency are also causes of hyperhomocysteinemia. The recognition that homocysteine may play a role in hypercoagulability should raise consideration of nutritional replacement in patients with malignancy or pregnancy. Similarly, patients with known hypercoagulability due to inherited defects of the APC pathway should maintain adequate stores of folic acid, B (12), and B (6).

PROTHROMBIN 20210A

One of the newest detected causes of hypercoagulability is prothrombin 20210A allele, an abnormality described in 1996. (23) Frequency of this abnormality varies from 0.7% to 6.0% among whites, with rare appearances among Africans and Asians, suggesting that the defect may have also appeared after the divergent migrations of the populations. (38) The combination of prothrombin 20210A with other defects such as factor V Leiden, protein S deficiency, protein C deficiency, or antithrombin deficiency has been reported. (39) The mechanism by which prothrombin 20210A allele is responsible for hypercoagulability is uncertain.

OTHER INHERITED DISORDERS

Other inheritable hypercoagulable diseases such as increased levels of factor VIII have been recently reported. (40) In addition, dysplasminogenemia, hypoplasminogenemia, decreased release of tissue plasminogen activator, and increased concentrations of plasminogen activator inhibitor may occur rarely but are not well established. (41) Dysfibrinogenemias are usually manifested as bleeding disorders because of defective fibrin formation, but thrombotic complications may occur when the defective fibrin is resistant to the lytic effects of plasmin. Recent descriptions of elevated levels in factor VIII suggest an etiologic mechanism for recurrent thromboembolic disease (42); factor VIII elevations may be increased by inherited and acquired factors.

ANTIPHOSPHOLIPID SYNDROME

The "lupus anticoagulant" is an acquired biologic abnormality characterized as an "anticoagulant" in vitro but associated with excessive clotting in vivo. This abnormality, also referred to as the antiphospholipid syndrome, should be suspected in young persons with arterial disease such as myocardial infarctions and acute neurologic events (cerebrovascular accidents and transient ischemic attacks). In addition, this syndrome is seen in women with recurrent pregnancy loss or in patients with increased thrombosis especially in unusual locations such as retinal veins, cerebral vessels, and hepatic venous channels (Budd-Chiari syndrome). (43-47) Patients with antiphospholipid syndrome may have mild thrombocytopenia as well. (48) This disorder is sometimes suspected when an unexplained prolongation of the partial thromboplastin time is found.

OTHER ACQUIRED DISORDERS

Malignancy, pregnancy, surgery, connective tissue diseases, lymphoproliferative diseases, myeloproliferative disorders, and dysproteinemias are recognized causes of hypercoagulability, but the mechanisms are unclear and may vary with each situation. With malignancy, excessive clotting is allegedly related to thrombo-plastin-like effects produced by tumor cells or their products. Mucin-producing malignancy has a high association of thrombosis. Excessive clotting with malignancy may also be caused by concomitant infections, effects of chemotherapy, malnutrition and possible folate deficiency with its consequences on homocysteine, and prolonged bed rest. In addition, venous access devices that are commonly used in cancer patients predispose to clotting (19-51); in fact, cancer patients often receive low-close warfarin (1 to 2 mg/day) to lessen the frequency of veno-occlusive disease. (52) Cancer patients also are relatively resistant to anticoagulation and have more episodes of recurrent thrombosis. (53) Pregnan cy associated clotting may relate to excess thromboplastin production; hypercoagulability is more frequent with pregnancy complications, such as abruptio placenta, amniotic fluid embolization, and retained dead fetus. Mechanisms of hypercoagulability with surgery are less clear but may relate to tissue trauma and/or the effects of bed rest. Previous clotting also predisposes to recurrence; some factors include clotting associated abnormalities in the anatomy of the vasculature and associated increased levels of coagulation factors as acute phase reactants. (42)

HEPARIN-INDUCED HYPERCOAGULABILITY

Heparin associated thrombocytopenia is often seen, but "heparin-induced hypercoagulability" is infrequent. In the hypercoagulable state, IgG antibodies form against platelet-heparin complexes that are sequestered on platelets at platelet Fc receptors and on endothelial cells where they may cause serious vascular occlusive disease and thrombocytopenia. Recently, it has been recognized that warfarin accelerates this phenomenon by further decreasing proteins of the protein C pathways, thereby enhancing hypercoagulability. (54) The treatment of heparin-induced hypercoagulability, including purpura fulminans, requires immediate discontinuance of heparin administration. Hirudin (leech anticoagulant) and argatroban (synthetic antithrombin) (55) are approved by the Food and Drug Administration and are the recommended treatment. Other options include ancrod (snake venom with antifibrinolytic activity), danaparoid (heparin, chrondroitin, and dermatan), and plasmapheresis. Low molecular weight heparin (LMWH) is risky be cause of potential cross reactivity with heparin antibodies.

TESTING FOR HYPERCOAGULABILITY

General screening for defects associated with hypercoagulability is often cost inefficient because the frequency of thrombosis in the general population is relatively low. Even when the population to be screened is at greater risk, such as pregnant women or women taking oral contraceptives, the overall incidence of thrombosis is still too low to justify the cost. However, assessment is reasonable for patients in whom thrombosis has occurred. A complete assessment for hypercoagulability can be expensive, as shown by Table 3. This list is reasonably complete, but many tests may be avoided with the input of appropriate clinical information. As an example, complete blood count, prothrombin time, and partial thromboplastin time may quickly point out possibilities such as lupus anticoagulant, heparin-induced hypercoagulability, and others. Costs may be further decreased with tests for the functional activity of coagulation proteins rather that measurements of protein levels (antigens).

In the setting of an acute thrombosis, the investigation for underlying defects is often difficult. Clotting, inflammation, and acute phase reactants alter coagulation regulatory proteins. Examples of variations in coagulation proteins as reflected by various conditions are shown in Table 4. (56-58) The testing of individuals who are already receiving anticoagulants should also be avoided because anticoagulants as well as the acute event confound the measured laboratory values. Moreover, it is unlikely that the data achieved from an investigation during acute thrombosis will alter the patient's treatment during the initial thrombotic event or for the subsequent few months. In some instances, a diagnosis can be inferred by a family study. When prolonged anticoagulation is used, later testing for underlying defects can be considered if a temporary cessation (7 to 10 days) of anticoagulation is possible. If it is necessary to test patients while they are taking anticoagulants, DNA techniques can be used for fact or V Leiden, MTHFR, and prothrombin 20210A. Levels of antithrombin can be obtained in patients who are heparinized, but these values are also influenced by circumstances noted in Table 4. Abnormalities that are detected or strongly implicated during the acute event should be tested again months later for confirmation. The diagnosis of hyperhomocysteinemia can be obtained by quantitative blood tests; inborn errors in metabolism are assayed for MTHFR, methionine synthase, B (12) mutants, or transport defects.

The clinical expressions of thrombosis depend on the genetic and acquired abnormalities of coagulation and their interactions. The frequency of multiple factors acting concurrently to increase the frequency of hypercoagulability is well established. (14,16-19,22-28) Also, the frequency of thrombosis in individual patients changes from time to time depending on their overall health profile. The presence of high-risk situations, such as malignancy, pregnancy, use of estrogens, and surgery, increase the chances of hypercoagulability in those with either inherited or acquired coagulation defects.

The testing for antiphospholipid syndrome requires both inhibitor assays (Russell's venom screening tests) and a search for antibodies against phospholipids and cardiolipins. (46,47) Mixing tests and coagulation assays for lupus anticoagulants are best performed in the absence of heparin or warfarin. Confirmation of antiphospholipid syndrome laboratory markers should be repeated at least 3 months later. Finally, laboratory testing for heparin associated antibody can identify its presence by functional and antigen assays; however, the diagnosis of heparin-induced hypercoagulability remains a clinical diagnosis.

TREATMENT OF ABNORMALITIES

The treatment of patients with abnormalities can be divided into acute therapy, long-term management, and prophylaxis in individuals with defects but no clinical illness. The management of acute thrombosis for most causes of hypercoagulability involves the use of heparin or LMWH (with the exception of "heparin associated hypercoagulability"). Currently, the effectiveness, safety, and outpatient use of LMWH (59) has resulted in a major change in clinical practice patterns. The use of warfarin is still required for most of these defects (inherited and acquired), but the duration of treatment is still unsettled. In general, the longer anticoagulants are used, the lower the frequency of recurrent thrombosis. However, longer use of anticoagulants raises added risks such as bleeding.

The prophylactic use of warfarin in individuals who are at risk with one or more hypercoagulable defects but in whom thromboembolic disease has never occurred is speculative, except for the use of LMWH in high-risk events such as surgery, trauma, or immobilization. It is important to remember that the use of warfarin for abnormalities of the protein C pathway requires that heparin or LMWH be started before the initiation of warfarin therapy. Protein C has the shortest half-life of the vitamin K-dependent factors, and the initiation of warfarin alone may deplete protein C levels rapidly enough to cause increased hypercoagulability. (60) Preparative use of heparin or LMWH obviates the complications of warfarin-induced skin necrosis. In cases with evidence of resistance to warfarin therapy, newly developed component therapy with protein C or antithrombin concentrates should be considered. (61,62)

Anticoagulation for pregnant women with hypercoagulability due to defects of the APC pathway is a concern, especially since warfarin can be teratogenic. If it is being used, warfarin should be stopped before anticipated pregnancy. During pregnancy, subcutaneous heparin or LMWH can be used until time of delivery. After delivery, warfarin is resumed but only after pretreatment with heparin or LMWH. Warfarin is present in milk during lactation; although the quantities may be small, many neonatologists recommend the avoidance of warfarin in lactating women.

Patients with malignancy deserve special consideration. Although acute thrombosis requires traditional treatment, long-term success may depend on effective treatment of the underlying malignancy such as is seen in acute promyelocytic leukemia. In addition, patients with malignancy also have other factors that predispose to clotting (venous access devices, prolonged bed rest, poor nutrition, infections). In many cancer centers, prolonged use of low-dose warfarin (1 to 2 mg/day) is used as prophylaxis.

Treatment of patients with hypercoagulability associated with antiphospholipid syndrome requires special considerations. The presence of laboratory abnormalities indicative of the syndrome in the absence of clinical evidence of disease does not mandate treatment. When anticoagulation is needed, warfarin is used. (63) In high-risk situations such as postoperative states, heparin compounds can be used before warfarin. The addition of steroids or immunosuppressive agents is of unproven benefit in the antiphospholipid syndrome. Nonetheless, sometimes it is used, especially if clinical and laboratory parameters are available to judge effectiveness. During pregnancy in a patient with antiphospholipid syndrome, subcutaneous heparin, LMWH, steroids, or aspirin can be tried. If fetal loss occurs despite these efforts, then the use of intravenous gammaglobulin for future pregnancies may be necessary. Of course, warfarin is contraindicated in pregnancy.

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(62.) Gabriel DA: The use of antithrombin III in the treatment of disseminated intrasvascular coagulation. Semin Hematol 1994; 31:60-64

(63.) Khamashta MA, Cuadrado MJ, Mujic F, et al: The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332:993-997

(64.) Hillarp A, Zoller B, Svensson PJ, et al: The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78:990-992

(65.) Brown K, Luddington R, Williamson D, et al: Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene. Br ] Haematol 1997; 98:907-909

(66.) Cumming AM, Keeney S, Salden A, et al: The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population. Br ] Haematol 1997; 98:353-355

TABLE 1. Defects Responsible for Hypercoagulability

Inherited

Activated protein C resistance (factor V Leiden)

Protein S deficiency

Protein C deficiency

Antithrombin deficiency

Hyperhomocysteinemia

Prothrombin 20210A allele

Dysplasminogenemia

High plasminogen activator inhibitor

Dysfibrinogenemia

Elevated factor VIII

Acquired

Antiphospholipid syndrome

Hyperhomocysteinemia

Miscellaneous

Thrombocythemia

Dysproteinemia

Heparin-induced thrombocytopenia

Estrogens

Birth control pills

Hormone replacement therapy

Noncoagulant factors

Malignancy

Pregnancy

Bed rest

Surgery

Trauma

Miscellaneous
TABLE 2

Frequency of Inherited Defects and Hypercoagulability (*)

                            Gene         Cause of
Disorder                 Frequency  Hypercoagulability

APC resistance           3.6%-6.0%      10%-64%
Protein S deficiency     0.5%           1.4%-7.5%
Protein C deficiency     0.33%          1.4%-8.6%
Antithrombin deficiency  0.1%           0.5%-4.9%
Prothrombin 20210A       0.7%-6.0%      5.0%-7.1%


(*)From Olds et al. (26)

APC = Activated protein C.

Data on prothrombin 20210A are approximated from multiple sources. (23,
64-66)
TABLE 3.

Charges for Hypercoagulability Tests (*)


Complete blood count, including
platelet morphology                      18.00
Prothrombin time, partial
thromboplastin time                      47.25
Tests for connective issue               87.00
APC resistance determination
(factor V Leiden)                       175.00
Antigenic and activity of protein C
and protein S                           443.00
Antithrombin III antigen and
activity                                120.00
Tests for lupus anticoagulant           272.00
Heparin-induced antibody testing        148.00
Homocysteine levels                     122.00
Methylenetetrahydrofolate reductase     175.00
Prothrombin 20210A                      175.00
Total                                $1,782.25

(*)Data obtained from nationally recognized reference laboratory.

APC = Activated protein C.

Testing is often more expensive when ordered on hospitalized patients.
TABLE 4

Factors Responsible for Altered Coagulation Values (*)

Situation                     Antithrombin  Protein C  Protein S

Pregnancy                     Decrease      Increase   Decrease
Oral contraceptive use        Decrease      Increase   Decrease
Acute deep venous thrombosis  Decrease      Decrease   Decrease
Disseminated intravascular    Decrease      Decrease   Decrease
coagulation
Surgery                       Decrease      Decrease   Decrease
Liver disease                 Decrease      Decrease   Decrease
Inflammation                  None          None       Decrease
Heparin                       Decrease      None       None/Increase
Oral anticoagulants           Increase      Decrease   Decrease

(*)Data from Adcock et al. (23)

Malignancy can represent one or more of these factors, such as
inflammation, liver disease, surgery, disseminated intravascula
coagulation.

KEY POINTS

* The best clue for the presence of hypercoagulability is a positive family history.

* The defects that are responsible for hypercoagulability can be divided into inherited defects and acquired forms.

* General screening for defects associated with hypercoagulability is often cost inefficient because the frequency of thrombosis in the general population is relatively low.

* Treatment of patients with abnormalities can be divided into acute therapy, long-term management, and prophylaxis in individuals with defects but no clinical illness.