Dr Shameem Mahmood November 2015 1 Division of Medicine Royal Free Hospital Campus National Amyloidosis Centre University College of London Medical School London United Kingdom 2 Haemophilia Department Royal Free Hospital ID: 916214
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Slide1
Bleeding diathesis, thrombotic tendencies and endothelial dysfunction in systemic AL patients
Dr Shameem MahmoodNovember 2015
1
Division of Medicine, Royal Free Hospital Campus, National Amyloidosis Centre, University College of London Medical School, London, United Kingdom
2
Haemophilia Department, Royal Free Hospital,
London
, United Kingdom
Slide2Background
Systemic light chain (AL) amyloidosis is known to be associated with an increased bleeding diathesis, including the pathognomonic peri-orbital bruising.
Little
data exists as to the interplay of different coagulation factors, and prothrombotic risk in these patients, where thromboprophylaxis is an inherent part of our day to day practice
.
Von Willebrand Factor (vWF) is a multimeric adhesive glycoprotein which promotes platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions under high shear-rate conditions. VWF acts as a carrier for FVIII, acting to protect FVIII from rapid proteolysis. It has also been used as a surrogate marker in endothelial dysfunction.
Immunoglobulin light chains form amyloid fibrils and are deposited in different tissues in systemic light chain (AL) amyloidosis.
Slide3Aims
We sought to report the coagulation abnormalities in newly diagnosed systemic AL patients:Bleeding risksCoagulation abnormalities and any prognostic implications
Endothelial
dysfunction
Thrombotic risks in patients with a low albumin level
Slide4Methods
We conducted a prospective study on 100 patients with suspected light chain amyloidosis, with 74 systemic AL between May-December 2013. Each patient had a detailed baseline assessment of organ involvement as per standard protocol, and completed a Royal Free Hospital v4 adapted bleeding questionnaire.
Assays
for vWF:Ag, Protein S, Protein C, Anti-thrombin III, fibrinogen, ADAMTS13, and all clotting factors were performed.
We assessed the endothelial dysfunction using vWF antigen as a surrogate marker following chemotherapy.
Slide5Results – bleeding risks
22 patients reported bleeding symptoms by the bleeding questionnaire, cutaneous (n=17), oral (n=7), epistaxis (n=5), haemarthrosis (n=1), muscle haematoma (n=1) and following surgery (n=2).Symptom duration – 4 (0.5-36) months
Factor X deficiency – 2(2.7%)
Prolongation of the PT, APTT and TT occurring in 5 (6.7%), 5 (6.7%) and 35 (47.3%).
Elevated fibrinogen levels were present in 42 (56.8%)
Slide6Baseline patient characteristics
Slide7Results – unexpected findingsScatter plots comparing FVIII and vWF:Ag levels in all
patient groups respectively.
Slide8Overall survival stratified
according to vWF:Ag and FVIII>280IU/L
respectively
.
Slide9Variables associated with survival
Slide10Results – Endothelial dysfunction
Pre and post chemotherapy comparison of vWF:Ag and
FVIII
Slide11Results – Thrombotic risk with an albumin less than 25g/L.
Slide12Discussion/Conclusion
Newly diagnosed systemic AL patients are at risk of increased pro-thrombotic and bleeding diathesis. There is no questionnaire which reflects the degree of bleeding risk, with cutaneous vessel fragility accounting for most. FX deficiency was present in 2 (2.7%).
One striking finding was an elevated vWF:Ag and FVIII in greater than 90% of newly diagnosed systemic AL patients, which
may reflect
a higher prothrombotic environment and likely endothelial dysfunction.
An elevated FVIII and vWF:Ag level greater than 280IU/L carried a significant survival disadvantage. The reasons are unclear, but may arise from endothelial damage and thromboembolic consequences.
We also examined the effects of chemotherapy in a subset of patients, showing that a fall in vWF:Ag levels may reflect endothelial changes.
Slide13Discussion/Conclusion
Understanding of the coagulation cascade has shown that elevated levels of FVIII and fibrinogen, lower levels of protein S and anti-thrombin contribute to a prothrombotic tendency. The latter findings were found in patients with
an albumin less than 25g/L.
This raises the issue of strong consideration for anticoagulation in these patients.
Systemic AL carries bleeding risks, thrombotic risks with the vascular endothelium an important factor in this equation.
Slide14Thank you
AcknowledgementsPatientsAshutosh D Wechalekar
Sajitha Sachchithanantham
Thirusha Lane
Darren Foard
Taryn Youngstein
Rabya Sayed
Ketna Patel
Marianna Fontana
Candida Quarta
Carol
J
Whelan
Helen
J
Lachmann
Julian
D
Gillmore
Philip
N
Hawkins
National Amyloidosis Centre clinical staff
Bleeding
Thrombosis
Risk Factors
Treatment
Endothelial
Dysfunction
Haemophilia Department,
Royal Free Hospital
Anne Riddle
Keith Gomez