Abstract
In 1916 Paul Kaznelson (1892-1959), a 26-year-old medical student at German University in Prague, was the first to describe splenectomy for what would be recognized today as immune thrombocytopenic purpura (ITP). From his physical examination, microscopy of a blood smear, and what was then known about the life cycle of platelets, he concluded that his patient’s bleeding diathesis and enlarged spleen were linked: she had no platelets because they were being destroyed by the organ. He convinced the chief of surgery to remove the patient’s spleen, a landmark operation that succeeded beyond “the wildest expectations”. He stayed on faculty, but his promising academic career was derailed by virulent antisemitism, first in his own university medical school, then his home country. Forced into exile in 1939 he found refuge in the United Kingdom, which allowed him to practice medicine but denied him formal residency. At war’s end he found himself unwanted in the West by his Russian heritage and citizenship in an Iron Curtain country. Czechoslovakia’s newly installed communist regime barred his repatriation due to the ambiguous circumstances of his wartime residency in England. Today treatment of ITP is directed toward controlling autoimmune reaction against platelet antigens. Splenectomy is done only after nonsurgical options have been exhausted. The operation and its history are a fading coda to the story of a medical prodigy whose career was crushed by prejudice and world events.
The “Grave” of Platelets
Erich Frank (1884-1957), then at the medicine clinic at the University of Breslau, published in 1915 his observations on 3 children who, unknown at the time, likely had immune thrombocytopenic purpura (ITP), an autoimmune destruction of platelets in the spleen. All were aged 12 years at presentation, developing widespread purpura and spontaneous bleeding from the gums, nasal mucosa, gastrointestinal tract, and in the girl menorrhagia. The children otherwise had no other illnesses that could explain their bleeding. 1
Blood smears from the patients were nearly devoid of platelets. Frank called it “essential thrombocytopenia” because he could find no other cause. 1 The only reason he could fathom was that the spleen somehow had an inhibitory effect on the formation of blood cells, including platelets. 2
Just 1 year later a precocious 26-year-old medical student solved not only the pathogenesis of Frank’s disease but its cure. Paul Kaznelson (1892-1959), assigned to the internal medicine clinic at German University in Prague, saw a 36-year-old woman with a nosebleed that refused to stop. It was the most recent occurrence of many she had suffered since her childhood. Her skin was covered with ecchymoses, some as large as dinnerplates, interspersed with innumerable petechiae. Since menarche at age 15 she had menorrhagia, 1 of which required adrenaline-soaked tampons to control. In young adulthood she had a remission from the worst of the bleeding episodes, but heavy menses and nosebleeds continued to plague her. 3
In an era before sophisticated laboratory and imaging tests, Kaznelson turned first to his physical examination. Her heart rate was 100 but the radial arterial pulse was “exceptionally delicate and barely palpable.” The carotid pulse was “also small.” Her blood pressure as 115/50 using the new Riva-Rocci device (1896) and auscultation of the pulse described by Nicholai Korotkoff (1905).4,5
Kaznelson searched for any other ailment that might cause abnormal bleeding. Her lungs were clear, making extrapulmonary tuberculosis less likely. 6 Pressing the sternum and tibias did not elicit pain, an indication that abnormal white cells did not distend her marrow. 7 He looked for signs of leukemia on her blood smear. Both her red and blood cells were normal.
Instead, her platelets were completely absent.
The only notable physical sign was splenomegaly, a finding not noted in Frank’s patients. The spleen protruded 3 fingerbreadths below the left costal margin. By chance 2 years previously the clinic had another patient with thrombocytopenia and an enlarged spleen.
The spleen unlocked the mystery of both how the platelets disappeared and a possible cure. From the literature Kaznelson knew that the spleen was where red cells and leukocytes were removed from the bloodstream. The organ, he thought, might also be eliminating platelets.
Whatever destructive processes that were going on in the spleen, a normal marrow continued to make blood cells. Animal experiments proved that platelets were formed even after splenectomy. Another clinic patient with hemolytic anemia yielded another clue: a stray megakaryocyte appeared on the peripheral blood smear, proving that the marrow was still capable of making fresh platelets independent of any destruction of cells in the periphery. 3
Kaznelson concluded that the spleen was the site of the platelet destruction. “The spleen is not the site of platelet formation,” he wrote, “but rather their grave.” (Die Milz ist nicht die Bildungsstätte der Biutplättchen, sondern ihr Grab”). 3
“The Success Exceeded the Wildest Expectations”
Renaming the malady “splenic thrombolytic purpura” appropriate to his understanding of the pathogenesis, Kaznelson proposed “a new therapeutic approach to improving the unbearable condition in which our patient had been for 10 years arose: splenectomy.” ( … eines neuen therapeutischen Weges zur Besserung des unerträglichen Zuständes, in dem sich unsere Patientin seit zehn Jahren befand: die Milzexstirpation). 3
Now he needed to convince a surgeon to do the procedure. Secure his reasoning was sound the student convinced Hermann Schloffer, professor of surgery at the German University in Prague, to remove the patient’s spleen. Schloffer was nothing less than bold. His signal achievement in surgery was the first transsphenoidal resection of a pituitary tumor in 1907 when he was director of surgery in Innsbruck. (His biosketch in the neurosurgical literature makes no mention of the splenectomy on Kaznelson’s patient). 8
At the time Kaznelson downplayed the risk of removing the spleen, noting both animals and humans survived after its removal. The spleen has since been recognized for its role in immune homeostasis and protection against infection in human patients, beginning in 1952 when Harold King and Harris Schumaker of Indianapolis described overwhelming post-splenectomy infections in 5 patients who underwent splenectomy in infancy. 9
At surgery the straps that secured the patient’s arms to the operating table left bloody welts. Schloffer was undeterred by the bleeding from his incisions and the raw surfaces he dissected. The operation proceeded without complications.
“The success was surprising and exceeded the wildest expectations,” Kaznelson wrote of the operation. (Der Erfolg war überraschend und übertraf die kühnsten Erwartungen). 3 On the second day after surgery, the student used a lancet for a droplet of blood for a cell count and smear, a simple bloodletting that once took days to stop.
This time the bleeding ceased almost immediately. The platelet count, which at most had only been 300 per cubic millimeter, now exceeded 500 000. Oozing from her gums ceased, and in 2 weeks, the unsightly bruises that covered her body began to fade. “The patient,” Kaznelson wrote in triumph, “presents the picture of complete recovery. 3 ”
“Like a Mother Who Follows Her Child”
ITP and Splenectomy
The name of the disease changed as its pathogenesis became clearer. From Frank’s original term, essential thrombocytopenia, and Kaznelson’s new name, splenogenic thrombolytic purpura, it acauired a new name, idiopathic thrombocytopenic purpura, abbreviated ITP.
The suspicion that platelet destruction in the spleen was triggered by autoantibodies to platelets was confirmed by William Harrington of St. Louis in 1950. In a harrowing self-experiment, he infused blood from a patient with ITP into his own bloodstream. The patient’s serum precipitated a profound thrombocytopenia to near zero within hours. He suffered a major seizure during the crisis. For the 4 days his platelet count remained dangerously low. The number began to recover, ultimately returning to normal values.10,11
From then the disease was called immune thrombocytopenic purpura, conveniently preserving the acronym. 3 With the delineation of the immune responses in ITP, patients today first undergo non-surgical interventions, such as corticosteroids, intravenous immunoglobulin, and more recently, polyclonal anti-RhD and thrombopoietin receptor agonists. 12 Given the long-term immune and infectious risks from splenectomy, surgery is done once after all else has failed. 10
Erich Frank
Like Kaznelson Frank showed a gift for medical scholarship from the first years of his training. As a resident in 1912, before his 1915 publication on thrombocytopenia, he had published a case report of a man who developed diabetes insipidus after a bullet lodged in the sella from a self-inflicted gunshot to the temple. 13 The paper was the first clinical evidence of the role of the hypothalamus and posterior pituitary in water and sodium homeostasis.
His career flourished with his appointment as assistant professor in Strasbourg in 1913, then as professor of medicine in Breslau in 1919. He was appointed head of internal medicine at the Wenzel-Hancke Municipal Hospital in 1926 at the young age of 42. There he and his associates developed the first effective oral antidiabetic drug, one that was not widely used because of undesired toxic effects. 14
Identified by Nazi authorities as Jewish through his mother, he was fired from the university and hospital as part of the purge of Jews that followed the boycott of April 1, 1933. He was among the hundreds of prominent professors, teachers, physicians, scientists that fled Naziism under Hitler and found refuge in Turkey under Kemal Ataturk’s regime. 15 There he used the academic model of clinical care and research to modernize the department of medicine at Istanbul University and one of its teaching hospitals, the Vakif Gureba Hospital. At war’s end he had many offers of positions in medical schools in the US and Germany. Frank chose to remain in his adopted country. 14
Paul Kaznelson
Details on Kaznelson’s personal life are scant. Yataro Yoshida, a hematologist in Kyoto, wrote a brief biography of Kaznelson and his contributions to the field. After medical school, he remained at the German University where he continued his work in hematology, including the first description of a patient with pure red cell aplasia (1922) and studies on iron deficiency anemia (1929). 16
Unlike Frank, Kaznelson’s professional advancement was slow. He joined the faculty in 1926 when he was 34 and was locked in a junior position until he reached privatdozent in 1937 at 45, a level in the German system roughly equivalent to associate professor in the US. 17
His promotion was impeded because he was a Jew in an overtly antisemitic institution. In the 1930s the medical faculty of the German University in Prague was an early center of Nazi support in Czechoslovakia, with many physicians of German extraction declaring their support for National Socialism. Among the professors that supported Nazi racial and political goals was Schloffer, the chief of surgery who did the splenectomy for Kaznelson’s original patient with ITP. 18
The suicide of the Jewish physician Josef Gach revealed the depth of the antisemitism in the German University. The work climate in Schloffer’s surgical clinic was so toxic that it drove Gach to kill himself. “Schloffer and Wenzel have driven me to death,” Gach wrote in the note he left behind, referring also to one of Schloffer’s followers. 18 Gach’s death prompted a mild uproar in the popular press that prompted a response by the official journal of the German Medical Association in Czechoslovakia. It denied any wrongdoing by the German physicians and suggested that Gach had suffered from “certain genetic disorders” and “a long-standing brain disease. 18 ”
In contrast to the support the Nazis enjoyed among the university faculty, the Czech government recognized Hitler as a direct threat to its sovereignty. Germany still took over Czechoslovakia, beginning with the success of the Sudeten German Party in the parliamentary elections in 1935 and ending with the acceptance of the Czech government to the terms of the Munich Agreement in September 1938. In March 1939 Hitler proclaimed the Czech nation a protectorate under the German Reich. In June the “final solution to the Jewish question” of the Nuremberg laws were applied to Jews in Czechoslovakia. 19
Life for Kaznelson became intolerable. In 1939 he fled to Switzerland, then France. He arrived in Liverpool in 1940 and practiced in several British facilities. He returned to Prague after the war and set up practice north of the Czech Republic. The communist regime that now controlled the country did not recognize his passport, presumably because of his education and employment at the Nazi-sympathizing German University and his taking refuge in the West during the war, ignoring the fact that he had fled the country because of antisemitic persecution. 16
Frustrated in his attempts at repatriation in 1950 he sought residency in the United Kingdom. His application was rejected, but he was allowed to reside and work in the country. His wife, who he married after the war, decided to stay in Czechoslovakia where she owned land. His biographer Yoshida speculates the reasons for the disapproval were his Russian heritage, his frequent travel to visit his wife in a communist country, and the Cold War tension between the West and the Soviet bloc. 16
He died in 1959 in Germany. Kaznelson’s enthusiasm and brilliance as a medical student faded under decades of ostracism and antisemitism. Persecution and threats to his life forced him into exile to a country that refused to fully accept him and to where his wife refused to move. His death was a forlorn ending to a career that held such promise when it began.
Unable to practice in an academic center like when he was a young man, he remained current with the literature, especially hematology. In 1942 when he was in exile in England, he wrote a letter to the editor of the British Medical Journal responding to an article on splenectomy for ITP, which he called haemorrhagica purpura. “I believe I have had the longest experience with the operation,” he wrote in understatement, “and like a mother naturally follows the ways of her child, I watched its development especially closely since my first cases in Prague. 20 ”
Footnotes
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.