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Year : 2018  |  Volume : 31  |  Issue : 3  |  Page : 900-904

Thrombophilia testing in adults: a systematic review

1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Teaching Hospital, Shebin El Kom, Egypt

Date of Submission19-Oct-2016
Date of Acceptance11-Dec-2016
Date of Web Publication31-Dec-2018

Correspondence Address:
Ghada A Elgammal
Shebin El Kom, El-Menoufia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-2098.248753

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The aim of this study was to carry out a systematic review to summarize diagnosis and management of thrombophilia in adults.
Data sources
In September 2016, Medline, articles in Medscape, AAFP and PubMed were searched.
Study selection
The initial search presented 250 articles. Only six articles met the inclusion criteria. The selected articles covered thrombophilia clinical presentation, investigation to confirm the diagnosis, and management in adults.
Data extraction
Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest.
Data synthesis
There was heterogeneity in the collected data. It was not possible to perform meta-analysis. Significant data were collected and then a structured review was carried out.
Six articles were reviewed, five articles and one systematic review, summarizing the clinical presentation investigation and testing of thrombophilia. Patients with thrombophilia presented with deep vein thrombosis and pulmonary embolism, usually occuring in the legs, characterized by pain, swelling, and heaviness due to damage in the veins. Testing of thrombophilia include protein C, protein S, factor V Leiden, antithrombin III, prothrombin G 20210 mutation, and hyperhomocystenemia. Other factors include elevated factor VIII, elevated factor XI, dysfibrinogenemia, factor XII defeciency, and plasminogen defeciency. As soon as the diagnosis is made, vitamin K antagonist (e.g., warfarin) should be added to heparin. Monitoring of anticoagulation is carried out by the prothrombin time, expressed in terms of international normalized ratio.

Keywords: hemostasis, heridatary and aquired thrombophilia, protein C, protein S testing

How to cite this article:
Shoeib SA, Abd El Hafez MA, Elgammal GA. Thrombophilia testing in adults: a systematic review. Menoufia Med J 2018;31:900-4

How to cite this URL:
Shoeib SA, Abd El Hafez MA, Elgammal GA. Thrombophilia testing in adults: a systematic review. Menoufia Med J [serial online] 2018 [cited 2020 Feb 28];31:900-4. Available from: http://www.mmj.eg.net/text.asp?2018/31/3/900/248753

  Introduction Top

Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surrounding tissue. The first important component that contributes to hemostasis is the coagulation system, and the second important component starts with platelet activation, which not only contributes to the hemostatic plug but also accelerates the coagulation system[1].

Thrombophilia is defined as an inherited or acquried abnormality of hemostasis predisposing to thrombosis[2].

The etiology of thrombophilia depends on the triad of endothelial damage, abnormal blood flow, and a change in the systemic balance of procoagulant and anticoagulant factors in the pathogenesis of thromboembolism[3].

Currently, the most commonly tested inherited thrombophilias include deficiencies of antithrombin, protein C (PC) or protein S (PS), and the gain of function mutations factor V Leiden (FVL) and prothrombin G20210A, which affect either the procoagulant or the anticoagulant pathways. Lupus anticoagulant (LA), anticardiolipin antibodies, and anti-2-glycoprotein 1 antibodies, all laboratory features of acquired thrombophilic antiphospholipid syndrome (APS), are also usually included in a thrombophilia testing panel. Elevated levels of several coagulation factors, including factors VIII, IX, and XI, also increase the risk for thrombosis[4].

Time of testing, patient age, sex, liver function, hormonal status, and pregnancy are important preanalytic variables to consider before investigating for thrombophilia. Timing is critical; coexistent on going or early thrombosis and/or heparin and warfarin therapy muddy the laboratory interpretation[5]. For example, heparin will decrease antithrombin III, and warfarin blocks synthesis of active PC and PS. The acute management of venous thromboembolism (VTE) is rarely influenced by the immediate demonstration of a specific defect. Thus, the laboratory investigation of thrombophilia should be delayed for 6 months after the acute thrombosis, and 3–4 weeks after discontinuation of warfarin[6].

Kovacs et al.[7] argue that testing a patient during the acute thrombotic event is practical and useful as long as the results are interpreted appropriately and tests with abnormal results are repeated 3 months later.

Immediate testing for certain thrombophilias is more clearly indicated, for initial heparin treatment of a patient with LA who has VTE. The LA often prolongs the patient's baseline partial thromboplastien time; if this is not documented before starting the heparin therapy, the elevated partial thromboplastien time may lead to a false conclusion that the patient's anticoagulation is therapeutic, when in fact, it is subtherapeutic; in such cases, the anti-Xa assay must guide the heparin therapy[8].

A second example is when patients are suspected of having VTE due to the APS. Immediate detection of a LA could require prolonged warfarin therapy to prevent recurrence. In addition, a chromogenic factor X may be informative when the international normalized ratio is therapeutic, to confirm that the LA is not falsely increasing it[9].

  Materials and Methods Top

The guidelines developed by the center for review and dissemination were used to assess the methodology and outcome of the selected studies.

Search strategy

Several databases were searched, including Medline, articles in Medscape, AAFP, and PubMed. The search was performed in September 2016 and included all articles published. There was no restriction according to language.

Study selection

Three researchers assessed all the researches to decide their inclusion in the study. The inclusion criteria were as follows:

  1. Hemostasis
  2. Thrombophilia
  3. Testing of thrombophilia
  4. Management of thrombophilia

  5. Participants: Adults with thrombophilia

    Intervention: Early investigation and management

    Comparative: Thrombophilia testing

    Outcomew: Proper health.

First, the article title and abstract were screened. Then the selected articles were read in full and further assessed for eligibility. All references from the eligible articles were reviewed to identify additional studies.

Data extraction

Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Conclusion and comments on each study were made. There was heterogeneity in the collected data. It was not possible to perform meta-analysis. Significant data were collected and then a structured review was carried out.

  Results Top

After searching several databases, we selected six studies. The studies were deemed eligible as they fulfilled the inclusion criteria. There was a high degree of heterogeneity regarding diagnosis and management of thrombophilia.

  Discussion Top

Management of VTE includes evaluation for hypercoagulable state, especially if the VTE occurs in young patients, is recurrent, or is associated with a positive family history. These laboratory tests are costly, and surprisingly, there is little evidence showing that testing leads to improved clinical outcomes. Thrombophilia screening is important in a subgroup of clinical scenarios, such as when there is a clinical suspicion of antiphospholipid antibody (APLA) syndrome, heparin resistance, or warfarin necrosis, with thrombosis occurring in unusual sites (such as mesenteric or cerebral deep VTE) and for pregnant women or those seeking pregnancy or considering estrogen-based agents[10].

The most common thrombophilias are the hereditary gene polymorphisms for FVL and prothrombin G20210A gene mutation (PTGM). These are inherited in an autosomal dominant pattern and can be found in up to 3–7% of the population with a northern or southern European ancestry. FVL and PTGM are rare in Asian and African populations. Whereas the inherited deficiencies mentioned are common. The inherited defeciencies of antithrombin III, (PC), and (PS) are rare yet more strongly associated with thrombotic events[11].

Hyperhomocysteinemia is the result of vitamin B deficiencies (B6, B9 or folate, and B12) or mutations of specific enzymes, such as methylenetetrahydrofolate reductase or cystathionine β-synthase[12].

Early pregnancy loss is the most common pregnancy complication, and acquired and inherited thrombophilia conditions are associated with a risk for pregnancy failure[13].

Elevated factor VIII levels also incur a risk for thrombosis. However, laboratory detection of high levels is inconsistent, and its value in management is limited[14].

APS merits special attention because it can lead to serious consequences, including death from venous or arterial thrombosis and fetal loss. APS is an acquired thrombophilia, and a family history of thrombosis is typically not helpful. APS is characterized by venous or arterial thrombosis in the presence of APLAs, unexplained thrombocytopenia, or prolongation of the activated partial thromboplastin time, or specific pregnancy-associated morbidity (three or more pregnancy losses occurring before 10 weeks of gestation, premature births due to placental insufficiency, or eclampsia and unexplained fetal death after 10 weeks of gestation). The history and physical findings are critical to determine the nature and frequency of thromboembolic events in this population and to detect underlying autoimmune disorders (in particular, systemic lupus erythematosis). The presence of APLAs is suggested by physical findings associated with ischemia or infarction of the skin, viscera, or central nervous system, deep VTE, or the presence of livedo reticularis, digital ischemia, or gangrene[15].

Initial laboratory evaluation for suspected APS includes anticardiolipin immunoglobulin G and M antibodies, anti-β2-glycoprotein 1 immunoglobulin G and M antibodies, and the LA test. The APLA tests are repeated in 12 weeks to confirm the persistence of these antibodies, and a third test several weeks later may be required, particularly if the second test result is normal[16].

Although APS may be associated with a slightly higher risk for VTE recurrence, controversy continues as to whether this justifies the longer duration of anticoagulation beyond the recommendations for those with unprovoked VTE. In those who present with venous or arterial thrombosis, repeated blood testing for the persistence of APLAs may help determine the duration of treatment[17].

Laboratory investigation of PS deficiency is more complex with three distinct assay types: PS activity measures function as a cofactor for APC; free PS is an immunologic measure of the unbound fraction; and total PS antigen quantifies free and bound PS. Each assay has its own drawbacks, and they must be interpreted together to accurately diagnose PS deficiency. Because PS activity secondarily measures APC-dependent anticoagulant activity, many variables must be considered before ordering and/or interpreting values. False low values are found in up to 10–15% of healthy people. Free PS antigen is more reliable and can diagnose 95–99% of PS deficiencies. Inherited PS deficiency occurs in 1–13% of thrombophilic patients with VTE. Types I, II, and III do not differ in clinical manifestations or severity[8].

The FVL point mutation (G1691A) renders the first factor V cleavage site more resistant to the APC/PS complex, and hence APCR. Up to 8% of the Caucasians in the USA are heterozygous for FVL, and 1 in 5000 are homozygous. FVL occurs more rarely in African Americans and people of Hispanic or Arabic descent. FVL heterozygotes have a 3–7-fold and homozygotes an 80-fold increased risk for VTE; a second risk factor (oral contraceptives, pregnancy, PS deficiency) in a FVL heterozygous person synergistically increases the risk for VTE. Most laboratories use a strategy to first screen for APCR with the second-generation (V-deficient) test. If the APCR result is abnormal, genotyping for FVL is reflexively performed.

DNA analysis alone would not identify acquired APCR (such as LA) or rare factor V mutations that can also cause APCR[18].

P20210 is the second-most prevalent inherited VTE risk factor, resulting in an increased concentration of functional prothrombin and, subsequently, the generation of more thrombin. P20210 is present in ~2–3% of Caucasians, Hispanics, and Arabs but is rare in Africans and Asians. P20210 occurs in 6–8% of all patients with VTE and 18% of patients with VTE who also have thrombophilia. P20210 is determined only by DNA analysis because the prothrombin activity does not adequately identify the presence of P20210[19].

The inherited deficiencies of AT, PC, and PS account for only 1–5% of all patients with VTE. All are caused by a large number of different mutations and are inherited in an autosomal dominant manner with variable penetrance. The peak presentation with a first thrombotic event is early, between 15 and 35 years of age. Laboratory evaluation includes functional and antigenic assays; it is extremely important to exclude an acquired deficiency and to consider different analytic variables that can affect results[20].

The risk for VTE in heterozygous AT deficiency is increased 5–50-fold compared with the general population. There is a 50% risk for VTE developing during a patient's lifetime or during pregnancy. Diagnosis of quantitative (type I) or qualitative (type II) deficiency can be made with an algorithmic approach[21].

PC deficiency accounts for 2.5–5% of unselected patients with a first VTE.

Heterozygous deficiency increases VTE risk by 7-fold and carries an increased risk for warfarin-induced skin necrosis. Homozygous-deficient newborns have purpura fulminans; replacement therapy and anticoagulation are required for survival. However, there have been reports of patients with homozygous PC deficiency with a milder clinical course. Quantitative and qualitative PC deficiency can be diagnosed by using an algorithm[22].

VTE in most cases is initially treated with a combination of heparin and vitamin K antagonists. The heparin can be either unfractionated (UFH) or of low molecular weight, and prepared from UFH by either enzymatic or chemical cleavage methods. Low molecular weight has better pharmacokinetic properties than does UFH, and adequate anticoagulant control can be achieved with a twice daily or single daily dose given subcutaneously. Heparin is discontinued after a few days when the functional levels of vitamin K-dependent coagulation proteins have dropped into the therapeutic range. The effect of vitamin K antagonist therapy should be regularly monitored by prothrombin time–international normalized ratio, and it is usually continued for 3–6 months depending on the severity of the thrombosis and its cause[23].

  Conclusion Top

Conclusive evidence supporting widespread thrombophilia screening is lacking, but testing of those subgroups at the highest risk may be useful until data from well-designed, controlled trials comparing different durations of anticoagulation with specific thrombophilic states are available. Treatment should be based on clinical risk factors and less on laboratory abnormalities. For those patients or physicians who choose to test in the presence of clear-cut risk factors to acquire a deeper understanding of the clotting condition, discussion of the implications of results should be disclosed: the identification of abnormalities does not usually alter management beyond that based on clinical risk, and the lack of finding a defect does not exclude a hypercoagulable state because the patient may still possess an abnormality yet to be discovered. If testing will change management, it may be appropriate to proceed. If long-term anticoagulation is preferred on the basis of positive test results, the risk for bleeding should be considered.

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Conflicts of interest

There are no conflicts of interest.

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