Your approach to managing this patient can be divided into a few key steps:

  1. Establish the diagnosis.
  2. Evaluate for secondary causes.
  3. Assess the disease severity – does this merit treatment?

We have already performed the first and second steps. Our third task is to evaluate the risks and benefits of the available treatment options, and then determine which (if any) are appropriate for our patient.

In general, the benefits of pharmacologic therapy are maximized in people with very severe or symptomatic anemia, or people with bothersome ischemic symptoms. The risks are minimized in people who are younger and less frail, with fewer comorbidities. It is important to weigh these risks and benefits before treating.

Treatment options

Below, we will discuss some of the treatment options available to our patient:

  • Conservative measures: these are non-pharmacologic means to reduce symptom burden and the degree of anemia. These are generally called “thermal protective measures”, as they focus on reducing cold exposure and therefore ischemic symptoms. These include layering warm clothing, wearing gloves, and avoiding cold food or drinks.
  • Rituximab: This anti-CD20 antibody targets B-cells and thereby reduces anti-I antibody production. This can be combined with fludarabine (a purine analogue and antimetabolite) or bortezomib (a proteasome inhibitor) to reduce the B-cell population. However, as long-lived plasma cell clones can persist despite these therapies, complete response is rare.
  • Anti-complement: Monoclonal antibodies such as eculizumab (anti-C5) and sutimlimab (anti-C1) target components of the complement cascade involved in hemolysis. As such, they are useful for limiting anemia – they do not address ischemic symptoms, as the ischemic symptoms are due to RBC clumping rather than hemolysis.
  • Plasmapheresis: By filtering IgM antibodies from the patient’s blood, plasmapheresis offers a rapid and effective (though temporary) means of reducing anti-I antibody burden. This can be used in situations where the patient is experiencing critical hemolysis, in which there is no time to wait for the therapies above to take effect. Plasmapheresis can also be used in the preoperative setting to reduce the burden of anti-I antibodies prior to a major surgical procedure, particularly if the patient is felt likely to experience hypothermia.

Would you treat this patient at this time? Why or why not? (see next slide for considerations).

You elect to observe this patient, as treatment carries significant risk and his symptoms are relatively mild. You discuss your reasoning with your patient, and he agrees that avoiding pharmacotherapy makes sense in his situation. You counsel him on thermal protective measures, and you monitor his CBC and his hemolytic markers regularly.

As you read further into the outcomes of patients with CAD and CAS, you find that even with pharmacotherapy complete response is rare, and that disease is frequently refractory (experts attribute this to long-lasting plasma cell clones). Based on a few papers, you find partial response occurs in 40-60% of patients, though definitions of what constitutes a “partial response” vary from study to study.

Thankfully, though your patient still has indicators of hemolysis on his lab work, he remains clinically stable for the next 2 years.

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