Fragmentation Haemolysis – Microangiopathic Haemoltic Anaemia (Maha)

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DIFFERENTIAL SLIDES LEGEND

CYCLE 47 SLIDE 5 – JANUARY 2016

FRAGMENTATION HAEMOLYSIS – MICROANGIOPATHIC HAEMOLTIC ANAEMIA (MAHA)

Schistocytes (from Greek schistos for "divided" or schistein for "to split", and kytos for "hollow" or "cell") are fragmented red blood cells that can take on different shapes. They can be found as triangular, helmet shaped, or comma shaped with pointed edges. Schistocytes are most often found to be microcytic with no area of central pallor. Their lifespan is lower than that of a normal red blood cell (120 days). This is due to their abnormal shape which can cause them to undergo hemolysis or be removed by macrophages in the spleen.

Schistocyte formation occurs as a result of mechanical destruction (fragmentation hemolysis) of a normal red blood cell. This occurs when there is damage to the blood vessel and a clot begins to form. The formation of the fibrin strands in the vessels occurs as part of the clot formation process. The red blood cells get trapped in the fibrin strands and the sheer force of the blood flow causes the red blood cell to break. The resulting fragmented cell is called a schistocyte.

A normal schistocyte count for a healthy individual is <0.5% although usual values are found to be <0.2%. A schistocyte count of >1% is most often found in thrombotic thrombocytopenic purpura (TTP), although they are more often seen within the range of 3-10% for this condition. A schistocyte count of <1% but greater than the normal value is suggestive of disseminated intravascular coagulation (DIC), but is not an absolute diagnosis. The standard for a schistocyte count is a microscopic examination of a peripheral blood smear.

Fragmentation haemolysis may occur in the presence of prosthetic materials, due to altered flow following cardiovascular surgery, due to trapping or adherence of red cells in arteriovenous malformations and as a result of the destruction of red cell in pathologically altered small blood vessels - microangiopathic hemolytic anemia. Characteristic features of fragmentation haemolysis are the appearance of schistocytes on the blood film and the presence of intravascular haemolysis. Depending on the underlying vascular pathology, there may be a reduction in the platelet count and evidence of DIC. The rate of red cell destruction also varies according to the pathogenesis, so the signs of intravascular haemolysis vary from the absence of haptoglobin, elevated LDH and minimal haemosiderinuria to acute intravascular destruction with haemoglobinaemia and haemoglobinurea.

Conditions that present with schistocytes on a peripheral blood smear include microangiopathic hemolytic anemia, traumatic hemolytic anemia, Waring Blender syndrome, Heart-valve hemolysis, disseminated intravascular coagulation, severe burns, and uremia. In most of the conditions, schistocytes are formed by fibrin formation and entrapment of red blood cells leading to fragmentation due to the force of blood flow in the vessels.

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MAHA - Note fragmentation of red cells, low platelets and leucoerythroblastic changes

CLASSIFICATION OF ANAEMIAS CAUSED BY FRAGMENTATION HAEMOLYSIS

Vascular origin Pathogenesis Platelets

Cardiac haemolysis Prosthetic heart valves Normal Patches, grafts Periprosthetic or perivalvular leaks Arteriovenous malformations Kasabach-Merritt syndrome Very low Malignant haemangioendotheliomas Microangiopathic TTP/HUS Low Malignant disease Normal/Low Vasculitis Normal/Low Pre-eclampsia, HELLP Low Renal vascular disorders Normal/Low DIC Low *HUS – Haemolytic Uraemic Syndrome *HELLP – Haemolysis with elevated liver function tests and low platelets

DIC DIC is caused by a systemic response to a specific condition including sepsis and severe infection, malignancy, obstetric complications, massive tissue injury, or systemic diseases. Disseminated intravascular coagulation is an activation of the coagulation cascade which is usually a result of an increased exposure to tissue factor. The activation of the cascade leads to thrombi formation which causes an accumulation of excess fibrin formation in the intravascular circulation. The excess fibrin strands causes mechanical damage to the red blood cells resulting in schistocyte formation and also thrombocytopenia and consumption of clotting factors. Schistocyte values between 0.5% and 1% are usually suggestive of DIC.

TTP TTP is caused by primary platelet activation. Thrombotic thrombocytopenic purpura leads to increased amounts of large von Willebrand factor which then attach to activated platelets and mediate further platelet aggregation. Platelets end up being removed and the resulting fibrin strand formation remains. These fibrin strands along with the stress from the blood flow cause fragmentation of the red blood cells, leading to schistocyte formation. In TTP, a schistocyte count between 3-10% is common, but >1% is suggestive of the disease.

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Heart Valve Hemolysis Leaky prosthetic heart valves and other cardiac assisted devices can lead to microangiopathic hemolytic anemia, thrombocytopenia, and schistocyte formation. The force from the blood flow over the high pressure gradient from the prosthesis leads to fragmentation of red cells and schistocyte formation. This is rare and only occurs in about 3% of patients.

HUS HUS is haemolytic anaemia, acute kidney failure (uraemia), and thrombocytopenia. HUS is caused by E. coli bloody diarrhea and specific strains of shiga toxin. The bacteria in HUS cause damage to the endothelium which results in platelet activation and formation of micro-thrombi. Red cells get trapped in the fibrin strands of the micro-thrombi and become sheared by the force of blood flow leading to schistocyte formation.

CAUSES OF MAHA

Disease Microangiopathy

HUS Endothelial cell swelling, micro thrombi in renal vessels

TTP Platelet plugs, micro-aneurysms, small- vessel thrombi

Renal cortical necrosis Necrotizing arteritis Acute glomerular nephritis Malignant hypertension Pre-eclampsia Fibrinoid necrosis HELLP Polyarthritis nodosa Vasculitis Wegener granulomatosis SLE Homograft rejection Micro-thrombi in transplanted organ

Mitomycin C Uncertain

Cyclosporin Renal vessel abnormalities

Carcinomatosis Abnormal tumour vessels Intravascular coagulation (disseminated or localized) Primary pulmonary hypertension Abnormal vasculature

Kasabach-Merritt Large vascular changes Thrombosis

References 1. Postgraduate Haematology By Douglas R. Higgs, David M. Keeling, Atul B. Mehta 2. https://en.wikipedia.org/wiki/Schistocyte

Questions 1. What is a schistocyte and when does it occur? 2. Discuss the conditions that present with schistocytes. 3. Define fragmentation haemolysis.

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