Amyloidosis and Bleeding: Pathophysiology, Diagnosis, and Therapy

doi:10.1053/j.ajkd.2006.03.036

American Journal of Kidney Diseases

Volume 47, Issue 6, June 2006, Pages 947-955

https://doi.org/10.1053/j.ajkd.2006.03.036 Get rights and content

Amyloid diseases can be associated with potentially life-threatening hemorrhage. Pathogenetic factors contributing to the abnormal bleeding tendency in this setting are heterogeneous and depend on the type of amyloidosis and pattern of organ involvement. In patients with light-chain (AL) amyloidosis, acquired hemostatic abnormalities, including coagulation factor deficiencies, hyperfibrinolysis, and platelet dysfunction, can be regarded as the most important pathogenetic factors. In patients with other types of amyloidosis, acquired hemostatic defects are rare, and amyloid deposition has also been reported to be the main cause of abnormal bleeding manifestations. Amyloid angiopathy with increased fragility of blood vessels and impaired vasoconstriction may promote bleeding in this setting. Rupture of solid organs caused by amyloid deposition also was reported. Whereas therapeutic options in bleeding caused by local amyloid deposition are restricted to supportive measures and, in severe cases, surgery, acquired hemostatic defects may be treated according to the causative mechanism. In this review, we focus on bleeding risks in patients with amyloid diseases. Current concepts with regard to pathophysiology, diagnosis, and treatment are summarized and discussed.

Section snippets

Bleeding Manifestations in Systemic Amyloidosis

Spontaneous or peri-interventional hemorrhage was reported in approximately one third (15% to 41%) of patients with systemic amyloidosis during the course of the disease.13, 14, 15 Cerebral bleeding, gastrointestinal bleeding, and bleeding after diagnostic procedures such as organ biopsy are the most relevant bleeding manifestations.

Pathophysiology of Abnormal Bleeding in Amyloidosis

Pathomechanisms predisposing to abnormal hemorrhage in patients with systemic amyloidosis are heterogeneous. They depend on the type of amyloidosis and pattern and extent of organ involvement. Coagulation factor deficiencies are restricted mainly to patients with AL amyloidosis and were reported in only selected cases of other amyloid diseases. This might be explained by preferential involvement of the liver and spleen in patients with AL amyloidosis and an interaction of amyloidogenic light

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Clinical Outcomes of Percutaneous Coronary Intervention in Amyloidosis, Sarcoidosis, and Hemochromatosis
2024, Journal of the Society for Cardiovascular Angiography and Interventions
Infiltrative diseases (IDs), including amyloidosis, sarcoidosis, and hemochromatosis, are characterized by abnormal cellular infiltration in multiple organs, including the heart. The prognosis of percutaneous coronary intervention (PCI) patients with underlying IDs has not been well-studied. We evaluated the prevalence of IDs in patients undergoing PCI and their association with post-PCI outcomes.
The National Inpatient Sample (NIS) 2016-2020 database was used to identify PCI patients with ICD-10 codes for a retrospective analysis. PCI patients were then divided into those with and without underlying IDs, which included amyloidosis, sarcoidosis, and hemochromatosis. Multivariable logistic regression was performed for composite post-PCI outcomes analyses.
Among 2,360,860 patients admitted to undergo PCI, 7855 patients had underlying IDs. The highest prevalence was observed for sarcoidosis (0.2%) followed by hemochromatosis (0.07%) and amyloidosis (0.04%). Underlying amyloidosis was associated with worse composite post-PCI outcomes (odds ratio [OR], 1.6; 95% CI, 1.1-2.44; P = .02), including higher in-hospital mortality (OR, 1.9; 95% CI, 1.1-3.4; P = .04), higher risk of intra/post-PCI stroke (OR, 4.0; 95% CI, 1.1-16.0; P = .04), but not major bleeding (OR, 2.2; 95% CI, 0.97-5.03; P = .058). In contrast, underlying sarcoidosis (OR, 1.1; 95% CI, 0.87-1.41; P = .4), and hemochromatosis (OR, 1.18; 95% CI, 0.77-1.8; P = .44) were not associated with composite post-PCI outcomes. Amyloidosis patients undergoing PCI also had higher hospitalization charges ($212,123 vs $141,137; P = .03) and longer length of stay (8.2 vs 3.9 days; P < .001).
Underlying amyloidosis was associated with worse post-PCI outcomes including higher in-hospital mortality, intra/post-PCI stroke, and socioeconomic burden. A multidisciplinary approach and future studies are needed to investigate the screening and treatment strategies in these patients.
Investigating patients for bleeding disorders when most of the “usual” ones have been ruled out
2023, Research and Practice in Thrombosis and Haemostasis
A State of the Art lecture titled “Investigating Patients for Bleeding Disorders When Most of the Usual Ones Have Been Ruled Out” was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Mild to moderate bleeding disorders (MBDs) in patients in whom no diagnosis of an established disorder, such as platelet function defect, von Willebrand disease, or a coagulation factor deficiency, can be identified are classified as bleeding disorders of unknown cause (BDUCs). Prospective data from the Vienna Bleeding Biobank and other studies have revealed a high proportion of BDUCs of up to 70% among patients with MBD who have a similar bleeding phenotype as other MBDs. As BDUC is a diagnosis of exclusion, the accuracy of the diagnostic workup is essential. For example, repeated testing for von Willebrand disease should be considered if von Willebrand factor values are <80 IU/dL. Current evidence does not support the clinical use of global assays such as thromboelastography, platelet function analyzer, or thrombin generation potential. Rare and novel bleeding disorders due to genetic variants in fibrinolytic factors or natural anticoagulants are rare and should only be analyzed in patients with specific phenotypes and a clear family history. In BDUC, blood group O was identified as a risk factor for increased bleeding severity and bleeding risk after hemostatic challenges. Future studies should improve the phenotypical characterization and ideally identify novel risk factors in BDUC, as a multifactorial pathogenesis is suspected. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.
Surgical Management of Breast Amyloidosis
2023, Clinical Breast Cancer
Amyloidosis is characterized by extracellular deposition of insoluble misfolded beta-pleated proteins. Amyloid disease involving the breast is rare and there is a paucity of literature guiding surgical management in caring for these patients. In this article we review medical and surgical management with an emphasis on post mastectomy breast reconstruction. We propose an algorithm for breast reconstructive options based on unique considerations in this patient population. An institutional database at the Medical College of Wisconsin was used to identify patients diagnosed with breast amyloidosis from 2011 to 2021. We utilized the electronic medical record to present patient demographics, diagnostic and treatment data regarding the medical and surgical management of these patients. Five women were identified with a median age of 70 years and a median follow up of 19 months (range, 9-80 months). All patients were diagnosed with light chain (AL) type of amyloidosis. Systemic amyloidosis was identified in 3 patients and localized disease was identified in 2 patients. Concurrent breast malignancy was identified in 2 patients who underwent skin-sparing mastectomies followed by breast reconstruction with both prosthetic and autologous techniques. Both prosthetic and autologous reconstructive techniques are safe in patients with amyloidosis, however careful consideration and preoperative work-up are warranted to avoid complications in this vulnerable population. Further studies are warranted to improve surgical outcomes in patients with amyloidosis involving the breast.
Impaired fibrinolysis and increased clot strength are potential risk factors for thrombosis in lymphoma
2023, Blood Advances
Thrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding and thrombosis risk is poorly understood. In this prospective cohort study, we investigated the dynamics of fibrinolysis in patients with hematological cancer. Fibrinolysis was investigated before treatment and 3 months after treatment initiation. A dynamic clot formation and lysis assay was performed beyond the measurement of plasminogen activator inhibitor 1, tissue- and urokinase-type plasminogen activators (tPA and uPA), plasmin-antiplasmin complexes (PAP), α-2-antiplasmin activity, and plasminogen activity. Clot initiation, clot propagation, and clot strength were assessed using rotational thromboelastometry. A total of 79 patients were enrolled. Patients with lymphoma displayed impaired fibrinolysis with prolonged 50% clot lysis time compared with healthy controls (P = .048). They also displayed decreased clot strength at follow-up compared with at diagnosis (P = .001). A patient with amyloid light-chain amyloidosis having overt bleeding at diagnosis displayed hyperfibrinolysis, indicated by a reduced 50% clot lysis time, α-2-antiplasmin activity, and plasminogen activity, and elevated tPA and uPA. A patient with acute promyelocytic leukemia also displayed marked hyperfibrinolysis with very high PAP, indicating extreme plasmin generation, and clot formation was not measurable, probably because of the extremely fast fibrinolysis. Fibrinolysis returned to normal after treatment in both patients. In conclusion, patients with lymphoma showed signs of impaired fibrinolysis and increased clot strength, whereas hyperfibrinolysis was seen in patients with acute promyelocytic leukemia and light-chain amyloidosis. Thus, investigating fibrinolysis in patients with hematological cancer could have diagnostic value.
The Missing Factor(s): Disseminated Amyloidosis Causing Coagulopathy Refractory to Plasma Transfusion
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View all citing articles on Scopus

: Originally published online as doi:10.1053/j.ajkd.2006.03.036 on April 27, 2006.

: Support: None. Potential conflicts of interest: None.

View full text

ReviewAmyloidosis and Bleeding: Pathophysiology, Diagnosis, and Therapy

Section snippets

Bleeding Manifestations in Systemic Amyloidosis

Pathophysiology of Abnormal Bleeding in Amyloidosis

Lancet

Ann Pathol

Kidney Int Suppl

J Urol

Obstet Gynecol

Blood

J Gastrointest Surg

Blood

Blood Rev

Am J Med

Am J Gastroenterol

J Urol

Obstet Gynecol

Urology

Am J Ophthalmol

Am J Ophthalmol

Lancet Neurol

Blood Rev

Molecular mechanisms of amyloidosis

N Engl J Med

Amyloid: Toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis

Amyloid

Changes in renal function in patients with familial amyloid polyneuropathy treated with orthotopic liver transplantation

Nephrol Dial Transplant

Orthotopic liver transplantation for hereditary fibrinogen amyloidosis

Transplantation

Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival

J Clin Oncol

Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome

Rheumatology (Oxford)

Anti-tumor necrosis factor alpha therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritidesA followup report of tolerability and efficacy

Arthritis Rheum

High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosisAn 8-year-study

Ann Intern Med

Transmissibility of systemic amyloidosis by a prion-like mechanism

Proc Natl Acad Sci U S A

Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy

Br J Haematol

Scintigraphic imaging and turnover studies with iodine-131 labelled serum amyloid P component in systemic amyloidosis

Eur J Nucl Med

Clotting alterations in primary systemic amyloidosis

Haematologica

Primary systemic amyloidosisClinical and laboratory features in 474 cases

Semin Hematol

Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis

Br J Haematol

Cerebral amyloid angiopathiesA pathologic, biochemical, and genetic view

J Neuropathol Exp Neurol

Amyloidosis in rheumatoid arthritis—Clinical study of 124 histologically proven cases

Ryumachi

Cerebral amyloid angiopathyIncidence and complications in the aging brain. II. The distribution of amyloid vascular changes

Stroke

Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy

Ann Neurol

Massive gastrointestinal hemorrhage in a case of amyloidosis secondary to rheumatoid arthritis

Scand J Rheumatol

Gastric amyloidosis with massive bleeding requiring emergency surgery

J Gastroenterol

Secondary amyloidosis in progressive systemic sclerosis

Clin Rheumatol

Massive hemorrhage and pseudo-obstruction of the small intestine caused by primary AL amyloidosis associated with gastric cancerReport of a case

Surg Today

Systemic distribution of β2-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysisReport of seven cases and review of the literature

Arch Pathol Lab Med

Development of gastrointestinal β2-microglobulin amyloidosis correlates with time on dialysis

Am J Surg Pathol

Gastrointestinal complications of beta2-microglobulin amyloidosisA case report and review of the literature

Arthritis Rheum

Risk factors for bleeding complications in percutaneous renal biopsy

Clin Exp Nephrol

Hemorrhagic bullous amyloidosis. A histologic, immunocytochemical, and ultrastructural study of two patients

Arch Dermatol

Haemorrhagic diathesis as an early symptom of systemic amyloidosis

Dtsch Med Wochenschr

Cutis laxa in hereditary gelsolin amyloidosis

Br J Dermatol

Review
Amyloidosis and Bleeding: Pathophysiology, Diagnosis, and Therapy

Systemic distribution of β₂-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysisReport of seven cases and review of the literature

Development of gastrointestinal β₂-microglobulin amyloidosis correlates with time on dialysis

Gastrointestinal complications of beta₂-microglobulin amyloidosisA case report and review of the literature