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.
1. Spronk HMH, Cannegieter S, Morange P, et al. Theme 2: Epidemiology, Biomarkers, and Imaging of Venous Thromboembolism (and postthrombotic syndrome). Thromb Res. 2015;136 Suppl 1:S8-S12. doi:10.1016/j.thromres.2015.07.035
2. Morelli VM, Brækkan SK, Hansen J-B. Role of microRNAs in Venous Thromboembolism. Int J Mol Sci. 2020;21(7):E2602. doi:10.3390/ijms21072602
3. Wells PS, Ihaddadene R, Reilly A, Forgie MA. Diagnosis of Venous Thromboembolism: 20 Years of Progress. Ann Intern Med. 2018;168(2):131-140. doi:10.7326/M17-0291
4. Kruger PC, Eikelboom JW, Douketis JD, Hankey GJ. Deep vein thrombosis: update on diagnosis and management. Med J Aust. 2019;210(11):516-524. doi:10.5694/mja2.50201
5. Tsuji A, Wada H, Matsumoto T, et al. Elevated levels of soluble fibrin in patients with venous thromboembolism. Int J Hematol. 2008;88(4):448-453. doi:10.1007/s12185-008-0173-5
6. Seo W-W, Park M-S, Kim SE, et al. Neutrophil-Lymphocyte Ratio as a Predictor of Venous Thromboembolism after Total Knee Replacement. J Knee Surg. 2021;34(2):171-177. doi:10.1055/s-0039-1694043
7. Tang J, Zhu W, Mei X, Zhang Z. Plasminogen activator inhibitor-1: a risk factor for deep vein thrombosis after total hip arthroplasty. J Orthop Surg Res. 2018;13(1):8. doi:10.1186/s13018-018-0716-2
8. Sudo A, Wada H, Nobori T, et al. Cut-off values of D-dimer and soluble fibrin for prediction of deep vein thrombosis after orthopaedic surgery. Int J Hematol. 2009;89(5):572-576. doi:10.1007/s12185-009-0323-4
9. Oswald E, Velik-Salchner C, Innerhofer P, et al. Results of rotational thromboelastometry, coagulation activation markers and thrombin generation assays in orthopedic patients during thromboprophylaxis with rivaroxaban and enoxaparin: a prospective cohort study. Blood Coagul Fibrinolysis. 2015;26(2):136-144. doi:10.1097/MBC.0000000000000203
10. Kobayashi H, Akamatsu Y, Kumagai K, et al. The use of factor Xa inhibitors following opening-wedge high tibial osteotomy for venous thromboembolism prophylaxis. Knee Surg Sports Traumatol Arthrosc. 2017;25(9):2929-2935. doi:10.1007/s00167-016-4065-6
11. Hartono F, Yusuf I, Suhadi B, Fachruddin A, Augustinus Y. Trauma magnitude of the meta-epyphyseal cancellous affects the incidence of deep vein thrombosis. A prospective cohort study on the dynamic of Collagen I, Collagen IV, Tissue factor, P-Selectin and Nitric Oxide in the thrombus formation following hip and knee surgeries. Ann Med Surg (Lond). 2021;63:102190. doi:10.1016/j.amsu.2021.102190
12. Izumi M, Ikeuchi M, Aso K, et al. Less deep vein thrombosis due to transcutaneous fibular nerve stimulation in total knee arthroplasty: a randomized controlled trial. Knee Surg Sports Traumatol Arthrosc. 2015;23(11):3317-3323. doi:10.1007/s00167-014-3141-z
13. Niimi R, Hasegawa M, Shi DQ, Sudo A. The influence of fondaparinux on the diagnosis of postoperative deep vein thrombosis by soluble fibrin and D-dimer. Thromb Res. 2012;130(5):759-764. doi:10.1016/j.thromres.2011.11.046
14. Qin J, Liang H, Shi D, et al. A panel of microRNAs as a new biomarkers for the detection of deep vein thrombosis. J Thromb Thrombolysis. 2015;39(2):215-221. doi:10.1007/s11239-014-1131-0
15. Yukizawa Y, Inaba Y, Watanabe S, et al. Association between venous thromboembolism and plasma levels of both soluble fibrin and plasminogen-activator inhibitor 1 in 170 patients undergoing total hip arthroplasty. Acta Orthop. 2012;83(1):14-21. doi:10.3109/17453674.2011.652886
16. Zhu X, Yao Y, Yao C, Jiang Q. Predictive value of lymphocyte to monocyte ratio and monocyte to high-density lipoprotein ratio for acute deep vein thrombosis after total joint arthroplasty: a retrospective study. J Orthop Surg Res. 2018;13(1):211. doi:10.1186/s13018-018-0910-2
17. Yamaguchi T, Wada H, Miyazaki S, et al. Fibrin-related markers for diagnosing acute-, subclinical-, and pre-venous thromboembolism in patients with major orthopedic surgery. Int J Hematol. 2016;103(5):560-566. doi:10.1007/s12185-016-1954-x
18. Wang W, Duan K, Ma M, et al. Tranexamic Acid Decreases Visible and Hidden Blood Loss Without Affecting Prethrombotic State Molecular Markers in Transforaminal Thoracic Interbody Fusion for Treatment of Thoracolumbar Fracture-Dislocation. Spine (Phila Pa 1976). 2018;43(13):E734-E739. doi:10.1097/BRS.0000000000002491
19. Cheng J, Fu Z, Zhu J, Zhou L, Song W. The predictive value of plasminogen activator inhibitor-1, fibrinogen, and D-dimer for deep venous thrombosis following surgery for traumatic lower limb fracture. Ann Palliat Med. 2020;9(5):3385-3392. doi:10.21037/apm-20-1604
20. Li J, Zhang F, Liang C, Ye Z, Chen S, Cheng J. The Diagnostic Efficacy of Age-Adjusted D-Dimer Cutoff Value and Pretest Probability Scores for Deep Venous Thrombosis. Clin Appl Thromb Hemost. 2019;25:1076029619826317. doi:10.1177/1076029619826317
21. Xia Z-N, Xiao K, Zhu W, et al. Risk assessment and management of preoperative venous thromboembolism following femoral neck fracture. J Orthop Surg Res. 2018;13(1):291. doi:10.1186/s13018-018-0998-4
22. Ma J, Qin J, Hu J, et al. Incidence and Hematological Biomarkers Associated With Preoperative Deep Venous Thrombosis Following Foot Fractures. Foot Ankle Int. 2020;41(12):1563-1570. doi:10.1177/1071100720943844
23. Kolb G, Bodamer I, Galster H, et al. Reduction of venous thromboembolism following prolonged prophylaxis with the low molecular weight heparin Certoparin after endoprothetic joint replacement or osteosynthesis of the lower limb in elderly patients. Thromb Haemost. 2003;90(6):1100-1105. doi:10.1160/TH03-01-0062
24. Cofrancesco E, Cortellaro M, Corradi A, Ravasi F, Bertocchi F. Clinical utility of prothrombin fragment 1+2, thrombin antithrombin III complexes and D-dimer measurements in the diagnosis of deep vein thrombosis following total hip replacement. Thromb Haemost. 1998;79(3):509-510.
25. Reikerås O, Clementsen T. Time course of thrombosis and fibrinolysis in total knee arthroplasty with tourniquet application. Local versus systemic activations. J Thromb Thrombolysis. 2009;28(4):425-428. doi:10.1007/s11239-008-0299-6
26. Green L, Lawrie AS, Patel S, et al. The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation. Br J Haematol. 2010;151(5):469-476. doi:10.1111/j.1365-2141.2010.08433.x
27. Johnson GJ, Leis LA, Bach RR. Tissue factor activity of blood mononuclear cells is increased after total knee arthroplasty. Thromb Haemost. 2009;102(4):728-734. doi:10.1160/TH09-04-0261
28. Mont MA, Jones LC, Rajadhyaksha AD, et al. Risk factors for pulmonary emboli after total hip or knee arthroplasty. Clin Orthop Relat Res. 2004;(422):154-163. doi:10.1097/01.blo.0000128971.35014.31
29. Misaki T, Kitajima I, Kabata T, et al. Changes of the soluble fibrin monomer complex level during the perioperative period of hip replacement surgery. J Orthop Sci. 2008;13(5):419-424. doi:10.1007/s00776-008-1266-y
30. Chotanaphuti T, Ongnamthip P, Silpipat S, Foojareonyos T, Roschan S, Reumthantong A. The prevalence of thrombophilia and venous thromboembolism in total knee arthroplasty. J Med Assoc Thai. 2007;90(7):1342-1347.
31. Craven S, Dewar L, Yang X, Ginsberg J, Ofosu F. Altered regulation of in-vivo coagulation in orthopedic patients prior to knee or hip replacement surgery. Blood Coagul Fibrinolysis. 2007;18(3):219-225. doi:10.1097/01.mbc.0000264704.90039.5d
32. Reikerås O, Clementsen T, Bjørnsen S. Time course of thrombosis and fibrinolysis during total hip surgery. J Orthopaed Traumatol. 2006;7(4):187-191. doi:10.1007/s10195-006-0146-5
33. Schellhaass A, Walther A, Konstantinides S, Böttiger BW. The diagnosis and treatment of acute pulmonary embolism. Dtsch Arztebl Int. 2010;107(34-35):589-595. doi:10.3238/arztebl.2010.0589
34. Niimi R, Hasegawa M, Sudo A, Shi D, Yamada T, Uchida A. Evaluation of soluble fibrin and D-dimer in the diagnosis of postoperative deep vein thrombosis. Biomarkers. 2010;15(2):149-157. doi:10.3109/13547500903367276
35. Lin C, Chen Y, Chen B, Zheng K, Luo X, Lin F. D-Dimer Combined with Fibrinogen Predicts the Risk of Venous Thrombosis in Fracture Patients. Emerg Med Int. 2020;2020:1930405. doi:10.1155/2020/1930405
36. Wang H, Pei H, Ding W, Yang D, Ma L. Risk factors of postoperative deep vein thrombosis (DVT) under low molecular weight heparin (LMWH) prophylaxis in patients with thoracolumbar fractures caused by high-energy injuries. J Thromb Thrombolysis. 2021;51(2):397-404. doi:10.1007/s11239-020-02192-7
37. Du Y-Q, Tang J, Zhang Z-X, Bian J. Correlation of Interleukin-18 and High-Sensitivity C-Reactive Protein with Perioperative Deep Vein Thrombosis in Patients with Ankle Fracture. Ann Vasc Surg. 2019;54:282-289. doi:10.1016/j.avsg.2018.06.013
38. Hasegawa M, Wada H, Miyazaki S, et al. The Evaluation of Fibrin-Related Markers for Diagnosing or Predicting Acute or Subclinical Venous Thromboembolism in Patients Undergoing Major Orthopedic Surgery. Clin Appl Thromb Hemost. 2018;24(1):107-114. doi:10.1177/1076029616674824
39. Hasegawa M, Wada H, Wakabayashi H, et al. The relationships among hemostatic markers, the withdrawal of fondaparinux due to a reduction in hemoglobin and deep vein thrombosis in Japanese patients undergoing major orthopedic surgery. Clin Chim Acta. 2013;425:109-113. doi:10.1016/j.cca.2013.07.009
40. Intiso D, Di Rienzo F, Iarossi A, et al. Thrombocytosis after hip and knee surgery in the rehabilitation setting: is it an occasional phenomenon? Relationship with deep venous thrombosis and functional outcome. BMC Musculoskelet Disord. 2015;16:90. doi:10.1186/s12891-015-0550-1
41. Liu L, Ling J, Ma Z, Yuan Q, Pan J, Yang H. Changes in von Willebrand factor and ADAMTS-13 in patients following arthroplasty. Mol Med Rep. 2015;11(4):3015-3020. doi:10.3892/mmr.2014.3041
42. López Y, Páramo JA, Valentí JR, Pardo F, Montes R, Rocha E. Hemostatic markers in surgery: a different fibrinolytic activity may be of pathophysiological significance in orthopedic versus abdominal surgery. Int J Clin Lab Res. 1997;27(4):233-237. doi:10.1007/BF02912463
43. Ma J, Qin J, Shang M, Zhou Y, Zhang Y, Zhu Y. Incidence and risk factors of preoperative deep venous thrombosis in closed tibial shaft fracture: a prospective cohort study. Arch Orthop Trauma Surg. Published online November 21, 2020. doi:10.1007/s00402-020-03685-z
44. Nemeth B, van Adrichem RA, van Hylckama Vlieg A, et al. Venous Thrombosis Risk after Arthroscopy of the Knee: Derivation and Validation of the L-TRiP(ascopy) Score. Thromb Haemost. 2018;118(10):1823-1831. doi:10.1055/s-0038-1670660
45. Pazzagli M, Mazzantini D, Cella G, Rampin E, Palla A. Value of thrombin-antithrombin III complexes in major orthopedic surgery: relation to the onset of venous thromboembolism. Clin Appl Thromb Hemost. 1999;5(4):228-231. doi:10.1177/107602969900500404
46. Jørgensen LN, Lind B, Hauch O, Leffers A, Albrecht-Beste E, Konradsen LA. Thrombin-antithrombin III-complex & fibrin degradation products in plasma: surgery and postoperative deep venous thrombosis. Thromb Res. 1990;59(1):69-76. doi:10.1016/0049-3848(90)90272-e
47. Watanabe H, Kikkawa I, Madoiwa S, Sekiya H, Hayasaka S, Sakata Y. Changes in blood coagulation-fibrinolysis markers by pneumatic tourniquet during total knee joint arthroplasty with venous thromboembolism. J Arthroplasty. 2014;29(3):569-573. doi:10.1016/j.arth.2013.08.011
48. Watanabe H, Madoiwa S, Sekiya H, et al. Predictive blood coagulation markers for early diagnosis of venous thromboembolism after total knee joint replacement. Thromb Res. 2011;128(6):e137-143. doi:10.1016/j.thromres.2011.07.030
49. Xie X, Liu C, Lin W, et al. Deep vein thrombosis is accurately predicted by comprehensive analysis of the levels of microRNA-96 and plasma D-dimer. Exp Ther Med. 2016;12(3):1896-1900. doi:10.3892/etm.2016.3546
50. Yoshioka K, Kitajima I, Kabata T, et al. Venous thromboembolism after spine surgery: changes of the fibrin monomer complex and D-dimer level during the perioperative period. J Neurosurg Spine. 2010;13(5):594-599. doi:10.3171/2010.5.SPINE09883
51. Zhu Y, Chen W, Li J, et al. Incidence and locations of preoperative deep venous thrombosis (DVT) of lower extremity following tibial plateau fractures: a prospective cohort study. J Orthop Surg Res. 2021;16(1):113. doi:10.1186/s13018-021-02259-y
52. Zixuan L, Chen W, Li Y, et al. Incidence of deep venous thrombosis (DVT) of the lower extremity in patients undergoing surgeries for ankle fractures. J Orthop Surg Res. 2020;15(1):294. doi:10.1186/s13018-020-01809-0
53. Zuo J, Hu Y. Admission deep venous thrombosis of lower extremity after intertrochanteric fracture in the elderly: a retrospective cohort study. J Orthop Surg Res. 2020;15(1):549. doi:10.1186/s13018-020-02092-9
54. Ota S, Wada H, Abe Y, et al. Elevated levels of prothrombin fragment 1 + 2 indicate high risk of thrombosis. Clin Appl Thromb Hemost. 2008;14(3):279-285. doi:10.1177/1076029607309176
55. Hou H, Ge Z, Ying P, et al. Biomarkers of deep venous thrombosis. J Thromb Thrombolysis. 2012;34(3):335-346. doi:10.1007/s11239-012-0721-y
56. Kakkos SK, Gohel M, Baekgaard N, et al. Editor’s Choice – European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021;61(1):9-82. doi:10.1016/j.ejvs.2020.09.023
57. Yang P, Li H, Zhang J, Xu X. Research progress on biomarkers of pulmonary embolism. Clin Respir J. Published online July 2, 2021. doi:10.1111/crj.13414
58. Wu M, Zhang S, Sun Y, Gu R. Effect of defibrase on deep vein thrombosis following the surgical treatment of pelvic fracture. h and.:6.