Abstract
Chnages in hemostasis are often seen in children with ALL. Although increased thrombin generation is already present at diagnosis, thromboembolism is reported only after start of therapy, indicating a relationship between disease and treatment. We present results of a prospective study on coagulation and fibrinolysis in 64 children with newly diagnosed ALL. The DCOG ALL-9 remission induction protocol consists of weekly vincristine IV and oral dexamethasone 6 mg/m2 during 4 weeks. From day 29, dexamethasone is tapered and Asparaginase Paronal® is introduced, twice weekly at 6000 IU/m2 IV for 2 weeks. Results from the introduction of Paronal are given as medians (25th – 75th perc):
| . | Day 29 Paronal 1 . | Day 33 Paronal 2 . | Day 36 Paronal 3 . | Day 40 Paronal 4 . | Day 43 . |
|---|---|---|---|---|---|
| *1p<0.0001; *2p=0.001; *3p=0.003; *4p=0.0007 | |||||
| Fibr mg/L | 1.1 (0.8–1.6) | 00.9 *1 (0.6–1.2) | 0.8 (0.5 – 1.3) | 1.1 (0.5 – 1.6) | 1.5*3 (0.9 – 2.2) |
| F V IU/ml | 1.35 (1.24–1.5) | 1.38 (1.14–1.77) | 1.37 (1.0–1.58) | 1.37 (1.13–1.62) | 1.41 (1.15–1.63) |
| F II | 1.33 (1.2–1.47) | 1.17*1 (1.0–1.34) | 1.17 (0.96–1.29) | 1.17 (0.95–1.3) | 1.17 (0.94–1.3) |
| F VII | 1.12 (0.8–1.4) | 1.48*1 (1.16–1.67) | 1.46 (1.28–1.62) | 1.54 (1.31–1.95) | 1.52 (1.29–1.89) |
| F IX | 1.68 (1.47–2.0) | 1.1*1 (0.83–1.37) | 1.1 (0.82–1.35) | 0.95 (0.73–1.15) | 0.88 (0.66–1.17) |
| F X | 1.47 (1.25–1.81) | 1.25*1 (1.1–1.48) | 1.26 (0.96–1.47) | 1.24 (1.1–1.48) | 1.2 (0.87–1.41) |
| AT III | 1.47 (1,41–1.66) | 1.1*1 (0.95–1.2) | 0.95*1 (0.87–1.1) | 0.9*2 (0.75–1.1) | 0.84 (0.71–1.0) |
| Prot C act | 1.68 (1.44–2.0) | 1.21*1 (1.1–1.41) | 1.15*4 (0.94–1.31) | 1.1 (0.92–1.32) | 1.0 (0.8–1.18) |
| Prot C ag | 1.5 (1.22–1.73) | 1.0*1 (0.84–1.29) | 1.0 (0.8–1.23) | 0.93 (0.78–1.21) | 0.93 (0.76–1.1) |
| Prot S total | 1.0 (0.92–1.16) | 0.8*1 (0.69–0.94) | 0.8 (0.65–0.9) | 0.79 (0.67–0.95) | 0.84 (0.62–0.95) |
| Prot S free | 1.0 (0.85–1.16) | 0.66*1 (0.55–0.78) | 0.59*2 (0.47–0.74) | 0.59 (0.46–0.71) | 0.56 (0.42–0.7) |
| F 1+2 mmol/L | 1.1 (0.77–1.49) | 1.1 (0.80–1.48) | 1.19 (0.73–1.59) | 1.1 (0.8–1.46) | 1.15 (0.87–1.6) |
| TAT μg/L | 4.4 (3.1–9.1) | 3.9 (2.65–6.1) | 3.15 (2.3–5.3) | 3.0 (2.5–4.35) | 4.1 (2.70–9.3) |
| Alpha–2 AP | 1.29 (1.17–1.41) | 0.96*1 (0.84–1.11) | 0.98 (0.8–1.1) | 0.9 (0.69–1.1) | 0.9 (0.7–1.1) |
| Plasminogen | 1.16 (1.0–1.31) | 0.78*1 (0.64–0.98) | 0.78 (0.65–0.91) | 0.79 (0.65–1.0) | 0.82 (0.63–1.1) |
| PAP μg/L | 215 (117.5–428) | 91*1 (59.5–187.5) | 93 (56–163) | 88 (62–141) | 82 (52–170.5) |
| . | Day 29 Paronal 1 . | Day 33 Paronal 2 . | Day 36 Paronal 3 . | Day 40 Paronal 4 . | Day 43 . |
|---|---|---|---|---|---|
| *1p<0.0001; *2p=0.001; *3p=0.003; *4p=0.0007 | |||||
| Fibr mg/L | 1.1 (0.8–1.6) | 00.9 *1 (0.6–1.2) | 0.8 (0.5 – 1.3) | 1.1 (0.5 – 1.6) | 1.5*3 (0.9 – 2.2) |
| F V IU/ml | 1.35 (1.24–1.5) | 1.38 (1.14–1.77) | 1.37 (1.0–1.58) | 1.37 (1.13–1.62) | 1.41 (1.15–1.63) |
| F II | 1.33 (1.2–1.47) | 1.17*1 (1.0–1.34) | 1.17 (0.96–1.29) | 1.17 (0.95–1.3) | 1.17 (0.94–1.3) |
| F VII | 1.12 (0.8–1.4) | 1.48*1 (1.16–1.67) | 1.46 (1.28–1.62) | 1.54 (1.31–1.95) | 1.52 (1.29–1.89) |
| F IX | 1.68 (1.47–2.0) | 1.1*1 (0.83–1.37) | 1.1 (0.82–1.35) | 0.95 (0.73–1.15) | 0.88 (0.66–1.17) |
| F X | 1.47 (1.25–1.81) | 1.25*1 (1.1–1.48) | 1.26 (0.96–1.47) | 1.24 (1.1–1.48) | 1.2 (0.87–1.41) |
| AT III | 1.47 (1,41–1.66) | 1.1*1 (0.95–1.2) | 0.95*1 (0.87–1.1) | 0.9*2 (0.75–1.1) | 0.84 (0.71–1.0) |
| Prot C act | 1.68 (1.44–2.0) | 1.21*1 (1.1–1.41) | 1.15*4 (0.94–1.31) | 1.1 (0.92–1.32) | 1.0 (0.8–1.18) |
| Prot C ag | 1.5 (1.22–1.73) | 1.0*1 (0.84–1.29) | 1.0 (0.8–1.23) | 0.93 (0.78–1.21) | 0.93 (0.76–1.1) |
| Prot S total | 1.0 (0.92–1.16) | 0.8*1 (0.69–0.94) | 0.8 (0.65–0.9) | 0.79 (0.67–0.95) | 0.84 (0.62–0.95) |
| Prot S free | 1.0 (0.85–1.16) | 0.66*1 (0.55–0.78) | 0.59*2 (0.47–0.74) | 0.59 (0.46–0.71) | 0.56 (0.42–0.7) |
| F 1+2 mmol/L | 1.1 (0.77–1.49) | 1.1 (0.80–1.48) | 1.19 (0.73–1.59) | 1.1 (0.8–1.46) | 1.15 (0.87–1.6) |
| TAT μg/L | 4.4 (3.1–9.1) | 3.9 (2.65–6.1) | 3.15 (2.3–5.3) | 3.0 (2.5–4.35) | 4.1 (2.70–9.3) |
| Alpha–2 AP | 1.29 (1.17–1.41) | 0.96*1 (0.84–1.11) | 0.98 (0.8–1.1) | 0.9 (0.69–1.1) | 0.9 (0.7–1.1) |
| Plasminogen | 1.16 (1.0–1.31) | 0.78*1 (0.64–0.98) | 0.78 (0.65–0.91) | 0.79 (0.65–1.0) | 0.82 (0.63–1.1) |
| PAP μg/L | 215 (117.5–428) | 91*1 (59.5–187.5) | 93 (56–163) | 88 (62–141) | 82 (52–170.5) |
Four weeks of dexamethasone results in hypofibrinogenemia, which decreases further during Paronal infusions. AT III and prot C show an initial rise during dexamethasone, and a subsequent significant decrease during Paronal, never in ‘thrombogenic ranges’. However, median prot S values of 0.59 IU/ml are thrombogenic. The significant decrease of α2-AP, plasminogen and PAP point to a decreased fibrinolytic potential. The increased thrombin generation (increased F1+2 and TAT) can be attributed to both disease and treatment. We conclude that the hypercoagulable situation during dexamethasone is in part counterbalanced by low fibrinogen levels. However, addition of Paronal increases the risk for thrombosis by low concentrations of prot S and a decreased fibrinolytic potential due to decreased levels of α2-AP and plasminogen.
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