Hereditary and Acquired Hypercoagulability

Updated: Jun 02, 2020
  • Author: Paul Schick, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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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 ClotsInherited Blood-Clotting Problems, and the Deep Vein Thrombosis Health Center.

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COVID-19

The media have alerted the public about clotting complications in COVID-19 cases. [2, 3] Several physicians have observed abnormal clot formation and strokes in patients with COVID-19, with clots developing at sites of intravenous procedures and during attempts to remove clots in the brain. Abnormal clotting does not always correlate with the severity of COVID-19.

Han et al documented prominent changes in blood coagulation in patients with SARS-CoV-2 infection (COVID-19). [4] Strokes associated with COVID-19 have been reported in young people, even in patients in their 30s and 40s. [5]

Coagulation tests have been done in COVID-19 patients to determine the mechanism for abnormal coagulation. Increased D-dimer levels were found. [4] Increased D-dimer levels and abnormal findings on other coagulation studies indicate hypercoagulation with a severe inflammatory state, rather than disseminated intravascular coagulation (DIC), as others have suggested. [6]  Italian researchers have used thromboelastography (TEG) and standard coagulation tests to confirm hypercoagulability. [7]

The possibility of DIC in COVID-19 patients should be more rigorously studied by assessing peripheral smears for microangiopathy and evidence for platelet and fibrinogen consumption.  This may lead to choosing tests that could predict abnormal coagulation and stroke in these cases.

An obvious goal would to be to prevent abnormal coagulation and stroke in COVID-19 patients. Kollias et al suggested that D-dimer elevation may be predictive and anticoagulation should be considered in those patients. [8] Several articles strongly encourage using, and carrying out trials of, anticoagulation and other therapies to manage abnormal bleeding and stroke in COVID-19 infections. [8, 9]

Interim guidance from the International Society of Thrombosis and Haemostasis (ISTH) includes the following recommendations for patients with COVID-19 [10] :

  • If D-dimer levels are markedly raised (eg, 3- to 4-fold increase), consider hospital admission, even in the absence of other severe symptoms.
  • Monitor coagulation markers once or twice daily. Along with D-dimer, other markers (in decreasing order of importance) to consider are prothrombin time, platelet count (for thrombocytopenia), and fibrinogen.
  • Start prophylactic-dose low molecular weight heparin, in the absence of any contraindications (active bleeding and platelet count less than 25 × 10 9/L); monitoring advised in patients with severe renal impairment.
  • If coagulation markers worsen, consider experimental therapies (eg, antithrombin supplementation, recombinant thrombomodulin).

Zhang et al have reported a positive lupus anticoagulant (antiphospholipid antibodies) in three COVID-19 patients. [11] Lupus anticoagulants are thought to represent immune system hyperactivity. They can occur in severe infections, only to regress when infections are controlled. The presence of lupus anticoagulants in COVID-19 patients suggests a hyperactive immune system response that may be either a cause of COVID-19 pathophysiology or a response to the infection. The basis for abnormal coagulation in COVID-19 cases needs to be studied and understood.

Wright et al reported that TEG assay and D-dimer results can identify COVID-19 patients at high risk for venous thromboembolism (VTE), stroke, and renal failure. In their study of 44 COVID-19 patients admitted to the intensive care unit, a complete lack of clot lysis at 30 minutes on TEG was a significant predictor of VTE, with an area under the receiver operating characteristic curve (AUROC) of 0.742 (P = 0.021). A D-dimer cutoff of 2600 ng/mL was a significant predictor of need for dialysis, with an AUROC of 0.779 (P = 0.005). [12, 13]

Overall, patients with no clot lysis at 30 minutes on TEG assay and a D-dimer value above 2600 ng/mL had a rate of VTE of 50%, compared with 0% for patients with neither risk factor (P = 0.008). Rates of hemodialysis in patients with both or neither risk factors were 80% and 14%, respectively (P = 0.004). [12, 13]

The authors point out that these patients had high-normal or frankly elevated PT and PTT levels, demonstrating the importance of using whole-blood coagulation assays to determine risk. They conclude that, “further clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.” [12, 13]

 

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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. [14] 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. [15] 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. [16] 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. [17]

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. [18, 19, 20] 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. [21]

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. [22]

Thrombosis, especially venous thromboembolism, may complicate hypereosinophilia. Conditions associated with chronic hypereosinophilia include Churg–Strauss syndrome, hypereosinophilic syndrome (HES), and chronic eosinophilic leukemia. [23]

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. [24]

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 whites in the United States 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. [25]

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. [25]

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 white. 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.

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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. [26, 27] 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. [27] 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. [27]

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 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 [28, 29] :

The risk for thrombosis increases with age and associated immobility.

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