Thrombotic Disease Diagnosis
1.???? What is Thrombotic Disease？
Thrombotic diseases are disorders where blood clots form in the arteries or veins, disrupting blood flow and leading to serious complications. They are categorized into arterial and venous thrombosis, with the latter including deep vein thrombosis (DVT) and pulmonary embolism (PE). These diseases are prevalent and affect individuals of varying ages and conditions, especially those with cancer or during pregnancy [1]. Disseminated Intravascular Coagulation (DIC) is also a serious coagulation disorder that causes microthrombosis in small blood vessels throughout the body and is accompanied by severe bleeding tendency. It is a paradoxical state of "excessive coagulation" and "excessive bleeding" in the body and is often observed in critically ill patients.
2.???? What is the Challenges with Diagnosing Thrombotic Disease？
2.1? Current Diagnosis Approach
Clinical Evaluation
Risk Assessment: Medical history, physical examination, and assessment of risk factors (e.g., recent surgery, immobility, cancer, hormone therapy).
Well’s Score: A clinical prediction rule that estimates the probability of DVT or PE based on specific criteria and symptoms.
Testing techniques
1) Ultrasound: This test uses sound waves to check the blood flow in your arteries and veins.
2) Blood tests: These may include tests to see how well your blood can clot. Some indicators are usually used in coagulation function testing:
? a) Prothrombin Time (PT)
? b) Activated Partial Thromboplastin Time (APTT)
? c) Thrombin Time (TT)
? d) Fibrinogen
? e) Coagulation Factor Activity Assay
? f) D-dimer
? g) Fibrin(ogen) Degradation Products (FDP)
? h) Thromboelastography (TEG)
3) Venography: For this test, a dye is injected into your veins. Then X-rays are taken to show blood flow and look for clots. The dye makes your veins easier to see on the X-rays.
4) MRI, MRA or CT: The imaging procedure that is used will depend on the type of blood clot you have and where it is located.
2.2 Diagnostic Challenges in Thrombotic Diseases:
Current biomarkers for detecting thrombosis, such as D-dimer and fibrin degradation products (FDP), are limited by their latent detection of thrombosis [2]. These markers only elevate when thrombosis has already formed and started to degrade. There is a critical demand for biomarkers that can provide early warning signs, identify the risk of thrombosis or bleeding at an early stage, and allow healthcare professionals to intervene even before symptoms appear.
3.???? Thrombus Biomarker in Different Clinical Scenarios
3.1? Introduction for Serum Thrombus Biomarkers
Novel thrombus biomarkers, such as Thrombin-Antithrombin Complex (TAT), Plasmin-α2 Plasmin Inhibitor Complex (PIC), Thrombomodulin (TM), and Tissue Plasminogen Activator Inhibitor Complex (t-PAIC), are gaining attention from healthcare professionals for their potential in providing early warnings of thrombosis. These biomarkers help in the early detection and management of thrombotic events, contributing to better patient outcomes.
The TAT is recognized as a marker of activation of the coagulation system, PIC is an indicator of activation of the fibrinolysis system, TM can monitor the function of endothelial cells, and t-PAIC is a fibrinolytic marker. These are important markers in the process of venous thrombosis, which can be significantly elevated even before thrombus [3].
3.2 Venous thromboembolism（VTE）
Thrombotic markers play a significant role in diagnosing VTE in high-risk populations such as malignant cancer patients and those undergoing surgery. They can be assessed before and after surgery to monitor the risk of VTE development or during cancer follow-up to predict the risk of VTE.
For total joint arthroplasty patients, TAT/PIC ratio showed the largest AUC (0.78) on postoperative day 6, with a sensitivity of 97.14% and a negative predictive value of 94.12%, making it a potential prognostic index for VTE during the early phase postoperatively [4].
For malignant tumors patients, the combination of TAT, PIC, TM, and t-PAIC with D-dimer and FDP significantly improves the diagnostic efficiency for VTE in malignant tumors patients. The combination of these six markers achieves the highest AUC (0.937), with a sensitivity of 89.8% and specificity of 88.5%, outperforming the diagnostic efficiency of D-dimer and FDP alone [3].
The combined use of these biomarkers with traditional markers like D-dimer and FDP enhances both diagnostic accuracy and prognostic assessment, thereby improving clinical outcomes in managing VTE.
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3.3 Disseminated Intravascular Coagulation（DIC）
In disseminated intravascular coagulation (DIC), biomarkers like soluble thrombomodulin (sTM) and t-PAIC are crucial for early detection and prognosis. Elevated levels of sTM and t-PAIC are independent predictors of poor outcomes in septic patients, associated with lower 60-day survival rates (HR =1.012 for sTM and HR =1.014 for t-PAIC). sTM is particularly sensitive for identifying early septic shock and DIC, with a high predictive accuracy (AUC up to 0.864). When combined with clinical scores such as APACHE II, age, and t-PAIC, the predictive accuracy for 60-day mortality improves (AUC up to 0.809) [3].
Assessing TAT, PIC, tPAIC, and sTM together enhances the diagnostic performance for DIC, achieving an AUC of 0.807, better than using single biomarkers. Higher levels of TAT, t-PAIC, and sTM are linked to poorer 28-day mortality outcomes and are significantly elevated in pre-DIC stages compared to non-overt DIC. The diagnostic and prognostic effectiveness of these biomarkers varies with different underlying diseases, indicating the need for disease-specific approaches. Notably, these biomarkers show different levels in patients with hematological malignancies and solid tumors and are especially elevated in septic DIC patients, suggesting the potential for tailored diagnostics [5].
3.4 Anticoagulant & Thrombolysis Monitoring
Rivaroxaban is an oral anticoagulant that acts directly on coagulation factor Xa and inhibits thrombin activation by reversibly binding to the active site of factor X. Rivaroxaban anti-Xa activity assay can be used to monitor the drug concentration, but it does not represent the therapeutic effect. TAT measures the level of thrombin in the blood, which can directly indicate the inhibitory effect of the drug on thrombin [6].
Thrombolytic therapy is widely used to treat acute ischemic stroke (AIS) patients. Alteplase, a tissue plasminogen activator (t-PA), is a standard treatment for eligible AIS patients as it can dissolve blood clots and restore blood flow to the affected area of the brain. Combined test of PIC, D-dimer, and fibrinogen provided a quantitative reflection of the impact of IV alteplase on the fibrinolytic system. PIC levels decreased by nearly 50% every 3 hours after peaking, indicating a direct correlation between the timing and the effects of alteplase on fibrinolysis. Besides, PIC returned to its normal range after 24 hours, which coincided with the expected duration of alteplase's effect. Notably, PIC was found to decrease 3 hours earlier than D-dimer and FDP, suggesting it could be a sensitive indicator of fibrinolytic activity [7].
4.???? Conclusions
Innovative biomarkers such as sTM, t-PAIC, TAT and PIC could significantly improve diagnostic accuracy and enhance early detection and prognosis of thrombotic diseases. However, the effectiveness of these biomarkers varies across different conditions, indicating a need for tailored diagnostic strategies. Moving forward, the development and integration of disease-specific biomarkers and advanced monitoring techniques will be crucial in improving patient outcomes and personalized care in thrombotic diseases.
Reference
[2] Zhang, Jin et al. “Identification of soluble thrombomodulin and tissue plasminogen activator-inhibitor complex as biomarkers for prognosis and early evaluation of septic shock and sepsis-induced disseminated intravascular coagulation.” Annals of palliative medicine vol. 10,10 (2021): 10170-10184. doi:10.21037/apm-21-2222
[3] Zhou, Kun et al. “Diagnostic and Prognostic Value of TAT, PIC, TM, and t-PAIC in Malignant Tumor Patients With Venous Thrombosis.”?Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis?vol. 26 (2020): 1076029620971041. doi:10.1177/1076029620971041
[4] Cheng, Yuying et al. “Clinical Impact of Coagulation and Fibrinolysis Markers for Predicting Postoperative Venous Thromboembolism in Total Joint Arthroplasty Patients.”?Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis?vol. 25 (2019): 1076029619877458. doi:10.1177/1076029619877458
[5] Mei, Heng et al. “Evaluation the combined diagnostic value of TAT, PIC, tPAIC, and sTM in disseminated intravascular coagulation: A multi-center prospective observational study.”?Thrombosis research?vol. 173 (2019): 20-26. doi:10.1016/j.thromres.2018.11.010
[6] 文梦,赵慧茹,赵育婧,等. 血栓分子标志物对下肢深静脉血栓形成的诊断及抗凝疗效的评价[J]. 临床检验杂志,2019,37(9):671-674. DOI:10.13602/j.cnki.jcls.2019.09.07.
[7] Liu, Yonge et al. “Quantitatively monitoring acute ischemic stroke patients post recombinant tissue plasminogen activator treatment.”?Health science reports?vol. 4,1 e218. 21 Dec. 2020, doi:10.1002/hsr2.218
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Thrombus Testing
TAT . PIC . TM . t-PAIC . FDP . D-Dimer (CLIA) performed on FC-2100
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