16 – Are there any serological biomarkers for the diagnosis of DVT/PE?
Sofiene Kallel, Meriem Souissi, Lalit Maini, Yasim Khan, Lokesh Goyal, Nishant Bhatia.
Response/Recommendation: There are makers that can be used for detecting the presence of deep venous thrombosis/pulmonary embolism (DVT/PE). The most commonly used serological biomarker is the D-dimer. However, there are some other markers that are also available such as: PAI-1, SF, FDP, TAT and PF 1+2.
Strength of Recommendation: Grade-B. Fair evidence (Level II or III studies with consistent findings) for using serological markers.
Rationale: DVT and PE together referred to as venous thromboembolism (VTE), are a major contributor to the global burden of disease, with high morbidity and mortality1. VTE are associated with serious short- and long-term complications including recurrence, post-thrombotic syndrome, chronic thromboembolic pulmonary hypertension, and death2. As an estimated 20% of patients with PE will die on or before the first day after diagnosis, timely diagnosis is critical3. Clinical features that are suggestive of DVT (symptoms, signs, clinical risk factors) cannot be used individually to confirm or exclude the diagnosis of VTE. However, when incorporated in the diagnostic workup and individualized pre-test probability of DVT can aid decision-making strategies. The diagnosis of DVT requires a multifaceted approach, based on clinical features, a pre-test probability scoring system (such as the Wells or modified Geneva score), laboratory tests and results of the imaging studies tests (such as compression ultrasound for DVT and computer tomography (CT) or ventilation/ perfusion lung scan for PE)4. Our systematic review aimed to find serological markers other than D-dimer in diagnosing DVT/VTE in orthopaedic patients.
D-dimer is the most commonly used serological marker for diagnosing VTE, it’s a split product from the cross-linked fibrin clot, but it has low specificity of VTE since many other conditions such as cancer, inflammation, and pregnancy are associated with elevated D-dimer levels. D-dimer has also the important drawback of being affected by anticoagulant treatments2. However, a negative D-dimer can be of more value due to its high negative predictive value. The test is mainly used as a rule-out screening tool. A patient with a positive D-dimer test, however, would require further investigations to confirm or refute the diagnosis.
Numerous serological markers have been studied for diagnosing VTE. We identified 50 such markers5–54, out of these Plasminogen activator inhibitor-1 (PAI-1), soluble fibrin (SF), fibrinogen degradation product (FDP), Thrombin antithrombin-III (TAT) complexes, Prothrombin fragment 1+2 (PF) 1+2, and fibrinogen have been frequently used in patients with orthopaedic conditions. These serological markers can be classified according to the pathophysiology of DVT or thrombotic disease, one is coagulation markers, such as D-dimer, Factor VIII, thrombin generation (TG), and fibrin monomer (FM), while the other is inflammatory markers, including P-selectin, inflammatory cytokines, microparticles (MP) and leukocyte count55.
PAI-1 is a single chain glycoprotein, which inhibits the plasma fibrinolytic activity. It is a good marker for early diagnosis of DVT/VTE on a postoperative day one after joint replacement surgeries. It has a sensitivity of 78% and specificity of 72 % at a cut-off value of 53.5 ng/mL (Normal range 2.5–80 ng/mL). The area under the curve (AUC) on a receiver operating curve (ROC) range from 0.79 to 0.847,10,15,20,28,42,47.
SF is regarded as an indicator of acute fibrin formation and a precursor of fibrin thrombi. The advantage of measuring soluble fibrin is the considerably longer half-life in the circulation. It is also a marker for early diagnosis with sensitivity ranging from 67.9% to 98.5% and specificity ranging from 38.2% to 80.1% at different cut-off values (Normal range < 7.0 μg/ml). The AUC on a ROC range from 0.67 to 0.735,8,10,13,28,34,39,47,48.
FDP are generated when fibrinogen, soluble fibrin, or cross-linked fibrin is lysed by plasmin. It has a sensitivity ranging from 31.3% to 98.6% and a specificity of 68.1 % to 74.3. The AUC on a ROC range from 0.61 to 0.7117,18,28,38,39,42,46,56.
TAT is induced by thrombin and is a sensitive parameter of the latent activator of the clotting pathway. It has a sensitivity ranging from 71% to 79% and a specificity of 27 % to 41%. The AUC on a ROC is 0.829,10,15,24,26,31,46.
PF 1+2 is cleaved from the amino-terminal end of human prothrombin when the zymogen is activated by factor Xa to yield thrombin. It has a sensitivity ranging from 73% to 86% and specificity of 31 % to 44%9,24–26,31,32,42,54.
Fibrinogen is a soluble protein in the plasma that is broken down to fibrin by the enzyme thrombin to form clots. It has a sensitivity of 62% and specificity of 46 % at a cut-off value of 3.2 g/L (Normal range 2.0–4.0 g/L). The AUC on a ROC range from 0.42 to 0.5910,18,19,21,32,35,36,43.
In the diagnosis of acute-phase VTE using Fibrin-related markers (FRM), plasma FDP, D-dimer and SF levels were significantly high in the patients with acute VTE, as previously reported. These findings suggest that FRM are useful for the diagnosis of acute VTE. Meanwhile, both FDP and D-dimer were significantly higher in the patients with chronic VTE than in the patients without VTE, but SF levels were not, suggesting that SF is not useful for diagnosing subclinical VTE. This is because the half-life of SF which has been reported to be within 1 day is not sufficiently long to diagnose subclinical VTE17,57.
Studies have reported that elevated levels of factor VIII (above 230-250%) are associated with an increased risk of VTE. Additionally, there is evidence that levels are associated with an increased risk of a VTE recurrence. Factor VIII levels are increased as part of the acute phase reaction and higher levels are found in individuals with a non-O blood group. Although factor VIII is a good biomarker of primary and recurrent VTE no interventional trials have been performed to guide clinicians1.
Newer markers like miRNA’s had reported to good have sensitivity and specificity with AUC result 0.959 to 1.0014. However, a number of studies are less to draw any conclusions on newer markers like granule membrane protein (GMP-140), elastase-derived cross-linked fibrin degradation products (e-XDP), microparticle-tissue factor (MP-TF), urinary PF 1+2, and tissue plasminogen activator inhibitor complex (t-PAIC).
The levels of these serological markers may be affected by the chemoprophylactic drug is given to patients for example defibrase can significantly reduce plasma D-dimer levels58. Rivaroxaban results in a smaller increase in PF 1 + 2 and TAT levels as compared with Enoxaparin8.
Combining these marker values using a mathematical model may provide a better diagnostic tool with good sensitivity and specificity. The cut-off values of these markers may be specified as per the indicated use and timing in the disease process.
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