A 71 year old lady with a history of malaise and weight loss is admitted to hospital overnight under a general medical team for investigations of blurry vision. The intensive care team was involved to offer advice when on the following morning some abnormal blood results became available.

Parameter

Patient Value

Normal Adult Range

Haemoglobin

76

115 - 160

White Cell Count

23.8 x 10

4.0 - 1 1.0

Platelets

198 x 10 / L

150 - 450

Blood Film

2% Plasma cells and rouleaux formation

Parameter

Patient Value

Normal Adult Range

Sodium

137 mmol/L

135 - 145

Potassium

4.3 mmol/L

3.2 -4.5

Chloride

106 mmol/L

100 - 1 10

Bicarbonate

25 mmol/L

22 - 27

Urea

15.0 mmol/L*

3.0 - 8.0

Creatinine

280 umol/L*

70 - 120

Total Calcium

2.75 mmol/L*

2.15 - 2.60

Phosphate

1.3 mmol/L

0.7 — 1.4

Albumin

26 g/L*

33 — 47

Globulins

92.3 g/L*

25 — 45

What are the major abnormalities, and how would you explain them?

The original college viva was: 

Hematology OSCE

Data sets provided for interpretation included

a)  Leukemoid reaction
b)  A raised APTT, INR and low fibrinogen
c)  A macrocytosis with an underlying myelodysplastic syndrome
d)  A raised APTT which corrected with normal plasma

This was not a satisfying or informative OSCE stem,  the viva was rewritten completely and is therefore not representative of what the college examiners would have wanted. The data set comes from Question 7.3, from the first paper of 2016.

Anyway: the major abnormalities are:

  • Anaemia
  • Leukocytosis
  • Plasmacytosis
  • Rouleaux RBCs
  • Renal failure
  • Hypercalcemia
  • Markedly elevated globulins

Overall, this sounds like multiple myeloma.

What are other possible causes of raised serum globulin levels?
  • Acute stress response
    • raised haptoglobin
    • raised α1 antitrypsin
    • raised transferrin
  • Polyclonal γ-globulin increase
    • Liver disease
    • Chronic infection
    • Connective tissue diseases
  • Monoclonal γ-globulin increase
    • Myeloma
    • Waldenstrom's macroglobulinemia
    • primary amyloidosis
    • lymphoma
    • monoclonal gammopathy
What are the possible causes of plasmacytosis?
  • MGUS
  • Multiple myeloma
  • Waldenström's macroglobulinemia
  • Solitary plasmacytoma
  • Systemic AL amyloidosis
  • POEMS syndrome
  • Adenocarcinoma of the colon
  • Pulmonary tuberculosis
  • Cirrhosis of the liver
  • Aplastic anaemia
  • Syphilis
  • Leprosy
  • Varicella zoster infection
  • Serum sickness
  • Primary infection and reactivation of Epstein–Barr virus
  • Acute respiratory infections
  • Parvovirus B19 infection
  • Rubella
  • Hepatitis virus A infection
What is rouleuax? What are the implications of rouleaux formation?

This is a form of reversible RBC aggregation, and it seems to be a cause of some altered blood rheology. The rouleaux are stacks of red blood cells which form due to macromolecule bridging between their surface molecules. In 1926 Eric Ponder published on the subject, and his paper contains beautifully drawn diagrams of his experimental design. In short, anything which might increase your ESR will cause rouleaux formation, and thus the differentials include a broad range of conditions:

  • Infection of any sort
  • Inflammatory disease of any sort
  • Hyperviscosity syndromes
  • Multiple myeloma (or any sort of hyergammaglobulinaemia)
  • Malignancy of any sort
  • Dehydration
  • Diabetes
  • Chronic liver disease (albumin has a counter-aggregatory effect on RBCs)
Fundoscopy reveals dilated, tortuous retinal veins, as well as flame-shaped haemorrhages. To what could this be attributed?

This, in combination with the history and blood findings, suggests hyperviscosity. Specifically, dilated retinal veins suggests central retinal vein occlusion.

The medical oncology team are concerned about hyperviscosity syndrome. What are the other features of hyperviscosity syndrome?
  • Severe headaches
  • A fluctuating conscious state
  • Stroke, seizures, coma (usually, venous cerebral infarction)
  • Constitutional symptoms: fatigue, malaise, lethargy
  • Haemorrhagic symptoms:  gingival or mucosal bleeding, or epistaxis.
  • Blurred vision due to central retinal vein occlusion
  • Headaches due to increased intracranial pressure (due to venous occlusion)
  • Renal failure
  • Aggravated heart failure (more difficult to pump the viscous blood)
  • Priapism
What specific management would you offer?

The major issue here is the hyperviscosity of the blood. Specific management of the myeloma would not result in a sufficiently rapid clearance of the paraprotein, and therefore a blood purification therapy such as plasmapheresis would be required.

The oncology team recommend plasmapheresis. What are the physical principles of this therapy?
  • Plasmapheresis may refer to a variety of procedures, all involving the therapeutic separation of blood into components.
  • Separation of blood into cellular and fluid components offers the opportunity to discard or modify those components. 
  • This separation is usually accomplished by means of either a centrifuge or by the less frequently used method of porous membrane filtration.
  • Unlike dialysis or haemofiltration, there is no size barrier: plasmapheresis removes the whole plasma with molecules of all sizes.
  • Some blood components are then reinfused into the patient with or without modification, and the rest may be discarded or stored.
  • If plasma is being removed,  volume is replaced with 4% albumin or FFP.

   Characteristics of a disease process which make plasmapheresis an effective option:

  1. The disease has to be caused by some circulating factor, i.e. it has to be present in the blood
  2. That factor has to have a sufficiently long plasma half-life, such that "turning off" the process of its production will still result in significant amounts of it persisting in the bloodstream.
Which blood components are removed by plasmapheresis?

Undesirable blood components:

  • Antibodies
  • Immune complexes
  • Abnormal plasma proteins, eg. myeloma light chains
  • Immunoglobulins
  • Protein-bound drugs
  • Monoclonal antibody drugs, eg. rituximab
  • Immune complexes
  • Cryoglobulins
  • Myeloma light chains
  • Bacterial endotoxin
  • High molecular weight toxins, eg. animal venom
  • Cholesterol-containing lipoproteins /triglycerides
  • Abnormal cells (eg. leukaemia blasts, excess RBCs or platelets)

Desirable blood components which you'd rather keep:

  • Antithrombin
  • Pseudocholinesterases and plasma esterases
  • Useful antibodies, including monoclonal biological agents
  • Useful medications
  • Nutrients, eg. glucose, amino acids, water-soluble vitamins
  • Diagnostically interesting antibodies (i.e. for serology)
What are the indications for urgent plasmapheresis?

Urgent plasma exchange:

  • TTP
  • Catastrophic antiphospholipid syndrome
  • Hyperviscosity syndrome (eg. myeloma)
  • Guillain-Barre syndrome
  • Myasthenia gravis
  • Acute fulminant hepatitis with encephalopathy
  • Amanita phalloides poisoning

Less urgent plasma exchange:

  • Erythrodermic cutaneous T-cell lymphoma
  • Wegeners granulomatosis
  • Goodpasture's syndrome
  • Eaton-Lambert syndrome
  • Babesiosis
  • Autoimmune haemolytic anaemia
  • Cryoglobulinaemia
  • Dermatomyositis/polymyositis
  • Hemolytic uremic syndrome
  • Familial hypercholesterolaemia
  • Focal segmental glomerulosclerosis
  • Paraproteinaemic polyneuropathy
  • Antibody-mediated renal transplant rejection
  • Fulminant Wilson's disease.

One should note that in their list of indications, the college noted some Grade II, III and IV recommendations, such as:

  • HELLP syndrome
  • Multiple sclerosis
  • HIV-related neuropathy
  • Pemphigus
  • Coagulation inhibitors
  • DIC
  • Overwhelming sepsis syndromes eg meningococcaemia
  • Reye’s syndrome
  • Paraquat poisoning
What are the complications of plasmapheresis?
  • Due to vascular access
    • all the complications of large CVAD insertion: CLABSI, bleeding, vessel damage, etc etc
  • Due to the circuit exposure
    • Low fibrinogen and coagulopathy
    • Haemolysis and thrombocytopenia
    • Hypothermia
    • Complement activation
  • Due to anticoagulation
    • Paraesthesia due to hypocalcemia (due to regional citrate anticoagulation)
    • Bleeding complications
    • HITS
  • Due to the replacement fluid
    • Urticaria
    • Febrile reaction to blood products
    • Anaphylaxis
  • Due to the unavoidable removal of useful blood components
    • Loss of useful drugs
    • Immunosuppression
    • Anaphylaxis
    • Hypothermia
  • Due to volume loss
    • Hypotension
    • Vasovagal syncope
    • Nausea and vomiting

Disclaimer: the viva stem above is the original CICM stem, acquired from their publicly available past papers. However, because the college do not make the rest of the viva text or marking criteria available, the rest has been confabulated. It sounds like a plausible viva and it can be used for the purpose of practice, but all should be aware that it does not represent the "true" canonical CICM viva station. 

References

Mehta, Jayesh, and Seema Singhal. "Hyperviscosity syndrome in plasma cell dyscrasias." Seminars in thrombosis and hemostasis. Vol. 29. No. 05. Copyright© 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2003.

Triger, D. R., and Ralph Wright. "Hyperglobulinaemia in liver disease." The Lancet 301.7818 (1973): 1494-1496.

McLeod, Bruce C. "Therapeutic apheresis: use of human serum albumin, fresh frozen plasma and cryosupernatant plasma in therapeutic plasma exchange."Best Practice & Research Clinical Haematology 19.1 (2006): 157-167.

Reimann, P. M., and P. D. Mason. "Plasmapheresis: technique and complications." Intensive care medicine 16.1 (1990): 3-10.

Winters, Jeffrey L. "Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines." ASH Education Program Book 2012.1 (2012): 7-12.

Oh's Manual: Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister.

Szczepiorkowski, Zbigniew M., et al. "Guidelines on the use of therapeutic apheresis in clinical practice—Evidence‐based approach from the apheresis applications committee of the American Society for Apheresis." Journal of clinical apheresis 25.3 (2010): 83-177.

Russi, Gianpaolo, and Piero Marson. "Urgent plasma exchange: how, where and when." Blood Transfusion 9.4 (2011): 356.