Fatal Bleeding Due to Acquired Factor IX and X Deficiency: A Rare Complication of Primary Amyloidosis; Case Report and Review of the Literature

Ericson, Stephanie; Shah, Nihar; Liberman, Justin S.; Aboulafia, David M.

doi:10.1016/j.clml.2013.08.007

Cited by 10 publications

(10 citation statements)

References 28 publications

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“…59 Interestingly, combined FIX and FX deficiency is also reported in some patients with systemic amyloidosis. [60][61][62] These patients showed severe to fatal bleeding complications. [60][61][62] Based on our results, it is possible that combined deficiency of FIX and FX could also significantly increase the hemorrhagic incidences in some of the systemic amyloidosis patients.…”

Section: Discussionmentioning

confidence: 98%

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Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms

Singh

Chen

Horn

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Background The contact system is initiated by factor (F) XII activation and the assembly of high molecular weight kininogen (HK) with either FXI or prekallikrein (PK) on a negatively charged surface. Overactivation of this system contributes to thrombosis and inflammation in numerous diseases. To develop effective therapeutics for contact system disorders, a detailed understanding of this pathway is needed. Methods We performed coagulation assays in normal human plasma and various factor‐deficient plasmas. To evaluate how HK‐mediated PK and FXI activation contributes to coagulation, we used an anti‐HK antibody to block access to domain 6 of HK, the region required for efficient activation of PK and FXI. Results FXI's binding to HK and its subsequent activation by activated FXII contributes to coagulation. We found that the 3E8 anti‐HK antibody can inhibit the binding of FXI or PK to HK, delaying clot formation in human plasma. Our data show that in the absence of FXI, however, PK can substitute for FXI in this process. Addition of activated FXI (FXIa) or activated PK (PKa) abolished the inhibitory effect of 3E8. Moreover, the requirement of HK in intrinsic coagulation can be largely bypassed by adding FXIa. Like FXIa, exogenous PKa shortened the clotting time in HK‐deficient plasma, which was not due to feedback activation of FXII. Conclusions This study improves our understanding of HK‐mediated coagulation and provides an explanation for the absence of bleeding in HK‐deficient individuals. 3E8 specifically prevented HK‐mediated FXI activation; therefore, it could be used to prevent contact activation‐mediated thrombosis without altering hemostasis.

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Section: Discussionmentioning

confidence: 98%

“…Acquired FX deficiency is also frequently found in patients with systemic amyloidosis 59 . Interestingly, combined FIX and FX deficiency is also reported in some patients with systemic amyloidosis 60–62 . These patients showed severe to fatal bleeding complications 60–62 .…”

Section: Discussionmentioning

confidence: 99%

Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms

Singh

Chen

Horn

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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“…Around 15% of patients only have an acquired factor X deficiency. These patients often present with acute bleeds sometimes involving the mucosa [ 59 - 61 ]. To note, baseline factor X is not predictive of bleeding risk in this subset of patients.…”

Section: Coagulation In Al Amyloidosismentioning

confidence: 99%

Multidisciplinary supportive care in systemic light chain amyloidosis

2022

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The immunoglobulin light-chain amyloidosis is a multisystemic disease which manifests by damage to the vital organs by light chain-derived amyloid fibril. Traditionally, the treatment has been directed to the underlying plasma cell clone with or without high dose chemotherapy followed by autologous stem cell transplantation using melphalan based conditioning. Now with the approval of highly tolerable anti-CD38 monoclonal antibody daratumumab based anti-plasma cell therapy in 2021, high rates of hematologic complete responses are possible even in patients who are otherwise deemed not a candidate for autologous stem cell transplantation. However, despite the progress, there remains a limitation in the strategies to improve symptoms particularly in patients with advanced cardiac involvement, those with nephrotic syndrome and autonomic dysfunction due to underlying systemic AL amyloidosis. The symptoms can be an ordeal for the patients and their caregivers and effective strategies are urgently needed to address them. The supportive care is aimed to counteract the symptoms of the disease and the effects of the treatment on involved organs’ function and preserve patients’ quality of life. Here we discuss multidisciplinary approach in a system-based fashion to address the symptom management in this dreadful disease. In addition to achieving excellent anti-plasma cell disease control, using treatment directed to remove amyloid from the vital organs can theoretically hasten recovery of the involved organs thereby improving symptoms at a faster pace. Ongoing phase III clinical trials of CAEL-101 and Birtamimab will address this question.

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“…The circulating half‐life of factor X in these individuals is shortened due to adsorption of factor X onto amyloid fibrils . A review of 60 patients from the Mayo Clinic found that the level of factor X deficiency was not predictive of perioperative complications related to bleeding, thrombosis, or death . Despite the lack of correlation with factor X activity levels, serious hemorrhagic complications can occur in patients with acquired factor X deficiency, particularly during invasive procedures .…”

mentioning

confidence: 99%

“…A review of 60 patients from the Mayo Clinic found that the level of factor X deficiency was not predictive of perioperative complications related to bleeding, thrombosis, or death . Despite the lack of correlation with factor X activity levels, serious hemorrhagic complications can occur in patients with acquired factor X deficiency, particularly during invasive procedures . The Mayo Clinic review of 60 patients reported a 13% postprocedure complication rate out of 112 procedures performed, resulting in 12 bleeding complications and one death .…”

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confidence: 99%

Importance of pharmacokinetic studies in the management of acquired factor X deficiency

Lim

McCarthy

Chen

et al. 2015

European J of Haematology

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Up to 14% of individuals with systemic AL amyloidosis develop acquired factor X deficiency, which occurs due to adsorption of factor X onto amyloid fibrils. Although baseline factor X levels are not predictive of bleeding risk in these patients, serious hemorrhagic complications can occur, particularly during invasive procedures. Optimal management strategies to attenuate bleeding risk in these patients are unknown. We describe our experience in the management of acquired factor X deficiency, secondary to systemic AL amyloidosis, in a case series of three patients who received prothrombin complex concentrates (PCCs) for treatment and prevention of bleeding events. We performed a retrospective review extracting information on baseline demographics, laboratory data, pharmacokinetic (PK) studies, and clinically documented bleeding events. Our case series demonstrates that individuals with acquired factor X deficiency secondary to amyloidosis have variable laboratory and clinical responses to PCCs. This is likely due to distinct amyloid loads and fibril sequences, leading to different binding avidities for factor X. Our data emphasize the importance of performing PK testing prior to any invasive procedures to determine the dose and frequency interval to achieve adequate factor X levels for hemostasis, given the variable response between individuals.

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Fatal Bleeding Due to Acquired Factor IX and X Deficiency: A Rare Complication of Primary Amyloidosis; Case Report and Review of the Literature

Cited by 10 publications

References 28 publications

Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms

Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms

Multidisciplinary supportive care in systemic light chain amyloidosis

Importance of pharmacokinetic studies in the management of acquired factor X deficiency

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