March 2018, Dr Chee L Khoo
We all know a bit about d-dimer. We all know that it can be a useful marker for the diagnosis of venous thromboembolism (VTE). It can be used to guide the optimal duration of anti-coagulation in VTE. It is also useful in assessing the risk of recurrence in patients who already had a VTE event especially in patients with cancer. How well do you know d-dimer?
When fibrinogen is activated by thrombin, the fibrin monomers form a weak network of protofibrils. The strength of the fibrin network is enhanced by Factor XIIIa which crosslinks the protofibrils. When the fibrin is degraded by fibrin bound plasmin, d-dimer is produced.
D-dimer is detected by monoclonal antibodies and can be measured by whole blood agglutination, enzyme-linked immunosorbent or immunofluorescent assays (ELISA and ELFA respectively) or latex agglutination assays. Whole blood agglutination is only semi-quantitative and yield either a positive or negative result whereas the other two uses two monoclonal antibodies and can quantify d-dimer levels. Because of different sensitivities of monoclonal antibodies and different methodology and instrumentation used, assays used in different laboratories are not comparable.
Use in diagnosis of VTE
D-dimer is a sensitive marker for detection of thrombosis, but it lacks specificity. It is elevated in most patients with thrombosis but is also elevated with advanced age, pregnancy, after surgery and chronic conditions. . Therefore, It is only useful if the pre-test probability is low. Thus, the diagnosis in primary care starts with assessment of pre-test probability using validated scoring systems such as the Wells score for DVT and the Wells or Geneva score for PE.
If the pre-test probability of DVT is unlikely, a negative d-dimer has <1% chance or being falsely negative. A positive d-dimer should proceed to further imaging.
If the pre-test probability of DVT is likely, then one should proceed straight to ultrasound. If the US is positive, a DVT is confirmed irrespective of what the d-dimer result is. If the US is negative and d-dimer is also negative, then we can safely rule out a DVT. But if the US is negative but d-dimer is positive, then a repeat US may be in order within a week.
Using the Geneva score, patients with low and intermediate pre-test probability, a negative d-dimer can rule out PE while a positive d-dimer will require further investigations (VQ scan or CT angiography). In patients with high pre-test probability, one should proceed straight to radiological investigations.
Use in predicting the next VTE
It is uncertain what the optimal duration of anti-coagulation therapy should be in patients with the first unprovoked DVT or PE. They need at least 3 months of therapy but current guidelines suggest extending the duration unless the bleeding risk is high. Various scores have been used to allow a more individualised approach:
HERDOO2
- Hyperpigmentation,
- Oedema,
- Redness in either leg;
- D-dimer level > 250 mg/l;
- Obesity with body mass index > 30; or
- Older age, >65 years
DASH
- D-dimer
- Age,
- Sex, and
- Hormonal therapy
Patients with a positive d-dimer test while on anti-coagulant therapy or one month after stopping have about twice the risk of recurrence as those with a negative test and the risk of recurrence in men is about 2-fold higher than that in women. In men with a positive d-dimer there is a 15-18% risk of recurrence at 12 months while the risk in patients with negative d-dimer is 8-10%. The risk in women is 10% if d-dimer is positive and 5% if negative at 12 months. This risk is high enough to justify ongoing anti-coagulant therapy especially with reduced doses of apixaban and rivaroxaban if d-dimer is positive one month after stopping anti-coagulation therapy.
Use in Cancer patients
Patients with cancer are at increased risk of VTE. Various scoring systems have been validated to better assess the risks in these patients but more prospective management studies are needed.
Use in medically ill hospitalised patients
Hospitalised medically ill patients are at risk of VTE while in hospital and for up to 3 months after discharge. To reduce this risk, current guidelines recommend thrombo-prophylaxis for such patients while in hospital, but recommend against extended prophylaxis after hospital discharge.
Standardisation of d-dimer assays and further investigation of cut-off adjustment by age or pre-test clinical probability would increase the effectiveness of the test for the diagnosis of VTE. Although d-dimer may be useful for risk assessment in other disorders, additional studies are needed to establish its role.
Access the abstract here.
Reference
Jeffrey I. Weitz,, James C. Fredenburgh, John W. Eikelboom. A Test in Context: D-Dimer. J Am Coll Cardiol 2017 Nov 07;70