Thrombotic thrombocytopenic purpura

International Classification (ICD)	M31.-
Symptoms	Thrombocytopenia, Petechenia, Anemia, Neurological symptoms, visual deterioration, Fever, Headache, Kidney damage
Possible causes	Blood clot, Defect of the metalloprotease ADAMTS13, Infectious disease, Autoimmune disease, Medication
Possible risk factors	Infection, Pregnancy, surgical interventions, reduced activity of ADAMTS13 protease, Fever, Diarrhea, Medication
Possible therapies	Plasmapheresis (blood exchange), Fresh Frozen Plasma (FFP)

Basics

Thrombotic thrombocytopenic purpura (also known as thrombotic thrombocytopenic purpura, Moschcowitz syndrome or TTP) is an autoimmune disease in which platelet-rich, small blood clots (microthrombi) form in the smallest blood vessels. The clots usually consist of large von Willebrand factor complexes and platelets. The cause of the disease is a deficiency of the metalloprotease ADAMTS 13 ("a disintegrin and metalloprotease with thrombospondin repeats 13"). In the normal state, this protease cleaves von Willebrand factor and thus counteracts blood clots. Another characteristic of TTP is a severe deficiency of blood platelets (thrombocytes).

Thrombozyten (iStock / gaetan stoffel)

Frequency

The disease may occur with a sudden onset from complete health. It affects about 1.5 - 6 per 1 million inhabitants per year. Women are affected twice as often as men. TTP, although very rare, is believed to be underdiagnosed. Differentiation between TTP and hemolytic uremic syndrome (HUS) - another microangiopathic disorder - is not always possible with certainty.

Causes

Thrombotic thrombocytopenic purpura, like hemolytic uremic syndrome (HUS), is a so-called thrombotic microangiopathy. Here, the formation of blood clots leads to a disturbance of the blood flow in the smallest blood vessels. This disruption then leads to an oxygen deficiency in the organs supplied (e.g. kidney or brain). The most common form of TTP is the acquired form (about 95% of cases). This is triggered by antibodies against the metalloprotease that normally cleaves von Willebrand factor (ADAMTS 13). The protease ADAMTS 13 plays a major role in the coagulation cascade, with a deficiency leading to an increased incidence of blood clots.

The following causes are possible for acquired TTP:

Rheumatic diseases
Certain drugs (e.g. cytostatics)
In the course of pregnancy (due to the increase in estrogen)

The congenital form of TTP is also known as Upshaw-Schulman syndrome or cTTP ("congenital TTP"). It is responsible for about 5% of all cases of the disease and often occurs in early childhood (about 50-60% of cases). However, some patients become symptomatic only at the age of 30 - 40 years. cTTP is due to a congenital reduction in ADAMTS13 activity, with over 100 responsible mutations currently known. In most cases, a decrease in ADAMTS 13 activity or decreased secretion of metalloprotease triggers the disease.

Possible triggers for a cTTP flare include:

Antimalarial drugs
Gemcitabine (cytostatic drug)
Quetiapine (antipsychotic)
Cyclosporine
Tacrolimus
Infections

Trigger

The causes of acquired TTP or of a disease flare-up in the course of TTP are usually influenza or gastrointestinal infections. In addition, drugs such as quinine, Tiklyd or mitomycin can trigger TTP.

Symptoms

Symptoms that may occur with thrombotic thrombocytopenic purpura include the following:

General symptoms: Fatigue, fever, headache.
Neurological symptoms: Due to reduced blood flow to certain areas of the brain caused by small blood clots, there may be disturbances in consciousness, motor function, sensitivity, vision, and speech.
Petechenia: Due to a lack of platelets, there are punctate bleeding signs in the skin (also called petechiae).
Anemia: The red blood cells (erythrocytes) are mechanically damaged by the blood clots in the arterioles and capillaries, resulting in anemia.
Thrombocytopenia: A blood test reveals a severely reduced level of platelets (thrombocytes) in the peripheral blood. The reason for this is that platelets are used up more quickly due to excessive blood clotting and cannot be replenished sufficiently.
Restriction of kidney function (renal insufficiency)

Diagnosis

A thorough anamnesis (medical interview) provides information on whether risk factors that can trigger a TTP episode (for example, infections, fever) are present in affected individuals. In addition, a physical examination and a neurological status are performed to detect any neurological symptoms at an early stage.

Blutausstrich (iStock / toeytoey2530)

Diagnostic indications for TTP are platelet deficiency (thrombocytopenia), LDH elevation (lactate dehydrogenase) and destroyed red blood cells (fragmentocytes) in the blood smear. The diagnosis is then confirmed by decreased ADAMTS 13 activity, antibodies to ADAMTS 13, and the presence of large von Willebrand complexes. Reduced activity of ADAMTS13 protease can be detected by gel electrophoretic multimer analysis of von Willebrand factor in blood plasma.

In cTTP, anti-ADAMTS13 antibodies are generally absent, in contrast to the acquired form of TTP.

Therapy

The main goal in the treatment of acute TTP is to reduce or prevent clot formation (microthrombi) in the vascular circulation, usually by plasmapheresis (blood exchange) with FFP (fresh frozen plasma) administration. In addition, the administration of Rituximab (monoclonal anti-CD20 antibody) can be helpful in the acute stage of the disease. Among other things, this agent destroys the B cells in which the antibodies against ADAMTS 13 are formed.

Other treatment options include:

Dialysis or hemofiltration
Administration of glucocorticoids

Transfusion of platelets (thrombocytes), to compensate for platelet deficiency, should be omitted in all cases. Such a transfusion can lead to a worsening (aggravation) of the clinical picture.

In general, therapy should be initiated in the first 4-8 hours after a suspected diagnosis of TTP. Plasma exchange is currently considered the mainstay of therapy. This is to achieve an exogenous supply of ADAMTS13 activity. In addition, externally supplied ADAMTS13 binds circulating antibodies in the blood and may thus contribute to a rebound in platelet counts.

Ein verengtes Blutgefäß (iStock / Dr_Microbe)

Prognose

TTP is a medical emergency and treatment should be initiated within a few hours. If left untreated, the disease has a mortality rate of approximately 72 - 94 %. Thrombotic organ complications, such as myocardial infarction, often occur in the first few hours. In about one-third of those affected, TTP recurs in the form of relapses. Even with therapy, the mortality rate of TTP is approximately 10-20%. Rarely, the disease occurs as a familial form caused by a genetic defect.