Investigations
1st investigations to order
FBC
Test
Should be assessed in all patients.
Unexplained anaemia may be associated with occult malignancy.[50]
Unexplained persistent elevation of packed cell volume (PCV), WBC, 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 heparin-induced thrombocytopenia. Thrombocytopenia is a common feature of disseminated intravascular coagulation.[71]
Result
anaemia; elevated PCV; elevated WBC; elevated or reduced platelet count
peripheral blood smear
Test
Ordered if haemolytic anaemia or chronic disseminated intravascular coagulation suspected, and when FBC indices are abnormal.
Features of microangiopathic haemolytic anaemia include red cell fragmentation in association with thrombocytopenia.
Pancytopenia and macrocytes may suggest paroxysmal nocturnal haemoglobinuria.
Result
presence of red cell fragmentation, spherocytes, thrombocytopenia, pancytopenia, or macrocytes may suggest underlying pathology; presence of nucleated red blood cells, sickle-shaped cells, and Howell-Jolly bodies in sickle cell anaemia
activated partial thromboplastin time (aPTT)
Test
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 increase risk of recurrent venous thromboembolism.[120]
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 disseminated intravascular coagulation.[120]
Over/underfilling the citrate tube can lead to erroneous results.
Result
reduced or prolonged
fibrinogen
Test
Should be assessed in cases of suspected hypercoagulable state.
Reduced level in the presence of other features supports a diagnosis of disseminated intravascular coagulation (DIC) or dysfibrinogenaemia.[21][121]
Elevated level is associated with a twofold increase risk of venous thromboembolism.[79]
Result
elevated fibrinogen is associated with prothrombotic state; reduced fibrinogen may indicate underlying DIC or dysfibrinogenaemia
prothrombin time (PT)
Test
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 disseminated intravascular coagulation (DIC) in the presence of other supporting features (i.e., prolonged activated partial thromboplastin time, 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.
Over/underfilling the citrate tube can lead to erroneous results.
Result
prolonged PT may indicate underlying DIC
D-dimer
Test
Should be assessed in cases of suspected hypercoagulable state.
Marker of fibrinolysis; elevation may indicate activation of coagulation system.
D-dimer is elevated in association with acute venous thromboembolism (VTE); it does not establish an underlying hypercoagulable state.
Elevated levels associated with more than 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]
Result
normal or elevated
serum albumin
Test
Should be assessed in cases of suspected hypercoagulable state to investigate the possibility of nephrotic syndrome.
Reduced levels suggest nephrotic syndrome.
Result
low in nephrotic syndrome
serum creatinine
Test
Should be assessed in cases of suspected hypercoagulable state to investigate the possibility of nephrotic syndrome.
Elevated levels suggest nephrotic syndrome.
Result
elevated in nephrotic syndrome
serum cholesterol
Test
Should be assessed in cases of suspected hypercoagulable state to investigate the possibility of nephrotic syndrome.
Elevated levels suggest nephrotic syndrome.
Result
elevated in nephrotic syndrome
serum triglycerides
Test
Should be assessed in cases of suspected hypercoagulable state to investigate the possibility of nephrotic syndrome.
Elevated levels suggest nephrotic syndrome.
Result
elevated in nephrotic syndrome
Investigations to consider
heritable thrombophilia test
Test
The basic test includes protein C, free protein S, 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), antithrombin activity, and polymerase chain reaction for prothrombin gene mutation (G-20210-A; also referred to as F2 c.*97G>A variant).[117]
Routine testing for heritable thrombophilia is 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 haematological 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 can be affected by anticoagulants.[128] Consult local guidance when considering heritable thrombophilia testing.
Result
positive in inherited thrombophilia
polymerase chain reaction (PCR) for factor V Leiden
Test
Genotyping should be performed upon detection of activated protein C resistance or where there is a family history of factor V Leiden.[117] Genotyping may be performed as a first-line test in some laboratories.
Result
positive
antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2 glycoprotein 1 antibodies)
Test
Guidelines recommend testing, or consideration of testing, for aPLs (lupus anticoagulant, anti-cardiolipin antibodies, anti-beta-2 glycoprotein 1 antibodies) in: young patients (<50 years of age) 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 ischaemic stroke (<50 years of age) in the absence of identifiable risk factors for cardiovascular disease; women with pregnancy morbidity (recurrent or late pregnancy loss).[115][133]
If aPLs are present upon initial testing, repeat testing after at least 12 weeks is required to confirm persistence.[115][133] 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.
Result
positive
homocysteine level
factor VIII level
Test
Rarely measured as it does not impact management.
Most important laboratory marker of thrombotic risk in black people.[14]
Levels >150 U/litre associated with an up to 10-fold increased risk of first venous thromboembolism (VTE) and a sixfold risk for recurrent VTE in black people.[31][32][33]
Testing should be avoided at presentation of acute thrombosis because factor VIII: is an acute-phase reactant and may be elevated due to generalised inflammation (in the context of acute thrombosis); and levels could be misleadingly low in the context of a large thrombosis associated with factor VIII consumption.[117]
Result
elevated
myeloproliferative neoplasm panel
Test
Myeloproliferative neoplasm panel (JAK2, CALR, and MPL) is considered in patients with thrombosis at an unusual site and with FBC abnormalities suggestive of a myeloproliferative disorder.[115][135] JAK2 mutation is found in >95% of patients with polycythaemia vera and up to 50% of patients with essential thrombocythaemia and myelofibrosis.[66] Splanchnic vein thrombosis can be presenting feature of occult myeloproliferative disorder.[65][136]
Result
positive
flow cytometry for paroxysmal nocturnal haemoglobinuria
Test
Suggested for patients with thrombosis at an unusual site (e.g., splanchnic vein thrombosis) or when associated with pancytopenia and/or haemolytic anaemia.[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] Multicolour analysis enables detection of small clones to a level of 0.01%.[134]
Result
positive
heparin-induced thrombocytopenia (HIT) test
Test
Should be avoided in the absence of clinical features to suggest a diagnosis.
Pre-test probability should be assessed using '4T score', which includes: 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][76]
Platelet activation assays have a sensitivity of 85%, which can be improved by the use of washed platelets in experienced laboratories.
Enzyme-linked immunosorbent assay (ELISA) for IgG has high sensitivity (80% to 100%) but lower specificity.
Results should be interpreted according to assay used and pre-test clinical probability.[137]
Result
4T score: 6-8 indicates high clinical suspicion for HIT, score of 4-5 indicates intermediate clinical suspicion for HIT, score of 0-3 indicates low clinical suspicion for HIT; ELISA positive for HIT antibodies
chest x-ray
Test
Considered in patients with unprovoked (idiopathic) venous thromboembolism to rule out occult malignancy.[138]
Result
may detect presence of lung nodules, pleural effusion, or mediastinal abnormality, which suggests underlying occult malignancy
abdominal CT
Test
Considered in patients with suspected malignancy.
Significantly increases detection of an occult malignancy.[53]
Superior to abdominal ultrasound and tumour markers in detection of occult malignancy. However, survival benefit with early detection has not been demonstrated.[53]
Result
may detect occult malignancy
abdominal ultrasound
Test
Used if CT not available to detect any occult malignancy.
Result
may detect occult malignancy
tumour markers
Test
Can be used as part of an extensive screening strategy in the detection of occult malignancy in those with unprovoked (idiopathic) venous thromboembolism (VTE). However, tumour markers are not specific and are not sensitive to the cancers most commonly associated with VTE.[138]
Markers include prostate-specific antigen, carcinoembryonic antigen for colon and rectal cancers, and CA 125 for epithelial ovarian cancer.
Result
may be positive
24-hour urine collection for protein, or spot urine for protein/creatinine ratio
Test
Considered in cases of suspected nephrotic syndrome.
Proteinuria >3.5 g/dL required for diagnosis of nephrotic syndrome.[67]
Result
proteinuria in nephrotic syndrome
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