Immune Thrombocytopenia (ITP)


As knowledge has advanced within the fields of medicine, molecular biology, and immunology, our understanding of the pathogenesis of immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenia purpura, has also progressed.

Ancient Times

Before the discovery of platelets, the presence of ITP was evidenced by the appearance of red-purple skin lesions called purpura. (Purpura is the Latin word for “purple.”) Originally, this Latin word derived from the Greek porphyra, the word for a type of Mediterranean shellfish from which a reddish dye could be obtained.1  

In ancient Greece and Rome, physicians such as Hippocrates and Galen identified purpura as a clinical symptom often accompanied by fevers.1 Now, researchers understand that not all patients with ITP have purpura at the time of diagnosis. Previously, patients who had ITP without this visible manifestation of disease were overlooked.2

Through the Centuries

From the 11th through 18th centuries, several physicians recorded cases and documented their observations relating to ITP.1,3

Possible Early ITP Cases

In 1025, a Persian physician and philosopher, Abu Ali al-Hussain Ibn Abdallah Ibn Sina (better known by his Latin name, Avicenna), described a case of chronic purpura that might have been ITP in his magnum opus, The Canon of Medicine.1

In 1556, a Portuguese physician, Amatus Lusitanus, documented a possible case of ITP in Curationum Medicinalium Centuriae. The doctor described an afebrile boy who presented with dark macules and bloody discharges over a period of several days. The boy recovered spontaneously from his illness.1 

In 1658,  Lazarus de la Rivière, physician to the King of France, mentioned “purple specks or spots like flea-bitings” and equated them with what Italian physicians called petechiae. He was the first to suggest that purpura resulted from a possible systemic bleeding disorder due to “thinness of the blood.”1

Developing an Understanding of the Disease

In 1735, a German physician, Paul Gottlieb Werlhof, used the phrase morbus maculosus haemorrhagicus to describe the case of a 16-year-old girl. He detailed that the girl’s bleeding began from her nose and mouth, after which she vomited thick, black blood and purplish-black spots developed on her neck and arms. These symptoms appeared following an infection. A second girl presented to Werlhof with purpura and epistaxis. Although the symptoms of one of the girls remitted spontaneously, the other experienced repeated relapses.4 After these 2 case descriptions had been published in Werlhof’s work entitled Disquisitio medica et philologica de variolis et anthracibus, the condition was called Werlhof’s disease — a term that is sometimes still used instead of ITP.1,4

In 1808, the English physician and dermatologist Robert Willan documented various types of skin diseases in On Cutaneous Disease. He observed that purpura simplex (which most closely equates to ITP) occurred most frequently in children and women. The petechiae or purpura are found over the arms, legs, breasts, and abdomen but are largest on the legs.1

In 1899, a German physician, Henoch, differentiated between dry purpura, which he called purpura simplex, and wet purpura, which he called purpura haemorrhagica. Today, bleeding underneath the skin is called dry purpura, whereas bleeding in the mucosal membranes is called wet purpura.1

Discovery of Platelets

In the 19th century, Joseph Jackson Lister improved the microscope by solving the problem of chromatic aberration. By combining lenses to neutralize chromatic aberration, he improved image resolution.1

Following this advancement in microscopy, two English physicians, George Gulliver and William Addison, independently drew their renditions of platelets in 1841. Addison connected platelets with fibrin formation as he witnessed coagulation occur under the microscope.1

In 1842, Alfred Donné, a French physician, observed 3 particles found in blood — erythrocytes, leukocytes, and (presumably) platelets — which he described as “les globulins du chyle.”1 

In 1865, Max Schultze, who primarily investigated white blood cells, described platelets as small, colorless spheres or “granular masses.” He believed that they were fragments of degenerated or disintegrated leukocytes.1

In 1874, a Canadian physician, William Osler, described platelets as normal cells found within circulating blood. He claimed they did not derive from leukocyte degeneration, but he was unable to explain their origin.1    

In 1879, Paul Ehrlich developed a technique for staining blood films to assist in differentiating among blood cells.1

In 1882, an Italian pathologist, Giulio Bizzozero, first coined the term platelets. He described and demonstrated the independent role of platelets in hemostasis, suggesting that hemostasis was different from blood coagulation. Like Osler, he was unable to determine the origin of platelets.1

Making the Connection

In 1883, Brohm and Krauss were the first researchers to make the connection between the purpura simplex described by Werlhof and thrombocytopenia.1,4 

In 1887, a Belgian histologist, Denys, confirmed the theory of Brohm and Krauss. He demonstrated that platelet levels were lower during the active phase of purpura and rose after hemorrhaging had stopped.1,4

In 1890, William Henry Howell, a physician and the first professor of physiology at Johns Hopkins University in Baltimore, first documented the existence of megakaryocytes.1,5

In 1906, a pathologist in Boston, James Homer Wright, studied the bone marrow of cats and hypothesized that platelets originate from megakaryocyte fragments.1

Controversy Regarding ITP Pathophysiology

Theories on the pathogenesis of ITP became controversial throughout the first half of the 20th century. Some believed that platelets were destroyed peripherally, whereas others suggested that platelet production was impaired.1,4 

In 1905, Marino hypothesized that immune-mediated mechanisms were the cause of ITP.1 

In 1915, the German physician Ernest Frank published Die Essentielle Thrombopenia, in which he suggested that a toxic substance produced by the spleen suppressed megakaryocytes. He suspected that this was the cause of ITP.1,4 

However, in 1916, Paul Kaznelson, a medical student in Prague, challenged Frank’s theory when he observed that removal of the spleen actually relieved the symptoms of ITP. Instead, he suggested that platelet destruction occurred in the spleen.1,4,6

Read more about ITP pathophysiology

Harrington-Hollingsworth Experiment

In 1951, William Harrington and James Hollingsworth, 2 physicians working in St. Louis, Missouri, undertook an experiment that settled the controversy regarding the pathogenesis of ITP. They observed that the symptoms of a child born to a mother with chronic ITP resolved within 3 weeks after birth. They suspected that an antiplatelet humoral factor had been passed from mother to child.1 To test their idea, Harrington found a middle-aged woman with chronic ITP who shared his blood type. Harrington and the patient exchanged blood via transfusion. Harrington experienced a seizure, the platelet levels in his blood dropped significantly, and symptoms of thrombocytopenia, such as epistaxis, rectal bleeding, gingival bleeding, and cutaneous and mucosal petechiae, developed. His platelet count returned to normal after a week. This experiment clearly demonstrated that ITP is caused by decreased platelet survival secondary to a humoral factor.1

Read more about ITP clinical trials

Immune-Mediated Pathogenesis of ITP

Until this point, ITP had been referred to as idiopathic thrombocytopenia purpura because evidence was lacking to prove the cause of the disorder. 

In 1951, the same year as the Harrington-Hollingsworth experiment, Evans and colleagues documented a correlation between Coombs-positive hemolytic anemia and ITP, and they suggested that an antiplatelet autoantibody was the cause of thrombocytopenia.1,4

Future studies confirmed that patients with ITP had high levels of platelet-associated immunoglobulin G (IgG) antibodies and that these antibodies could attack platelets surrounding and budding off megakaryocytes.1,7-9 

Van Leeuwen and colleagues studied platelets of patients with ITP and platelets of patients with a condition called Glanzmann thrombasthenia. The platelets of patients with Glanzmann thrombasthenia lack sufficient amounts of specific glycoproteins (IIb and IIIa) on their surface membranes. The researchers demonstrated how IgG antibodies bound to normal platelets in patients with ITP; however, the same IgG antibodies bound to only a fraction of the platelets in patients with Glanzmann thrombasthenia. They theorized that individuals with ITP produce autoantibodies against glycoproteins IIb or IIIa on the surface of platelets.10

Van Leeuwen’s theory was proved correct when several other studies demonstrated the presence of autoantibodies against glycoproteins IIb/IIIa and many other antigens on the surface of platelets in patients with ITP.11-14

As understanding of the autoimmune pathogenesis of the disorder advanced, the name idiopathic thrombocytopenic purpura was changed to immune thrombocytopenic purpura. At present, the condition is called immune thrombocytopenia.2 

Read more about ITP etiology

References

  1. Stasi R, Newland AC. ITP: a historical perspective. Br J Haematol. 2011;153(4):437-450. doi:10.1111/j.1365-2141.2010.08562.x
  2. McCrae K. Immune thrombocytopenia: no longer ‘idiopathic.’ Cleve Clin J Med. 2011;78(6):358-373. doi:10.3949/ccjm.78gr.10005
  3. Freedman J, Blanchette M. Idiopathic thrombocytopenic purpura (ITP): a historical odyssey. Acta Paediatrica. 1998;87(s424):3-6. doi:10.1111/j.1651-2227.1998.tb01226.x
  4. Liebman HA. Immune thrombocytopenia (ITP): an historical perspective. Hematology. 2008;2008(1):205. doi:10.1182/asheducation-2008.1.205
  5. William Henry Howell. Portrait Collection. The Johns Hopkins Medical Institutions. Accessed October 23, 2022.
  6. Yoshida Y. Historical review. The light and shadow of Paul Kaznelson: his life and contribution to hematology. Ann Hematol. 2008;87(11):877-879. doi:10.1007/s00277-008-0553-1
  7. Pisciotta AV, Stefanini M, Dameshek W. Studies on platelets: morphologic characteristics of megakaryocytes by phase contrast microscopy in normals and in patients with idiopathic thrombocytopenic purpura. Blood. 1953;8(8):703-723.
  8. Shulman NR, Marder VJ, Weinrach RS. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Physiologic, serologic and isotopic studies. Ann N Y Acad Sci. 1965;124(2):499-542. doi:10.1111/j.1749-6632.1965.tb18984.x
  9. Dixon R, Rosse W, Ebbert L. Quantitative determination of antibody in idiopathic thrombocytopenic purpura. Correlation of serum and platelet-bound antibody with clinical response. N Engl J Med. 1975;292(5):230-236. doi:10.1056/NEJM197501302920503
  10. van Leeuwen EF, van der Ven JT, Engelfriet CP, von dem Borne AE. Specificity of autoantibodies in autoimmune thrombocytopenia. Blood. 1982;59(1):23-26.
  11. Woods VL, Kurata Y, Montgomery RR, et al. Autoantibodies against platelet glycoprotein Ib in patients with chronic immune thrombocytopenic purpura. Blood. 1984;64(1):156-160.
  12. Woods VL, Oh EH, Mason D, McMillan R. Autoantibodies against the platelet glycoprotein IIb/IIIa complex in patients with chronic ITP. Blood. 1984;63(2):368-375.
  13. Kiefel V, Santoso S, Weisheit M, Müeller-Eckhardt C. Monoclonal antibody–specific immobilization of platelet antigens (MAIPA): a new tool for the identification of platelet-reactive antibodies. Blood. 1987;70(6):1722-1726.
  14. McMillan R, Tani P, Millard F, Berchtold P, Renshaw L, Woods VL. Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP. Blood. 1987;70(4):1040-1045.

Reviewed by Harshi Dhingra, MD, on 10/27/2022.

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