Supplementation of fibrinogen concentrate in children with severe acquired hypofibrinogenaemia during chemotherapy for acute lymphoblastic leukaemia: our experience

Dear Sir,

Bleeding and thrombosis are not infrequent problems in children receiving treatment for acute lymphoblastic leukaemia (ALL); these serious complications are associated with the administration of asparaginase, which induces depletion of antithrombin and fibrinogen. Thrombotic complications often make necessary to suspend asparaginase with possible effects on the child’s outcome. Thrombocytopenia and low fibrinogen levels increase the risk of bleeding and haemorrhagic complications of ALL therapy and, in particular, of mini-invasive procedures (lumbar puncture, bone marrow aspirate and biopsy, etc.).

Prophylactic supplementation of plasma and plasma-derived coagulation products remains controversial in these patients; recommendations for prevention and management are lacking due to a weak evidence base, resulting in considerable variation in practice^1,2.

Hypofibrinogenaemia is defined by a decreased level of fibrinogen between 0.5 g/L and the lower limit of the normal range for the local laboratory (usually 1.5 g/L); severe hypofibrinogenaemia (fibrinogen <0.5 mg/L) is generally corrected by the administration of fresh frozen plasma (FFP) or cryoprecipitate³.

FFP contains other coagulation factors that may increase the risk of thrombosis and has several limitations including a low fibrinogen content, which means that large volumes must be given, and the risk of transfusion-related complications (e.g., transfusion-related acute lung injury [TRALI])^3,4. The depletion of asparagine, obtained by administration of asparaginase, represents one of the cornerstones of antineoplastic chemotherapy of ALL; as FFP contains asparagine, we could speculate that administration of FFP may partly antagonize the effects of chemotherapy with asparaginase⁵.

Cryoprecipitate contains a higher concentration of fibrinogen than FFP, but the amount is variable and cannot be determined accurately; moreover cryoprecipitate includes factor VIII and von Willebrand factor, which could increase the risk of thrombosis³. Furthermore we must keep in mind the possible risk of viral transmission that accompanies the use of FFP and cryoprecipitate³.

Supplementary fibrinogen can also be provided by fibrinogen concentrate, as an alternative to FFP and cryoprecipitate. Fibrinogen concentrate is produced from pooled human plasma, pasteurised, purified and lyophilised; it is subjected to viral inactivation procedures that minimise the risk of transmission of viral agents and its concentration is standardised⁴.

Fibrinogen replacement therapy is currently indicated as prophylaxis and therapy of haemorrhage in congenital and acquired fibrinogen deficiency^3,4. Fibrinogen concentrate is now the predominant therapeutic option for the prophylaxis and treatment of bleeding in patients with congenital afibrinogenaemia and in secondary prophylaxis in patients with life-threatening bleeding and a high risk of recurrence (e.g. intracranial haemorrhage); several studies have documented its efficacy and its successful administration as prophylaxis and therapy in cases of acquired hypofibrinogenaemia (loss or dilution coagulopathy, trauma, cardiac and thoracic surgery, obstetric haemorrhage, liver failure, disseminated intravascular coagulation)^3,4.

No Author has so far reported the administration of fibrinogen concentrate for the correction of acquired hypofibrinogenaemia in children with ALL during chemotherapy.

Haemocomplettan (CSL Behring, Marburg, Germany) is a human pasteurised, highly purified, plasma-derived fibrinogen concentrate, and a number of studies have evaluated the effects of fibrinogen supplementation with this agent in patients suffering from various forms of congenital or acquired hypofibrinogenaemia³.

We administered fibrinogen concentrate (Haemocomplettan) to seven children (median age 10 years; minimum 2 maximum 15; males 4, females 3) during chemotherapy for ALL; they were enrolled in the AIEOP ALL 2000 and AIEOP-BFM ALL 2009 protocols.

Patients were treated with PEG-asparaginase (5/7), E. coli asparaginase (1/7), and Erwinase (1/7). They presented with severe acquired hypofibrinogenaemia (fibrinogen <0.5 mg/L; median 0.43 mg/L; minimum 0.18, maximum 0.5), secondary to asparaginase administration, during the induction phase of chemotherapy. Five of the seven patients had a prolonged prothrombin time; none of the patients showed clinical signs of coagulopathy but presented with thrombocytopenia so we considered them at high risk of bleeding and decided to administer replacement therapy with fibrinogen concentrate. The median dose of fibrinogen concentrate given was 35 (minimum 20, maximum 70) mg/kg/daily for 1 day (4/7 patients) or 2 days (3 patients).

Levels of fibrinogen higher than 0.7 mg/L were achieved in five of the seven patients and prothrombin time normalised in three of five patients just after the first administration of fibrinogen concentrate (the characteristics of the patients and results are summarised in Table I). Prothrombin time was not normalised and fibrinogen levels remained below 0.7 mg/L in two patients who had received the lowest dose of fibrinogen concentrate (20 mg/kg/daily, 1 patient for 1 day, 1 patient for 2 days); one of these patients needed FFP. No patients showed bleeding or experienced thromboembolic complications following the replacement of fibrinogen with fibrinogen concentrate. Although our experience is limited, supplementation with fibrinogen concentrate at adequate dosages in children with acquired hypofibrinogenaemia and altered haemostatic balance secondary to asparaginase, seems to be safe and useful in normalising the levels of fibrinogen and prothrombin time.

Table I.

Characteristics of the patients treated with fibrinogen concentrate.

Pt	Sex	Age	ALL immuno-phenotype	Type of Asp	Level of Fbg at day 0	Days of therapy with FbgC	Dose of FbgC	Level of Fbg at the end of therapy with FbgC
1)	M	15	T	Erw	44	2	30	84
2)	M	4	B	E. coli	50	1	45	147
3)	F	2	B	PEG	43	1	50	78
4)	M	10	T	PEG	43	1	35	132
5)	F	3	B	PEG	43	2	70	99
6)	F	12	B	PEG	26	1	20	62
7)	M	12	T	PEG	18	2	20	45

Pt: patient; Fbg: fibrinogen; FbgC: fibrinogen concentrate; Asp: asparaginase; Erw: erwinase.

The management of altered haemostatic balance in children receiving asparaginase for ALL is strongly debated; in the event that you decide to treat the haemostatic derangement, we think it would be advisable to correct the severe impairments of individual factors, i.e. fibrinogen and antithrombin. The severe hypofibrinogenaemia could be corrected by supplementation with fibrinogen concentrate rather than FFP or cryoprecipitate. The administration of fibrinogen concentrate in place of FFP or cryoprecipitate, at an adequate dosage and in selected cases, could reduce the risk of giving other clotting factors that may be prothrombotic and it could reduce the risk of transmission of viral infection. In addition the use of fibrinogen concentrate as an alternative to FFP would avoid both the risk of TRALI and especially the exposure of the patient to a source of asparagine which could counteract the antineoplastic action of asparaginase.

Obviously, our observations need to be confirmed by additional clinical trials focusing on the management of altered haemostatic balance in children with ALL and on the dosing, efficacy and safety of the fibrinogen concentrate.