Table 1.
Included Studies of Laboratory Biomarkers of Thrombosis for Use In Hematologic Malignancy
| Study | Subjects | VTE n (%) | Biomarker | Relationship to VTE vs no VTE |
|---|---|---|---|---|
| Aue 2011[20] | 32 adults with relapsed CLL | 5 (15%) | d-dimer | Median 0.5 ug/mL vs 0.42 ug/mL, p >0.05 |
| Protein S deficiency | 0/5 vs 5/27 | |||
| Low antithrombin | 0/5 vs 3/27 | |||
| FVL mutation | 0/5 vs 2/27 | |||
| Prothrombin gene mutation | 0/5 vs 2/23 | |||
| Auwerda 2007[22] | 135 adults with untreated myeloma | 14 (10%) | vWF (Ag, collagen-binding, Rco) | No relationship |
| FVIII | No relationship | |||
| Protein C activity | No relationship | |||
| Protein S activity | No relationship | |||
| Antiphospholipid antibody (LAC, ACA IgG & IgM) | No relationship | |||
| FV Leiden | No relationship | |||
| FII variant | No relationship | |||
| Ay 2008[26] | 91 adults with myeloma or lymphoma (596 solid tumor) | 4 (4.4%) | P-selectin | Median 45.9 [35.4–62.8] vs 42.1 [32.9–52.2] p = 0.025 HR for sP-selectin > 75th percentile: 2.3 (95% CI 1.2–4.5) |
| Ay 2009[12] | 94 adults with myeloma or lymphoma (727 solid tumor) | 7 (7.4%) | D-dimer | 0.96 (0.50–2.34) ug/mL vs 0.71 (0.34–1.33) ug/mL HR for 2-fold increase: 1.3 (95% CI 1.1–1.5) |
| F1+2 | 310 (213–416) pmol/L vs 249 (190–353) pmol/L p = 0.003 HR for 2-fold increase: 1.8 (95% CI: 1.3–2.6) |
|||
| Ay 2011[23] | 152 adults with myeloma or lymphoma (881 solid tumor) | 10 (6.6%) | Peak thrombin generation | 56 [431–677] nM vs 499 [360–603] p = 0.014 HR per 100nM increase: 1.15 (95% CI 1/02–1.30) |
| Azik 2013[32] | 92 adults 100 days post-HSCT | 5 (5.4%) | FV leiden | 0/5 vs 8/87 p >0.05 |
| MTHFR mutation | 0/5 vs 17/87 >0.05 | |||
| Prothrombin G20210A | 0/5 vs 2/87 >0.05 | |||
| Hyperhomocysteinemia | 1/5 vs 19/87 >0.05 | |||
| Elevated lipoprotein (a) | 1/5 vs 19/87 >0.05 | |||
| Protein C (mean) | 68±10% vs 76±21% >0.05 | |||
| Protein S (mean) | 76±12% vs 87±30% >0.05 | |||
| Antithrombin III (mean) | 102±11% vs 104±18% >0.05 | |||
| Beinart 2004[17] | 117 adults with ALL | 9 (7.7%) | Fibrinogen | < 50mg/dL: Specificity: 90%, LR: 6, RR: 10 (p = 0.0145) |
| Boersma 2016[21] | 168 adults with heme malignancy + CVC | 15 (8.9%) | FVIII (mean) | 203±62 % vs 166±59% p = 0.023 |
| PAI-1 (median) | 12.2 (3.5–22.7) vs 4.9(1.7–10.2) p = 0.062 | |||
| PAI-1 > 12.2 IU/mL | 8/15 vs 34/153 p = 0.008 | |||
| Protein S (mean) | 100±34 vs 93±29 p =0.417 | |||
| APC resistance (median) | 3.0 (2.63–3.79) vs 3.11 (1.76–4.80) p = 0.632 | |||
| Couturier 2015[18] | 708 adults with ALL/LL | 22 (3.1%)* | Fibrinogen (mean, at diagnosis) | 3.3 vs 4, p = 0.149 |
| Median AT nadir | 47.5 vs 51, p = 0.25 | |||
| Gheldof 2017[29] | 53 adults with acute leukemia | 4 (7.5%) | EVs (thrombin generation) | Elevated peak/lag ratio: 3/8 vs 0/47 |
| EVs (tissue factor activity) | >2pg/mL: 2/7 vs 1/48 | |||
| Kovacs 2014[16] | 153 adults post-auto HSCT for myeloma | 8 (5.2%) | d-dimer | 233.19 (47.00–715.00) ng/mL vs 200.11 (161.13–248.53) ng/mL |
| FVIII | 1.71 (1.13–2.91) IU vs 1.38 (1.27–1.49) IU | |||
| TAT | 3.43 (0.00–37.50) pg/mL vs 2.18 (1.65–2.89) ug/mL | |||
| Libourel 2016[11] | 404 adults with AML | 12 (4.7%) | d-dimer | d-dimer 0.5–4.0 mg/L: HR 2.79 (95% CI 0.84–9.28) d-dimer >4.0 mg/L: HR 12.03 (95% CI 3.39–42.64) |
| Alpha-2-antiplasmin | ≤ 0.8 IU/mL: HR 5.99 (95% CI 1.34–26.76) | |||
| Antithrombin | ≤ 0.8 IU/mL: HR 3.16 (95% CI 0.79–12.62) | |||
| Fibrinogen | <1: HR 12.38 (95% CI 1.54–99.18) | |||
| Mitrovic 2014[14] | 63 adults with APL | 9 (14.3%) | F II G20210A | OR 3.00 (95% CI 0.17–53.71) |
| FV Leiden | OR 3.00 (95% CI 0.17–53.71) | |||
| PAI-1 4G/5G | OR 0.10 (95% CI 0.01–0.91) | |||
| MTHFR C677T | OR 2.66 (95% CI 0.56–12.65) | |||
| Negaard 2008[13] | 93 adults with hematologic malignancy | 8 (8.6%) | Fibrinogen | No relationship |
| Antithrombin | No relationship | |||
| F1+2 | No relationship | |||
| D-dimer | No relationship | |||
| Tissue factor | No relationship | |||
| FVIIa-Antithrombin | No relationship | |||
| FVII | No relationship | |||
| FVIIa | No relationship | |||
| Free TFPI-1 | No relationship | |||
| Total TFPI-1 | No relationship | |||
| TFPI-1 activity | No relationship | |||
| Nowak-Gottl 2003[30] | 336 children with ALL | 30 (8.9%) | FV G1691A, FII G20210A, protein S, protein C, antithrombin deficiency, elevated Lp[a] | 46.5% of children with any one of these factors developed VTE |
| Nowak-Gottl 1999[31] | 289 children with ALL | 32 (11%) | MTHFR, P G20210A, FV Leiden, Lp(a), Protein C, Protein S, Antithrombin | VTE occurred in 27/58 subjects with a tested defect vs 5/231 patients without |
| Posch 2015[27] | 99 adults with lymphoma/myeloma | 5 (5%) | Soluble VEGF | HR (per 10pg/mL increase): 1/94 (95% CI 1.00–1.09) |
| Reidl 2013[28] | 273 adults with lymphoma/melanoma | 14 (5%) | Mean platelet volume | HR (per 1fL increase): 0.87 (95% CI 0.72–1.06) HR (MPV <75th percentile): 0.59 (95% CI 0.37–0.95) |
| Rozen 2016[24] | 56 children with ALL | 3 (5.4%) | Thrombin generation | Endogenous thrombin potential & peak values elevated in 2/3 with VTE |
| Rudd 2005[19] | 30 children with ALL | 4 (13%) | Antithrombin | Decreased level (compared to baseline) with all new thromboses (p = 0.012) |
| Protein C | No relationship | |||
| Protein S | No relationship | |||
| Streetly 2005[15] | 15 adults with myeloma | 3 (20%) | d-dimer | Elevated (>500 ug/L) in all cases |
| Undas 2015[25] | 48 adults with myeloma | 10 (21%) | Antiplasmin | 101.5 [86.3–111.8]% vs 104.1 [90.2–110.5]% p > 0.05 |
| Plasminogen | 97.5 [87–103.8] % vs 105.8 [97.4–113.1]% p = 0.03 | |||
| PAI-1 activity | 11 [9.9–12.8] vs 8.3 [6.4–10.5]% p = 0.004 | |||
| Factor VIII | 192.5 [183.5–266.5] % vs 188 [166.5–223]% p > 0.05 | |||
| Wermes 1999[33] | 73 children with ALL | 10 (27%) | FV Leiden, prothrombin mutation, MTHFR mutation, protein S, protein C, antithrombin deficiency | One of the above seen in 4/6 patients with VTE, 14/67 without |
*
CNS thrombosis only,
**
remaining 3 patients had DIC
vWF: von Willebrand Factor Ag: antigen, Rco: ristocetin cofactor, FVIII: factor VIII, LAC: lupus anticoagulant, ACA: anticardiolipin antibody, FV: factor V, FII: factor II, HR: hazard ratio, HSCT: hematopoietic stem cell transplant, LR: likelihood ratio, RR: risk ratio, CVC: central venous catheter, ALL: acute lymphocytic leukemia, LL: lymphoblastic lymphoma, AT: antithrombin, EV: extracellular vesicles, TFPI: tissue factor pathway inhibitor, VEGF: vascular endothelia growth factor, NHL: non-Hodgkin lymphoma, ()= range/95% CI, [] = IQR