Utility of factor X concentrate for the treatment of acquired factor X deficiency in systemic light-chain amyloidosis

To the editor:

Coagulation abnormalities are frequent in systemic light-chain (AL) amyloidosis,¹  6.3% to 14% present with acquired factor X (FX) deficiency reported,^1-3  with baseline FX levels not predictive of bleeding risk.⁴  Rapid clearance of ¹³¹I-labeled FX from the circulation to areas of amyloid deposition, particularly within the spleen,^5,6  suggests adsorption on amyloid fibrils as a major cause of FX deficiency in AL. Other proposed explanations include synthetic dysfunction caused by liver involvement or vitamin K deficiency and discordance between FX activity and FX antigen.¹  Until recently, treatment of FX deficiency was limited to therapeutic options including fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), activated PCCs (aPCC), or recombinant factor VIIa (rFVIIa)⁷ —each with significant risks in this fragile patient population. Forty-four percent of patients in a larger series had complications when treated with rFVIIa preoperatively, including bleeding, thrombosis, or death.⁴  In addition to FFP, PCC, aPCC, or rFVIIa, tranexamic acid, plasma exchange,⁸  and splenectomy³  were anecdotally reported as treatments for FX deficiency in AL, the latter aimed at removing the splenic amyloid fibril burden. Because of a variable amount of FX in FFP, large volumes are needed to achieve a hemostatic effect with risk of fluid overload in patients with cardiac involvement. A serious concern arises regarding thrombotic risks of FVIIa or aPCC in patients with AL amyloidosis who are elderly with cardiovascular risk factors and often nephrotic as a result of renal involvement (hence inherently prothrombotic).

BPL (Bio Products Laboratory Ltd., Elstree, United Kingdom) have developed a high-purity plasma–derived FX concentrate which is currently undergoing phase 3 clinical trials for patients with hereditary FX deficiency. One patient with inherited FX deficiency presenting with a shoulder hemarthrosis achieved good hemostatic response after FX dose of 25 IU/kg per day⁹  with a biological half-life of 24 to 48 hours.

This is an initial report of using high purity FX (HP-FX) concentrate in 2 patients with systemic AL amyloidosis and acquired FX deficiency. Two patients with biopsy-proven AL amyloidosis, with evidence of liver involvement, and a large amyloid load on ¹²³I serum amyloid P component scintigraphy, presented with a forearm hematoma (patient 1) and a ruptured spleen and knee hemarthrosis (patient 2) caused by acquired FX deficiency (both with FX levels of 8 U/dL), with patient characteristics illustrated in the supplemental Table (available on the Blood Web site). The bleeding episode in each case was treated with HP-FX concentrate given as a single dose of 40 IU/kg (FX activity assessed by one-stage clotting prothrombin time–based assays) and hemostasis achieved in conjunction with supportive measures. There was a striking difference between FX recovery reported in patients with inherited FX deficiency compared with our AL patients, the latter showing less predictable kinetics and a more rapid decline to baseline in 2 to 4 hours (Figure 1), consistent with the theory of FX adsorption on amyloid fibrils. Each patient with AL amyloidosis has a different amyloid load and a unique fibril sequence with a potentially different avidity for binding FX—both likely to lead to large differences in the half-life and dose needed, as in patient 2, with a larger load and earlier decrease in FX levels.

In summary, high-purity FX concentrate is useful in treating bleeding caused by acquired FX deficiency in systemic AL amyloidosis. Higher and/or more frequent dosing is likely to be required to achieve adequate FX levels for hemostasis with frequent monitoring of FX levels given the unpredictable kinetics; target FX thresholds similar to patients with inherited FX deficiency: 10 to 15 IU/dL for minor bleeding and >50 IU/dL for major bleeding, trauma, or surgery. HP-FX has the advantage that the hemostatic response can be monitored and the treatment tailored to the patient’s individual needs.