Thrombotic Thrombocytopenic Purpura 

Introduction

During any kind of injury, wound or minor cut to the small blood vessels, our body initiates a defence process to prevent blood flow, called blood clotting. A blood clot is formed of blood cells called platelets, and fibrin threads. Although blood clots help in excessive bleeding, there are disorders associated with faults in the process whereby there is uncontrollable bleeding or excessive clots being formed at different locations.

Instead of a normal process of wound healing, known as blood homeostasis, there is abnormal homeostasis happening in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is a rare, life-threatening haematological condition affecting mainly the adult population and is less commonly seen in children. Thrombocytopenic purpura (TTP) is caused when there is a deficiency of ADAMTS13 enzyme. The ADAMTS13 enzyme is helpful in converting the inactive clotting factor von Willebrand factor into its active form. As a result, the precursor form of von Willebrand factor is not activated, leading to the formation of microthrombi or small blood clots within the capillaries and arterioles. This causes ischaemia, a blockage of blood supply to the tissues due to clots. 

Thrombocytopenic purpura falls under Thrombotic microangiopathy (TMA), a heterogeneous disease with various root causes. It is characterised by:  

• Microangiopathic haemolytic anaemia (a kind of anaemia in which the red blood cells are destroyed due to the blood clot)
• Thrombocytopenia (decreased platelet levels in the blood) with or without ischaemia of multiple organs

Thrombocytopenic purpura and disseminated intravascular coagulation lead to thrombocytopenia. Although TTP and disseminated intravascular coagulation seem similar on a superficial level, the aetiologies are completely different. Thrombocytopenia causes bleeding beneath the surface of the skin that appear as purple spots called purpura.

There are two types of TTP based on the cause:

• (Inherited TTP) or (congenital TTP) - thrombocytopenic purpura detected at birth or during pregnancy. The child is born with a defect in the ADAMTS13 gene
• (Acquired thrombotic thrombocytopenic purpura) or (immune TTP) or (idiopathic TTP) - self-destruction of ADAMTS13 enzymes caused by the IgG class of autoantibodies. ADAMTS13 activity is lost as a result

Acute thrombotic thrombocytopenic purpura begins with fever, neurological manifestations (such as headache, seizure, coma, confusion, stroke, and transient focal defect), and cardiac and renal failure.

Haemolytic uraemic syndrome is a kind of thrombotic microangiopathy observed in children, triggered by infections and other sources. Often, most patients end up with renal failure.¹

Causes

Von Willebrand factor is produced from the precursors of platelet cells called megakaryocytes, and cells lining the blood vessels called endothelial cells. Von Willebrand factor is a clotting factor participating in blood clot formation. Von Willebrand factor helps in sending out platelets to the damaged blood vessels, platelet aggregation and forming a clot to heal the wound. Von Willebrand factor is initially inactive and made active by the ADAMTS13 enzyme. Due to the absence of ADAMTS13 enzyme, the large von Willebrand factor starts aggregating, exacerbating the process and forming microthrombi in the arterioles and capillaries. The inactive form is a large polymer and, due to the ADAMTS13 deficiency, these long von Willebrand factor proteins do not get cleaved into smaller active enzymes. Therefore, these polymers of von Willebrand factor aggregate platelets to form microthrombi causing thrombocytopenia and haemolytic anaemia involving organ damage mainly to the brain, heart and kidneys.²

Inherited mutations

Thrombocytopenic purpura is caused by the inherited recessive mutation of  ADAMTS13 gene. Only 5% of cases contribute towards inherited TTP, and approximately 95% of them are acquired thrombotic thrombocytopenic purpura.

Autoimmune disorders

Immune-mediated TTP is an autoimmune disorder whereby autoantibodies fight against ADAMTS13 enzymes. As a result, TTP patients are diagnosed with ADAMTS13 deficiency. 

Pregnancy

Thrombocytopenic purpura is observed in patients with other critical conditions such as vascular endothelial injury, sepsis, trauma, and cancer. During pregnancy, TTP presents with challenging conditions and also a high mortality rate.³ Thrombosis occurs in the placenta and therefore leads to foetal death.⁴

Certain medications

A few of the medications that cause thrombocytopenia are ampicillin, glycoprotein IIb/IIIa inhibitors (including abciximab, eptifibatide, and tirofiban), heparin, seizure medications (such as carbamazepine), sulfonamides (such as trimethoprim/sulfamethoxazole), vancomycin, and aspirin.

Symptoms

A TTP patient presents the following features:

60% of patients show up Neurological manifestations. They are:

• Headache
• Transient cerebral ischaemia (insufficient blood supply to the brain)
• Stroke 
• Altered sensorium
• Mental disorders
• Ataxia (lack of muscle coordination)
• Epilepsy (seizures along with unusual sensation and behaviour)
• Focal neurological deficit (movement, sensation, speech and senses are disturbed)

Renal presentations are:

• Haematuria (bloody urine)
• Proteinuria (protein in urine)
• Renal insufficiency

Additional symptoms include:

• Anaemia
• Thrombocytopenia

Diagnosis

The ADAMTS13 gene is a differentiable marker. It is the most sensitive and specific marker for thrombocytopenic purpura. Anti-ADAMTS13 IgG autoantibody is measured by an ELISA test to detect immune thrombocytopenia. Immune TTP is confirmed by severe deficiency of ADAMTS13 below 10%.

Congenital TTP/inherited TTP is identified by genetic analysis of the ADAMTS13 gene through sequencing.

Additionally, the following diagnostic tests are used to get a complete outline of the condition so that treatment can begin.

Firstly, haematological tests are run to assess blood cell count including red blood cells (RBC), haemoglobin, haptoglobin, white blood cells (WBC), reticulocytes and platelets.

A typical blood test of a patient with TTP would show the following report:

• Low haemoglobin
• Low haptoglobin 
• High WBC 
• Very low platelets 
• High reticulocytes
• High bilirubin and lactate dehydrogenase (LDH)

These are followed by biochemical tests such as:

• Liver tests to assess levels of bilirubin, LDH, and electrolytes
• Cardiac tests to assess cardiac troponin IC levels 
• Renal function tests to assess plasma urea and creatinine levels, glomerular filtration rate, proteinuria, and haematuria

The presence of schistocytes (also called reticulocytes) is detected on the blood smear. They are the broken red blood cells. The shear force exerted by the blood, as it moves through the narrow space between the clot in small blood vessels, leads to breakage and fragmented RBC.

A direct antiglobulin test is used to detect the antibodies found on the red blood cells that are autoimmune and are the cause of RBC destruction and haemolytic anaemia.

Furthermore, complementary tests are also required to investigate the extent of organ damage.

Treatment

Thrombocytopenic purpura is an emergency disease that requires immediate treatment. This is especially true if the diagnosis shows TTP along with disseminated intravascular dissemination. Immediate treatment can prevent organ damage and the death of the patient. The first line of treatment would be plasma exchange therapy.

Plasma exchange therapy (plasmapheresis)

Plasma exchange therapy is the process in which the plasma of the patient is separated and replaced with treated plasma. Plasma is the liquid part of the blood without blood cells. Daily plasma exchange therapy is the first line of treatment for congenital TTP. The required ADAMTS13 enzyme is supplied while removing the autoantibodies.³ Plasma exchange therapy is continued for at least 2 days until the platelet levels have increased back to normal and there is clinical improvement.

Immunoglobulin therapy

Patients who are resistant to steroids are given immunoglobulin therapy intravenously. The antibodies from the donors are injected to treat the disease.

Corticosteroids

Corticosteroids are used to suppress the autoantibodies. Plasma infusion along with corticosteroid treatment is required. 

Rituximab

Rituximab is used for immune-mediated TTP. Rituximab is a monoclonal antibody that is used to immunosuppress the ADAMTS13 enzyme autoantibodies. Studies also suggest that the use of rituximab can prevent the relapse of thrombocytopenic purpura. Rituximab is usually given during acute thrombotic thrombocytopenic purpura that is in the initial days of development.

Complications

TTP patients need to be extra cautious after the treatment since there are complications that can follow. Patients who survive TTP are at a higher chance of getting depression, cognitive problems and also developing autoimmune disorders later on. Moreover, there are risks of relapse, developing chronic morbidities, and showing poor quality of life with high death rates.⁵

Genetics

The ADAMTS13 gene plays a key role in transmitting the disease for idiopathic TTP.

Prevention

If you are a patient with existing comorbidities or are on medications that increase the risk of developing TTP, monitor your condition every now and then by consulting your doctor.

Summary

Thrombotic thrombocytopenic purpura is a condition in which blood clots are formed in small blood vessels of the body leading to microangiopathic haemolytic anaemia and thrombocytopenia. As a result, ischaemia of various organs leads to organ failure and death. The main causative factor is ADAMTS13 enzyme deficiency and thus the diagnosis is based on quantifying the enzyme level and performing genetic analysis accompanied by blood tests. Treatment involves plasma infusion therapy, corticosteroids, monoclonal antibodies, and immunoglobulin therapy.