Hereditary and Acquired Hypercoagulability  

Updated: Jan 05, 2018
Author: Paul Schick, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP 

Overview

Practice Essentials

Patients with acquired hypercoagulable states or hereditary thrombophilia are more likely to develop clots, venous thrombosis, and arterial thrombosis, than healthy individuals. Venous thrombosis and pulmonary embolism are associated with significant morbidity and mortality.

The most common acquired risk factors for hypercoagulability and thrombosis are as follows[1] :

  • Advanced age
  • Immobilization
  • Inflammation
  • Pregnancy
  • Oral contraceptive use
  • Obesity
  • Diabetes mellitus
  • Hormone replacement therapy
  • Cancer (especially adenocarcinoma)
  • Antiphospholipid syndrome
  • Sickle cell anemia and other hemolytic anemias

Given the high prevalence of obesity and diabetes in the United States, and the aging of the population, the incidence of thrombosis is likely to increase.

Idiopathic (unprovoked) venous thrombotic events are defined as the occurrence of venous thrombosis in the absence of any of the risk factors listed above. About 50% of patients presenting with a first idiopathic venous thrombosis have an underlying thrombophilia.

Hereditary thrombophilias should be suspected in individuals with a history of recurrent thromboembolism, thrombosis at a young age, and/or a family history of thrombosis. Hereditary thrombophilias include the following:

  • Factor V Leiden
  • Prothrombin 20210A
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency

Deficiencies of anticoagulant factors may also be acquired.

The objectives of this article are to provide an overview of hereditary thrombophilia and acquired hypercoagulability, to discuss indications for initiating a workup, and to review the selection and interpretation of laboratory tests for these disorders. The indications and options for anticoagulant therapy and prophylaxis, as well as the advantages and adverse effects of low molecular weight heparin (LMWH), direct thrombin, and factor Xa inhibitors are discussed.

For patient education information, see Blood Clots, Inherited Blood-Clotting Problems, and the Deep Vein Thrombosis Health Center.

Pathophysiology

Hemostasis is highly regulated to maintain a delicate balance between controlling bleeding in response to injury and avoiding excess procoagulant activity, to prevent hypercoagulability and thrombosis. The Virchow triad identifies the three underlying factors that are thought to contribute to thrombosis: hypercoagulability, hemodynamic dysfunction (ie, stasis—from immobilization or peripheral venous obstruction—or turbulence), and endothelial injury/dysfunction.

Hypercoagulability can result from the release of procoagulants from tumor cells or the presence of antiphospholipid antibodies (lupus anticoagulants). Insufficient inactivation of procoagulants due to impaired regulatory antithrombotic pathways can result in hypercoagulability. The presence of factor V Leiden or a mutant prothrombin can cause hypercoagulability.  

The neutralization of activated factor Xa and thrombin are impaired in antithrombin (AT) deficiency. The formation of activated protein C (APC), which is a key down-regulator of factor V and factor VIII, may be impaired by protein C deficiency or protein S deficiency. Such deficiencies may be hereditary or acquired.[2] The ability of APC to inactivate factor V and factor VII can be impaired in individuals with mutant factor V such as factor V Leiden. This is known as APC resistance. Individuals with a mutant prothrombin (variously termed prothrombin G20210A, prothrombin G2010A, and mutant factor II) generate excess prothrombin that is associated with hypercoagulability.

Normal endothelium provides a non-thrombotic surface. Injury to endothelium is accompanied by loss of protective molecules and expression of adhesive molecules, procoagulant activity, and mitogenic factors, leading to development of thrombosis, smooth muscle cell migration, and proliferation and atherosclerosis.[3] In Behcet disease, a generalized autoimmune vasculitis and endothelial dysfunction occurs, with protean consequences that include  thrombosis, mucocutaneous lesions, uveitis, and neurological abnormalities.

Thrombosis during pregnancy can be due to increased procoagulant factors, impaired fibrinolysis, venous stasis, and endothelial cell injury.[4] The risk of thrombosis is increased in patients on hormone replacement therapy. However, whether this risk is due to increased procoagulants or the presence of an underlying thrombophilia is not clear.[5]

Lupus anticoagulants are antiphospholipid antibodies that are associated with acquired hypercoagulability. The mechanisms for hypercoagulability in these patients remains poorly understood, but alteration of the regulation of hemostasis and endothelial cell injury might be responsible.[6, 7, 8] The inappropriate name for these antibodies is due to their initial discovery in patients with lupus—although they can also occur in individuals without lupus—and to their anticoagulant effect in vitro.

Non-O blood type is associated with an approximately two-fold increase in risk for venous thrombembolism. An inherited thrombophilic condition in association with non-O blood type further increases risk. A weaker, less well documented, association exists between non-O blood type and arterial thrombosis.[9]

In addition to thrombophilias resulting from individual mutations, an inherited susceptibility to venous thromboembolism may result from multigenic action. Research on multiple polymorphisms within the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways confirms a complex interrelationship that appears to increase the risk of venous thromboembolism.[10]

Activated protein C (APC) resistance

The ability of APC to inactivate factor V and factor VIII can be impaired in individuals with mutant factor V, such as factor V Leiden.  This is known as APC resistance. Individuals with a mutant prothrombin (variously termed prothrombin 20210A, prothrombin G2010A, and mutant factor II) generate excess prothrombin that is associated with hypercoagulability.[11]

Factor V Leiden

Factor V Leiden is resistant to APC and hence not inactivated (APC resistant). About 20-60% of patients with thromboembolism have a form of APC resistance, and factor V Leiden is responsible for 95% of APC resistance. 

Factor V Leiden (named after the city in the Netherlands where it was first identified, in 1994) results from a specific point mutation in the factor V gene, which is located in the long arm of chromosome one. Glutamine (Q) is substituted for arginine (R)-506 in the heavy chain of factor V (R506Q).  The amino acid substitution alters the APC cleavage site on factor V, causing a partial resistance to inactivation. 

About 5% of Caucasian Americans are heterozygous carriers of factor V Leiden. The carrier frequency among African Americans, Asian Americans, and Native Americans is less than 1% and in Hispanics is 2.5%. Carrier frequency is especially high—up to 14%—in whites of Northern European and Scandinavian ancestry. Inheritance is autosomal dominant. Most heterozygote carriers are asymptomatic while homozygotes have a high incidence of clinical thrombosis.[12]

The 5% of APC resistance not due to factor V Leiden results from a variety of factors. These include other genetic mutations, as well as acquired conditions such as pregnancy, oral contraceptives, and lupus anticoagulant, all of which may also cause APC resistance.[12]

Prothrombin G20210A

Prothrombin G20210A is a polymorphism in a noncoding region (nucleotide 20210A) of the factor II (prothrombin) gene that consists of replacement of guanine with adenine, and results in elevated prothrombin levels. This mutation occurs primarily in Caucasians. Heterozygotes are at minimal risk for thrombosis, but homozygotes are 2- to 3-fold increased risk for developing thrombosis.

Additional risks

While persons who are heterozygous for factor V Leiden and prothrombin G20210A are at minimal risk for thrombosis, the presence of a second risk factor such as immobilization and pregnancy greatly increases the risk for thrombosis. The screening of patients for mutant Factor V and prothrombin during pregnancy and prior to initiation of hormone replacement therapy to determine whether prophylactic anticoagulation is indicated appears to be logical, but it is controversial.

Epidemiology

Frequency

United States

Lupus anticoagulants and antiphospholipid syndromes are present in 4-14% of the population. Table 1 shows the incidence of hereditary hypercoagulable disorders in the general population and the risk for thrombosis and recurrent thrombosis.[13, 14] Other underlying risk factors are elevated levels of factor VIII, fibrinogen, and other coagulation factors. Increases in type-1 plasminogen activator inhibitor (PAI-1), D-dimers, and homocysteine are also reported to be risk factors.

Table 1.  Prevalence of Acquired or Hereditary Hypercoagulable Disorders and Risks of Venous Thrombosis. (Open Table in a new window)

Condition

Prevalence in General Population (%)

Relative Risk of VTE (%)

Relative Risk of Recurrent VTE (%)

Factor V Leiden

(heterozygous)

3-7

4.3

1.3

Prothrombin 20210A

(heterozygous)

1-3

1.9

1.4

Protein C deficiency

(heterozygous)

0.02-0.05

11.3

2.5

Protein S deficiency

(heterozygous)

0.01-1

32.4

2.5

Antithrombin deficiency

(heterozygous)

0.02-0.04

17.5

2.5

VTE = Venous thromboembolism

A study by Couturaud et al sought to identify risk factors and quantify the risk of venous thromboembolism in first-degree relatives of patients with a first episode of unprovoked venous thromboembolism.[14] The investigators found a prevalence of 5.3% of previous venous thromboembolism in the first-degree relatives. The strongest predictor of venous thromboembolism in this group was thrombosis at a young age. However, the presence of factor V Leiden or G20210A prothrombin genes in patients were weak independent predictors of venous thromboembolism in relatives.[14]

Mortality/Morbidity

Morbidity and mortality in patients with hypercoagulable states and thrombophilia are primarily due to venous thrombosis and pulmonary embolism. Pulmonary embolism is associated with a 1-3% mortality rate. The incidence of factor V Leiden and prothrombin 20210A is significantly greater than that of protein C, protein S, and antithrombin III (ATIII) deficiencies. However, the risk of venous thrombosis in protein C, protein S, and antithrombin III (ATIII) deficiencies is greater than in factor V Leiden and prothrombin 20210A, as shown in Table 1, above.

The risk for thrombosis can be markedly increased in patients with two or more risk factors for thrombosis. Any multiplicity of risk factors, whether hereditary thrombophilias or acquired risks, increases the risk for thrombosis.

Race-, Sex-, and Age-related Demographics

For details on the effects of race and sex on hereditary and acquired hypercoagulability, see the following articles[15, 16] :

The risk for thrombosis increases with age and associated immobility.

 

Presentation

History and Physical Examination

There are no specific clinical symptoms or signs directly attributable to acquired hypercoagulability or hereditary thrombophilic disorders. Rather, the clinical expressions of an underlying thrombophilia are predominantly venous thrombosis and pulmonary embolism.

Hereditary thrombophilia should be suspected in patients with a history of any of the following:

  • Recurrent venous thromboembolism
  • Venous thrombosis before age 40 years
  • A family history of venous thromboembolism
  • Thrombosis in unusual sites (eg, mesenteric vein, renal vein, hepatic, or cerebral thrombosis)

An association between hypercoagulability and severe obstructive sleep apnea has been reported.[17]

Purpura fulminans in infancy could suggest protein C deficiency. Deficiency of protein S or antithrombin III may also cause this disorder.

Thrombophilic disorders are usually associated with venous thrombosis. However, protein S, protein C, antithrombin deficiencies, and lupus anticoagulants have been associated with arterial thrombosis.

Patients with protein C and S deficiencies can develop warfarin-induced skin necrosis when placed on warfarin, since protein C and S are vitamin K–dependent factors and, hence are suppressed.

Lupus anticoagulants

Antiphospholipid antibodies (lupus anticoagulants) occur in about 20% of patients with systemic lupus erythematosus (SLE), but they are also associated with other autoimmune diseases. In addition, these antibodies may occur in patients taking phenothiazines, phenytoin, hydralazine, quinine, amoxicillin, and oral contraceptives.

Clinical criteria for indicating the presence of lupus anticoagulants (Sapporo criteria for the antiphospholipid syndrome) are as follows:

  • One or more episodes of arterial, venous, or small-vessel thrombosis, affecting any organ or tissue
  • Pregnancy morbidity: The risk for maternal and fetal morbidity increases after the 10th week of pregnancy; fetal mortality in pregnancy can include spontaneous abortions, prematurity, and stillbirths
  • Three or more unexplained consecutive spontaneous abortions after the 10th week of gestation

Causes

The most common acquired causes for hypercoagulability are the following:

  • Immobilization
  • Diabetes mellitus
  • Advanced age
  • Pregnancy
  • Obesity
  • Oral contraceptives use
  • Inflammation
  • Hormone replacement therapy
  • Cancer

Antiphospholipid antibodies (lupus anticoagulant) should also be considered.

Hereditary thrombophilias include the following:

 

 

 

DDx

Diagnostic Considerations

A number of disorders and conditions are associated with thrombosis, including the following:

Specific sites of thrombosis are discussed in Budd-Chiari Syndrome.

 

Workup

Laboratory Studies

The decision to initiate a laboratory workup for thrombophilia is complex.[18, 19, 20, 21] A workup for thrombophilia is usually indicated only in patients with one or more of the following risk factors:

  • Recurrent thromboembolic episodes
  • Thromboembolism at a young age (ie, <40 y)
  • A family history for thromboembolism
  • Thrombosis in an unusual site

Of patients with idiopathic venous thrombosis, which is defined as venous thromboembolism without any obvious risk factor, about 50% have an underlying thrombophilia. Therefore, some authors have recommended performing a thrombophilia workup in patients with idiopathic venous thrombosis.

The decision to order a thrombophilia workup can be difficult, because the identification of an underlying thrombophilia might not affect therapeutic strategy. If thrombophilia is detected in a patient with no history of thromboembolism, anticoagulation is usually not necessary. Conversely, patients with recurrent thromboembolic events should be anticoagulated even if their workup uncovers no evidence of an underlying thrombophilia or a lupus anticoagulant.

Inherited thrombophilia is often a consideration in children who develop thrombotic disease. Although identification of an inherited disorder is unlikely to influence acute management of the thrombotic event or the duration of anticoagulation, it may lead to diagnosis of the disorder in affected family members, who can then be counseled regarding their thrombotic risk.[22]

Some benefits may exist with testing patients for thrombophilia and antiphospholipid syndrome (lupus anticoagulants).The presence of more than one risk factor results in an incidence rate of venous thrombosis that is greater than the sum of the individual risks. For example, women with a prothrombotic mutation who are taking estrogen have a 25-fold greater risk of venous thrombosis than women without the mutation who are on estrogen.[23]

Patients who have an identifiable thrombophilic risk factor should be advised to have blood relatives tested, as this information would be important for their physicians, in  deciding whether to recommend oral contraception or hormone replacement therapy. Also, this will help determine whether these relatives should receive anticoagulation during surgery or immobilization.

In addition to the challenge of deciding who should be tested, clinicians need to be aware of when to test—or more precisely, when not to. Many of the tests (coagulation-based studies) should not be done while patients are on anticoagulants or during active thrombosis.

Numerous tests are available for each of the hypercoagulable disorders or thrombophilia. A D-dimer assay is useful as a general test for verifying the presence of thrombosis. Testing for specific disorders is described below.

Antiphospholipid syndrome

Antiphospholipid syndrome (lupus anticoagulant)[6, 7] screening tests are as follows:

  • Activated partial thromboplastin time (aPTT)
  • Prothrombin time (PT)
  • Mixing studies

Confirmation of the diagnosis is based on the following study results:

  • Prolonged phospholipid-dependent dilute Russell viper venom time (dRVVT), Increased titers of anticardiolipin antibodies (IgG and IgM)
  • Increased titers of anti-β(2)glycoprotein 1 antibodies (IgG and IgM)

Confirmatory test results should be positive on two occasions 12 weeks apart. Efforts to standardize these tests have been made, to enable reliable diagnosis of lupus anticoagulants and prediction of the risk for thrombosis. It has been suggested that the risk of thrombosis is greater when results from several of these tests are positive.[24]

For full discussion, see Antiphospholipid Syndrome and Antiphospholipid Antibody Syndrome and Pregnancy

Factor V Leiden

In patients with suspected factor V Leiden, coagulation testing with an activated protein C (APC) resistance assay should be done first, because a small fraction of APC resistance disorders are due to mutations other that factor V Leiden. In this assay, the ratio of aPTT testing performed with and without added APC is reported as the APC resistance (or sensitivity) ratio.[12]

A ratio of <2.3 suggests abnormal resistance to APC of hereditary origin. In patients who carry the factor V Leiden mutation, those who are homozygous have a very low APC resistance ratio, typically 1.1 to 1.4, while in heterozygous carriers  the ratio is usually 1.5 to 1.8.[12]

Patients with an abnormally low APC resistance assay result should undergo genetic testing for factor V Leiden. This test, which is a polymerase chain reaction (PCR) assay, can identify carriers and determine whether they are heterozygous or homozygous.

Antithrombin and prothrombin abnormalities

Available studies for antithrombin deficiency include both functional and antigenic assays. Functional studies should always be performed, because some cases of antithrombin deficiency may be associated with normal antigen levels. The functional study is a chromogenic heparin cofactor assay, which measures the ability of antithrombin to bind heparin and neutralize thrombin or factor Xa. Antithrombin deficiency can be acquired or represent either of two major hereditary types, and further immunologic assessment or DNA sequencing can be done to characterize the specific defect present.

For full discussion, see Antithrombin Deficiency.

Prothrombin (factor II) deficiency can be acquired (eg, due to severe liver disease, vitamin K deficiency, or development of an anti-prothrombin antibody) or hereditary. PCR testing can identify the prothrombin G20210A mutation. For more information, see Factor II.

Protein C deficiency

Although both functional (amidolytic) and antigen assays for protein C are available, functional (amidolytic) studies should always be performed to diagnose protein C deficiency, because some cases of protein C deficiency may be associated with normal antigen levels. For full discussion, see Protein C Deficiency

Protein S deficiency

For protein S deficiency, free antigen, total antigen, and functional assays are available. All three should be performed, because variants of protein S deficiency include the following:

  • Low total protein S, normal free protein S
  • Low-normal total protein S, low free protein S
  • Normal total and free protein S, functionally abnormal protein S

For full discussion, see Protein S Deficiency.

Precautions

Tests for hypercoagulability are affected by a number of conditions. Therefore, precautions are important when ordering laboratory studies to rule out an underlying thrombophilia. Limitations on studies that can be performed while patients are undergoing anticoagulation therapy include the following:

  • Testing for antithrombin functional activity should not be done while the patient is on unfractionated heparin or low molecular weight heparin (LMWH)
  • Testing for protein C or S functional activity should not be done while patients are on warfarin, since protein C and protein S are vitamin K–dependent proteins
  • Testing for APC resistance should be deferred when patients are on anticoagulant therapy, since this test is a coagulation assay; however, genetic tests of factor V Leiden can be ordered
  • DRRVT and phospholipid dependence for confirming lupus anticoagulants should not be done while the patient is being anticoagulated, since they are coagulation-based tests, but testing for anticardiolipid antibodies or anti-β(2)glycoprotein 1 antibodies can be performed during anticoagulation
  • Antithrombin, protein S, and protein C levels may be decreased during acute thromboembolism; therefore, both protein assays and functional assays of these proteins could be inaccurate during the acute phase of thromboembolic disease

The tests should be performed in laboratories that specialize in testing for thrombophilia. In addition, the results can be difficult to interpret, so interpretation is best done by a physician with considerable experience with thrombophilias.

 

Treatment

Medical Care

The goal of this article is not to review the management of thrombotic episodes, which is described in Deep Venous Thrombosis and Pulmonary Embolism. Management of specific prothrombotic disorders is detailed in the following Medscape reviews:

However, indications for anticoagulation to prevent thromboembolism in patients at risk should be considered (ie, primary anticoagulation or prophylaxis). Indications for primary prophylaxis include the following:

  • Prolonged hospitalization
  • Postoperative status
  • Immobilization
  • Certain orthopedic disorders
  • Active cancer

Primary prophylaxis in patients with thrombophilia during pregnancy is controversial. Patients with thrombophilia, a history of thrombosis, and other risk factors could be considered for prophylactic anticoagulation, especially during the first 6 weeks postpartum, when the risk of thrombosis is greatest. Anticoagulation should be strongly considered during pregnancy and in the postpartum period in patients with lupus anticoagulants.[25]

Conners provided guidance for the use of antepartum and postpartum prophylaxis with low molecular weight heparin (LMWH)  in women with a known thrombophilia or prior venous thrombosis. Management of LMWH prophylaxis use around labor and delivery was also reviewed.[26]

A multicenter study of 2554 patients revealed that after a first unprovoked venous thromboembolism (VTE), men have a 2.2-fold higher risk of recurrent VTE than do women; this risk remained 1.8-fold higher in men after adjustment for previous hormone-associated VTE in women.[27] In patients with a first provoked VTE, risk of recurrence does not differ between men and women, with or without adjustment for hormone-associated VTE. This information might be useful when deciding on whether long-term anticoagulation is indicated.

Patients who have a venous thrombotic event or pulmonary embolus should be anticoagulated (secondary anticoagulation). Warfarin,[28] heparin, and low molecular weight heparin (LMWH) have been used to manage venous thrombosis and pulmonary embolism. The direct oral anticoagulants (direct thrombin and direct Xa inhibitors) have become widely used for the treatment of VTE.

The decision to institute long-term or extended anticoagulation is complex, and it should be based on evidence of recurrent thrombosis and the assessment of all risk factors. The benefits of anticoagulation must outweigh the risk of bleeding, especially in elderly patients.

Some organizations recommend that patients with lupus anticoagulants be treated more aggressively. For example, the American College of Chest Physicians recommends 12 months of anticoagulation and consideration of long-term anticoagulation after a single thrombotic event in patients with antiphospholipid syndrome.[29]

Recommendations conflict on the optimal international normalized ratio (INR) level in patients with lupus anticoagulants who are on warfarin. In most cases, an INR of 2.0 to 3.0 is adequate. However, a higher INR might be desirable in patients with severe recurrent thromboembolic disease.

The risk of thrombosis should outweigh the risk of bleeding, especially in older patients, when deciding on anticoagulation.

Although strategies for assessment of thrombosis risk in adults are well established, similar guidelines for pediatric patients are lacking. Rühle and Stoll discuss risk prediction models for pediatric VTE.that have the potential for improving  thromboprophylaxis in children.[30]

Thrombin Inhibitors and Factor Xa Inhibitors

Direct factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and direct thrombin inhibitors (dabigatran), especially oral agents, have been developed as alternatives to warfarin. They have been approved for use in VTE prophylaxis, VTE treatment, and stroke prevention in non-valvular atrial fibrillation. In patients with heparin-induced thrombocytopenia, fondaparinux, a long-acting anti-Xa agent, is thought to have advantages over the short-acting antithrombin agents argatroban and bivalirudin.[31]

Direct oral anticoagulants have several possible advantages over warfarin, including the following:

  • No or limited interaction with other drugs and diet
  • Metabolic half-lives that allow for once- or twice-daily dosing
  • No need to monitor due to predictable pharmacokinetics
  • Possibly less bleeding complications

However, continued evaluation of the value of direct oral anticoagulants in complex thrombotic syndromes (eg, antiphospholipid antibody syndrome) and cancer patients is important before these agents are widely used in these complex cases.

Considerable efforts have recently been made to evaluate the role of oral and parenteral thrombin inhibitors and Xa inhibitors in preventing and managing thrombosis. The value of combining these agents with traditional warfarin and heparin therapy has been assessed. Disparate clinical settings such as patients with cancer, elderly patients, pregnancy, coronary artery disease, and surgical patients were studied. Although these studies have provided new information, many of them concluded that more information was needed to safely use new and standard anticoagulation therapy to provide optimal thrombosis prevention and management. these agents.[32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]

Hospital formularies will be challenged to appropriately use and manage these new medications.[35] The introduction of new-generation anti-Xa and direct thrombin inhibitors in patients receiving antiplatelet therapy was associated with a dramatic increase in major bleeding events.[36]

Consultations

A hematologist experienced in the diagnosis and management of thrombophilias and hypercoagulable disorders should be consulted. Equally important is that the laboratory evaluations for thrombophilia are carried out in laboratories with extensive experience with these tests.

Monitoring of Anticoagulation and Management of Bleeding

Unfractionated heparin therapy is monitored by measuring aPTT. Warfarin therapy is monitored by measuring PT (INR). The therapeutic ranges for heparin and warfarin are well established. However, the therapeutic ranges of direct thrombin and direct Xa inhibitors are not known.[43]

In general, LMWHs are administered without routine laboratory monitoring because the dosage effects are fairly consistent. The most common method for monitoring LMWH is a chromogenic assay for anti–factor Xa activity. This assay does not accurately estimate risk for bleeding or whether anticoagulation is sufficient to prevent thrombosis.

In practice, monitoring of LMWH is complicated by several factors.[44] The formulations available for clinical use vary in their composition and relative amounts of anti–factor IIa and anti–factor Xa activity. The optimal anti–factor Xa levels vary among these preparations. Thus, the physician must understand the characteristics of the LMWH being prescribed.[45]

The peak plasma concentrations are achieved at periods of about 4 hours following subcutaneous administration, and this is the time at which blood is usually drawn for monitoring. However, because of different dosage regimens (once or twice daily) and the possibility of different clearance rates, there is no perfect method for the optimum timing of monitoring or determination of desired target levels.[46]

Moreover, standardization of the chromogenic assay for anti–factor Xa activity from different providers and in different laboratories is not yet ideal.[29] Although high doses of LMWH are considered to pose a greater risk of bleeding, no correlation has been shown between anti–factor Xa activity levels and actual incidence of bleeding in patients. Likewise, the assay has limited predictive value for predicting antithrombotic efficiency.

Guidelines for monitoring of LMWH have been issued by the American College of Chest Physicians[47] and the British Committee for Standards in Haematology.[48] Both organizations indicate that routine monitoring is unnecessary for most patients. However, monitoring to be ascertain that no excess heparin accumulates in the blood should be conducted in patient subgroups such as the following:

  • Overweight and underweight individuals
  • Children
  • Patients with reduced creatinine clearance
  • Patients undergoing prolonged therapy (eg, for cancer)
  • Pregnant women (especially in the third trimester)

Monitoring thrombin inhibitors

The Ecarin clotting time (ECT),[49] activated clotting time,[50] and activated factor X tests have been used to monitor antithrombin agent therapy. The Ecarin clotting time is thought to be the most reliable test, but further clinical experience with this assay would be important to establish a more complete track record.[49] Unfortunately, the Ecarin clotting time is not available at most medical centers.

Reversal of anticoagulation

A major consideration in the administration of anticoagulants is the reversal of anticoagulation in patients who bleed. All currently available anticoagulants carry similar risks of serious bleeding episodes. Unfractionated heparin is readily reversible with protamine, but protamine carries some risk of hypotensive and anaphylactic reactions. Warfarin can be reversed in a short time by the administration of fresh frozen plasma, but reversal with vitamin K can take several hours.

Protamine has limited ability to reverse bleeding due to LMWH. Reversal agents such as low molecular weight protamines[51] and cationic concatemeric peptides[52] are under investigation but have not yet entered clinical use.

No antidote for factor Xa inhibitors (eg, fondaparinux, rivaroxaban) is currently available. The long half-lives of LMWH and fondaparinux and the possibility of continued release into the circulation from the site of subcutaneous injection further complicates the reversal process.

Likewise, no antidotes are available for lepirudin, bivalirudin, and argatroban, or for the oral direct thrombin inhibitors that are currently in clinical trials.

Recombinant factor VIIa has been proposed as a reversal agent for patients who bleed while undergoing anticoagulation. However, as yet there have been no controlled studies to determine its efficacy. Thrombosis may be a significant risk of recombinant factor VIIa therapy.

In summary, it has been proposed that monitoring LMWH and direct thrombin inhibitors is not necessary since their effects are predictable.[53] This recommendation is in part due to the lack of reliability or unavailability of the tests for monitoring LMWH and thrombin inhibitors. For example, factor Xa levels are not reliable for determining whether the level of anticoagulation is sufficient to prevent thrombosis, as well as not reliable for predicting the risk for bleeding.

The inadequacy of monitoring tests and the fact that antidotes are not available places patients who bleed at considerable risk, especially because some of the LMWH and thrombin inhibitors have a long half-life.[54] The reversal of bleeding due to LMWH and thrombin inhibitors, especially if the agent has a long half-life, has been difficult.

Recent developments in monitoring thrombin and Xa inhibitors and in developing antidotes

There has been progress in developing antidotes to direct thrombin and factor Xa inhibitors.[55] Idarucizumab, a humanized monoclonal antibody that binds to and inactivates dabigatran, has received expedited approval from the US Food and Drug Administration (FDA).

Andexanet alfa is a genetically engineered factor Xa molecule that has no procoagulant activity but can bind with and neutralize both direct factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) and the factor Xa inhibitors that act through antithrombin (LMWHs and fondaparinux). A phase 3b–4 study of andexanet for treatment of acute major bleeding in patients receiving a factor Xa inhibitor is currently recruiting participants.

 

Medication

Medication Summary

See Medical Care.

 

Follow-up

Deterrence/Prevention

If a patient is known to have a lupus anticoagulant or a thrombophilia, it is important to avoid oral contraceptives and hormone replacement therapy. Also, prophylactic anticoagulation should be considered in patients with additional risk for venous thrombosis, such as immobilization or surgery.

The risk of venous thrombosis is considerably greater in patients with two hereditary thrombophilias or with a thrombophilia and an acquired hypercoagulable disorder. Prophylactic anticoagulation should be considered in these circumstances.

Prognosis

The risk of thrombosis in a person with hypercoagulability varies with the underlying condition (see Epidemiology). The prognosis is probably worse in patients with antithrombin III deficiency and lupus anticoagulants than in those without these factors.

 

Questions & Answers

Overview

Which conditions are patients with hereditary and acquired hypercoagulability at higher risk of developing?

What are the most common risk factors for acquired hypercoagulability and thrombosis?

How do obesity and diabetes affect the incidence of acquired hypercoagulability?

What are idiopathic venous thrombotic events?

What are the hereditary thrombophilias?

What is the role of the Virchow triad in the pathogenesis of hereditary and acquired hypercoagulability?

What is the pathogenesis of hypercoagulability?

What is the role of hemodynamic dysfunction in the pathogenesis of hereditary and acquired hypercoagulability?

What is the role of endothelial injury in the pathogenesis of hereditary and acquired hypercoagulability?

Which factors increase the risk of acquired hypercoagulability during pregnancy?

What is the pathophysiology of hereditary and acquired hypercoagulability in lupus?

What is the pathophysiology of hereditary and acquired hypercoagulability in non-O blood type?

What is the role of genetics in the pathogenesis of hypercoagulability?

What is the role of activated protein C (APC) resistance in the pathogenesis of hypercoagulability?

What is the role of factor V Leiden resistance in the pathogenesis of hypercoagulability?

What causes factor V Leiden in the pathogenesis of hypercoagulability?

What is the incidence of factor V Leiden in hereditary and acquired hypercoagulability?

What is the role of prothrombin G20210A in the pathophysiology of hereditary and acquired hypercoagulability?

When should patients be screened for factor V Leiden and prothrombin G20210A to prevent hypercoagulability?

What is the prevalence of hereditary and acquired hypercoagulability in the US?

What is the incidence of venous thromboembolism in first-degree relatives of patients with hereditary and acquired hypercoagulability?

What is the mortality rate for hereditary and acquired hypercoagulability?

What significantly increases the risk for hereditary and acquired hypercoagulability?

Which age group is at highest risk for hypercoagulability?

Presentation

What are the clinical symptoms of underlying hereditary and acquired hypercoagulability?

What history findings suggest a hereditary thrombophilic disorder?

Which disorders are suggested in the presence of purpura fulminans in infancy?

Which conditions may cause arterial thrombosis?

Which disorders are associated with antiphospholipid antibodies (lupus anticoagulants)?

What are the Sapporo diagnostic criteria for antiphospholipid syndrome?

What are the most common acquired causes for hypercoagulability?

DDX

Which conditions should be included in the differential diagnosis of hereditary and acquired hypercoagulability?

Workup

When is a workup for hereditary and acquired hypercoagulability indicated?

Is thrombophilia workup indicated in patients with idiopathic venous thrombosis?

What are the challenges in the decision to order a workup for hereditary and acquired hypercoagulability?

What are the indications for a workup for hereditary and acquired hypercoagulability in children?

What are the benefits of testing for thrombophilia and antiphospholipid syndrome (lupus anticoagulants) in hereditary and acquired hypercoagulability?

What are the testing recommendations for patients who have an identifiable thrombophilic risk factor?

Which tests are available to detect hereditary and acquired hypercoagulability?

Which screening tests are used for antiphospholipid syndrome (lupus anticoagulant) in hereditary and acquired hypercoagulability?

How is the diagnosis of antiphospholipid syndrome (lupus anticoagulant) confirmed in hereditary and acquired hypercoagulability?

Which lab tests are performed in patients with suspected factor V Leiden?

Which lab results suggest factor V Leiden APC resistance in hereditary and acquired hypercoagulability?

What is the role of antithrombin deficiency studies in the evaluation of hereditary and acquired hypercoagulability?

Which studies are performed in the diagnosis of a protein C deficiency in hereditary and acquired hypercoagulability?

Which studies are performed in a diagnosis of a protein S deficiency in hereditary and acquired hypercoagulability?

What are the limitations of lab studies used to rule out an underlying thrombophilia in hereditary and acquired hypercoagulability?

Treatment

What are the indications for primary prophylaxis in hereditary and acquired hypercoagulability?

What is included in the medical care for hypercoagulability during pregnancy?

What are the treatment options for a venous thrombotic event or pulmonary embolus in hereditary and acquired hypercoagulability?

What is the basis for the decision to institute long-term or extended anticoagulation in hereditary and acquired hypercoagulability?

What is the basis for the decision to institute long-term or extended anticoagulation in patients with lupus anticoagulants in hereditary and acquired hypercoagulability?

How is the risk of thrombosis versus the risk of bleeding weighed in the treatment of hereditary and acquired hypercoagulability?

How is thrombosis risk assessed in pediatric patients with hereditary and acquired hypercoagulability?

What is the role of direct factor Xa inhibitors and direct thrombin inhibitors in the treatment of hereditary and acquired hypercoagulability?

What are the advantages of direct factor Xa inhibitors and direct thrombin inhibitors in the treatment of hereditary and acquired hypercoagulability?

What is the role of oral and parenteral thrombin inhibitors and Xa inhibitors in the prevention of thrombosis?

Which specialist consultations are needed for the treatment of hereditary and acquired hypercoagulability?

How is unfractionated heparin therapy monitored during the treatment of hereditary and acquired hypercoagulability?

How is low molecular weight heparin (LMWH) monitored during the treatment of hereditary and acquired hypercoagulability?

What are the factors that complicate the monitoring of low molecular weight heparin (LMWH) in the treatment of hereditary and acquired hypercoagulability?

What are the American College of Chest Physicians (ACCP) and British Committee for Standards in Haematology guidelines for monitoring low molecular weight heparin (LMWH) in the treatment of hereditary and acquired hypercoagulability?

How are thrombin inhibitors monitored during the treatment of hereditary and acquired hypercoagulability?

How bleeding episodes managed in hereditary and acquired hypercoagulability?

What is the role of protamine in the treatment of hereditary and acquired hypercoagulability?

What methods are used to reverse anticoagulation due to factor Xa in the treatment of hereditary and acquired hypercoagulability?

What is the role of recombinant factor VIIa in the treatment of hereditary and acquired hypercoagulability?

What is the role of monitoring during anticoagulation therapy for hereditary and acquired hypercoagulability?

What is the role of idarucizumab in the treatment of hereditary and acquired hypercoagulability?

Follow-up

What are indications for prophylactic anticoagulation in hereditary and acquired hypercoagulability?

What is the prognosis of hereditary and acquired hypercoagulability?