Anemia in the setting of increased reticulocyte count, elevated LDH, decreased haptoglobin, elevated plasma free hemoglobin, elevated indirect bilirubin, and a negative Coomb’s test (see Anemia) raises suspicion for a microangiopathic hemolytic anemia (MAHA). A peripheral smear may elicit schistocytes (see above picture).
Initial workup in the suspicion for a microangiopathic hemolytic anemia should include a DIC panel (which usually includes PT/INR, PTT, Fibrinogen, D-Dimer, and Platelet Count), a peripheral smear, ADAMTS-13 activity if suspicious for TTP, and stool cultures if suspicious for HUS.
Thrombotic Thrombocytopenic Purpura (TTP)
- Presentation: Thrombocytopenia, renal injury, fever, neurologic symptoms
- Pathogenesis: Anti-ADAMTS-13 antibodies inhibit ADAMTS-13 (a protease which cleaves VWF), leading to increased hyaline clots, which causes shearing of platelets and red blood cells
- Platelets: Decreased
- Hemoglobin: Decreased
- Peripheral smear: Positive for schistocytes
- Fibrinogen, D-Dimer, PT/INR, PTT all within normal range
- ADAMTS13 activity level of less than 10% is definitive (1)
- Prednisone and plasma exchange
Disseminate Intravascular Coagulation (DIC)
- Presentation: Usually very sick patients, potentially hemodynamically unstable. May have thromboses and/or significant bleeding from several orifices
- Pathogenesis: Several different etiologies (obstetric complication, trauma, transfusion reaction, sepsis, malignancy, etc.) lead to a very complicated pathway which largely includes widespread inflammation and tissue factor over-expression, leading to over-activation of the coagulation cascade (see Coagulation). This leads to widespread thromboses, which consumes coagulation factors, predisposing the patient to problematic bleeding (2)
- Platelets: Decreased
- Hemoglobin: Decreased
- Peripheral Smear: Positive for Schistocytes
- Fibrinogen: Decreased
- D-Dimer: Elevated
- PT/INR: Prolonged
- PTT: Prolonged
- Definitive management is treatment of the underlying etiology
- Support with platelets, pRBCs, FFP, and cryoprecipitate as needed
Hemolytic Uremic Syndrome (HUS)
- Presentation: Thrombocytopenia, renal injury
- Pathogenesis: Typically, but not always, caused by Shiga-like toxin (usually from Enterohemorrhagic E. coli O157-H7 (EHEC) or Shigella dysenteriae) that binds to several different cell types, including glomerular endoethelial cells and white blood cells. This leads to inflammation and microvascular thrombosis (causing consumption of platelets). This microvascular thromboses causes shearing of passing red blood cells (3)
- Diagnosis: Markers may be similar to TTP (excluding reduced ADAMTS-13 activity), making the diagnosis difficult. Typically, the renal failure is the predominant feature of HUS, there will be a history of a diarrhea illness, and there will be a lack of fever and neurologic abnormalities (4)
- Hemolytic anemia in the setting of thrombocytopenia, renal injury, and normal ADAMTS-13 activity
- Stool cultures for E. coli O157:H7 or O104:H4, Shigella species
- Typically supportive, however, as the diagnosis may not always be clearly made from TTP, one might have a low threshold for initiating a plasma exchange, especially in a rapidly deteriorating patient (5)
- Eculizumab, a monoclonal antibody against C5, is indicated in treatment of “atypical HUS” (HUS not caused by Shiga-like toxin)
- Suspect in: Hypertension in addition to MAHA
- Pathogenesis: Elevated blood pressures cause disruption of vascular endothelium, leading to microangiopathic inflammation and thrombosis, leading to shearing of red blood cells
- Diagnosis: Hypertension in the setting of hemolytic anemia and normal ADAMTS-13 activity
- Management: Supportive management and gradual lowering of the blood pressure. However, like HUS, one should have a low threshold to initiate plasma exchange if TTP cannot be definitively ruled out or if a patient is deteriorating rapidly
Hemolysis, Elevated Liver enzymes, Low Platelets (HELLP) Syndrome (6)
- Suspect in: Pregnant, hypertensive women with a hemolytic anemia
- Pathogenesis: Genetic predispositions and poor placentation lead to ischemic injury of the placenta, which in turn, releases antiangiogenic factors which activates vascular endothelium and causes microangiopathy in the mother. This allows for shearing of red blood cells (hemolysis), causes ischemic injury to the liver (elevated liver enzymes), and causes consumption of platelets (low platelets)
- Elevated Liver enzymes
- Low Platelets (Thrombocytopenia)
- IV Magnesium sulfate
- Nifedepine, labetalol, or hydralazine for blood pressure control
- Delivery if able
- If patient and baby stable and 24-34 weeks gestation, may administer steroids and undergo expectant management
- Chiasakul, T., & Cuker, A. (2018, November 30). Clinical and laboratory diagnosis of ttp: An integrated approach. Hematology. American Society of Hematology. Education Program. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246034/.
- Papageorgiou, C., Jourdi, G., Adjambri, E., Walborn, A., Patel, P., Fareed, J., Elalamy, I., Hoppensteadt, D., & Gerotziafas, G. T. (n.d.). Disseminated intravascular Coagulation: An update On Pathogenesis, diagnosis, and Therapeutic Strategies. Clinical and Applied Thrombosis/Hemostasis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710154/.
- Noris, M., & Remuzzi, G. (2005, April 1). Hemolytic uremic syndrome. American Society of Nephrology. https://jasn.asnjournals.org/content/16/4/1035.
- Furlan, M., & Lämmle, B. (2000, August 1). Haemolytic‐uraemic syndrome and thrombotic thrombocytopenic purpura-new insights into underlying biochemical mechanisms. OUP Academic. https://academic.oup.com/ndt/article/15/8/1112/1808683#107986585.
- George, J. N., & Nester, C. (n.d.). Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS. Uptodate. https://www.uptodate.com/contents/thrombotic-microangiopathies-tmas-with-acute-kidney-injury-aki-in-adults-cm-tma-and-st-hus?search=hus&topicRef=89549&source=see_link.
- Khalid, F. (2021, August 1). HELLP syndrome. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK560615/.