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PirjoMustonen

Evaluation of Thrombophilia

Essentials

  • Thrombophilia is divided into inherited and acquired types.
  • Experts are not unanimous about the indications for thrombophilia testing, and there are no controlled clinical trials on the effectiveness of testing.
  • Unnecessary thrombophilia testing should be avoided. Unconsidered testing has many drawbacks (transient "false positive" results due to anticoagulant therapy or acute thrombosis, unnecessary costs, and inconvenience and worry for the patient).
  • Testing for thrombophilia is only indicated in a small proportion of patients with venous thrombosis or pulmonary embolism and in an even smaller proportion of patients with arterial thrombosis.
  • This article describes the situations where testing for thrombophilia can be regarded as justified according to the prevailing expert opinion.
  • Asymptomatic relatives are tested if indicated, but only for the hereditary defect detected in the index person.
  • Association with pregnancy complications is multifaceted and many aspects remain unclear; the issue is comprehensively addressed in an international recommendation (ACCP 2012).
  • There may be a latent malignancy behind idiopathic venous thrombosis or pulmonary embolism. Investigations for malignancies should only be performed in selected patients based on disease history and basic examinations.

Causes of inherited thrombophilia

  • Abnormalities predisposing to inherited thrombophilia, their prevalence and the associated risk of thrombosis are described in table T1.
  • Most patients are heterozygous. Homozygous patients are rare and at a significantly greater risk of developing thrombosis; homozygosity for antithrombin deficiency, for example, apparently leads to death already during foetal life.
  • It should be borne in mind that, with the investigation methods currently available, the underlying cause of a familial predisposition to venous thrombotic events can only be identified in about 60% of cases. A number of factors that increase the thrombotic tendency are yet to be ”identified”. Thus, if a patient with a strong family history presents with thrombosis, the patient should be treated as if he or she has thrombophilia even if the results of thrombophilia testing are normal.
  • A diagnosis of inherited thrombophilia on the basis of a single abnormal test result can only be made in the case of a gene defect. A definitive diagnosis requires an abnormal result from two separate samples and a comparable result in a first-degree relative.

Prevalence of inherited coagulation factor abnormalities that predispose to thrombophilia and the associated risk of venous thrombosis

Predisposing factorPrevalence in the western countriesThrombotic risk as compared with general population (approximately)
Factor V Leiden (APC resistance, FV Leiden, FV R506Q, FV G1691A) heterozygous3-8%Low-risk thrombophilia
3 ×
Factor V Leiden (APC resistance, FV Leiden, FV R506Q, FV G1691A) homozygous<0.2%High-risk thrombophilia
>30 ×
G20210A point mutation in the prothrombin gene, heterozygous0.7-4%Low-risk thrombophilia
3 ×
G20210A point mutation in the prothrombin gene, homozygous<0.1%High-risk thrombophilia
>30 ×
Protein C deficiency1) 0.2-0.5%High-risk thrombophilia
10 ×
Protein S deficiency2) 0.2-0.5%High-risk thrombophilia
10 ×
Antithrombin deficiency 3) 0.02-0.1%High-risk thrombophilia
Great variation between families, up to > 100 ×
1) Either quantitative deficiency of protein C (Type 1 deficiency) or qualitative impairment of its functional activity (Type 2 deficiency). Over 160 gene defects have been described. A single mutation (PC W380G) causes the majority of type 2 protein C deficiency cases in Finland.
2) Either quantitative deficiency of protein S or qualitative impairment of its functional activity. Over 200 gene defects have been described.
3) Either quantitative deficiency of antithrombin (Type 1 deficiency) or qualitative impairment of its functional activity (Type 2 deficiency). The thrombotic risk is related to the type and degree of the deficiency. Over 100 different gene defects are known. In Finland, type 2 deficiency is caused predominantly by a single mutation (Pro73Leu).
Causes of acquired (non-inherited) thrombophilia

Antiphospholipid antibodies

  • Antiphospholipid antibodies (Table T2)
    • Lupus anticoagulant
    • Anticardiolipin antibodies
    • Anti-beta-2-glycoprotein I antibodies
  • Antiphospholipid antibodies may occur independently or in association with certain autoimmune diseases. 20-40% of patients with SLE have antiphospholipid antibodies; see article on SLE Systemic Lupus Erythematosus (Sle).
  • Antibodies are not hereditary, but a familial tendency to autoimmune diseases may predispose to the formation of antiphospholipid antibodies.
  • Antiphospholipid antibodies often occur transiently in association with infections, for instance.
  • Persistently elevated antiphospholipid antibodies (= positive results from two different samples spaced at least 12 weeks apart) increase the risk of venous and arterial thrombosis as well as pregnancy-related complications. A test result that is strongly positive for antiphospholipid antibodies is clinically considerably more significant than a weakly positive test (see Table T2).
  • For a diagnosis of antiphospholipid syndrome there must be both a persistent, clearly positive antiphospholipid test result and the clinical criteria must be met (see Table 2).

Clinical significance of antiphospholipid antibodies. The risk of thrombosis increases moving down in the Table.

Antiphospholipid antibody findingDefinitionRisk of thrombosis
Persistently weakly positive antiphospholipid, anticardiolipin or anti-beta-2-glycoprotein 1 antibodiesWeakly positive* = anticardiolipin and/or anti-beta-2-glycoprotein 1 antibodies positive result in at least two samples taken ≥ 12 weeks apart, but low titre (laboratory-specific limit)The diagnostic criteria for antiphospholipid syndrome are not met even if there are clinical manifestations.
Persistently strongly positive lupus anticoagulant , anticardiolipin or anti-beta-2-glycoprotein 1 antibodiesStrongly positive* = lupus anticoagulant positive and/or high-titre anticardiolipin antibodies and/or high-titre anti-beta-2-glycoprotein 1 antibodies found in at least two samples taken ≥ 12 weeks apart (laboratory-specific titre limit)The diagnostic criteria for antiphospholipid syndrome are met only if clinical manifestations are also observed.
Persistent triple positivity (the more strongly positive, the more significant the finding)Strongly positive = all (lupus anticoagulant + anticardiolipin antibodies + anti-beta-2-glycoprotein 1 antibodies) persistently positiveThe diagnostic criteria for antiphospholipid syndrome are met only if clinical manifestations are also observed.
Antiphospholipid syndromeClinical manifestation (history of venous and/or arterial thrombosis and/or pregnancy-related complication, see Systemic Lupus Erythematosus (Sle)) plus the laboratory criteria for strongly positive antiphospholipid antibodies are met.High risk (see deep vein thrombosis Deep Vein Thrombosis and SLE Systemic Lupus Erythematosus (Sle))
Catastrophic antiphospholipid syndromeThe criteria for antiphospholipid antibodies are met plus generalized microthrombosis, multiorgan failure and typically thrombocytopeniaVery high risk
* So-called Sydney criteria, ISTH 2006
Increased factor VIII activity
  • F VIII is an acute phase protein transiently elevated in many kinds of acute situations.
  • Only high F VIII levels (over 180%) measured 6 months after an acute thrombosis have been shown in epidemiological studies to be associated with an increased risk of venous thrombosis.
  • A high F VIII level (over 180%) is considered to be a risk factor for low-risk thrombophilia, and its significance in clinical practice as far as management guidelines are concerned is thought to be minor. F VIII testing is an appropriate tool for doctors familiar with coagulation disorders in special situations.
  • Not all laboratories measure the F VIII levels routinely as part of thrombophilia testing.

Homocysteinaemia

  • No evidence exists on the benefit of evaluating the blood levels of homocysteine in patients with thrombosis.

Latent malignancy

  • 3-5(-10)% of patients with idiopathic venous thrombosis / pulmonary embolism are diagnosed with a new malignancy during one-year follow-up.
  • Half of the new malignancies are found in association with diagnostic CT for pulmonary embolism.
  • Routine imaging is not recommended (see below).

Indications for aetiological investigations of thrombophilia

Venous thrombosis and pulmonary embolism

  • According to current understanding and guidelines the duration of treatment depends more on the clinical features of the venous thrombosis, including presentation (primary or recurrent event?), aetiology (provoked or idiopathic event?) and extent (below knee or proximal DVT/PE?), than on a diagnosed thrombophilia.
  • Performing examinations to investigate thrombophilia is indicated only in selected patients.
  • There is no consensus regarding the indications for thrombophilia screening. Today, the attitude to screening is more reserved than only 10-20 years ago.
  • According to a Finnish guideline, laboratory evaluation for thrombophilia (thrombophilia tests) is indicated in the following cases:
    • In a patient < 50 years of age, in whom permanent anticoagulation would not generally be recommended, at least if the venous thrombosis / pulmonary embolism is idiopathic or occurs during pregnancy or the use of oral contraceptives.
    • In a patient ≥ 50 years of age who has any of the following:
      • recurrent idiopathic venous thrombosis / pulmonary embolism
      • strong family history
      • thrombosis at an unusual site (portal, mesenteric, splenic, hepatic, cerebral sinus / cerebral or renal vein thrombosis).
  • Routine imaging for latent malignancy is not recommended. Imaging should be used for any patients potentially at risk.
    • Patients who have had an idiopathic venous thrombosis or pulmonary embolism should have a careful clinical examination (history and physical examination, including palpation of the abdomen and breasts) and the following tests done: complete blood count with differential, ionized calcium, ALT, ALP, chemical screening of urine. They should be asked whether they have participated in age-group-specific cancer screening.
    • Do not hesitate to perform mammography in women over 40. Other imaging should only be done if indicated by any of the above examinations.
    • The following types of venous thrombosis have been found to be more commonly associated with malignancy:
      • thrombosis of the internal jugular, axillary, subclavian or innominate vein or vena cava in the absence of a venous catheter
      • thrombosis of visceral (hepatic, portal, splenic, mesenteric) veins
      • concomitant bilateral thrombosis in the lower extremities
      • thrombosis appearing during adequate anticoagulant therapy.

Arterial thrombosis

  • Looking for hereditary thrombophilia in patients with arterial thrombosis is not useful even if they are young.
  • Investigation of acquired thrombophilia should be considered if the patient has a myocardial or cerebral infarction in the absence of atherosclerotic arterial disease or other clear aetiological factor (such as a coronary artery spasm, dissection, embolism, small vessel disease, atrial fibrillation, cardiomyopathy, paradoxical embolism, malignancy).
  • Arterial thrombosis of unknown aetiology may sometimes be due to acquired thrombophilia (antiphospholipid antibodies, heparin-induced thrombocytopenia [HIT], paroxysmal nocturnal hemoglobinuria [PNH, including erythrocytes, granulocytes and monocytes], Jak2-positive myeloproliferative disease, such as polycythaemia vera or essential thrombocytosis). Pay attention to haematocrit levels > 0.45 and platelet levels > 400, in particular.

Asymptomatic people

  • Hereditary thrombophilia should be sought only after careful consideration in asymptomatic people with a first-degree relative with inherited thrombophilia.
    • Young women should be tested subject to certain criteria when choosing the method of contraception or planning pregnancy. Consult local guidelines.
    • It is more important to evaluate the possibility of high-risk thrombophilia than that of low-risk thrombophilia.
    • Screening of asymptomatic close family members of the patient (if this is decided on) should be performed only for the specific type of inherited thrombophilia identified.
    • A diagnosis of thrombophilia in a healthy individual is not an indication for commencing anticoagulant therapy, but prophylaxis can be enhanced in situations where the patient is predisposed to thrombosis (pregnancy, surgery).
    • An asymptomatic carrier should not be unnecessarily made to feel that he/she has a medical condition; thrombosis will only develop in a small proportion of the carriers of a gene defect.

Laboratory examinations and their timing

Thrombophilia tests

Type of thrombophiliaTests (B = blood, P = plasma)
InheritedP antithrombin III
B factor V gene, DNA test
P protein C
P protein S
B prothrombin gene, DNA test
P thrombin time
AcquiredP thromboplastin time
P cardiolipin, IgG antibodies
P cardiolipin, IgM antibodies*
P lupus anticoagulant, dRVVT*
P lupus anticoagulant, PTT*
P beta-2-glycoprotein, IgG antibodies
P F-VIII
*If the screening test for thrombophilia is positive, testing should be followed up with a confirmatory test
A sample for thrombophilia testing should primarily be taken one month after the end of treatment. The minimum intervals in special situations are ≥ 2 weeks, ≥ 2-4 days and ≥ 24 hours for warfarin, DOACs and LMWH, respectively. In any case, please check the practice at your laboratory.
The sample can be taken at the acute stage before starting anticoagulant therapy but it should then be noted that reactions associated with the acute situation often cause transiently abnormal findings.
Any preceding use of anticoagulants and the date of their discontinuation should be indicated on the laboratory request form.
If it is not possible to stop the anticoagulant therapy, reliable thrombophilia testing can still be carried out to some degree during the therapy, although this is rarely necessary. In such a case, it is imperative that the current medication is indicated on the laboratory request form.

    References

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