Recombinant activated factor VII as an additional agent in the management of bleeding in patients with chemotherapy-induced thrombocytopenia

Dear Sirs,

Chemotherapy-induced thrombocytopenia is a serious complication of intensive anti-tumour therapy and is associated with an increased risk of bleeding¹. Recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordisk, Bagsvaerd, Denmark) has been recently preferred in the treatment of intractable haemorrhage. However, clinical experience with this agent in chemotherapy-induced thrombocytopenia remains limited almost exclusively to retrospective analyses of small groups of patients with considerable variability in rFVIIa dosing and evaluated parameters^2–5.

We performed a retrospective (a 6-year period), single-centre analysis of the therapeutic use of rFVII in adult patients with active haematological malignancies, life-threatening bleeding (blood loss of more than 150 mL/min or more than 50% of the intravascular volume within 3 hours or requiring transfusion of more than 10 units of packed red cells within 24 hours or at a site acutely threatening life), severe chemotherapy-induced thrombocytopenia (platelet count <50×10⁹/L), and a negative personal history for an EMEA-approved indication for rFVIIa.

The efficacy and safety of rFVIIa, selected laboratory parameters (haemoglobin, haematocrit, platelet count, prothrombin time, activated partial thromboplastin time, thrombin time), total volume of infusions (crystalloids, colloids) and transfusions (packed red cells, fresh frozen plasma, aphaeretic platelet concentrates) were analysed. Laboratory parameters were evaluated immediately before (time interval: −0.5 to −2.0 hours) and immediately (+0.5 to +2.0 hours), 24 hours (+16.5 to +33.0 hours) and 48 hours (+41.5 to 57.5 hours) after the first rFVIIa dose; given the retrospective design of the study, samples collected closest to the defined times were accepted. All laboratory tests were performed with commercial analysers and reagents (Siemens Healthcare Diagnostics Inc., Newark, United States of America; Bayer Healthcare, Fernwald, Germany). The infusion and transfusion therapy was evaluated comparing the 48-hour periods before and after the first rFVIIa dose. The patients were followed for 30 days. The treatment was considered effective if the single rFVIIa dose led to the cessation of macroscopic blood loss and stabilisation of the circulation for more than 24 hours, and no detectable progression of bleeding at adequate imaging examination 24–48 hours after administration of the rFVIIa. The treatment was considered to have had a transient effect if the bleeding was arrested for a shorter period or rFVIIa doses had to be repeated. In order to identify factors associated with the efficacy of rFVIIa, patients in whom a single rFVIIa dose was effective (group 1) were compared to those in whom it was ineffective (group 2).

Eight patients (2 women, 6 men) with a median (range) age of 55.5 (41–74) years were included in the study. Five had acute myeloid leukaemia, two had multiple myeloma and one had mantle cell lymphoma; none was studied after haematopoietic stem cell transplantation. Eight bleeding episodes were evaluated, of which one was induced (case 1), while the other seven were spontaneous (Table I). The median initial rFVIIa dose was 95 (14–111) μg/kg, the time between the first rFVIIa dose and the onset of bleeding was 7.25 (2–201) hours and the platelet count immediately before administration of rFVIIa was 22 (1–48)×10⁹/L. rFVIIa was given as a bolus injection, which was repeated in two patients. None of the patients had relevant hypothermia, acidosis or hypofibrinogenaemia at the time of rFVIIa administration and none was refractory to platelet concentrates. Three patients received platelet concentrates within 1 hour before rFVIIa. Other haemostatics were concomitantly used in all cases without marked changes in agents and their doses prior to and after rFVIIa. Invasive procedures to decrease bleeding were not performed. The dose of rFVIIa and whether to use concomitant therapy were determined according to the agents’ availability and the patients’ conditions. Among the various anti-fibrinolytics, 4-aminomethylbenzoic acid was preferred because of the limited availability of other agents including tranexamic acid.

Table I.

Summary of cases.

			rFVIIa administration							Other haemostatic treatment		Transfusion therapy [mL]
Case N.	Gender (age [years])	Bleeding site	Clinical effect (1st dose)	1st dose (mean)* [μg/kg]	N. of doses	IDI [h]	TI [h]	PLTC† [x109/L]	Concomitant platelet replacement‡	Before rFVIIa	After rFVIIa	48 hours before 1st rFVIIa dose			48 hours after 1st rFVIIa dose
												PRC	FFP	PC	PRC	FFP	PC
1	M (49)	subclavian artery (CVC insertion)	bleeding stopped	14	1	-	2,0	27	none	ethamsylate, PAMBA, local (pressure, EPI)	ethamsylate, PAMBA, local (pressure)	170	220	320	0	0	0
2	M (45)	respiratory tract	bleeding stopped	51	1	-	3,5	16	PC (1 TU)	ethamsylate, terlipressin	ethamsylate, terlipressin	0	250	160	750	760	320
3	F (74)	intra-abdominal (kidneys, spleen)	bleeding stopped	100	1	-	7,5	19	PC (1 TU)	ethamsylate	ethamsylate	0	538	320	1,068	1034	320
4	M (66)	upper GIT	bleeding stopped	85	1	-	7,0	7	none	ethamsylate, terlipressin	ethamsylate, terlipressin	1,303	0	320	330	0	480
5	M (72)	upper GIT	transient (24 h)	106	1	-	5,0	48	none	ethamsylate, PAMBA, terlipressin	ethamsylate, PAMBA, terlipressin	617	0	160	1,194	433	332
6	M (42)	intra-abdominal (spleen)	no effect	93	1	-	27,0	26	none	ethamsylate, PAMBA	ethamsylate, PAMBA	280	262	320	693	1503	640
7	M (62)	soft tissues of the thorax wall	transient (12 h)	97 (56)	11	6, 12	24,0	38	PC (1 TU)	ethamsylate, PAMBA	ethamsylate, PAMBA	545	205	480	1,173	0	640
8	F (41)	upper and lower GIT	no effect	111 (111)	2	56	201,0	1	none	ethamsylate, PAMBA, terlipressin, octreotide	ethamsylate, PAMBA, terlipressin, octreotide	645	964	320	931	1,110	640

Legend CVC: central venous catheter; EPI: epinephrine; F: female; FFP: fresh-frozen plasma; GIT: gastrointestinal tract; h: hours; IDI: interdose interval; M: male; PAMBA: 4-aminomethylbenzoic acid; PC: aphaeretic platelet concentrate; PLTC: platelet count; PRC: packed red cells; rFVIIa: recombinant activated factor VII; TI: time interval from the onset of bleeding until rFVIIa administration; TU: transfusion unit;

^*in a case of repeated doses;

^†measured within 2 hours before rFVIIa;

^‡within 1 hour before rFVIIa.

The single rFVIIa dose was effective in four patients (cases 1–4). Six patients survived for more than 48 hours (cases 1, 2, 4, 5, 7 and 8) and three (cases 2, 4 and 7) survived for 30 days after the first dose of rFVIIa. In three cases (cases 5, 6 and 8) death was related to the treated haemorrhage. No deaths or serious complications were attributed to rFVIIa.

Corrections of the prothrombin time and activated partial thromboplastin time, together with a lack of marked changes in the thrombin time immediately, 24 and 48 hours after rFVIIa, were seen in the majority of cases: prothrombin time in all, activated partial thromboplastin time in five (cases 3–7) and thrombin time in seven (cases 1–6, 8). Compared to the levels immediately before the administration of rFVIIa, haemoglobin concentration and haematocrit were increased in five patients (cases 2–5, 7) 24 and 48 hours after rFVIIa. The platelet count was not markedly changed. No substantial reduction of transfusions or infusions was seen (Table I). The volume of packed red cells was decreased in one patient (case 1), the volume of fresh-frozen plasma in two patients (cases 1 and 7) and the volume of platelet concentrate in one patient (case 1). In the majority of patients (cases 3, 4, 6–8) the infusion volume increased after administration of rFVIIa.

The comparison of groups 1 (cases 1–4) and 2 (cases 5–8) revealed higher median rFVIIa doses (68 μg/kg vs 101 μg/kg) and platelet counts (18×10⁹/L vs 32×10⁹/L) immediately before rFVIIa in group 2, a greater increase in haemoglobin after rFVIIa in group 1 (17 vs 6 g/L 24 hours after; 11 vs 1 g/L 48 hours after) and earlier rFVIIa administration in group 1 (5.3 vs 25.5 hours). The packed red cells, platelet concentrates and infusion volume after rFVIIa were higher in group 2 (1,058 vs 750 mL, 640 vs 320 mL and 5,812 vs 3,745 mL, respectively), whereas the volume of fresh-frozen plasma was comparable (760 vs 772 mL). In comparison with the consumption before rFVIIa, in group 2 there was greater demand for all blood products and infusions after rFVIIa. No marked differences were seen in the platelet count after rFVIIa, concomitant haemostatic therapy or coagulation tests.

Although rFVIIa is expected to reduce transfusion therapy, the data from haemato-oncology patients are ambiguous, with most reports failing to describe a decrease in blood product requirements^2–5. We found no reduction in our cohort, although this was most likely due to the need for haemotherapy independently of bleeding (chemotherapy-related pancytopenia grade 3 or 4 in five patients [cases 2, 4–6, 8] before the haemorrhage) and relatively early rFVIIa administration in most cases (delayed replacement of the initial blood loss).

rFVIIa is usually regarded as the last therapeutic option. However, several experimental and clinical observations have shown that its early administration is associated with better haemostatic control. Similarly, its effect is expected to improve with prior intensive use of platelet concentrates, fresh-frozen plasma, and fibrinogen. In the cohort described here, early rFVIIa administration was associated with better outcome - all patients in group 1 but only one in group 2 (case 5) received rFVIIa less than 8 hours after the onset of bleeding. In contrast, patients in whom the rFVIIa had no clinical effect had not received the clotting factor within the first 24 hours of bleeding. Three patients - two from group 1 (cases 2, 3) and one from group 2 (case 7) with a transient effect of rFVIIa - received platelet concentrates in the hour before being given rFVIIa. These observations suggest that the efficacy of rFVIIa in thrombocytopenia is improved when its early administration is preceded by platelet replacement.

Interestingly, despite a reported relatively high prevalence (up to 6.5%) of thromboembolic events associated with the use of rVIIa, no such events occurred in our cohort of patients, probably because of the lack of patients at high risk (age over 65 years, disorders enhancing thrombosis).

In conclusion, in our experience rFVIIa appears to be a relatively efficient treatment option for life-threatening bleeding in patients with chemotherapy-induced thrombocytopenia and a haematological malignancy, especially when administered less than 8 hours after the onset of bleeding.