a raised D-Dimer test does NOT mean there is a clot - there are many other causes of a raised D-Dimer - even just the normal inflammatory response following a vaccination or a bruise!
the D-Dimer test
the D-Dimer test was originally designed to detect DIC as D-Dimers are plasmin fibrinolytic breakdown products òf the fibrin mesh that has been stabilised by Factor XIII.
generation of D-dimer requires the sequential activity of 3 enzymes:
thrombin
thrombin generated by the coagulation system converts soluble fibrinogen to fibrin monomers
each fibrinogen molecule is a symmetrical dimer composed of 3 pairs of 3 intertwined polypeptide chains, termed α, ß, and γ, that extend laterally from a central core
activated factor XIII (factor XIIIa)
fibrin strength is enhanced by factor XIIIa, a transglutaminase activated by thrombin, which cross-links the D domains of adjacent fibrin monomers, as well as the α-chains of opposing monomers to form D-dimer and α-polymers, respectively
plasmin
plasmin degrades the fibrin network when when fibrin-bound plasminogen is converted to plasmin by tissue plasminogen activator
plasminogen circulates in plasma, tissue plasminogen activator is released locally from endothelial cells in response to injury
plasmin formation is localized to fibrin, ensuring that degradation of circulating fibrinogen is minimal
fibrin-bound plasmin degrades the fibrin network into soluble fragments, the building block of which is (DD)E: a complex consisting of D-dimer generated from cross-linked adjacent D domains (DD) noncovalently bound to fragment E
further plasmin-mediated proteolysis of fragment E releases it from the (DD)E complex, and D-dimer then circulates in plasma with a half-life of approximately 8 h until it is cleared by the kidneys and the reticuloendothelial system 1)
localised fibrin production is an essential component of clot formation for haemostasis and also for localisation of infections, it is thus also formed in many inflammatory states, and also integral in tissue repair after injury, and thus D-Dimer levels are likely to be raised in these scenarios
the test was found to be of use in detecting thromboembolism.
average yearly increase in AAA diameter was positively correlated with plasma D-dimer (r=0.39, p<0.001). Plasma D-dimer was independently associated with AAA progression after adjusting for other risk factors, including initial AAA diameter2)3)
stroke (CVA) - atherothrombotic, cardioembolic acute strokes but not lacunar infarcts
ovarian hyperstimulation syndrome (OHSS) via raised prostaglandin levels which increase vascular permeability and result in extravasation of fluids into the third space and resultant haemoconcentration, increased viscosity and risk of VTE
other conditions:
HIV
cancer - may have very high levels, D-dimer levels >8000 ng FEU/ml were associated with an increased incidence of malignancy 4)
atrial fibrillation esp. in those with additional risk factors for stroke, such as hypertension, diabetes, or heart failure
this can be addressed by using age-related cut off values (in μg/L) of 10 x age once age > 50 yrs 5)
pregnancy
IVF:
mild rise at oocyte retrieval day (OPU) to only ~250ng/ml following standard long protocol using GnRH agonist 6)
1 week after administration of recombinant human chorionic gonadotropin (r-hCG) for IVF gave levels of around 750ng/dL 7)
consider ovarian hyperstimulation syndrome (OHSS) as a cause of SOB in patients following IVF with or without PE if D-Dimer is mildly raised or normal.
racial variation - higher in black population
functionally impaired - perhaps related to increased fibrin production in bone and osteoporosis, and similarly, impaired fibrinolysis is a feature common to comorbidities (eg, obesity, diabetes, smoking, advanced age)8)
upper limit of normal for D-Dimer
age < 50yrs: 0.5µg/mL
age > 50yrs: age in yrs/100 µg/mL
utility in pregnant patients
although there are D-Dimer cutoffs adjusted for trimesters, these have not been adequately validated and thus obstetricians generally DO NOT USE D-Dimer in pregnancy
consider discussing all suspected cases of PE with an obstetric service
uses a D-Dimer cut off for pregnant patients of 1.0µg/mL which was most efficient in 1st TM however, the study only was of around 500 patients with 20 PEs.
also requires NO clinical signs of deep-vein thrombosis, No haemoptysis, and pulmonary embolism NOT the most likely diagnosis for the 1.0µg/mL cut off to exclude a PE.
if D-Dimer < 0.5µg/mL then PE excluded even if one or more YEARS criteria present.
The DiPEP study11) looked at biomarkers and VTE in pregnant women and had concluded that D-dimer among other biomarkers were not reliable to rule VTE in or out in pregnancy
if in extremis, bedside echo and if PE suggested then emergency thrombolysis may be indicated
if not in extremis, look for other causes of SOB (do FBE, CRP, LFTs, lipase, CXR to help exclude pneumonia/viral pneumonitis, heart failure, check for significant anaemia, heart failure, biliary colic, etc) and if no other causes found then:
IF your gestalt for PE is high risk then do CXR and if normal, a V/Q scan
IF gestalt for PE is moderate risk then:
if 1st trimester can do D-Dimer and if < 1.0µg/mL then no imaging
otherwise, do bilateral leg doppler USS
if DVT found then treat as per PE
if no DVT then PE is unlikely
false negative D-Dimer results in VTE
clot burden is too small
early testing
delayed testing - levels fall to 25% of initial levels after 1-2 weeks
anticoagulant Rx - reduced D-Dimer levels by 25% within 24hrs of Rx
Simply-RED D-Dimer test:
whole blood agglutination method
sensitivity 66%, NPV 89%
if low pre-test probability of PE then NPV almost 100%
Mx of the patient with a raised D-Dimer
1. Is there a reasonable explanation for it?
for example: pregnancy, recent surgery, recent trauma / bruise / fractures, severe sepsis, recent vaccination, or known chronic raised DDimer due to malignancy
a significantly raised CRP is likely to suggest that a raised D-Dimer is a false positive
in general, D-Dimer should not be performed on these patients unless looking for very high levels for another cause such as snakebite or AZ vaccine thrombosis with thrombocytopenia syndrome (TTS / VITT / VIPIT) and if not doing this, the dDimer should probably be ignored and the patient treated on their merits as to their underlying presentation thus EXIT this algorithm.
2. Is the level greater than 5x upper limit of normal?
although in cases of high pre-test probability for PE, PE is 4x more likely with D-Dimers > 4ug/mL compared to 0.5-1.0ug/mL, such high levels also raise the possibility of the above conditions thus it is becomes less likely to just be the usual VTE such as PE/DVT without the above conditions without clinical evidence of a massive PE or extensive DVT and when pre-test probabilities of PE are lower
this is a bit like having a CRP > 100 with no RIF tenderness when considering appendicitis, whilst it may be appendicitis, other causes should be considered - thus if the clinical picture does not strongly support a large DVT/PE then a very high D-Dimer suggests there may be another cause
this is especially the case if the D-Dimer is > 8 ug/mL
3. Abnormally high levels adjusted for age but less than 5x the upper limit of normal
this may be a normal post-vaccination inflammatory response!
If the patient is on anticoagulants consider the possibility of occult bleeding such as retroperitoneal haemorrhage if there are other features such as pain to suggest this.
If none of the above are present:
if there are risk factors for aortic aneurysm such as age > 60, male, smoker, raised lipids or FH of AAA, then consider an outpatient screening abdominal USS assuming patient's presentation is stable and not of a ruptured AAA in which case an emergent CT aortogram should be considered
clinical utility in possible VTE:
as a method of excluding venous thromboembolism with a normal result (ie. no need to perform V/Q scan or CTPA if normal):
ONLY perform if:
low pre-test probability of venous thromboembolism:
patient < 50yrs age (unless you are happy to use the age-related cutoffs - see above)
heart rate : systolic BP ratio < 1
no unexplained hypoxia (ie. SaO2 > 95% on room air)
no haemoptysis
no calf swelling
no recent general aneasthetic past 4wks
AND other causes of raised levels unlikely:
ie. not for most inpatients & pts with substantial comorbidities
THUS only for previously well pts presenting to ED with new possible venous thromboembolism but low pretest probability of it
newer ELISA & whole blood agglutination:
not available in all hospitals
positive if > 500ng/ml
high negative predictive values (90%)
positive predictive value 30%
immunochromatographic bedside D-Dimer tests:
eg. Simplify by Agen Biochemical.
similar design to urine pregnancy test strips, results available in 10min
in the population whose Hamilton Score for DVT is “unlikely”, then the negative predictive value for an acute lower limb DVT is 98.8%.
unfortunately, in the group whose Hamilton Score is “likely DVT” the negative predictive value is only 82% and cannot be used to rule it out and thus USS is indicated.