🔅Thrombotic microangiopathy (TMA) is a rare but serious condition that affects the small blood vessels in the body.

– It causes blood clots to form inside the vessels, which can damage the organs they supply, such as the kidneys, brain, heart, and lungs.

– TMA can also cause hemolytic anemia (low red blood cell count due to destruction) and thrombocytopenia (low platelet count due to consumption).

Types and causes of TMA

– There are different types and causes of TMA, which can affect the diagnosis, treatment, and prognosis of the condition. Some of the common types and causes are:

1). Thrombotic thrombocytopenic purpura (TTP)

– This type of TMA is caused by a severe deficiency of an enzyme called ADAMTS13, which normally helps to regulate blood clotting by breaking down a protein called von Willebrand factor (vWF).

– Without enough ADAMTS13, vWF accumulates and causes platelets to stick together and form clots in the small vessels.

– TTP can be inherited (congenital) or acquired (immune-mediated). Acquired TTP is more common and is usually triggered by an autoimmune reaction that produces antibodies against ADAMTS13.

– TTP can affect any organ, but it often involves the brain and causes neurological symptoms such as confusion, seizures, or stroke.

2). Hemolytic uremic syndrome (HUS)

– This type of TMA is usually caused by an infection with a bacteria that produces a toxin called Shiga toxin, such as Escherichia coli O157:H7.

– The toxin; damages the lining of the blood vessels and activates the complement system, which is part of the immune system that helps to fight infections.

– The complement system also causes inflammation and clotting in the small vessels, especially in the kidneys.

– HUS can lead to kidney failure and may require dialysis or transplantation.

– HUS mainly affects children, but it can also occur in adults.

– There is also a rare form of HUS that is not related to infection but is caused by genetic mutations that affect the regulation of the complement system. This is called atypical HUS or complement-mediated HUS.

3). Secondary TMA

– This term refers to TMA that occurs as a complication of another condition or factor that causes damage to the blood vessels or triggers clotting.

– Some of the possible causes of secondary TMA are:

a). Malignant hypertension: This is a severe form of high blood pressure that damages the blood vessels and causes them to narrow and thicken.

b). Disseminated intravascular coagulation (DIC): This is a condition that causes widespread clotting and bleeding throughout the body due to an imbalance of clotting factors. It can be caused by severe infections, trauma, surgery, cancer, or other disorders.

c). Antiphospholipid antibody syndrome (APLA): This is an autoimmune disorder that produces antibodies against phospholipids, which are components of cell membranes and blood clotting factors. These antibodies interfere with normal blood clotting and increase the risk of thrombosis in various organs.

d). Systemic lupus erythematosus (SLE): This is another autoimmune disorder that causes inflammation and damage to various tissues and organs, including the blood vessels.

e). Scleroderma renal crisis: This is a complication of scleroderma, which is a connective tissue disorder that causes thickening and hardening of the skin and other organs. Scleroderma renal crisis occurs when scleroderma affects the kidneys and causes severe hypertension and kidney failure.

f). HIV-associated TTP: This is a rare form of TTP that occurs in patients with HIV infection. The exact mechanism is not clear, but it may be related to immune dysfunction or viral infection of endothelial cells.

g). Medications: Some drugs can cause TMA by inducing an allergic reaction, damaging the endothelial cells, or interfering with ADAMTS13 activity. Some examples are quinine, ticlopidine, clopidogrel, cyclosporine, tacrolimus, gemcitabine, mitomycin C, bevacizumab, and interferon alfa.

h). Pregnancy: TMA can occur during pregnancy or postpartum due to hormonal changes, placental abnormalities, or preeclampsia/eclampsia.

Diagnosis of TMA

– The diagnosis of TMA is based on clinical signs and symptoms, laboratory tests, and sometimes biopsy of affected organs. Some of the laboratory tests that are used to diagnose TMA are:

🔅 Complete blood count (CBC)

– This test measures the number and size of red blood cells, white blood cells, and platelets in the blood. TMA typically causes low red blood cell count (anemia), low platelet count (thrombocytopenia), and increased mean corpuscular volume (MCV), which indicates larger than normal red blood cells.

🔅 Peripheral blood smear

– This test examines a drop of blood under a microscope to look for abnormal shapes and sizes of blood cells. TMA causes fragmentation and destruction of red blood cells, which produces schistocytes (fragmented red blood cells) and helmet cells (red blood cells with one or more projections) on the blood smear. These are signs of MAHA. The blood smear may also show reduced or clumped platelets.

🔅 Lactate dehydrogenase (LDH)

– This is an enzyme that is released from damaged cells into the blood. TMA causes increased LDH levels due to hemolysis and tissue injury.

🔅 Haptoglobin

– This is a protein that binds to free hemoglobin in the blood and prevents its loss in the urine. TMA causes decreased haptoglobin levels due to hemolysis and hemoglobinuria.

🔅 Bilirubin

– This is a breakdown product of hemoglobin that is normally excreted in the bile. TMA causes increased indirect (unconjugated) bilirubin levels due to hemolysis and impaired liver function.

🔅 Coombs test

– This is a test that detects antibodies that bind to red blood cells and cause them to agglutinate or lyse. TMA causes a negative Coombs test, which means that the hemolysis is not immune-mediated.

🔅 ADAMTS13 activity

– This is a test that measures the activity of the enzyme ADAMTS13 in the blood. TMA caused by TTP typically shows severely reduced (<10%) ADAMTS13 activity due to autoantibodies or genetic mutations. TMA caused by other factors usually shows normal or mildly reduced (>10%) ADAMTS13 activity.

🔅 ADAMTS13 inhibitor

– This is a test that detects the presence of autoantibodies against ADAMTS13 in the blood. TMA caused by acquired TTP usually shows positive ADAMTS13 inhibitor, which confirms the diagnosis. TMA caused by congenital TTP or other factors usually shows negative ADAMTS13 inhibitor.

🔅 Shiga toxin

– This is a test that detects the presence of Shiga toxin or Shiga toxin-producing bacteria (such as E. coli O157:H7) in the stool or blood. TMA caused by HUS usually shows positive Shiga toxin, which confirms the diagnosis. TMA caused by other factors usually shows negative Shiga toxin.

🔅 Complement levels

– These are tests that measure the levels of various components of the complement system, which is part of the immune system that helps to fight infections and clear damaged cells. TMA caused by atypical HUS usually shows low levels of complement factors such as C3, C4, factor B, factor H, factor I, or factor H-related proteins due to excessive activation or consumption of complement. TMA caused by other factors usually shows normal or high levels of complement factors.

🔅 Genetic testing

– This is a test that analyzes the DNA for mutations in genes that are associated with TMA syndromes, such as ADAMTS13, complement factors, or coagulation factors. Genetic testing can confirm the diagnosis of congenital TTP or atypical HUS and identify family members who may be at risk.

Prevention and treatment of TMA:

– The prevention and treatment of TMA depend on the type and cause of the condition. Some of the general measures that can help prevent or treat TMA are:

1). Avoiding triggers such as infections, medications, or pregnancy complications that can cause or worsen TMA

2). Maintaining good hydration and blood pressure control to prevent kidney damage

3). Receiving supportive care such as blood transfusions, dialysis, or organ transplantation if needed

4). Receiving specific treatments such as:

🔅 Plasma exchange

– This is a procedure that removes plasma (the liquid part of blood) from the patient and replaces it with fresh frozen plasma from a donor.

– Plasma exchange can remove antibodies, toxins, or excess vWF that cause TMA and provide normal ADAMTS13 and complement factors that prevent TMA. Plasma exchange is the main treatment for TTP and some cases of secondary TMA.

🔅 Plasma infusion

– This is a procedure that adds fresh frozen plasma from a donor to the patient's blood without removing any plasma. Plasma infusion can provide normal ADAMTS13 and complement factors that prevent TMA. Plasma infusion is an alternative treatment for congenital TTP when plasma exchange is not available or contraindicated.

🔅 Immunosuppression

– This is a treatment that suppresses the immune system and reduces inflammation and antibody production.

– Immunosuppression can be achieved with drugs such as steroids, rituximab, cyclophosphamide, or azathioprine.

– Immunosuppression can be used to treat acquired TTP or secondary TMA caused by autoimmune disorders such as SLE or APLA.

🔅 Antibiotics

– These are drugs that kill bacteria and prevent infections. Antibiotics can be used to treat HUS caused by Shiga toxin-producing bacteria or secondary TMA caused by other bacterial infections.

🔅 Anticoagulation This is a treatment that prevents blood clotting.