DID YOU KNOW?
This condition is more common in women than in men, with a female-to-male ratio of 3:2.
TTP is a medical emergency and the present mortality rate is approximately 95% for untreated cases.
The survival rate is 80-90% with early diagnosis and treatment with plasma infusion and plasma exchange.
Prior to the 1960s the survival rate was a mere 3%.
One third of patients who survive the initial episode experience a relapse within the following 10 years.
TTP is most common in adults, although it can occur in neonates to persons as old as 90 years. The peak occurs in the fourth decade of life, with a median age at diagnosis of 35 years.
Dr Eli Moschcowitz first described TTP in 1924.
Background Information / Overview of TTP
Thrombotic Thrombocytopenic Purpura (TTP or Moschcowitz disease) is a life-threatening multisystem disorder that is considered a true medical emergency. This condition is characterized by the formation of clots, clumps of platelets (thrombi) in the blood vessels. Platelets are blood cells with an important role in clotting. Because a large number of platelets are used to form clots in people with this disorder, fewer platelets are available to circulate in the bloodstream. A reduced level of circulating platelets is known as Thrombocytopenia . These blood clots can cause serious medical problems if they block vessels and restrict blood flow to organs, such as the brain, kidneys, and heart. Resulting complications can be as simple as fever (in 60% of cases), fatigue and abdominal pain. Neurological changes such as altered mental status: confusion, generalized headaches, visual disturbances, seizures; coma (36%). Heart failure is also present in some cases. Thrombocytopenia can lead to bleeding just under the surface of the skin, resulting in purplish spots called Purpura, and bleeding in other body sites.
The disorder is also characterized by microangiopathic hemolytic anemia, in which the red blood cells break down prematurely, resulting in paleness, yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate.
Early recognition and treatment can significantly reduce these complications and the mortality of TTP.
Causes
The cause of TTP is currently unknown. Studies of the disease indicate that protein in the plasma called von Willebrand factor (vWF) may play a vital role. vWF is glycoprotein that is involved in blood clot formation. Von Willebrand factor (vWF) is an extremely large molecule composed of identical subunits (multimers). Each multimer is able to bind to platelets or damaged endothelium (lining of blood vessels) at the site of an injury. The greater the number of multimers, the more effective the binding. Ultra-large molecules of the factor (ULvWF) are therefore especially sticky but are not usually found circulating in the blood. They are normally broken down to smaller sizes, so vWF retains its adhesive properties without binding inappropriately to platelets and causing undesired clots. One of the possible causes of TTP is that in TTP, vWF is synthesised normally as ULvWF but its break down (cleavage) is defective. This is due to a lack of enzyme activity, called vWF cleaving protease. This deficiency may be inherited (genetic) or acquired later in life. The lack of ULvWF-cleaving protease activity was suggested to be due to the presence of antibodies that inhibit its activity or a severe deficiency of ULvWF-cleaving protease in the adult-onset TTP. In the case of the childhood, this may be due to a reduction in enzyme activity. Both mechanisms result in the presence of ultra-large von Willebrand factor within the circulation Circulating ULvWF leads to the inappropriate formation of platelet clumps (thrombi) particularly within blood vessels supplying the brain and kidneys. These give rise to the typical symptoms of TTP. Other possible causes of TTP are still being researched.
TTP develops suddenly and the exact cause is unknown. However there are certain factors that have been proven to trigger TTP.
1. Drugs
Several drugs known to trigger TTP: the anti-platelet drug clopidogrel (Plavix), oral contraceptive pills, quinine and cyclosporine. It is a very small percentage of the patients taking these drugs that will develop TTP.
2. Pregnancy
TTP can develop at any time during pregnancy, most often during the second trimester. It may affect the fetus.
3. Infections
Certain infections have been associated including HIV TTP may be the initial presenting syndrome of this infection. E coli infections are associated with TTP in small percentage of the cases
4. Systemic lupus erythematosus (SLE)
A small percentage of patients with SLE (an inflammatory connective tissue disease) may also develop TTP. Usually the episode of TTP follows the diagnosis of SLE by some years but it can sometimes precede it. Screening tests for SLE may therefore be performed.
5. Malignancy
Cancer of any type may be complicated by TTP. TTP can also occur after bone marrow or peripheral stem cell transplantation. Total body irradiation and cyclosporineare recognized risk factors.
Treatment
Plasmapheresis is the most important treatment for TTP. This is a procedure where the patient is attached to an apheresis machine. The patient's blood is removed in continuous small amounts. The machine separates the patient's blood into cells and a liquid part called plasma. The cells are returned to the patient, and the plasma is discarded. This removes the antibodies causing TTP that are in the plasma. Plasma (fresh frozen plasma or cryopoor supernatant) from normal donors is given to the patient during the procedure to replace the plasma that has been removed, and provides normal vWF cleaving protease activity. Plasma exchange is initially performed daily , until response and then the patient is weened off treatment. Plasma exchange treatment can last up to a month in some cases.
Medications: There are medications frequently used in combination with plasmapherisis to treat TTP. The most common drugs are:
Corticosteroids are sometimes used in combination with plasma exchange. Their immunosuppressive effects are thought to be important. Steroids may be given either intravenously or orally.
Folic acid is a vitamin required for healthy formation of red cells. The body cannot store large amounts of this vitamin and, in circumstances of excessive red cell production like TTP; folic acid deficiency can develop relatively quickly. Daily supplements are therefore given to prevent this.
The majority of patients will respond to the above treatments; however some patients require alternative treatments. The possible medications are: azathioprine, intravenous immunoglobulin, Vincristine, Rituximab and cyclophosphamide.
Other Therapies.
History
Dr Eli Moschcowitz of New York City first described TTP in 1924 when he noted that his 16 year-old patient had anemia; petechiae; microscopic hematuria; and at autopsy, disseminated microvascular thrombi. Since that time, the pathophysiology, etiology, and medical management of TTP have expanded. This life-threatening condition may have positive outcomes if recognized early and if medical intervention is initiated early.
Diagnostic Tests
There is no single test available to diagnose TTP. In the past, a pentad of signs and symptoms was associated with TTP: thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal failure, and fever. Current clinical practice diagnostic criteria include thrombocytopenia, red blood cell fragments seen on blood film, and significant elevations in serum LDH levels to suggest the diagnosis of TTP The following laboratory tests can help for the successful diagnosis of this condition.
--- Thrombocytopenia and anemia are noted.
--- Evidence of Thrombocytopenia may precede the appearance of fragmented RBCs and LDH elevation by several days.
--- CT scan of the head to assess for intracranial bleeding and stroke.
--- Bone marrow or gingival biopsy samples yield diagnostic lesions (hyaline thrombi) in 30-50% of cases.
Prognosis
The mortality rate associated with TTP is approximately 95% for untreated cases, but this has improved dramatically with survival rate of 80-90% for patients diagnosed and treated early Approximately one-third of patients experiencing a TTP episode have a secondary episode ( a relapse) within 10 years following their first attack. This represents only statistical data, at the present time there is no way of identifying the cases at risk of relapse. Individual differences in TTP patients are significant. That is why patients are recommended to remain under the care of a hematologist and to pay attention for the signs and symptoms of the condition.