Fibrinolysis Times As Outcome Measures Using ROTEM with Tpa-Induced Fibrinolysis in Chemotherapy Induced Thrombocytopenia
Authors: Heuvelmans Paul JL , Moenen Floor CJI , Straat Ron JMHE , Wetzels Rick JH , Henskens Yvonne MC , Beckers Erik AM 
Published: October 2019

Background: Despite prophylactic platelet (PLT) transfusions, used to prevent bleeding in chemotherapy induced thrombocytopenia(CIT), some patients will still bleed, whereas others are spared even without PLT transfusion. Little research has been done on (hyper)fibrinolysis as a risk factor for bleeding in CIT. In this study a tPA-induced fibrinolysis in ROTEM was analysed to gain more insight in clot formation and clot lysis times in patients with CIT before and after PLT transfusions.

Aim: to study clot vulnerability for fibrinolysis in CIT patients with tPA-ROTEM.

Method: patients, older than 18 years, treated for a hematological malignancy and receiving a prophylactic PLT transfusion for thrombocytopenia were included. Blood was collected before PLT transfusion (baseline) as well as 1 hour and 24 hours after transfusion. A modified, EXTEM based,ROTEM in the presence of tPA was used to study the occurrence of fibrinolysis. The maximum clot firmness (MCF) and the time to maximum clot firmness (MCF-t) were determined. Also, 100-10% lysis times (A), 100-85% lysis times (B) and 85- 10% lysis times (C) were calculated. Reference values for the tPA-ROTEM were obtained from 40 healthy volunteers.

Results: patient characteristics are shown in table 1. Baseline platelet counts and fibrinogen concentrations were median 6,000/mcL and 4,6 g/L, respectively (table 2). In the tPA-ROTEM a significant increase in MCF, MCF-t, 100-10% LT and 100-85% LT after transfusion was observed. The MCF remained significantly increased after 24 hrs (table 2). When baseline was compared to the healthy volunteers, the MCF, MCF-t were remarkably reduced in the CIT patients. The 100 -10% lysis time was significantly shorter in patients with CIT ( (27,4 versus 34,4 minutes, (P=0.020) (table 3), mainly due to a shorter 100 -85% LT (11.5 versus 17.9 (P<0,001). There were no differences in the 85 - 10% lysis times. A positive, moderate strength correlation was found between the 100-85% lysis times and fibrinogen concentrations (R=0,499 (P=0,035)).

Conclusion: Patients with CIT have a shorter lysis times as measured with tPA-ROTEM than healthy volunteers, mainly occurring during the first phase (100-85%) of fibrinolysis. Higher fibrinogen concentrations were associated with a longer duration of the initial phase. Lysis times outcomes in tPA-ROTEM may be applicable in clinical trials assessing PLT transfusions.

Table 1. Patient characteristics: N=20 SD Min- max Age 55 (mean) 13 23-72 Men (%) 10 (50%) Diagnosis 9 Acute myeloid leukaemia4 Multiple myeloma4 Non-Hodgkin Lymphoma3 Other Treatment 7 Induction therapy (35%)13 Consolidation therapy and stem cell transplantation (65%)

Table 2. Results from baseline, 1h and 24h measurements (all as median) Baseline n=18 1hN=19 24hN=18 Healthy volunteersN=40 Reference values Platelet Count median *109/L 6*# 33*# 21*# 173 150-400 x109/L Fibrinogenmedian (g/L) 4.58# 4.40# 4.64*# 3.18 1.70-4.00 Maximum Clot Firmness mm 23 # 38*# 34*# 59 Time to Maximum Clot Firmness Min. 11.5# 15.7* 15.3# 18.2 Lysis Onset Time Min. 23.0# 29.7*# 28.3# 36.1 Lysis Time Min. 38.9# 44.4*# 44.6# 52.6 * = P<0,05 versus baseline. # = P=<0,05 versus Healthy volunteers.

Table 3. Differences in lysis time speed between baseline measurement and healthy volunteers Unit Patient group baseline Healthy volunteers Mean difference P-value 100 - 10% lysis time Min. 27.4 34.4 7 0.020 100 - 85% lysis time Min. 11.5 17.9 6,4 <0.001 85 - 10% lysis time Min. 15.0 15.3 0,3 0.705

Disclosures

No relevant conflicts of interest to declare.