Thrombotic thrombocytopenic purpura

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Classification according to ICD-10
M31.1 Moschcowitz syndrome
ICD-10 online (WHO version 2019)

The thrombotic-thrombocytopenic purpura (also thrombotic-thrombopenic purpura or after its first description Eli Moschcowitz (1924) Moschcowitz syndrome , abbreviated TTP ) is a rare and life-threatening illness, in which platelet-rich blood clots develop, the small blood vessels ( capillaries ) especially of the brain and Clog the kidney, causing serious organ damage.

Epidemiology

TTP is a rare disease. The rate of new infections is around 3–7 per million people. The disease is most common between the ages of 30 and 40. Women are affected more often than men. In addition, people of African descent are more likely to be affected.

Pathophysiology

The thrombotic-thrombocytopenic purpura (formerly also thrombotic thrombocytopenic purpura ) is called thrombotic microangiopathy (TMP) just like the hemolytic-uremic syndrome (HUS, Gasser's disease ). These clinical pictures are based on a disruption of the blood flow in the arterioles and capillaries. As far as we know today, a disruption of the zinc protease ADAMTS13 is decisive for TTP . The protease cleaves the Von Willebrand factor (vWF), which is essential for cross-linking and the adherence of blood platelets to damaged vessel walls. If the ADAMTS13 activity is less than 10%, thrombi form in the smallest vessels of the body. These thrombi consist of large vWF multimers and activated blood platelets. The vascular occlusions lead to ischemia of the downstream tissues. The erythrocytes are also mechanically damaged by the vascular occlusions and disintegrate in the sense of hemolysis .

A distinction is made between the hereditary form and the acquired form of TTP. Hereditary TTP is caused by a mutation of the gene coding for ADAMTS-13. Around one hundred homozygous and compound heterozygous mutations have been described which reduce the activity of the metalloprotease. The severity of the disease correlates with the residual activity of the enzyme. Patients with less than 10% residual activity develop TTP. The first peak of illness occurs before the age of five. A second accumulation occurs in adulthood between 20 and 40 years. Patients with mutations have been described who have a residual activity of 50% into old age. However, there is no reliable correlation between the genotype and the frequency and severity of the disease, so that genes are sought which modify the activity of the ADAMTS-13 protease.

Acquired TTP is an autoimmune disease in which the body produces inhibitory antibodies against ADAMTS-13, which are detectable in the blood and form inactive immune complexes with the protease. The majority of cases are IgG antibodies. IgG4 antibodies are associated with an increased risk of recurrence. Antibodies of the IgA class or antibodies of the IgG1 subclass are associated with a poorer prognosis. Every fourth to every tenth blood donor has non-inhibitory antibodies against ADAMTS-13. A continuum is assumed from the development of non-inhibitory to inhibitory antibodies, the cause of which remains unclear to date. Asymptomatic allele carriers of an ADAMTS-13 mutation have an increased risk of developing an acquired TTP. The MHC-II isotypes DRB1 * 11 and DRB1 * 04 are also associated with a higher risk of disease.

Symptoms

A triad of symptoms is described as classic : In the laboratory, there is a drop in blood platelets ( thrombocytopenia ) in the peripheral blood, which is consumed faster than reproduced by the excessive coagulation. This leads to spot-shaped bleeding in the skin ( petechiae ). The erythrocytes are mechanically damaged and destroyed by the blood clots in the smallest vessels . It comes to the destruction of red blood cells and anemia . Damaged red blood cells can be detected in the blood smear as so-called fragmentocytes . Another characteristic are failures in motor skills, sensitivity, consciousness, eyesight and speech . These neurological symptoms are due to the reduced blood flow to areas of the brain. However, only 40% of the affected patients show this classic constellation of symptoms. Other symptoms described are headache, fever and mild kidney damage. Damage to the retina of the eye by blood clots with slow deterioration in vision has also been described.

Classification

So far there is no generally recognized classification of the TTP. Following various hypotheses on pathophysiology, today a distinction is often made between idiopathic, secondary and familial TTP.

Idiopathic TTP

By far the most common form of idiopathic TTP is considered an autoimmune disease of unknown cause with autoantibodies against the protease ADAMTS13. Inhibitory antibodies against ADAMTS13 could be detected in 13–100% of the patients, depending on the study. The reason for the scattering of these results are differences in the criteria according to which the patients were classified as affected by TTP. Another suspected antibody is directed against CD36, a glycoprotein on the platelet surface, which cross-links the platelets and could lead to thrombi.

Secondary TTP

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A trigger for a TTP can only be found in 15% of cases. In acquired or immune-mediated TTP (aTTP, acquired TTP), autoantibodies against ADAMTS13 , the von Willebrand factor- cutting protease, are formed. This leads to a consumption of blood platelets in aggregates of von Willebrand factors and blood platelets. These aggregates lead to microvascular thrombosis. As a result, tissue damage from lack of oxygen and z. T. fatal multiple organ failure . Evidence of immune-mediated TTP includes finding a severe ADAMTS13 deficiency of less than 10% of normal. An effective treatment is daily plasma exchange . The formation of autoantibodies can be reduced with immunosuppression by administering glucocorticoids and rituximab. A new type of therapy consists in the administration of caplacizumab. This is an immunoglobulin fragment that connects to the A1 domain of the von Willebrand factor and thereby prevents interaction with the platelet glycoprotein 1b-IX-V receptor. In the HERCULES study, a double-blind, randomized phase III study, treatment with caplacizumab normalized the platelet count more quickly and reduced the mortality from TTP. On September 3, 2018, caplacizumab received EU approval for the treatment of acquired thrombotic thrombocytopenic purpura under the trade name Cablivi®.

Possible triggers of a secondary TTP are pregnancy, bone marrow transplantation , drugs such as ovulation inhibitors , ciclosporin , some antibiotics (such as co- trimoxazole ), mitomycin C , ticlopidine , probably also clopidogrel , as well as infectious diseases such as HIV or bartonellosis , autoimmune diseases such as e.g. B. SLE , as well as cancers, in particular gastric adenocarcinoma . Also quinine , which in tonic water and some antimalarials is included, and drugs such as cocaine can be triggers of TTP.

Familial TTP

Familial or hereditary TTP ( Upshaw-Shulman syndrome ) is caused by a genetic defect in the so-called ADAMTS13 gene on chromosome 9 q34. This gene controls the production of the ADAMTS13 protease. So far 40 different mutations of the gene have been described, which are inherited as an autosomal recessive trait. The disease usually manifests itself shortly after birth. The characteristics of the TTP, however, are variable. Some patients remain inconspicuous for their entire life, others require therapy from time to time. In the worst case, the patients are dependent on permanent therapy. So far, no conclusions can be drawn about the severity of the disease from the type of mutation. The risk of an acute flare-up of the disease increases with the occurrence of fever, infections, and diarrhea. Operations and pregnancy are also associated with it.

therapy

  • The basis of the therapy is the exchange of blood plasma ( plasmapheresis ) with fresh frozen plasma (FFP). This removes antibodies against ADAMTS13 from the blood and supplies active protease from the donor plasma. The effectiveness has been proven in a randomized clinical study . The treatment leads to the resolution of the acute flare in 70% - 85% of the patients, but 10% - 20% of the patients die with an acute flare. More than half of the survivors had permanent organ damage and limitations, including neurological deficits. Relapses are common.
  • Alternatively, immunosuppressants such as vincristine , cyclophosphamide and azathioprine can further inhibit antibody production. The antibody rituximab , which is directed against a surface molecule of the antibody-producing B cells , can selectively block antibody formation. Corticosteroids are also used as a means of limiting immune reactions against one's own body . Attempts were also made to use inhibitors of platelet activation (e.g. ASA ) to influence the coagulation that causes the disease. The removal of the spleen as a therapeutic measure is hardly widespread anymore. The administration of platelets to correct thrombocytopenia is contraindicated and can lead to death. It is only considered in the event of life-threatening bleeding.
  • In 2018, the nanobody caplacizumab was approved for the treatment of adults suffering from an episode of acquired thrombotic thrombocytopenic purpura in conjunction with plasmapheresis and immunosuppression. This means that the acute phase of TTP ends for 75% of patients after 2.95 days compared to 4.5 days with the usual plasmapheresis. Only five plasma exchanges were required instead of the previous seven.
  • As a new attempt to improve the therapy, the administration of plasma purified from large vWF molecules instead of FFP is being tested.

forecast

If left untreated, the disease leads to death in around 90% of cases. The patients die of damage to the brain or heart caused by insufficient blood flow in the area of ​​the smallest vessels. Today's therapeutic measures enable the episode to be healed in 70–85%. In patients with idiopathic TTP, a relapse occurs in 36% of cases within ten years. Paradoxically, a high residual ADAMTS13 activity is a poor prognostic factor. The occurrence of neurological symptoms and their severity is also a poor prognostic factor.

Medical history

Thrombotic-thrombocytopenic purpura was first described by Eli Moschcowitz in 1924 as a combination of the five symptoms of hemolytic anemia with platelet deficiency, kidney failure, fever and neurological disorders. Before the introduction of plasmapheresis, the disease was fatal in almost all cases.

In 1977 and 1978 different working groups described a successful treatment of TTP using plasmapheresis. From 1982 to 1986 a randomized study on 104 patients in Canada showed the superiority of plasma exchange over the administration of FFPs without plasmapheresis. Another study at the same time showed an increase in the remission rate by combining plasmapheresis and steroids. Additional data on concurrent drug therapy and plasmapheresis came from a TTP-HUS registry in Oklahoma . As a result, combination therapy with corticosteroids was established in 2005 and 2006. In the early 2000s, attempts began to treat TTP using the monoclonal antibody rituximab in combination with plasmapheresis.

literature

Web links

Individual evidence

  1. ↑ a b c d e f R. Murrin, J. Murray: Thrombotic thrombocytopenic purpura: aetiology, pathophysiology and treatment. In: Blood Reviews , Volume 20, No. 1, 2006, pp. 51-60. PMID 16426943 .
  2. ↑ a b c d e f g Han-Mou Tsai: Current concepts in thrombotic thrombocytopenic purpura. In: Annual Review of Medicine , Volume 57, 2006, pp. 419-436. PMID 16409158 .
  3. ↑ a b c Johanna A. Kremer Hovinga: Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in P. Gresele et al. : Platelets in Thrombotic and Non-Thrombotic Disorders , Cambridge, 2017 pp. 851–871
  4. ↑ Bilal Beetari, Josef M. Schmidbauer, Tanja Krevet, Andreas Fischer, Klaus W. Ruprecht: Eye changes in thrombotic-thrombocytopenic purpura (Moschcowitz syndrome). In: Clinical monthly sheets for ophthalmology. 219, pp. 454-457, doi: 10.1055 / s-2002-32879 .
  5. ^ J Evan Sadler: Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura . In: Blood . tape 112 , no. 1 , July 1, 2008, ISSN  1528-0020 , p. 11-18 , doi : 10.1182 / blood-2008-02-078170 , PMID 18574040 , PMC 2435681 (free full text).
  6. ^ Paul Coppo, Michael Schwarzinger, Marc Buffet, Alain Wynckel, Karine Clabault: Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience . In: PloS One . tape 5 , no. 4 , April 23, 2010, ISSN  1932-6203 , p. e10208 , doi : 10.1371 / journal.pone.0010208 , PMID 20436664 , PMC 2859048 (free full text).
  7. ↑ GA Rock, KH Shumak, NA Buskard, VS Blanchette, JG Kelton: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group . In: The New England Journal of Medicine . tape 325 , no. 6 , August 8, 1991, ISSN  0028-4793 , pp. 393-397 , doi : 10.1056 / NEJM199108083250604 , PMID 2062330 .
  8. ^ Marie Scully, Beverley J Hunt, Sylvia Benjamin, Ri Liesner, Peter Rose: Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies . In: British Journal of Hematology . tape 158 , no. 3 , 2012, ISSN  1365-2141 , p. 323-335 , doi : 10.1111 / j.1365-2141.2012.09167.x , PMID 22624596 .
  9. ^ Marie Scully, Spero R Cataland, Flora Peyvandi, Paul Coppo, Paul Knöbl: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura . In: New England Journal of Medicine . tape 380 , no. 4 , January 24, 2019, ISSN  0028-4793 , p. 335-346 , doi : 10.1056 / NEJMoa1806311 .
  10. ↑ Overview of Cablivi and rationale for approval in the EU. (PDF) European Medicines Agency, accessed October 1, 2018 .
  11. ^ Marie Scully, Spero R. Cataland et al .: Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. NEJM, accessed October 1, 2019 .
  12. ↑ X. Zheng et al .: Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. In: Hematol. Oncol. Clin. North Am. , Vol. 21, No. 4, August 2007, pp. 609-632. PMID 14982878 .
  13. ↑ B. Konkle: Disorders of the platelets and the Vessel Wall in Dan L. Longo, Anthony S. Fauci et al. (Ed.): Harrison's Principles of Internal Medicine. 18th edition. Volume 1, p. 969.