Hematology

Hypercoagulable states

Jump to Section

Hypercoagulable states

What every physician needs to know about hypercoagulable states:

In the broadest sense, a hypercoagulable state is any acquired or inherited condition that increases the risk of thromboembolism. It is important to remember that all three elements of Virchow's triad, hypercoagulability, stasis and vessel wall disease, contribute to the pathogenesis of thromboembolism.

The focus of this section will be on processes that increase the coagulant potential of the blood.

Acquired causes of hypercoagulability are more common than inherited hypercoagulable states and often have more potent thrombotic stimuli.

Acquired causes of hypercoagulability include:

  • Major surgery

  • Major trauma

  • Active cancer

  • Antiphospholipid syndrome (APS)

  • Adverse drug reactions, that is, heparin-induced thrombocytopenia (HIT)

  • Inflammatory/infectious disease, for example, systemic lupus erythematosus, inflammatory bowel disease, HIV infection

  • Pregnancy/post-partum

  • Medications, for example, oral contraceptives, hormone replacement therapy, et cetera (see Table I)

Table I.

Acquired risk factors for venous thromboembolism

Except for APS and HIT, there are no laboratory diagnostic tests to identify precisely which patients with these acquired disorders are at risk for venous thromboembolism (VTE). Some comments about APS are included in this section, and the subject is discussed in more detail in a separate chapter. HIT is also the subject of a separate chapter.

Inherited hypercoagulable states are usually the result of heterozygous mutations; occasionally of double heterozygosity for two different gene defects; and, rarely, homozygous mutations in both alleles of a single gene. The propensity for and severity of thrombotic complications increases from heterozygous to double heterozygous to homozygous mutations. Unless stated otherwise, the comments throughout this section refer to heterozygous conditions. Inherited hypercoagulable states are shown (in approximate order of prothrombotic potential) in Table II and Table III.

Table II.

Inherited and acquired thrombophilia and venous thromboembolism risk

Table III.

Inherited and acquired thrombophilic disorders and incidence of venous thromboembolism

Antithrombin (III) deficiency

(15 to 20 fold relative risk [RR])

Annual incidence of thrombosis 1.8%, prevalence 1/2-5000.

Antithrombin (AT) binds and inactivates activated serine proteases such as factor Xa and factor IIa (thrombin). Its activity is accelerated 1,000 fold by heparin, which is the rationale for the use of heparin as an anticoagulant. Antithrombin deficiency can result from mutations that affect protein production (type I AT [antithrombin] deficiency) or synthesis of a dysfunctional protein (type II AT deficiency). Type I AT deficiency is the most common inherited form among patients with thrombosis (60% of all patients with thrombosis and AT deficiency), while type II deficiency is the most common form in the general population (88% of all members of the general public identified as having AT deficiency). Type II AT deficiency can be caused by mutations in the active site (so-called Type IIa AT deficiency, which is rarer but associated with a greater risk of VTE) and mutations in the heparin binding site (so-called Type IIb AT deficiency, which is more common and is associated with smaller increase in VTE risk).

Acquired causes of antithrombin deficiency include acute thrombosis, disseminated intravascular coagulation (DIC), heparin therapy, nephrotic syndrome, L-asparaginase therapy, and liver disease.

Protein C deficiency

(15 to 20 fold RR)

Annual incidence of thrombosis 1.5%, prevalence, 1/500.

Protein C circulates in an inactive proenzyme form that is activated by thrombin bound to the endothelial membrane proteins, thrombomodulin and endothelial protein C receptor. Activated Protein C functions as an anticoagulant by cleaving and inactivating activated factor V and VIII. These reactions are accelerated in the presence of free protein S. Mutations that reduce protein synthesis (type 1 protein C deficiency) or result in the production of a dysfunctional protein C (type 2 protein C deficiency) have been identified. Protein C is a vitamin K dependent coagulation protein.

Acquired protein C deficiency can result from vitamin K deficiency, vitamin K antagonist (for example, warfarin) therapy, acute thrombosis, DIC, or liver disease.

Protein S deficiency

(15 to 20 fold RR, prevalence 1/1200)

Protein S serves as a cofactor for protein C, optimizing its inactivation of activated factor V and VIII. Protein S exists in the plasma in two forms, one free, the other bound to C4b-binding protein, a complement regulatory protein. The equilibrium between free and bound protein S is influenced by the quantity of C4b-binding protein. Higher concentrations of C4b-binding protein lead to lower concentrations of free protein S. Since free protein S has greater protein C cofactor activity, reductions in free protein S are associated with reduced protein S activity. Free protein S also serves as a cofactor for tissue factor pathway inhibitor and its inactivation of factor Xa. Protein S deficiency can occur due to decreased production of protein S (type I protein S deficiency), production of a dysfunctional protein S (type II protein S deficiency), or production of a protein S protein that is preferentially bound to C4b-binding protein (type III protein S deficiency).

Acquired protein S deficiency can result from vitamin K deficiency, vitamin K antagonist (for example, warfarin) therapy, acute thrombosis, DIC, liver disease, as well as any condition that increases the concentration of C4b-binding protein, including pregnancy, estrogen therapy, and inflammatory disorders.

Factor V Leiden

Heterozygotes 5 fold RR, homozygotes 50 fold RR.

Prevalence of heterozygotes - American Caucasian 5%, American Latino 2%, African American 1%, Native Americans 1%, Asian Americans, 0.5%, Native Africans and Asians 0%.

Factor V Leiden is a mutation that disrupts the first activated protein C (APC) cleavage site in activated factor V. This mutation slows the inactivation of activated factor V, a critical cofactor for factor Xa activation of prothrombin. Cleavage of Factor V at this same site normally produces a form of factor V that serves as a cofactor for the inactivation of factor VIIIa; therefore, the Factor V Leiden mutation slows the inactivation of both factor Va and factor VIIIa, critical cofactors in the coagulation cascade.

Prothrombin gene G20210A mutation

Heterozygotes 2 to 3 fold RR

Prevalence of heterozygotes - American Caucasians 1 to 2%, African Americans 0.2%

The prothrombin G20210A gene mutation increases the translational efficiency of prothrombin mRNA (messenger RNA) resulting in approximately 25% increase in prothrombin protein levels.

Elevated factor VIII levels

3 to 5 fold RR

Prevalence of FVIII levels above 150% was 11% in controls in the Leiden Thrombophilia Study

The genetic basis of inherited elevations of factor VIII activity remains unclear. Factor VIII is a critical cofactor for factor IX in the activation of factor X. Consequently, elevated levels likely increase thrombin generation. Acquired elevations can be seen in conjunction with estrogen therapy, pregnancy, and in the presence of inflammatory disorders.

Elevated factor IX levels

2 to 3 fold RR

Prevalence: 10% of controls in the Leiden Thrombophilia Study had factor IX antigen levels above 129 IU/dL

Factor IXa activates factor X in conjunction with factor VIIIa. Elevated factor IX levels likely increase thrombin generation in affected individuals. Acquired elevation of factor IX levels can be seen in association with estrogen therapy.

Elevated factor XI levels

1.5 to 2.5 RR

Prevalence: 10% of controls in the Leiden Thrombophilia Study had factor XI antigen levels above 121 IU/dL

Factor XI activates factor IX in the intrinsic pathway, contributing to the formation of the tenase complex (factor IXa - factor VIIIa) and, thus, additional thrombin generation. The consequences of this thrombin burst are increased fibrin formation, platelet activation, and activation of thrombin activatable fibrinolysis inhibitor which reduces clot lysis.

Hyperhomocysteinemia

2 fold RR

Prevalence: 5% of individuals in the general population have mild hyperhomocysteinemia (15 to 30 micromol/L), homocystinuria prevalence 1/350,000 (homocysteine greater than 100 micromol/L, 50% of individuals with homocystinuria have thromboembolism by 30 years of age).

Homocysteine is a sulphur containing amino acid that is converted to methionine by methionine synthase with vitamin B12 as a cofactor and N5-methyl-tetrahydrofolate as a methyl donor. Homocysteine is converted to cysteine via cystathionine by cystathionine beta synthase (CBS) with vitamin B6 as a cofactor. Patients with homocystinuria have CBS mutations. High concentrations of homocysteine have been associated with vascular damage and an increased risk of venous and arterial thromboembolism.

Methylenetetrahydrofolate reductase gene mutation

homozygosity 1.5-fold RR

MTHFR gene mutation C677T- approximately 10% prevalence

Methylenetetrahydrofolate reductase is the enzyme responsible for conversion of N5, N10 methylene tetrahydrofolate into N5-methyl-tetrahydrofolate, the form necessary for conversion of homocysteine to methionine. Thermolabile mutations in this enzyme reduce enzyme stability and levels and, thus, can predispose affected individuals to hyperhomocysteinemia due to a deficiency of N5-methyltetrahydrofolate.

Plasminogen activator inhibitor-1 (PAI-1) polymorphism

PAI-1, 4G/4G homozygosity associated with 1.14 fold increased risk of VTE, compared to other alleles

Plasminogen activator inhibitor-1 binds to, and inactivates, plasminogen activators such as tissue plasminogen activator, thus reducing generation of plasmin. Consequently, high levels of PAI-1 that result from inheritance of two 4G alleles could reduce clot lysis and increase the risk for thromboembolism.

Dysfibrinogenemia

(rare, 400 families reported in the literature, associated with increased recurrence rate of thromboembolism)

Mutations in the α, β or, γ chains of fibrinogen can result in fibrinogen molecules that are resistant to fibrinolysis.

What features of the presentation will guide me toward possible causes and next treatment steps:

It is important to remember that the presence of thrombophilia has only been weakly associated with recurrent VTE and the results of testing have not been demonstrated to improve outcomes after a first event. This limitation should be recognised by clinicians and emphasized to patients who desire thrombophilic testing.

Clinical features that are associated with a greater chance of underlying thrombophilia include:

  • Unprovoked thromboembolism

- The presence of a strong provoking risk factor (e.g. surgery) suggests that an underlying hypercoagulable state is less likely to be present. However, many clinicians consider unprovoked VTE a reason to consider long-term anticoagulation, regardless of the presence of an underlying thrombophilic defect.

  • VTE at young age (age less than 50 years)

- Potent hypercoagulable states often precipitate VTE early in life. Fifty percent of AT deficiency patients have their first clot before age 50. In contrast, only 5-10% of patients with FV Leiden have a thrombotic event by age 60 years.

  • Recurrent VTE

- Suggests that thrombophilia may be present, particularly in the setting of recurrent unprovoked VTE. However, most clinicians would consider long term anticoagulation without pursuing a thrombophilia evaluation in this situation.

  • Unusual location

- Mesenteric vein thrombosis or cerebral venous sinus thrombosis are often associated with thrombophilia in the absence of other situational risk factors such as myeloproliferative neoplasm, paroxysmal nocturnal hemoglobinuria, or surgery.

  • Autoimmune disorder

- The presence of an autoimmune disorder indicates that APS could be present.

  • Thrombosis during treatment

- Thrombosis during treatment with unfractionated or low molecular weight heparin should prompt consideration of HIT.

Note: There is increasing recognition that thrombophilia testing has limited impact on therapeutic decision making or outcomes. Observational studies have noted that if APS is excluded, patients with positive results on hypercoagulable testing do not have a significantly higher risk of recurrence than patients without identifiable hypercoagulable states. This result is a consequence of the small number of patients with high risk hypercoagulable states (antithrombin, protein C and S deficiency, antiphospholipid syndrome, factor V Leiden homozygosity, or combined heterozygosity for factor V Leiden and the prothrombin gene mutation) and, perhaps, overly broad diagnostic criteria for hypercoagulable states (that is, antithrombin activity less than 80U/dL).

Factor V Leiden heterozygotes are only at 1.5 fold increased risk of recurrent VTE, a difference that, alone, does not warrant long-term therapy. In contrast, the clinical setting of a thrombotic event (for example, triggered versus unprovoked) has a major impact (10 fold difference) on recurrence rates. Since many investigators consider unprovoked VTE to be an indication for long-term anticoagulation, thrombophilia testing is probably not necessary in most patients.

Thrombophilia testing may be most helpful in the following situations:

  • Patient wants to know the reason for their thromboembolism

- Although that reason may not influence therapy in many instances.

  • Diagnosis of antiphospholipid syndrome may warrant long-term therapy

  • Diagnosis of antithrombin, protein C or protein S deficiency, or homozygosity for factor V Leiden warrants consideration of long-term therapy, as does compound heterozygosity for factor V Leiden and the prothrombin gene mutation

Hypercoagulable states to consider in patients with VTE are: antithrombin (III) deficiency, protein C deficiency, protein S deficiency, factor V Leiden, prothrombin gene mutation, antiphospholipid syndrome, dysfibrinogenemia, HIT, and chronic disseminated intravascular coagulation (the latter as seen in patients with cancer).

Hypercoagulable states to consider for arterial thromboembolism are: antiphospholipid syndrome, dysfibinogenemia, HIT and chronic DIC.

Hypercoagulable conditions to consider in selected situations:

  • Cancer

- Unprovoked venous or arterial thromboembolism in the older patient (age greater than 50 years), recurrent thromboembolism in the presence of therapeutic anticoagulation (INR [international normalized ratio] equals two or more), particularly in association with migratory thrombophlebitis and DIC (disseminated intravascular coagulation), should raise suspicions for the presence of an underlying cancer.

  • Myeloproliferative neoplasm (for example, polycythemia vera)

- Venous or arterial thromboembolism in the presence of findings consistent with a myeloproliferative neoplasm (for example, idiopathic absolute erythrocytosis, thrombocytosis, splenomegaly) should prompt consideration of these diseases. A red cell volume/plasma volume study, serum erythropoietin, and JAK2, CALR and MPL mutation should be considered for further evaluation.

  • Heparin-induced thrombocytopenia

- Venous or arterial thromboembolism in the presence of thrombocytopenia, or a significant reduction in platelet count (50%) or during therapy with unfractionated or low molecular weight heparin should raise suspicions for HIT. Consider pre-test probability assessment with the 4T score or HEP (HIT Expert Probability) score and testing with the heparin/platelet factor 4 immunoassay and/or serotonin release assay testing.

  • Paroxysmal nocturnal hemoglobinuria

- Venous or arterial thromboembolism in association with cytopenias, intravascular hemolysis, or esophageal spasm should raise concerns for the possibility of PNH. Consider testing for PNH with flow cytometry for CD55 and CD59.

Hypercoagulable states with unclear benefit of testing (arguably most hypercoagulable states except perhaps antiphospholipid syndrome). Testing for the following disorders is probably the least beneficial:

  • Elevated factor VIII levels

Associated with an increased risk of initial (3 to 5 fold) and recurrent VTE (up to 6 fold). However, factor VIII is also an acute phase reactant, and this can make interpretation of test results difficult. One large family study found elevated factor VIII activity to be associated with a modest risk of recurrent VTE (7% at two years), similar to factor V Leiden heterozygosity.

  • Elevated Factor IX levels

Not associated with an increased risk of recurrence in one large family study.

  • Elevated factor XI levels

Not associated with an increased risk of recurrent VTE in one large family study.

  • Hyperhomocysteinemia

Moderate elevations of homocysteine (15 to 30 mcmol/L) have been associated with a 2 fold increase in initial and recurrent venous and arterial thromboembolism in some studies, although a large family study found no increased risk associated with homocysteine levels greater than 18.5 micromolar. Furthermore, randomized controlled trials of vitamin supplementation found no reduction in arterial or venous thromboembolism despite normalization of homocysteine levels. Higher levels of homocysteine associated with homocystinuria (homocysteine greater than 100 micromol/L) are rare and typically resistant to vitamin supplementation. Therefore, the value of homocysteine measurement in the typical patient (in the absence of findings associated with homocystinuria) with thromboembolism is unclear.

  • Methyltetrahydrofolate reductase (MTHFR) gene mutations (C677T, A1298C)

Thermolabile mutations in MTHFR that can result in mild to moderate hyperhomocysteinemia in patients with limited folate and B12 intake. However, in developed countries these common thermolabile mutations have not been associated with hyperhomocysteinemia due to widespread availability of diets rich in nutrients. MTHFR mutations have not been shown to be a risk factor for thromboembolism; therefore, testing for these genetic variants is of questionable value in hypercoagulable assessments.

  • Plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphism

PAI-1 is a negative regulator of plasminogen activators (for example, tissue plasminogen activator). PAI-1 deficiency has been associated with a tendency for increased bleeding because of excessive fibrinolysis. Therefore, elevations in PAI-1 might be anticipated to contribute to hypercoagulability. The 4G PAI-1 allele is associated with higher PAI-1 levels, but it has not been associated with any significant increase in thrombotic potential in the absence of other more significant hypercoagulable states (for example, factor V Leiden). Therefore, testing for this entity is of unproven clinical value.

  • Dysfibrinogenemia

Four hundred families with dysfibrinogenemia have been reported. The mutations that impair fibrinolysis are associated with thrombosis. It remains unclear whether or not dysfibrinogenemia is a risk factor for recurrent thromboembolism.

What laboratory studies should you order to identify hypercoagulable disorders and how should you interpret the results?

Factor V Leiden

Diagnosis relies upon the activated protein C resistance assay and factor V Leiden DNA-based assays. The activated protein C resistance assay is the screening test for factor V Leiden. It is performed by adding activated protein C (APC) to patient plasma, diluted in factor V deficient plasma. Activated protein C cleaves factor V and thus prolongs the clotting time of the sample based upon the proportion of the patient's factor V that is mutated (that is, less susceptible to APC cleavage than normal) or unmutated (that is, normally susceptible to APC cleavage). The test is reported as a ratio of the clotting time, with addition of APC over the clotting time without APC. (See Table IV).

Table IV.

Thrombophila testing: tests, timing and artifacts

Example:

aPTT (activated partial thromboplastin time) in seconds with APC/aPTT without APC = 65 seconds/25 seconds = ratio 2.6.

Factor V normal ratio greater than 2.1

Factor V Leiden heterozygous ratio 1.6 to 2.0

Factor V Leiden homozygous ratio 1.2 to 1.5

The APC resistance assay can be done in the presence of heparin (up to 1.0 unit/mL), warfarin, or acute thrombosis.

Positive results are confirmed with DNA-based assays, that is, factor V Leiden PCR (polymerase chain reaction).

Heterozygotes have one copy of the factor V Leiden gene and a 1.56 fold increased risk (95% CI [confidence interval] 1.14 to 2.12) of recurrent VTE, compared to patients without factor V Leiden. Although the risk of recurrence in patients with factor V Leiden is increased, most experts do not consider factor V Leiden heterozygosity alone as a reason to continue anticoagulation indefinitely. This decision should be made in conjunction with other clinical factors influencing the risk of recurrence (for example, unprovoked versus triggered VTE).

Factor V Leiden homozygotes have mutations in both of their factor V alleles and are at 2.65 fold higher risk of recurrent VTE (95% CI 1.2 to 6.0). Compound heterozygotes for factor V Leiden and the G20210A prothrombin gene mutation are likely at increased risk of recurrent VTE (Odds Ratio [OR] 4.81; 95% CI, 0.50 to 46.3). Factor V Leiden carriers are not at increased risk for myocardial infarction or stroke.

Prothrombin gene G20210A mutation

Diagnosis relies upon DNA-based assays. These assays can be done in the presence of anticoagulation or acute thrombosis. Heterozygotes have one copy of the prothrombin gene mutation. Homozygotes have both of their prothrombin genes mutated. Heterozygosity for the prothrombin gene mutation is not associated with a significantly increased risk of recurrent VTE (OR, 1.45; 95% CI, 0.96 to 2.2). It remains unclear whether homozygotes for the prothrombin gene mutation are at increased risk of recurrent VTE. The prothrombin gene mutation is not an important risk factor for stroke except perhaps in children and young adults. Presence of the prothrombin gene mutation alone is not considered a justification for long-term anticoagulation.

Antithrombin deficiency

Initial diagnosis relies upon antithrombin activity assays. These assess the functional level of antithrombin in patient plasma by determining residual thrombin activity, using a chromagenic substrate, after addition of heparin and an excess of thrombin. The patient's antithrombin activity is inversely proportional to the (uninhibited) thrombin activity of the test mixture. Antithrombin antigen assays are immunoassays that are useful to determine the amount of protein in a patient's sample, but are not as sensitive as activity assays for antithrombin deficiency, because occasional patients have antithrombin deficiency due to the synthesis of a dysfunctional protein (rather than inadequate protein production).

Congenital AT deficiency is associated with a 15 to 20 fold increased risk of first thrombosis (1.8% per year) and an increased risk of recurrent VTE off anticoagulation (10% per year). The risk posed by AT deficiency for arterial thromboembolism is unclear. The presence of AT deficiency is considered an important risk factor for recurrence and, thus, its presence is considered justification to consider long-term anticoagulation.

Protein C deficiency

Protein C activity is the appropriate screening test for protein C deficiency, as it will identify patients with quantitative as well as qualitative protein C deficiency. Protein C antigen assays can be performed if the protein C activity is low, in order to determine the patient's deficiency type.

Congenital protein C deficiency is associated with a 15 to 20 fold increased risk of first thrombosis (1.5% per year) and an increased risk of recurrent VTE off anticoagulation (6% per year). Convincing evidence of an increased risk of arterial thromboembolism with protein C deficiency is lacking. Because of its strong association with recurrent VTE, protein C deficiency is considered an indication for long-term anticoagulation.

Protein S deficiency

Protein S activity is the preferred test for diagnosis of protein S deficiency, as it will identify patients with protein S production defects (type 1 protein S deficiency), patients who produce adequate quantities of a dysfunctional protein S (type 2 protein S deficiency), and patients with reductions in free protein S due to increased C4b-binding protein (type 3 protein S deficiency). Total and free protein S antigen assays can be ordered if protein S activity levels are low, in order to determine the type of protein S deficiency. It is important to note, however, that protein S activity assays have a high false positive rate (10-15%) such that abnormal tests should be repeated to confirm the diagnosis. This limitation of protein S activity tests has led some experts to recommend that free and total protein S antigen should be the initial tests in diagnosis of protein S deficiency although this approach could miss rare patients with type 2 protein S deficiency (normal levels of a dysfunctional protein S protein).

Protein S deficiency is associated with a significant risk for first thrombosis (1.9% per year) and recurrent VTE (8.4% per year). It is unclear if protein S deficiency is a risk factor for arterial thromboembolism in adults. The presence of protein S deficiency places patients at high risk for recurrent VTE and therefore, long-term anticoagulation is an appropriate consideration.

Antiphosphopholipid syndrome (APS)

The diagnostic criteria for the antiphospholipid syndrome include clinical events and positive laboratory assays, as outlined below. Laboratory abnormalities MUST be present on at least two assays performed at least 12 weeks apart (see Table V).

Table V.

Diagnostic criteria for antiphospholipid syndrome

APS is associated with one or more objectively confirmed symptomatic episodes of arterial, venous, or small vessel thrombosis. Histopathologic specimens must demonstrate thrombosis in the absence of vessel wall inflammation. Pregnancy losses are also considered objective manifestations of APS. To fulfill diagnostic criteria, the patient must have one or more unexplained fetal deaths at or beyond the 10th week of pregnancy with normal fetal morphology (or one or more premature births of a morphologically normal neonate before the 34th week of pregnancy due to eclampsia/severe preeclampsia/placental insufficiency) or three or more unexplained consecutive spontaneous abortions before the 10th week of gestation in the absence of maternal anatomic, chromosomal or hormonal abnormalities [or paternal chromosomal abnormalities]). (See Table V).

Laboratory tests include:

  • Positive test for lupus anticoagulant

Positive test for lupus anticoagulant using a phospholipid dependent clotting assay (aPTT, dilute Russell's viper venom time [dRVVT] assay, Kaolin clotting time, dilute prothrombin time (PT), with evidence of phospholipid dependence, present on two or more occasions at least 12 weeks apart.

  • IgG and IgM cardiolipin antibody

IgG or IgM cardiolipin antibody, measured using a standardized ELISA (enzyme-linked immunosorbent assay), that is present in medium or high titer (that is, greater than 40 GPL [IgG phospholipid titer] or MPL [IgM phospholipid titer] or greater than the 99th percentile), on two or more occasions at least 12 weeks apart.

  • Anti-Beta-2 glycoprotein-I immunoglobulin G or immunoglobulin M antibody

Anti-Beta-2 glycoprotein-I IgG or IgM antibody, measured using a standardized ELISA, that is present in high titer (greater than the 99th percentile) on two or more occasions at least 12 weeks apart.

Laboratory criteria for APS can be fulfilled by repeat positive results on one or more of the above laboratory tests. Tests for antibodies directed against phosphatidylserine, phosphatidyethanolamine, and phosphatidylinositol and prothrombin remain investigational and are not considered at the present sufficient to fulfill laboratory criteria for APS.

Antiphospholipid syndrome is associated with a variable risk of thromboembolism, depending upon the laboratory test abnormality. The presence of a lupus anticoagulant poses a 4 to 16 fold increased risk of thrombosis, whereas increased cardiolipin antibodies are associated with a 1 to 2.5 fold increased risk. Elevated beta-2 glycoprotein-I antibodies are associated with a 3.5 to 5 fold increased risk of thrombosis. Only IgG and IgM antibodies are associated with this increased risk. IgA antibodies are not considered to be associated with an increased risk of thrombosis at the present.

Lupus anticoagulants are associated with a 7 fold increased risk of recurrent thromboembolism, and cardiolipin antibodies are associated with a 2.5 fold increased risk. Antiphospholpid syndrome is associated with arterial and venous thromboembolism, as well as pregnancy morbidity.

The presence of antiphospholipid syndrome is considered an indication for long-term anticoagulation in patients with VTE and arterial thromboembolism. A recent systematic review noted that the overall quality of the evidence supporting these recommendations is low. Prophylactic UFH/LMWH and aspirin have been shown to increase the live birth rate in patients with recurrent miscarriage although the supportive studies are small.

Elevated factor VIII levels

Diagnosis requires measurement of factor VIII activity at least 6 months after the thrombotic event and in the absence of conditions that influence factor VIII activity, including inflammation, acute thrombosis, stress, pregnancy, heparin, direct thrombin inhibitors, exercise, and estrogens.

Elevated factor VIII levels have been associated with a 5 fold increased risk for first VTE (0.49% per year) and a 6 fold increased risk for recurrent VTE. A large family study found an annual risk of recurrence of 2.3% per year. Elevated factor VIII levels have been associated with myocardial infarction and arterial thromboembolism in family and case-control studies. It remains unclear whether elevated factor VIII activity warrants long-term anticoagulation in patients with VTE.

Elevated factor IX levels

Diagnosis requires measurement of factor IX antigen levels in the absence of vitamin K deficiency or vitamin K antagonist therapy. Although elevated factor IX antigen levels were associated with a 2.5 fold increased risk for first thrombosis in one study, a large family study found no increased risk of initial or recurrent thromboembolism. Elevated factor IX antigen has not been associated with arterial thromboembolism.

Elevated factor XI levels

One clinical study demonstrated a 2.2 fold increased risk of first thrombosis associated with this abnormality. A subsequent family study found no evidence of an increased risk of initial or recurrent thromboembolism. Elevated factor XI antigen levels have been associated with ischemic stroke in the ARIC (Atherosclerosis Risk in Communities) study. The value of laboratory testing for this entity remains controversial.

Hyperhomocysteinemia

Diagnosis is based upon fasting homocysteine levels. Homocysteine levels are affected by vitamin deficiencies (folate, vitamin B12, pyridoxine), renal failure, smoking, and older age. Since reduction of homocysteine levels with vitamin supplementation does not reduce recurrent thromboembolism, the value of homocysteine measurements in clinical management is questionable.

Methylenetetrahydrofolate reductase (MTHFR) genotype is determined by DNA testing

MTHFR genotype has not been demonstrated to influence clinical thrombosis outcomes.

PAI-1 4G/5G genotype analysis is done by DNA testing

PAI-1 genotype does not independently influence clinical outcomes.

What conditions can affect test results?

Factor V Leiden

The APC resistance assay may give misleading results in the presence of heparin concentrations greater than 1.0unit/ml or high-titer lupus anticoagulants. The DNA-based assay for factor V Leiden can be misleading in the event of DNA contamination (as is the case with all PCR assays (see Table IV).

Prothrombin gene G20210A mutation

Prothrombin gene mutation DNA-based assays can be misleading in the event of DNA contamination.

Antithrombin deficiency

Reductions in AT occur during acute thrombosis, DIC and heparin therapy. Warfarin therapy can lead to artifactual elevations of AT activity.

Protein C deficiency

Conditions associated with vitamin K deficiency (including warfarin therapy), acute thrombosis, and DIC can all lead to decreased protein C activity and antigen levels. Therefore, a prothrombin time should always be done whenever a protein C activity assay is performed. Heparin and direct thrombin inhibitors can result in elevated protein C activity.

Protein S deficiency

Since vitamin K deficiency can reduce protein S levels, a prothrombin time should always be ordered with protein S activity levels. Protein S activity should never be measured in patients on warfarin therapy. Since pregnancy and the post-partum period, as well as estrogen therapy and inflammatory states, are associated with increases in C4b-binding protein, protein S activity should not be measured in the presence of these conditions. Heparin therapy can increase protein S activity levels.

Antiphospholipid syndrome

The aPTT, when performed with a low phospholipid reagent, is a useful screening test for the presence of the lupus anticoagulant. The presence of unfractionated heparin (anti-Xa level > 1.0 unit/mL), direct thrombin inhibitors, low molecular weight heparin, fondaparinux and oral direct factor Xa inhibitors can result in prolongation of the aPTT and make mixing studies difficult to interpret.

The dRVVT is a sensitive and specific test for the presence of lupus anticoagulant. The dRVVT can be affected by warfarin, vitamin K deficiency, unfractionated heparin (anti-Xa level > 1.0 unit/mL), direct thrombin inhibitors, low molecular weight heparin, fondaparinux, and inhibitors of factor X, V and prothrombin that can result in prolonged dRVVT values and false positive results. Mixing studies performed on the dRVVT with pooled normal plasma generally correct vitamin K deficiency and warfarin-associated prolongation of the test results. Theoretically, the confirmation procedure of adding excess phospholipid to the patient sample prior to performing the dRVVT should not be affected by vitamin K antagonists or vitamin K deficiency; however, this is not always true.

Anticardiolipin antibody ELISA- Rheumatoid factor, syphilis and HIV infection can be associated with false positive anticardiolipin antibody test results.

Beta-2 glycoprotein-I antibody ELISA- Rheumatoid factor can be associated with a false positive results.

Elevated Factor VIII levels

Factor VIII is an acute phase reactant; therefore, false positive elevations can be seen in the presence of acute thrombosis, pregnancy, estrogen therapy, inflammatory disorders and infections. The lupus anticoagulant can interfere with assay results.

Elevated Factor IX levels

Factor IX antigen and activity levels can be reduced by vitamin K deficiency and vitamin K antagonist therapy. The lupus anticoagulant can interfere with factor IX activity assays.

Elevated Factor XI levels

Factor XI activity assays can be reduced by the lupus anticoagulant. Factor XI activity can be falsely elevated by activation that occurs after thawing a frozen sample.

Elevated homocysteine levels

Homocysteine levels can be elevated in patients with vitamin B12, folic acid or pyridoxine (vitamin B6) deficiency, as well as in renal failure, non-fasting samples and patients who are smoking.

MTHFR gene mutation

False positive results can occur in the presence of DNA contamination.

PAI-1 4G/5G polymorphism

False positive results can occur in the presence of DNA contamination.

What conditions can underlie hypercoagulable states?

These conditions are discussed extensively in "What every physician needs to know about hypercoagulable states".

When do you need to get more aggressive tests:

Factor V Leiden

If a patient has an abnormal activated protein C resistance assay, then factor V Leiden DNA mutation testing is indicated.

Prothrombin gene G20210A mutation

The prothrombin gene mutation is only identified by DNA testing. There is no screening test available.

Antithrombin deficiency

Patients are screened for the presence of antithrombin deficiency using the antithrombin activity assay. Antithrombin antigen assays can be used to confirm the diagnosis and identify the type of antithrombin deficiency. Type I AT deficiency is characterized by reduced antithrombin activity and antigen levels. Type I AT deficiency is caused by mutations that impair the synthesis of antithrombin. Type 2 AT deficiency is characterized by mutations in the AT gene that result in production of a dysfunctional protein (impairing either heparin binding or thrombin binding). The result is reduced antithrombin activity with normal levels of antithrombin antigen.

Protein C deficiency

Patients with possible protein C deficiency are screened for protein C activity levels. Protein C antigen levels are ordered in patients with reduced protein C activity to determine if they have type 1 protein C deficiency (reduced protein C activity and protein C antigen level [a quantitative defect]) or type 2 protein C deficiency (reduced protein C activity with normal protein C antigen level [a qualitative defect]). When evaluating patients for protein C deficiency, it is important that they are not vitamin K deficient or on a vitamin K antagonist. Therefore, a prothrombin time should always be ordered.

Protein S deficiency

In patients with low protein S activity levels, the activity level should be repeated and total and free protein S antigen levels should be measured.

Type 1 (quantitative) protein S deficiency results from mutations that impair protein S synthesis. Therefore, these patients will have low protein S activity, low total protein S antigen, and low free protein S antigen levels.

Type 2 (qualitative) protein S deficiency is due to mutations that result in production of a dysfunctional protein. These patients will have low protein S activity with normal total protein S and free protein S antigen levels.

Type 3 protein S deficiency is due to mutations that favor protein S binding to C4b-binding protein. This results in a lower proportion of free protein S. Since free protein S is more active as a co-factor for protein C, protein S activity is reduced. Test results in these patients show low protein S activity, normal total protein S antigen, and reduced free protein S antigen. Type 3 protein S deficiency can also be acquired, due to increases in C4b-binding protein, an acute phase reactant. Pregnancy, exogenous estrogen and inflammatory disorders can cause this form of acquired free protein S deficiency. In these latter patients, a type 3 pattern of protein S lab results will be found, but family studies will be negative. Elevated levels of C4b-binding protein can be used to confirm this type of acquired free protein S deficiency.

Similar to protein C testing, a prothrombin time should always be measured at the same time to exclude the possibility of vitamin K deficiency. Warfarin and other vitamin K antagonists should be discontinued at least 2 to 4 weeks before testing, in order to ensure accurate lab results. Protein S testing should not be done during pregnancy or the postpartum period (up to 12 weeks).

Antiphospholipid syndrome

Patients with positive test results for APS should have testing (aPTT with mixing studies, dRVVT with mixing studies, cardiolipin antibodies, anti-beta 2 glycoprotein-I antibodies) repeated at least 12 weeks later to confirm the diagnosis.

Elevated Factor VIII levels

Since factor VIII is an acute phase reactant, repeat factor VIII testing is probably warranted to confirm the presence of high factor VIII levels.

Elevated Factor IX levels

Repeat testing should be considered to confirm elevated levels. However, the value of factor IX antigen in management has been questioned.

Elevated Factor XI levels

Repeat testing should be considered to confirm elevated levels. However, the value of factor XI antigen in management has been questioned.

Hyperhomocysteinemia

Patients with extremely elevated levels of homocysteine should have genetic testing done to determine if they have mutations in cystathionine beta synthase. DNA testing of the methylenetetrahydrofolate reductase gene is also warranted. Blood samples for homocysteine levels should be measured when the patient has fasted for at least 8 hours prior to sampling. Homocysteine levels can also be obtained before and after initiating vitamin supplementation or drug therapy (for example, betaine).

Methylenetetrahydrofolate reductase (MTHFR) gene mutation testing

Not applicable.

Plasminogen activator inhibitor-1 4G/5G mutation

Not applicable.

What imaging studies (if any) will be helpful?

N/A

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Antithrombin deficiency

Antithrombin concentrate is recommended in VTE patients with antithrombin deficiency in high risk clinical situations such as surgery or delivery.

The dose of AT concentrate is calculated as follows: Desired AT level (usually 80 to 120%) - patient's current AT level multiplied by the body weight (in kilograms) divided by 1.4. For example, the dose of AT concentrate in units required to get an 80 kilogram patient with a baseline AT level of 50% to a level of 100% would be calculated as follows: 100-50 X 80/ 1.4 = 2857 units.

It is recommended that AT levels be measured at baseline, 20 minutes after infusion, 12 hours after infusion, and then prior to the next dose. Generally AT levels can be maintained by infusing 60% of the original loading dose on a daily basis. Since clinical events such as surgical procedures can increase consumption of AT, dosing should be based upon daily peak and trough levels.

Therapy is targeted to keep the antithrombin level at 80 to 120%.

Protein C deficiency

Homozygous protein C deficiency causes the thrombotic syndrome known as purpura fulminans. Patients typically become symptomatic with diffuse microvascular and macrovascular thrombosis soon after birth. Protein C concentrate should be administered to control this prothrombotic state, until effective anticoagulation can be achieved.

The initial dose of protein C concentrate is 100 to 120 units/kilogram, followed by 60 to 80 units per kilogram every 6 hours, to maintain a peak protein C activity of 100%. Dosing is adjusted to maintain this target level, while vitamin K antagonist therapy is gradually introduced in conjunction with a parenteral anticoagulant (unfractionated or low molecular weight heparin).

Protein C concentrate can also be used to prevent thrombosis in patients with homozygous protein C deficiency, and in selected patients with heterozygous protein C deficiency during risk periods when anticoagulation must be interrupted (during major surgery or delivery).

What other therapies are helpful for reducing complications?

All patients with known thrombophilia should receive adequate venous thromboembolism prophylaxis during risk periods (major surgery, trauma, medical illness, post-partum period).

It remains unclear whether vitamin supplementation is warranted in patients with hyperhomocysteinemia because randomized clinical trials failed to demonstrate a reduction in recurrent venous thromboembolism or stent restenosis in patients with hyperhomocysteinemia. Homocysteine reducing therapy (vitamin supplementation, betaine) is warranted in patients with homocysteinuria, although the success rate is low.

What should you tell the patient and the family about prognosis?

Factor V Leiden

Heterozygosity increases the risk of initial venous thromboembolism 5-7 fold, and homozygosity is associated with a 50 fold increased risk. The annual incidence of VTE in factor V Leiden heterozygotes is 0.49% per year. In homozygotes, the incidence of first thrombosis has been estimated to be 1.5% per year. Factor V Leiden heterozygosity is associated with a 1.56 fold (95% confidence interval [CI] 1.14 to 2.12) increased risk of recurrent VTE, compared with 2.56 fold (95% CI, 1.2 to 6.0) for homozygosity.

Most experts do not consider factor V Leiden heterozygosity alone as an indication for long-term anticoagulation. In contrast, many consider homozygosity as an indication for long-term therapy. Patients with compound heterozygosity for factor V Leiden and the prothrombin gene mutation are often considered at higher risk for recurrent VTE (odds ratio [OR] 4.81, 95% CI, 0.50 to 46.3).

Factor V Leiden does not increase the risk of arterial thromboembolism.

Since asymptomatic patients with factor V Leiden are not treated with prophylactic antithrombotic therapy, testing asymptomatic family members for factor V Leiden is not warranted.

Prothrombin gene G20210A mutation

Heterozygosity is associated with 2.8 fold (1.4 to 5.6) increased risk of initial VTE. However, it is not associated with a significant risk of recurrent VTE (OR 1.45, 95% CI 0.96-2.21). It remains unclear whether homozygotes for the prothrombin gene mutation are at increased risk of recurrent VTE.

The prothrombin gene mutation is not an important risk factor for stroke or myocardial infarction.

Antithrombin (III) deficiency

Heterozygosity is associated with a 15 to 20 fold relative risk of VTE. Homozygosity is rare, and may be likely to be lethal in utero. The annual incidence of thrombosis is 1.8% per year. The risk of recurrent VTE is 10% per year after discontinuation of anticoagulation. Therefore, long-term therapy is recommended for patients with antithrombin deficiency who have suffered an episode of VTE.

Antithrombin deficiency is not an important risk factor for myocardial infarction or stroke.

Protein C deficiency

Heterozygous deficiency is associated with a 15 to 20 fold relative risk of VTE, and an annual incidence of thrombosis of 1.5% per year. Protein C deficiency is associated with a 6% per year risk of recurrent VTE in the absence of anticoagulation. Therefore, long-term therapy is recommended for patients with protein C deficiency who develop VTE.

Protein C deficiency is not associated with myocardial infarction or stroke.

Protein S deficiency

Protein S deficiency is associated with a 15 to 20 fold risk for first thrombosis (1.9% per year). It is also associated with an increased risk of recurrent VTE (8.4% per year). Therefore, long-term therapy is indicated in patients with protein S who have suffered VTE.

It is unclear whether protein S deficiency is a risk factor for arterial thromboembolism.

Antiphospholipid syndrome (APS)

APS is an acquired thrombophilic disorder. Therefore, family members of a patient with APS need not worry about inheriting APS.

Hyperhomocysteinemia

Inherited metabolic disorders can result in hyperhomocysteinemia. Therefore, family testing of fasting homocysteine levels can be considered, although it remains unclear whether lowering modestly elevated homocysteine levels is associated with any clinical benefit.

Elevated factor VIII levels

Elevated factor VIII activity is an inherited thrombophilic disorder, but prophylactic anticoagulation is not indicated and so there is no rationale for family screening.

Elevated factor IX levels

Elevated factor IX antigen is an inherited thrombophilic disorder, of questionable significance. Prophylactic anticoagulation is not indicated and there is no rationale for family screening.

Elevated factor XI levels

This is an inherited thrombophilic disorder of unclear significance. Prophylactic anticoagulation is not indicated and there is no rationale for family screening.

Methylenetetrahydrofolate reductase (MTHFR) gene mutation

MTHFR does not significantly increase VTE rates. Therefore, family screening is not indicated.

PAI-1 4G/5G gene mutation

This mutation does not significantly increase the risk of VTE. Therefore, family screening is not warranted.

“What if” scenarios.

Hormonal contraceptives

Patients known to harbor thrombophilic disorders with or without previous thrombosis should avoid hormonal contraceptives. However, family screening is not indicated to determine the safety of hormonal contraceptives.

Pregnancy and thrombophilia

The 2012 ACCP Guideline suggests that patients with factor V Leiden or prothrombin gene mutation homozygosity and no previous VTE but a positive family history of VTE should be considered for ante- partum and post-partum prophylactic or intermediate dose LMWH or post-partum vitamin K antagonists (INR2-3). For pregnant women with factor V Leiden or prothrombin gene mutation heterozygosity or protein C or protein S or antithrombin deficiency and no previous VTE but a positive family history of VTE, ante-partum surveillance and post-partum prophylactic or intermediate dose LMWH or vitamin K antagonists (INR 2-3) (the latter not for protein C and S deficiency) is suggested. For patients with no personal or family history of VTE and factor V Leiden or prothrombin gene mutation heterozygosity, ante-partum surveillance and post-partum prophylactic or intermediate dose LMWH or vitamin K antagonists (INR 2-3) for at least 6 weeks. Ante-partum and post-partum surveillance is suggested for women with other hypercoagulable states and no personal or family history of VTE.

Management of pregnancy in patients with a previous idiopathic VTE

Patients with a previous idiopathic thrombotic event should receive ante-partum and post-partum anticoagulant prophylaxis, whether or not they have a thrombophilic defect.

Management of pregnancy in patients with a previous non-idiopathic VTE

  • Patients with a previous episode of VTE associated with a potent situational risk factor (for example, surgery, trauma) should receive post-partum anticoagulant prophylaxis (prophylactic or intermediate dose LMWH or vitamin K antagonist INR 2-3) and surveillance in the ante-partum period.

  • Patients with a pregnancy associated or hormonal therapy associated episode of VTE should consider ante-partum and post-partum (prophylactic or intermediate dose) prophylaxis.

The post-partum period extends at least 6 weeks post-delivery.

VTE prophylaxis

The presence of a thrombophilic defect should be considered a major risk factor when considering VTE prophylaxis for hospitalized patients.

Pathophysiology

Factor V Leiden

Factor V Leiden is a mutation that disrupts the first activated protein C (APC) cleavage site in activated factor V and slows the inactivation of activated factor V, a critical cofactor for factor Xa activation of prothrombin. Normal cleavage of Factor V at this site produces a form of factor V that serves as a cofactor for the inactivation of factor VIIIa; therefore, the factor V Leiden mutation slows the inactivation of both factor Va and factor VIIIa, both critical cofactors in the coagulation cascade.

Prothrombin gene G20210A mutation

This mutation increases the translational efficiency of prothrombin mRNA, resulting in approximately 25% increase in prothrombin protein levels. Prothrombin is a critical serine protease proenzyme in the coagulation cascade. Its activated form, thrombin, generates fibrin monomers and activates platelets, factor XIII (covalently cross-links and stabilizes fibrin polymers), factor XI (activates factor IX), and critical cofactors factor VIII and V. Consequently, increased prothrombin levels contribute to an increase in the thrombotic potential of the blood.

Antithrombin deficiency

This serine protease inhibitor binds and inactivates factors IIa (thrombin), Xa, IXa, XIa and XIIa. Its activity is potentiated several thousand-fold by binding to heparins (the rationale for the use of heparins as antithrombotic agents).

Protein C deficiency

This serine protease cleaves and inactivates factor VIIIa and Va. Its activity is accentuated when bound in a complex with protein S.

Protein S deficiency

This is a cofactor for protein C in the inactivation of factors Va and VIIIa. Free protein S is more active as a protein C cofactor, although recent research suggests that bound protein S is also somewhat effective. Free protein S also functions as a cofactor in TFPI inhibition of factor Xa.

Antiphospholipid syndrome

The pathogenesis of thromboembolism in APS is complex and incompletely understood. There is evidence to support disruption of endogenous anticoagulant mechanisms (including protein C and antithrombin function), activation of platelets and endothelial cells, induction of tissue factor expression, activation of complement, and interference with the anticoagulant function of annexin V.

Hyperhomocysteinemia

High levels of homocysteine have been associated with vascular damage, as well as impairment of the protein C pathway and induction of tissue factor expression. These alterations may underlie the putative hypercoagulable state associated with hyperhomocysteinemia.

Elevated Factor VIII levels

Factor VIIIa is a cofactor in the tenase complex with factor IXa. Elevated levels of factor VIIIa likely facilitate activation of factor X by factor IXa.

Elevated Factor IX levels

This serine protease (as IXa) activates factor X. Higher concentrations of factor IXa, in association with factor VIIIa, may increase the potential for factor X activation and, thus, for thrombin generation. Clinically, the impact of this defect is minimal.

Elevated Factor XI levels

Factor XI is activated by thrombin in a feedback loop that potentiates further thrombin generation and leads to reduced clot lysis via thrombin-activatable fibrinolysis inhibitor (among many other thrombin mediated procoagulant events). These connections may underlie the association of factor XI with a modest increase in prothrombotic potential. Clinically, the impact of this alteration is modest.

Methylenetetrahydrofolate reductase (MTHFR) gene mutations

Thermolabile mutations in MTHFR reduce the stability of this enzyme that is involved in generation of N5-methyl tetrahydrofolate, a cofactor in the conversion of homocysteine to methionine. The degree of hyperhomocysteinemia generated by this mutation is modest in individuals whose diets are rich in B vitamins. Consequently, this mutation does not have a significant impact on vascular outcomes.

Plasminogen activator inhibitor (PAI)-1 4G/5G mutation

PAI-1 is the principal inhibitor of plasminogen activators in the plasma. Therefore, higher levels of this fibrinolytic inhibitor may be associated with a tendency toward thrombosis. The 4G polymorphism of the PAI-1 gene favors transcriptional activity of the PAI-1 promoter, resulting in increased synthesis of PAI-1. Clinically, this polymorphism is not associated with a significant prothrombotic state.

What other clinical manifestations may help me to diagnose a hypercoagulable state?

Antiphospholipid syndrome is a common cause of recurrent pregnancy loss.

Criteria for initial thrombophilia testing:

  • APS

Three or more first trimester pregnancy losses, or one second or third trimester loss

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Lijfering, WM, Rosendaal, FR, Cannegieter, SC. "Risk factors for venous thrombosis - current understanding from an epidemiological point of view". Br J Haematol.. vol. 149. 2010. pp. 824-833.

(Lijfering and colleagues' review of the latest data on VTE risk factors.)

Sweetland, S, Green, J, Liu, B. "Million Women Study collaborators. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study". BMJ.. vol. 339. 2009. pp. b4583.

(A large population-based cohort study of the risk of venous thromboembolism associated with ambulatory and inpatient surgery)

Segers, K, Dahlbäck, B, Nicolaes, GA. "Coagulation factor V and thrombophilia: background and mechanisms". Thromb Haemost.. vol. 98. 2007. pp. 530-42.

(A comprehensive review of factor V Leiden from the researcher who discovered activated protein C resistance.)

Segal, JB, Brotman, DJ, Necochea, AJ. "Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review". JAMA.. vol. 301. 2009. pp. 2472-85.

(A metanalysis of the impact of factor V Leiden and the prothrombin gene mutation on the risk of recurrent of venous thromboembolism.)

Lijfering, WM, Brouwer, JL, Veeger, NJ. "Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives". Blood.. vol. 113. 2009. pp. 5314-5322.

(The largest retrospective family study yet conducted that provides valuable data on the impact of various thrombophilic mutations on the risk of initial and recurrent venous thromboembolism.)

Patnaik, MM, Moll, S. "Inherited antithrombin deficiency: a review". Haemophilia. vol. 14. 2008. pp. 1229-39.

(An excellent clinical review of antithrombin deficiency.)

Khor, B, Van Cott, EM. "Laboratory tests for protein C deficiency". Am J Hematol. vol. 85. 2010. pp. 440-2.

(A comprehensive review of laboratory testing in the diagnosis of protein C deficiency.)

Ten Kate, MK, van der Meer, J. "Protein S deficiency: a clinical perspective". Haemophilia.. vol. 14. 2008. pp. 1222-8.

(An in-depth review of laboratory and clinical aspects of protein S deficiency.)

Giannakopoulos, B, Passam, F, Ioannou, Y, Krilis, SA. "How we diagnose the antiphospholipid syndrome". Blood.. vol. 113. 2009. pp. 985-94.

(Evidence-based diagnosis of the antiphospholipid syndrome.)

Garcia, D1, Akl, EA, Carr, R, Kearon, C. "Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review". Blood. vol. 122. 2013 Aug 1. pp. 817-24.

(Systematic review of the clinical evidence supporting the risk of recurrent VTE in patients with APS.)

Ray, JG. "Hyperhomocysteinemia: no longer a consideration in the management of venous thromboembolism". Curr Opin Pulm Med.. vol. 14. 2008. pp. 369-73.

(A review of clinical trials examining the impact of vitamin supplementation on VTE outcomes in patients with hyperhomocysteinemia.)

Bertina, RM. "Elevated clotting factor levels and venous thrombosi". Pathophysiol Haemost Thromb. 2003,. vol. 33. 2004. pp. 395-400.

(A review of the impact of elevated coagulation factor on VTE incidence by the discoverer of factor V Leiden.)

Tsantes, AE, Nikolopoulos, GK, Bagos, PG, Bonovas, S, Kopterides, P, Vaiopoulos, G. "The effect of the plasminogen activator inhibitor-1 polymorphism on thrombotic risk". Thromb Res.. vol. 122. 2008. pp. 736-42.

(A metanalysis of studies examining the impact of the PAI-1 polymorphism on thrombotic risk.)

Bates, SM, Greer, IA, Middeldorp, S, Veenstra, DL, Prabulos, AM, Vandvik, PO. "American College of Chest Physicians. Venous thromboembolism, antithrombotic therapy and pregnancy. Antithrombotic therapy and prevention of thrombosis, 9th edition. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. vol. 141. 2012. pp. e691S-736S.

(The most recent ACCP guideline on VTE during pregnancy and its management.)
You must be a registered member of ONA to post a comment.

Sign Up for Free e-newsletters

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Genitourinary Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs