Approach

Many people with thrombophilia are asymptomatic; hereditary thrombophilia may, therefore, be diagnosed following routine tests.

The most common manifestations of a hypercoagulable state are deep vein thrombosis (DVT) and pulmonary embolism (PE), which are referred to together as venous thromboembolism (VTE). Whether thrombophilia also increases the risk of arterial thrombosis is less well established.

Although many factors that are likely to enhance the risk of thrombosis have been identified, detailed laboratory investigations fail to detect abnormalities in many patients who present with a history of thrombosis. In addition, testing for thrombophilia is controversial because the diagnosis of an underlying heritable thrombophilia in a patient with a VTE will not change the management, particularly in the acute setting.​[114][115][116]​ Routine testing for thrombophilia is, therefore, not recommended in most clinical scenarios.[115][116]

History and examination

Family history of VTE should be assessed together with the history of prior thrombosis (particularly the age at which VTE occurred), the presence of additional risk factors for VTE, location of VTE, and the diagnostic modality used to document VTE.[117]

Past medical history should focus on underlying conditions associated with VTE and medications that can predispose to VTE.

Types of inherited thrombophilia include:[3]

  • Antithrombin III deficiency

  • Protein C deficiency

  • Protein S deficiency

  • Plasminogen deficiency

  • Dysfibrinogenemia

  • Factor V Leiden

  • Prothrombin gene mutation

  • Elevated levels of factors VIII, IX, and XI

  • Elevated levels of thrombin-activatable fibrinolysis inhibitor

  • Elevated fibrinogen

  • Hyperhomocysteinemia

  • Sickle cell disease.

Causes of acquired thrombophilia include:[3]

  • Paroxysmal nocturnal hemoglobinuria (PNH)

  • Nephrotic syndrome

  • Myeloproliferative disorders

  • Disseminated intravascular coagulation (DIC)

  • Pregnancy/postpartum

  • Acute inflammatory state

  • Behcet disease

  • Antiphospholipid antibodies (e.g., lupus anticoagulants, anticardiolipin antibodies, anti-beta-2 glycoprotein 1 antibodies)

  • Malignancy

  • Chemotherapy

  • Surgery

  • Heparin-induced thrombocytopenia (HIT)

  • Oral birth control pill, estrogen therapy (e.g., hormone replacement therapy, selective estrogen receptor modulator therapy)

  • Smoking

  • Obesity

  • HIV infection

  • Long-haul flight (>4 hours).

Risk assessment for thrombosis and bleeding

Risk assessment for thrombosis and bleeding is important to guide appropriate treatment. Department of Health (UK): risk assessment for venous thromboembolism (VTE) Opens in new window

All surgical patients and medical patients with significant reduction in mobility should be formally assessed on hospital admission for risk of thrombosis and bleeding.

High risk of thrombosis is defined as the presence of any of the following:

  • Age >60 years

  • Active cancer/cancer treatment

  • Dehydration

  • Known thrombophilias

  • Obesity (BMI >30 kg/m²)

  • One or more significant comorbidities (e.g., heart disease, metabolic, endocrine, or respiratory pathology, acute infectious diseases, inflammatory conditions)

  • Personal history or first-degree relative with history of VTE

  • Use of hormone replacement therapy

  • Use of estrogen-containing oral contraceptive therapy

  • Varicose veins with phlebitis

  • Pregnancy or <6 weeks postpartum

  • Significantly reduced mobility >3 days

  • Hip or knee replacement

  • Hip fracture surgery

  • Total anesthetic and surgery time >90 minutes

  • Surgery involving lower limb with total anesthetic and surgery time >60 minutes

  • Critical care admission.

Low risk of thrombosis is defined as the absence of high-risk features. However, the above list is not exhaustive and clinicians should consider additional risks on a case-by-case basis.

Patients are defined as having excessive bleeding risk if any of the following features are present:

  • Hemophilia or other known bleeding disorder

  • Platelet count <75 x 10³/ microliter

  • Acute ischemic or hemorrhagic stroke in the previous month

  • Blood pressure >200 mmHg systolic or 120 mmHg diastolic

  • Severe liver disease (increased prothrombin time or known varices)

  • Active bleeding

  • Existing anticoagulant or antiplatelet therapy

  • Any surgical procedure with a known bleeding risk

  • Any neurosurgical procedure

  • Lumbar puncture, epidural anesthesia, or spinal anesthesia within the previous 4 hours.

Risk assessment for VTE is also advocated during pregnancy at prenatal booking, during any hospital admission, and following delivery. The Royal College of Obstetricians and Gynaecologists (UK) has published a risk assessment tool for this purpose.[118] RCOG: obstetric thromboprophylaxis risk assessment and management Opens in new window

Although the absolute risk of VTE in pregnancy remains low, it is a leading cause of maternal morbidity and mortality.[47][48] Risk is increased with a family history of VTE and heritable thrombophilia.[7][17][26] Pregnancy-related VTE risk is highest among women with type I antithrombin deficiency, homozygosity for factor V Leiden, or compound heterozygosity,[7][17][26] and those with a personal history of unprovoked or estrogen associated VTE.

Routine laboratory tests

The following tests may be indicated.

  • CBC: assessed in all patients. Unexplained anemia may be associated with occult malignancy.[50] Unexplained persistent elevation of packed cell volume or white cell or platelet count may suggest a myeloproliferative disorder.[119] An unexplained 30% to 50% fall in platelet count 5-10 days after starting heparin may suggest HIT. Thrombocytopenia is a common feature of DIC.[71]

  • Peripheral blood smear: ordered if hemolytic anemia or chronic DIC is suspected or when CBC indices are abnormal. Features of microangiopathic hemolytic anemia include red cell fragmentation in association with thrombocytopenia. Pancytopenia and macrocytes may suggest paroxysmal nocturnal hemoglobinuria.

  • Activated partial thromboplastin time (aPTT): in addition to being assessed in cases of suspected hypercoagulable state, should also be measured to establish a baseline prior to initiation of anticoagulation. Reduced aPTT at discontinuation of anticoagulation has been associated with a twofold increased risk of recurrent VTE.[120] The reduction in aPTT reflects increased levels of factors IX, VIII, and XI. Prolonged aPTT (using a thromboplastin sensitive to lupus anticoagulants) may suggest an underlying lupus anticoagulant. Prolonged aPTT in the presence of other features may support a diagnosis of DIC.[120]

  • Fibrinogen: should be assessed in cases of suspected hypercoagulable state. Reduced level in the presence of other features supports a diagnosis of DIC or dysfibrinogenemia.[21][121] Elevated level is associated with a twofold increased risk of VTE.[79]

  • Prothrombin time (PT): in addition to being assessed in cases of suspected hypercoagulable state, should also be measured to establish a baseline prior to initiation of anticoagulation. Prolonged PT is indicative of DIC in the presence of other supporting features (i.e., prolonged aPTT, low platelet count, low fibrinogen, increased D-dimer) and the underlying condition associated with its development.[121] Can be prolonged rarely by the presence of a lupus anticoagulant.

  • D-dimer (marker of fibrinolysis): should be assessed in cases of suspected hypercoagulable state. Elevation may indicate activation of coagulation system. Elevated levels of D-dimer are associated with more than a twofold risk of first VTE.[122] Normal D-dimer at completion of anticoagulation therapy is associated with low risk of recurrent VTE whereas elevated D-dimer predicts an increased risk of recurrent VTE.[111][123]

  • Serum albumin, creatinine, triglycerides, and cholesterol: should be assessed in cases of suspected hypercoagulable state to investigate the possibility of nephrotic syndrome. Abnormal renal function, hypoalbuminemia, hypercholesterolemia/triglyceridemia suggest nephrotic syndrome.

Heritable thrombophilia test

Controversial, because the diagnosis of an underlying heritable thrombophilia in a patient with a VTE will not change the management, particularly in the acute setting.​[114][115][116]​​​ Routine testing for thrombophilia is, therefore, not recommended in most clinical scenarios.[115][116]​ Select patients in specific clinical situations may warrant testing, but guideline recommendations are not uniform.[114][115][116]

Neonates and children with purpura fulminans should be tested for protein C and protein S deficiency.[115][124]

Testing may be considered in selected patients with thrombosis: at an unusual site (and with abnormal hematologic parameters); with a positive family history (and absence of a clear risk factor); at a young age (e.g., <50 years, with absence of a clear risk factor).[115][125][126]​​​[127]​​ Specialist advice may be needed before testing patients who are receiving anticoagulation because tests (e.g., protein C, S and antithrombin levels) can be affected by anticoagulants or a recent thrombosis (within 4 weeks).[128][129]​ Consult local guidance when considering heritable thrombophilia testing.

The basic test for heritable thrombophilia includes:

  • Protein C level

  • Free protein S antigen level[130]

  • Activated protein C resistance (activated protein C resistance can be used as a screening assay for factor V Leiden and, if detected, should prompt genotyping)[117][130]

  • Antithrombin level

  • Prothrombin gene mutation (G-20210-A; also referred to as F2 c.*97G>A variant).

Considerations when testing for heritable thrombophilia

  • Protein C, protein S and antithrombin levels can be reduced during acute VTE and in the presence of anticoagulants; reduced levels in these circumstances do not necessarily reflect true deficiency.[129][131][132]​​​​​

  • Thrombophilia testing should not be performed during acute VTE or during the initial 3-month course of anticoagulant therapy.[115]​​[116][129]

  • Liver disease, oral birth control pill, and hormone therapy can lead to reduced levels of antithrombin and proteins C and S.

  • ​Genetic testing should only be performed to try to identify underlying variants responsible for phenotypically identified deficiencies in antithrombin and proteins C and S if the findings will impact management.[115]

  • Testing for antithrombin deficiency can be considered during pregnancy if there is evidence of heparin resistance or a known family history of antithrombin deficiency.[115][116]​​

When heritable thrombophilia testing should be avoided

  • Neonates and children in the absence of a strong clinical indication (e.g., purpura fulminans, multiple unexplained thromboses). VTE is rare in children, and interpretation of levels of proteins C and S and antithrombin can be difficult, as normal levels are lower than the adult reference range. Thrombophilia screening is not routinely recommended for neonatal stroke.[115]​ Thrombophilia testing should be avoided in children with venous access associated thrombosis in the absence of a positive family history.[133]

  • US and UK guidelines recommend against heritable thrombophilia screening in women with recurrent miscarriage or a history of fetal loss, fetal growth restriction, preeclampsia and placental abruption.[115][134][135]​​​ Targeted assessment for inherited thrombophilia may be considered in specific clinical circumstances (e.g., personal history of VTE).[134] Consult local guidance.

  • Patients with central venous catheter-related thrombosis or retinal vein occlusion, or in unselected patients with an upper limb DVT.[115]​​

  • Older patients without a family history for heritable thrombophilia.[115][136] Testing these patients is unlikely to be informative and should be avoided.​​

  • Genetic testing for variants in genes that do not have a clinically significant link to thrombosis, such as methyltetrahydrofolate reductase (MTHFR), is not recommended.[115][137]

Other tests for thrombophilia

While not required as part of the heritable thrombophilia screen, the following may also be assessed.

  • Factor V Leiden: genotyping should be performed upon detection of activated protein C resistance or where there is a family history of factor V Leiden.[117][130]​ Genotyping may be performed as a first-line test in some laboratories.

  • Antiphospholipid antibodies (aPLs): guidelines recommend testing, or consideration of testing, for aPLs (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2 glycoprotein 1 antibodies) in:[115][138]

    • young patients (age <50 years) with unprovoked VTE, or VTE provoked by a minor risk factor

    • patients with acute multiple thrombotic events and evidence of organ failure suggestive of catastrophic antiphospholipid syndrome (CAPS)

    • women with a history of unprovoked VTE (testing to be performed outside of pregnancy)

    • patients with thrombosis at unusual sites in the absence of clear provoking factors

    • patients with arterial thrombosis in the absence of other vascular risk factors

    • neonates with multiple unexplained thromboses, particularly when there is evidence suggestive of CAPS

    • patients with ischemic stroke (<50 years of age) in the absence of identifiable risk factors for cardiovascular disease

    • women with pregnancy morbidity (recurrent or late pregnancy loss)

If aPLs are present upon initial testing, repeat testing after at least 12 weeks is required to confirm persistence.[115][138]​ Antiphospholipid syndrome is acquired; screening for antiphospholipid antibodies is not recommended in family members of patients with thrombosis.[115]​ Consult local guidance for further details regarding aPL testing.

  • Homocysteine: Homocysteine's role in hypercoagulability is controversial; current understanding is that hyperhomocysteinemia does not predispose to VTE.[37][38]​​​ Do not order a homocysteine assay as part of the thrombophilia work up.[130]

  • Factor VIII levels: rarely measured as result does not impact management. Most important laboratory marker of thrombotic risk in black people.[14] Levels >150 U/liter associated with an up to 10-fold increased risk of first VTE and sixfold risk for recurrent VTE in black people.[31][32][33]​ Factor VIII testing should be avoided at presentation of acute thrombosis because of the following reasons:[117]

    • Factor VIII is an acute-phase reactant and may be elevated due to generalized inflammation (in the context of acute thrombosis)

    • Factor VIII levels could be misleadingly low in the context of a large thrombosis associated with factor VIII consumption.

  • Flow cytometry for PNH: considered in patients with thrombosis at an unusual site (e.g., splanchnic vein thrombosis) and pancytopenia and/or hemolytic anemia.[115] Also considered for patients with stroke or arterial thrombosis associated with abnormal blood parameters.[115]​​ Investigation of choice for PNH diagnosis and measurement of clone size.[73] Multicolor analysis enables detection of small clones to a level of 0.01%.[139]

  • Myeloproliferative neoplasm panel (JAK2, CALR, and MPL): considered in patients with thrombosis at an unusual site and with CBC abnormalities suggestive of a myeloproliferative disorder.​[115][140]​​ JAK2 mutation is found in >95% of patients with polycythemia vera and up to 50% of patients with essential thrombocythemia and myelofibrosis.[66] Splanchnic vein thrombosis can be presenting feature of occult myeloproliferative disorder.[65][141]

  • HIT test: should be avoided in the absence of clinical features to suggest a diagnosis. The pretest probability should be assessed using the "4T score."[75][76]​ This includes the timing of fall in platelet count following initiation of heparin, percentage change in platelet count from baseline to nadir, presence/absence of thrombosis, and lack of alternate diagnoses for thrombocytopenia.[75] Platelet activation assays have a sensitivity of 85%, which can be improved by the use of washed platelets in experienced laboratories. ELISA for IgG has high sensitivity (80% to 100%), but lower specificity. Results should be interpreted according to the assay used and the pretest clinical probability.[142]

Imaging

Imaging may be undertaken to screen for malignancy.

  • Chest x-ray: considered in patients with unprovoked (idiopathic) VTE to rule out occult malignancy.[143]

  • Abdominal computed tomography (CT): significantly increases detection of an occult malignancy.[53] Superior to abdominal ultrasound and tumor markers in detection of occult malignancy. However, survival benefit with early detection has not been demonstrated.[53]

  • Abdominal ultrasonography: used if CT is not available to detect any occult malignancy.

Ancillary tests

Include for tumor markers (prostate-specific antigen, carcinoembryonic antigen for colon and rectal cancers, and CA 125 for epithelial ovarian cancer). They can be used as part of an extensive screening strategy for the detection of occult malignancy in those with unprovoked (idiopathic) VTE. However, tumor markers are not specific and are not sensitive to the cancers most commonly associated with VTE.[143]

24-hour urine collection for protein, or spot urine for protein/creatinine ratio, should be taken to rule out nephrotic syndrome if there is increased protein on urinalysis.[67]

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