Article Text

Download PDFPDF

Clinical effects of tranexamic acid on bleeding tendency due to fibrinolytic activation of AL amyloidosis
  1. Gaku Matsumoto1,
  2. Hideki Mori1,
  3. Takahiro Mori1 and
  4. Chika Sakaki2
  1. 1Department of General Internal Medicine, National Hospital Organisation Nagasaki Medical Center, Omura, Nagasaki, Japan
  2. 2Department of Hematology, National Hospital Organisation Nagasaki Medical Center, Omura, Nagasaki, Japan
  1. Correspondence to Dr Hideki Mori; mori.hideki.fu{at}mail.hosp.go.jp

Abstract

We report a case where tranexamic acid, which is an antifibrinolytic agent, was used to effectively treat bleeding tendency in a patient with immunoglobulin light chain (AL) amyloidosis. A male patient in his 80s without a history of bleeding disorders was admitted to our hospital for the examination of bleeding tendency and was diagnosed with a bleeding disorder due to AL amyloidosis. Blood tests revealed elevated plasmin-α2-plasmin inhibitor complex levels, suggesting fibrinolytic activation. Managing the bleeding was difficult; however, we suspected fibrinolytic activation associated with AL amyloidosis and initiated treatment with oral tranexamic acid, which markedly improved the bleeding disorder and abnormalities of the fibrinolytic system. Therefore, in cases of bleeding due to fibrinolytic activation of AL amyloidosis, tranexamic acid administration can be an effective treatment.

  • Haematology (incl blood transfusion)
  • Monoclonal gammopathy of undetermined significance associated neuropathy
  • Palliative care
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Background

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell proliferative disorder in which fibrils of monoclonal light chains are deposited in the kidneys, heart and other tissues. Spontaneous bleeding or abnormal hemostasis in the perioperative period is reported to occur in approximately one-third of patients with AL amyloidosis.1 The symptoms include purpura, petechial bleeding, bleeding during biopsy, gastrointestinal bleeding and cerebral bleeding.1–3 Mechanisms of bleeding tendency have been mentioned to include decreased coagulation factor X activity, fibrinolytic activation, acquired von Willebrand disease, the appearance of inhibitors of fibrin polymerisation, decreased platelet aggregation with abnormal platelet function, vitamin K deficiency with malabsorption in the digestive tract, decreased hepatic synthetic coagulation factors with liver insufficiency and vascular fragility due to the deposition of amyloid protein.3–5 The standard treatment approach for AL amyloidosis commonly involves using high-dose melphalan therapy combined with autologous peripheral blood stem cell transplantation to achieve remission. However, symptomatic treatment alone is frequently employed in cases where the applicability of standard treatment is compromised by factors, including performance status, comorbidities or the extent of organ impairment.6–9

Diagnosis of AL amyloidosis requires tissue biopsy6–11; however, a bleeding tendency precludes tissue biopsy in some cases,3 making the diagnosis difficult. Additionally, when the performance status of patients is impaired due to ageing or comorbidities, systemic therapy cannot be initiated in many cases. Therefore, a treatment that can control bleeding tendencies should be established.

We present the case of a patient with a history of bleeding tendency of unknown origin and report the possibility of tranexamic acid in effectively controlling bleeding tendency due to AL amyloidosis.12

Case presentation

A male patient in his 80s presented with comorbidities, including hypertension and paroxysmal atrial fibrillation. He had no history of bleeding tendency and no family history of coagulopathy. His drug history included oral candesartan cilexetil to treat hypertension. One year prior to hospital admission, he began to experience extensive subcutaneous haemorrhages in the extremities without any specific trigger. Anticoagulation therapy for paroxysmal atrial fibrillation was discontinued, and he was placed under observation. One week before admission, his family found him immobile at the entrance of his house. He was taken to a district general hospital; after undergoing physical examination and investigation, a cerebral haemorrhage was diagnosed. Blood tests at the district hospital revealed prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT). A CT scan of the head revealed subcortical bleeding in the left frontal lobe (figure 1), whereas that of the trunk showed haematomas in the bilateral axillae (figure 2). The severity of subcortical bleeding was determined to be 0 points on the National Institute of Health Stroke Scale. The patient was referred to our hospital by the district general hospital to investigate the cause of the bleeding. Physical examination revealed multiple subcutaneous haemorrhages of the extremities, and haematomas of approximately 60 mm in diameter were palpable in the axillae on both sides. Neurological examination revealed no obvious motor or sensory abnormalities.

Figure 1

A high absorptive zone of approximately 28 mm found in the medial part of the left frontal lobe.

Figure 2

A haematoma approximately 60 mm in diameter found in both axillae.

Investigations

Blood tests showed no abnormality in platelet count or bleeding time (leucocyte count, 6700/µL; haemoglobin, 11.7 g/dL and platelet count, 205 000/µL). Coagulation tests showed prolonged PT and aPTT (PT, 39.1%; international normalised ratio, 1.80 and aPTT, 68.7 s), and increased fibrinogen degradation products (FDP), thrombin-antithrombin-III complex (TAT) and plasmin-α2-plasmin inhibitor complex (PIC) (fibrinogen, 136.8 mg/dL; FDP, 6.6 µg/mL; TAT, 9.7 ng/mL and PIC, 10.3 µg/mL). The cross-mixing test of PT and aPTT showed a convex pattern on the bottom—suggesting a deficiency of coagulation factors—and measurement of coagulation factor activity showed decreased activity of coagulation factors II, V, IX and X (factor II, 60%; factor V, 32%; factor IX, 14% and factor X: 31%).

Other coagulation-related tests showed decreased plasminogen and antiplasmin activity (plasminogen activity, 12%; antiplasmin, 42%). Protein induced by vitamin K absence or antagonist-II and lupus anticoagulant were normal. Biochemical tests showed a decrease in the albumin/globulin ratio (albumin/globulin ratio, 0.44), serum protein electrophoresis showed IgG-λ type M protein and measurement of the free light chain (FLC) ratio showed a decrease in the κ/λ ratio (FLC κ, 31.3 mg/L; FLC λ, 146 mg/L and FLC κ/λ ratio, 0.21). Since no urinary Bence Jones protein was found, and bone marrow puncture showed an increase of 7.4% in abnormal plasma cells, monoclonal gammopathy of undetermined significance was diagnosed.

We suspected AL amyloidosis as the cause of the bleeding tendency, and although no obvious amyloid deposition was noted in the fat tissue biopsy, biopsies of the duodenum and rectum revealed amyloid deposition (figure 3). Additionally, the light chain immunostaining results led to the diagnosis of IgG λ type AL amyloidosis. Contrast-enhanced MRI of the myocardium revealed delayed contrast in the atrial septum, which was suspected to be a complication of cardiac amyloidosis. However, a myocardial biopsy could not be performed owing to the patient’s bleeding tendency. The cardiac function remained preserved, with no concurrent heart failure manifestations.

Figure 3

Pathology of the duodenal biopsy duodenal mucosa with apple green birefringence under polarised light microscopy. Left, H&E staining: ×100; right, congo red staining: ×400.

Differential diagnosis

In this case, amyloidosis was suggested as a differential diagnosis for the unexplained tendency towards bleeding. To assess amyloidosis, measurements were conducted using serum protein electrophoresis and the ratio of FLCs. IgG-λ type M protein was detected through serum protein electrophoresis. Furthermore, the presence of AL amyloidosis was suspected because of the observed increase in the ratio of FLCs. Bone marrow biopsy did not reveal the presence of abnormal plasma cells indicative of multiple myeloma. Although a biopsy of the abdominal wall fat was performed, no evident amyloid deposition was observed. However, amyloid deposition was observed in the tissue biopsies of the duodenum and rectum, leading to the diagnosis of systemic AL amyloidosis based on immunostaining results. Regarding the evaluation of other differential diseases, since the patient had no history of warfarin or heparin use, the differential diagnosis of bleeding tendency with prolonged PT and aPTT included hepatic failure, vitamin K deficiency, disseminated intravascular coagulation (DIC) and acquired haemophilia. Moreover, coagulation factor deficiency due to hepatic amyloidosis was mentioned as a differential diagnosis; however, liver biopsy was difficult because of bleeding. Contrast-enhanced MRI showed no abnormal liver morphology, signals in the liver parenchyma, or hepatobiliary enzymes; therefore, hepatic amyloidosis was ruled out. Additionally, vitamin K deficiency was ruled out owing to the absence of elevated protein induced by vitamin K absence or antagonist-II levels. The patient’s platelet count did not decrease, and the probability of DIC was considered low. Acquired haemophilia was ruled out based on the results of the cross-mixing test. We further suspected the possibility of haemorrhagic symptoms due to AL amyloidosis.

Noting the elevation of PIC—a marker of the fibrinolytic system—and the decrease in plasminogen and antiplasmin activities (PIC, 10.3 µg/mL; plasminogen activity, 12% and antiplasmin, 42%), we suspected that the bleeding symptoms were caused by fibrinolytic activation due to AL amyloidosis.

Figure 4 outlines this patient’s course from initial presentation to the final diagnosis.

Figure 4

Outlines of patient’s course from initial presentation to the final diagnosis.

Treatment

We considered treating the AL amyloidosis to achieve remission; however, the patient’s performance status was poor. Therefore, we decided that it would be difficult to initiate systemic therapy. Fortunately, no significant bleeding complications were observed until day 19 of hospitalisation; however, considering the reduced activity of coagulation factors, the occurrence of future bleeding was anticipated. Although four units of fresh-frozen plasma were administered on day 19 of hospitalisation to replenish coagulation factors, no improvement was observed in coagulation abnormalities or bleeding tendency. Owing to the elevated PIC and decreased activity of plasminogen and antiplasmin, we suspected fibrinolytic activation associated with AL amyloidosis. On hospitalisation day 21, the patient was started on tranexamic acid at 750 mg/day. Subsequently, bleeding tendency, abnormalities of fibrinolysis and coagulation and coagulation factor activity markedly improved (PT, 75.2%; international normalised ratio, 1.18; aPTT, 32.1 s; fibrinogen, 245.7 mg/dL; FDP, 5.9 µg/mL; TAT, 20.7 ng/mL; PIC, 3.34 µg/mL; plasminogen activity, 43%; antiplasmin, 81%; factor II, 76%; factor V, 66%; factor IX, 79% and factor X, 54%).

Outcome and follow-up

After initiating tranexamic acid therapy, the patient exhibited no bleeding tendency recurrence, such as new subcutaneous bleeding, and was discharged to a nursing facility on hospitalisation day 63. No bleeding symptoms were observed for 19 weeks after discharge from the hospital. Subsequently, the cerebral bleeding that was identified on hospitalisation progressed without the emergence of any new neurological findings until discharge. Additionally, no manifestation of heart failure symptoms was observed until discharge in relation to the suspicion of cardiac amyloidosis.

Discussion

In previous reports, hyperfibrinolysis, coagulation factor deficiency and platelet dysfunction have been found as possible mechanisms of bleeding tendency due to AL amyloidosis.4 Fibrinolytic activation by AL amyloidosis has been proposed to be caused by the production of urokinase-type plasminogen activator by plasma cells,13 activation of urokinase-type plasminogen activator on amyloid fibres14 and degradation of activated factor Xa by plasmin and its degradation products, thereby promoting plasminogen activation.15 16

Moreover, it has been reported that factor X may be deficient because of amyloid deposition, resulting in coagulation abnormalities14; however, in this case, factor II, V, IX and X activities decreased. There have been no case reports of multiple reductions in coagulation factor activity and recovery of multiple coagulation factor activity after tranexamic acid administration, therefore highlighting the novelty of our case report.17

In this case, fibrinolysis may have been activated by any of the abovementioned mechanisms. Tranexamic acid exerts its antifibrinolytic effect by inhibiting the adsorption of plasminogen to fibrin.18 Therefore, it may be an effective option when bleeding symptoms are mainly due to hyperfibrinolysis, as in this patient’s case. Furthermore, the improvement in the activity of multiple coagulation factors was possibly because of the administration of tranexamic acid, and although the mechanism of this improvement is not yet clear from previous reports, this case may help to clarify the pathogenesis of bleeding tendency in AL amyloidosis.

Bleeding symptoms due to AL amyloidosis can be fatal, and invasive procedures are crucial to diagnose the disease; therefore, controlling bleeding symptoms is clinically critical. Furthermore, in cases where fibrinolysis activation due to AL amyloidosis is suspected in the background, prior administration of tranexamic acid may help to control bleeding symptoms and make an earlier diagnosis. Additionally, tranexamic acid can be introduced relatively easily and may be an effective symptomatic treatment in patients who cannot receive curative chemotherapy because of old age or comorbidities that reduce the patient’s performance status. For the same reason, tranexamic acid for bleeding tendency may be an effective option in palliative care at the end of AL amyloidosis.

It should be noted that administering tranexamic acid for fibrinolytic activation due to DIC may exacerbate organ damage and lead to fatal outcomes.19 In our case, tranexamic acid was introduced after confirming no decrease in platelet counts suggestive of DIC. Therefore, tranexamic acid is an inexpensive and relatively safe drug that should be actively considered for this indication.

Learning points

  • Amyloidosis should be considered a differential diagnosis for bleeding tendency of unknown cause.

  • Haemorrhagic symptoms due to immunoglobulin light chain (AL) amyloidosis can be fatal; therefore, appropriate management is necessary.

  • In AL amyloidosis, the administration of tranexamic acid is an effective treatment when disseminated intravascular coagulation is negative, and some findings suggest fibrinolytic activation.

Ethics statements

Patient consent for publication

Acknowledgments

We would like to thank Dr Shiro Miura for his significant contribution to the pathological diagnosis of this case.

References

Footnotes

  • Contributors GM and HM were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content. GM, HM, TM and CS discussed this case and contributed to the final manuscript. HM gave final approval of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.