8/17 PPMC Report: AL-Amyloidosis

Today we discussed the case of a patient who presented with macroglossia and was found to have AL amyloid and multiple myeloma.

We reviewed physical exam findings to confirm macroglossia — including scalloped tongue and a thorough differential for macroglossia including amyloid, hypothyroidism, acromegaly, space occupying lesions (abscess v. hemangioma v. lymphangioma v. cyst etc.) and exceedingly rarely GCA (1).

Types of Amyloidosis:

Type of Amyloid Description
AL Deposits monoclonal light chains – associated with plasma cell dyscrasias but can occur alone!
AA Deposits amyloid A – associated with chronic inflammation (ie RA, IBD, spondyloarthropaties), frequently presents with nephrotic syndrome
Dialysis Related Deposits beta 2 microglobulin, has an osteoarticular prediliction
Hereditary/Familial Deposits transthyretin, alpha cahin of fibrinogen A, apolipoprotein
Age Related (Senile) Deposits transthyretin – clasicially cardiac presentation
Organ Specific 2/2 locally produced proteins rather than circulating

The PPMC Report Team did a thorough screen for other end-organ involvement including renal (nephrotic range proteinuria), hepatosplenomegaly, CHF/restrictive cardiomypoathy, peripheral neuropathy, and carpal tunnel syndrome. We also discussed the increased risk for bleeding diathesis in AL amyloid patients due to both liver involvement AND direct factor X deficiency due to factor X binding to amyloid fibrils.

PPMC Team identified the disease specific signs/symptoms of multiple myeloma…the CRAB!

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(hyperCalcemia >11, Renal dysfunction with Cr >2 , Anemia hgb <10, Bone disease >=1 lytic lesion)

We reviewed the different diagnostic criteria for plasma and lymphoplasmacytic cell dyscrasias (2):

PCD

We also reviewed the criteria for a patient with amyloidosis to qualify as having MM (3).  I may have misspoken during conference, so I just want to clarify here in this post: Patients with AL-amyloidosis who have >10% plasma cells on BMBx should be considered as having MM — Essentially pretend that smoldering myeloma doesn’t exist for AL-amyloid patients.

Our conference wrapped up with a discussion on cardiac amyloid and the medications in our arsenal to treat this disease: loop diuretics +/- spironolactone. Beta-blockers and CCB are contraindicated due to their negative inotropy and ACE-I are associated with significant hypotension (possibly unmasking some subclinical autonomic neuropathy). These patients should ALSO be considered for anticoagulation (with the help of a cardiologist) based on both rhythm and low atrial flow velocities.

 

References:

  1. Helfrich DJ, et al. Giant cell arteritis of the tongue presenting as macroglossia. J Rheumatol. 1988 Jun;15(6): 1026-8.
  2. American College of Physicians. MKSAP 17: Medical Knowledge Self-Assessment Program. Philadelphia: American College of Physicians,  2016.
  3. Kourelis TV et al. Coexcitent multiple myeloma or increased bone marrow plasma cells define equally high risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol. 2013 Dec;31(34):4319-24.

8/2 (HUP): acquired von Willebrand’s disease

Thanks to Dr. Adam Cuker for helping us through a case of a middle aged man with prolonged bleeding after a dental procedure, who was ultimately diagnosed with acquired von Willebrand’s disease secondary to a new diagnosis of multiple myeloma!

First, recall the importance of taking a good bleeding history (prior hemostatic challenges, menstrual history, family history), including over the counter drugs and supplements, many of which can (at least theoretically) cause bleeding by a variety of mechanisms.

In this case, we discussed the approach to an isolated prolonged PTT.

Screen Shot 2017-08-02 at 4.11.17 PM

The vast majority of the time, von Willebrand’s disease is inherited, but once in a while it can be acquired. Von Willebrand’s factor is synthesized by endothelial cells and megakaryocytes as a long multimer that is supposed to coil into a specific shape that allows it to accomplish its function. However, anything that disrupts this specific shape or permits greater clearance of the VWF multimer can lead to acquired VWD. There are several ways for von Willebrand’s disease to be acquired, and the image below summarizes them.

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NEJM 2009

We discussed the first line diagnostic workup for a patient with bleeding and an elevated PTT:

  1. Mixing study: with factor deficiency, the prolonged PTT should correct immediately with 50:50 mixing of the patient’s serum with control (normal) serum. With a factor inhibitor, the inhibitor takes a little while to find the factor molecule it inhibits, so the PTT will initially appear to correct (at 30 min), but will become prolonged when rechecked later (~60 min)
  2. Factor VIII level (remember that VWF serves a carrier molecule for FVIII)
  3. Von Willebrand Factor level: the threshold (currently <30%) that defines VWD is under some debate.
  4. VWF gel elecrophoresis: can be helpful in diagnosing type 1 (partial VWF deficiency) and type 3 (complete deficiency), but not type 2 (qualitative VWF defect).
  5. Ristocetin cofactor assay: ristocetin is an antibiotic that induces binding of VWF to GP1b on platelets; it basically mimics the same high shear forces in the microcirculation that cause VWF to bind to platelets. So the ristocetin assay evaluates the ability of VWF to bind to platelets; reduced binding should be seen in almost all types of VWD (except 2N).

This patient wound up being diagnosed with multiple myeloma as the trigger for his acquired VWD. Myeloma and MGUS are the two most common lymphoproliferative disorders associated with it (see reference 1 below).

Lastly- here’s the article I mentioned about triple therapy for treatment of influenza A!

References

  1. Federici, A. 2006. Acquired von Willebrand Syndrome: An Underdiagnosed and Misdiagnosed Bleeding Complication in Patients With Lymphoproliferative and Myeloproliferative Disorders. Seminars in Hematology. PMID 16427386
  2. Wong et al. Bleeding risks of herbal, homeopathic and dietary supplements: a hidden nightmare for plastic surgeons? Aesthet Surg J. 2012.
  3. Hung, I. et al. 2017. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. PMID 27884765
  4. Leebeek, F et al. 2016. Von Willebrand’s Disease. NEJM. PMID 27959741