In Morning Report on June 7th, we talked about hemolysis. In this post, I’ve included a teaching summary which covers symptoms of anemia to inquire about, approach to hemolysis, investigations, and management of some of the causes of hemolysis.

1. Presentation of Hemolysis

The presentation of hemolysis may include the following signs, symptoms, and features. (Remember to include history and examination for anemia)

2. Approach to Hemolysis

There are different approaches to hemolysis which includes immune-mediated versus non-immune mediated, intravascular versus extravascular, and acquired versus inherited. Here I have included an algorithm that starts by breaking it down via inherited versus acquired causes. See below:

3. Investigations for Hemolysis

Blood work investigations with the direction of the change that you would expect in the setting of hemolysis are included here:

• Reticulocyte count (high)
• LDH (high)
• Haptoglobin (low – generally absent)
• Unconjugated bilirubin (high)
• Some findings that you might see on the peripheral film are:
  • Spherocytes: extravascular hemolysis
  • Schistocytes: intravascular hemolysis

Other peripheral blood film abnormalities that you may see in the setting of specific causes of hemolysis are:

• Agglutination of cells: Cold agglutinin disease
• Organisms: infectious causes of hemolysis like malaria
• Heinz bodies: G6PD deficiency
• Sickle cells: sickle cell disease

4. Thrombotic Microangiopathies

Microangiopathic hemolytic anemia (MAHA) is characterized by non-immune, intravascular hemolysis. Thrombotic micorangiopathies (TMAs) are characterized by a MAHA (red cell destruction within the vasculature), thrombocytopenia and microthrombi leading to ischemic tissue injury.

One thrombotic microangiopathy is TTP or thrombotic thrombocytopenic purpura.

In TTP there is either deficiency or autoantibody against ADAMTS13 and therefore large von Willebrand multimers which bind to platelets and form platelet fibrin strands which then leads to intravascular hemolysis and ischemic tissue injury. The PLASMIC score can be used to determine risk of TTP and it is based on platelet count, creatinine, other parameters of hemolysis including bilirubin, haptoglobin, reticulocyte count, and INR < 1.5, associated conditions (no history of solid organ or hematopoietic stem cell transplant, no active cancer). One would send ADAMTS13 activity assay if intermediate to high risk, perform plasma exchange in the settings.

Hemolytic uremic syndrome is another TMA.

The diagnosis is clinically with hemolytic anemia, thrombocytopenia and renal damage which occur suddenly in a patient with a history of diarrhea in the last two weeks

For a definite diagnosis STEC infection should be proven (demonstration of Stx with stool serologic tests or stool cultures). Renal biopsy is not necessary for making a definite diagnosis.

5. Autoimmune Hemolytic Anemia

In autoimmune hemolytic anemia (AIHA), it’s important to first consider alternatives such as:

• transfusion reaction, alloimmune hemolysis after solid organ transplant, drug-related causes.
• The direct antiglobulin test (DAT) should be positive in AIHA, but can have DAT-negative AIHA
• DAT can be positive in other circumstances such as SLE, following drug therapies

An approach to AIHA adapted from the ASH paper (referenced below) is here:

*Paroxysmal cold hemoglobinuria (PCH) usually occurs in children and the hemolysis can be severe and intravascular but typically is following an infection.

If your agglutination test is negative (or positive and antibody titre < 64), to differentiate between warm AIHA and PCH, the Donath-Landsteiner test is used to look for biphasic hemolysin seen in PCH.

Warm (IgG) AIHA makes us approximately 65% of patients with AIHA. Warm AIHA is usually treated with prednisone as 1^st line, and 2nd line includes splenectomy / rituximab.

Primary cold agglutinin disease (CAD) is caused by an underlying lymphoproliferative bone marrow disorder; hemolysis is caused by IgM antibodies that are most active in vitro at low temperatures. In vivo, antibodies bind RBCs in peripheral circulation which can lead to Raynaud’s disease or acrocyanosis. (Read the ASH paper below for more details on the pathophysiology). Cold agglutinin syndrome (CAS) occurs when there is a clinically significant cold antibody that occurs in association with secondary disorders, such as post infectious from infections such as as mycoplasma, systemic lupus erythematosus, or malignant B cell lymphoproliferative disorder.

In terms of management of cold agglutinin disease, this includes:
1. Warm patient, avoid cold exposures
2. Plasmapheresis to remove IgM only if very severe
3. Rituximab
4. Limited role for steroids
5. Patients with acute severe intravascular hemolysis may also respond to the C5 inhibitor eculizumab, which blocks the terminal complement pathway

References:

1. ASH Publications: Anita Hill, Quentin A. Hill; Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2018; 2018 (1): 382–389. doi: https://doi.org/10.1182/asheducation-2018.1.382 Link – https://ashpublications.org/hematology/article/2018/1/382/277583/Autoimmune-hemolytic-anemia
2. TMAs – Arnold DM, Patriquin CJ, Nazy I. Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ. 2017;189(4):E153-E159. doi:10.1503/cmaj.160142 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266569/
3. Singh, A., Kotru, M. (2019). Laboratory Diagnosis of Microangiopathic Hemolytic Anemia Including TTP, DIC, and HUS. In: Saxena, R., Pati, H. (eds) Hematopathology. Springer, Singapore. https://doi.org/10.1007/978-981-13-7713-6_7
4. Chris Wynick, Joanne Britto, Daniel Sawler, Arabesque Parker, Mohammad Karkhaneh, Dawn Goodyear, Haowei Linda Sun; Validation of the Plasmic Score for Predicting ADAMTS13 Activity < 10% in Patients Admitted to Hospitals in Alberta with Suspected Thrombotic Thrombocytopenic Purpura. Blood 2019; 134 (Supplement_1): 2379. doi: https://doi.org/10.1182/blood-2019-126354
5. PCH – Kilty, M., & Ipe, T. S. (2019). Donath-Landsteiner test. Immunohematology, 35(1), 3–6.