Werlhof's Disease

WERLHOF'S DISEASE (Werlhof), "essential thrombocytopenia," purpura haemorrhagica, is named after the German author who first described it at the end of the 1730s. It was studied in more detail by Hayem (late 19th century, France), who emphasized the role of one of the main symptoms of the disease—a sharp decrease in the number of thrombocytes (Bizzozero's platelets) in the blood, or their absence (thrombocytopenia); he also pointed out the absence of blood clot retraction in Werlhof's disease. In more recent times, the clinical picture and pathogenesis of Werlhof's disease were developed by Duke in America, Frank in Germany, and others. The main symptom of the disease is bleeding, predominantly from the mucous membranes; equally characteristic are spontaneous hemorrhages in the skin, or those appearing under the influence of light trauma, ranging in size from a pinhead (petechiae) to the palm of the hand and larger. Among the mucous membranes, the nasal and gum mucosa rank first in terms of bleeding frequency, followed by the uterus, gastrointestinal tract, conjunctiva, and urinary bladder. In the vast majority of cases, two or more mucous membranes bleed, but in terms of intensity, bleeding from one may sharply prevail. Bleeding of other organs is also occasionally observed (kidney, ear, fundus of the eye, bloody tears). Bleeding in Werlhof's disease is mainly spontaneous (from mucous membranes); on the skin, bruises occur both spontaneously and upon trauma. Accidental cuts sometimes bleed longer than usual. Various surgical interventions (including splenectomy) usually proceed with normal blood loss, sometimes more profuse, but cases with a fatal outcome have not been described. Conversely, profuse bleeding is sometimes observed during tooth extractions. Hemorrhages into the joints are almost never observed; bruises on the palms and face are also relatively rare. The temperature in most chronic cases is normal, only occasionally showing slight elevations; during an acute paroxysm, it is usually elevated. No changes are usually observed in the internal organs (including the bleeding mucous membranes). The spleen is sometimes slightly enlarged. Skin itching and urticaria are sometimes noted. Paradoxically, menstruation in patients with Werlhof's disease often begins later than the normal time (at 15–18 years), but never earlier; however, once appeared, it is very profuse and often extremely irregular. During menstruation, all phenomena of hemorrhagic diathesis (bruises, etc.) often worsen; during menopause, uterine bleeding is very rare; upon the onset of pregnancy, bleeding in chronic cases of Werlhof's disease usually disappears; childbirth and abortion sometimes result in normal bleeding, sometimes more profuse. From these data, it follows that the ovarian hormone apparently has a stimulating effect on the manifestation of hemorrhagic diathesis. Regarding the red blood, only phenomena of secondary anemia are noted; leukocytes are normal. A characteristic symptom is a sharp decrease (down to 30,000 and below) in the number of thrombocytes. Thrombocytopenia is also accompanied by qualitative changes in the platelets (giant, tailed, pyknotic, and other forms). Equally characteristic is the absence of blood clot retraction (the absence of spontaneous separation of blood serum after its coagulation in a test tube). Blood coagulation time is usually normal; only occasionally is the onset of complete coagulation delayed. Bleeding time is usually prolonged (up to 1 hour and more). The Rumpel-Leede sign is sharply positive in the significant majority of cases. This entire hemorrhagic syndrome (thrombocytopenia, absence of blood clot retraction, prolonged bleeding time, positive Rumpel-Leede sign) is observed only during the period of bleeding, usually (but not always) disappearing outside of it.—A distinction is made between acute and chronic Werlhof's disease, with the latter subdivided into a continuous (continua) form, where bleeding (of varying intensity) is constantly observed in the patient (sometimes throughout life), and a recurrent (recurrens) form, in which the phenomena of hemorrhagic diathesis occur in attacks separated by long intervals of complete health (up to 20 years and more). Transitions from one form to another are often observed. There is, however, a range of data suggesting the necessity of separating most cases of the acute form from essential Werlhof's disease, classifying it, perhaps, as a secondary Werlhof symptom complex, which can be observed in almost all infectious diseases, as well as in leukemia, pernicious anemia, etc. Clinically (in terms of the bleeding pattern) and hematologically (thrombocytopenia, hemorrhagic syndrome), the secondary Werlhof symptom complex does not differ from essential Werlhof's disease, so that only consideration of all clinical and laboratory data allows for avoiding an incorrect diagnosis. In favor of the fact that most cases of the so-called acute form of Werlhof's disease should perhaps be separated from Werlhof's disease as a disease of a different etiology and pathogenesis, the following data speak: 1) in chronic Werlhof's disease, the ratio of male to female patients is approximately 1:3, while in acute cases it is 1:1 or more; 2) pregnancy is sometimes complicated by an acute Werlhof symptom complex (in rare cases, the disease is also transmitted to the fetus), whereas chronic Werlhof's disease never worsens during pregnancy, and bleeding even tends to decrease; 3) splenectomy gives a good therapeutic effect in most chronic cases of Werlhof's disease and no effect in the acute form; 4) the acute Werlhof symptom complex very much resembles an acute infectious disease in its course; and since any infectious disease (especially sepsis) can be complicated by an acute Werlhof symptom complex, this circumstance, together with all the above, gives reason to believe that the vast majority of cases of acute Werlhof's disease described in the literature are nothing more than unrecognized infections. On the other hand, during the course of chronic Werlhof's disease, exacerbations giving the picture of the acute form are sometimes observed, or the chronic form begins as if with an acute one. Levit and Malkova described a forme fruste of Werlhof's disease—these are predominantly women suffering from a mild form of bleeding (slight bleeding from mucous membranes, prolongation of menstruation, bruises). Blood examination usually reveals a normal number of thrombocytes. In favor of these cases belonging to Werlhof's disease are: 1) complete clinical similarity of the bleeding phenomena in both forms; the difference here is only in intensity; 2) transition of the disease from the forme fruste to classical Werlhof's disease and back; 3) presence of forme fruste phenomena in the intervals between attacks of the recurrent form of Werlhof's disease; 4) occasionally, even in patients with forme fruste of Werlhof's disease (who do not even complain of bleeding phenomena themselves), thrombocytopenia and a positive hemorrhagic syndrome are found; 5) often in the family of a patient suffering from classical Werlhof's disease, several members are found who exhibit phenomena of the forme fruste. The idea of recognizing the forme fruste as a mild form of Werlhof's disease also appears in older literature, where it is described as purpura simplex; however, the latter term is unsuitable because some authors also understand it to mean certain varieties of anaphylactoid purpura (see Purpura), which has nothing in common with Werlhof's disease. Recognition of the forme fruste of Werlhof's disease is of significant importance, as it 1) turns Werlhof's disease from a rare disease into a relatively frequent phenomenon, 2) speaks against the view of thrombocytopenia as a conditio sine qua non in the diagnosis of Werlhof's disease, and 3) expands the understanding of the significance of heredity in the etiology of Werlhof's disease. Until recently, the prevailing view was that Werlhof's disease was an exclusively acquired suffering. In recent years, however, a number of authors (Hess, Glanzmann, Krömeke, Levit) have described a relatively large number of cases where the factor of heredity definitely takes place. (Glanzmann, and after him Krömeke, describe their cases as "hemorrhagic thrombasthenia," wishing to emphasize the primary importance of thrombocytes in the pathogenesis of Werlhof's disease by the morphological changes in the platelets they noted—with their number being normal—and the alleged resulting absence of retraction.) The role of other etiological factors in Werlhof's disease has been studied even less; infection occasionally figures as a triggering factor, in a small number of cases—nervous shock (see also the aforementioned role of the ovarian hormone), and among occupational factors—benzene poisoning. However, the role of the latter, while indisputable regarding hemorrhagic aleukia, is not entirely proven regarding Werlhof's disease (at least its chronic form) (interesting in this regard is the study by Teleky and Weiner, who found phenomena of fairly clearly expressed anemia with a decrease in the number of thrombocytes in 11 female rubber factory workers, which passed after 8 weeks of rest). Among predisposing factors, in addition to the aforementioned role of sex, the significance of age should also be noted: the onset of the disease in a significant majority of all patients is noted before the age of 30.

The presence of familial occurrence in some cases, the negligible number of cases where an external agent could be assigned the role of an etiological factor, and the prolonged, chronic course of the suffering—all this gives the right to assume a genotypic (see Genotype) character of Werlhof's disease, at least in a portion of its cases. Regarding the pathogenesis of Werlhof's disease, according to E. Frank, thrombopenia in Werlhof's disease is the result of decreased production of platelets by the megakaryocytes of the bone marrow. The cause of the isolated suppression of this bone marrow function lies, according to Frank, in a pathological intensification of the inhibitory influence of the spleen on the megakaryocytes. Thrombopenia causes the main symptoms of the disease: bleeding and the absence of blood clot retraction. Kaznelson explains thrombopenia by an intensification of platelet destruction in the spleen. The effect of splenectomy in Werlhof's disease (see below), in any case, proves that some functional disturbance of the spleen is the immediate cause of this disease. At present, Frank's theory, insofar as it explains the entire symptomatology of the suffering by a decrease in platelets (hence the name "essential thrombopenia"), must be recognized as untenable. Arguments against it include: 1) the insignificance or prolonged absence of bleeding in some cases of Werlhof's disease where thrombopenia is sharply pronounced; 2) the absence of thrombopenia in forme fruste of Werlhof's disease, where bleeding nevertheless occurs; and 3) the presence of a clinical effect after splenectomy without a hematological one (in the sense of an increase in the number of platelets) and vice versa. These and other considerations have led many researchers to suggest that the primary cause of bleeding in Werlhof's disease lies in the insufficiency of the capillary endothelium. This is also supported by the results of studies by several authors who have clarified in recent years the important role of capillaries in stopping bleeding. It must be admitted, however, that we do not yet have direct evidence of vascular damage in Werlhof's disease. In general, it can be assumed that the same harmful agent causes damage to both the capillaries and the platelets, or their parent cells. The prognosis of chronic cases of Werlhof's disease quo ad vitam is generally good: death from bleeding is extremely rare; however, working capacity often suffers (anemia). In acute cases, a fatal outcome is somewhat more frequent. In differential diagnosis, it is necessary first of all (especially in acute cases) to exclude secondary Werlhof's syndrome (search for the underlying disease). The character of the rash (hemorrhages), thrombopenia, and the absence of joint pain distinguish Werlhof's disease from anaphylactoid purpura. Hemophilia is easily distinguished from Werlhof's disease by the fact that the former affects men, with very frequent hemorrhages into the joints; furthermore, blood clotting in hemophilia is sharply reduced, while the number of platelets is normal. Therapy for Werlhof's disease: Conservative therapy is completely powerless; prevention is unknown. In cases of threatening hemorrhage, blood transfusion is resorted to, which in most cases yields a good temporary effect. A great therapeutic success is the splenectomy proposed by Kaznelson in 1916. To date, about 100 operations have been described, with a favorable effect obtained in the vast majority of chronic cases (sometimes bordering on complete clinical recovery). The effect consists of both a rapid increase in the number of platelets and the cessation of bleeding phenomena, whereby thrombopenia often recurs while the clinical effect remains. Acute cases are contraindicated for surgery (almost always a fatal outcome). Indications for surgery: anemia due to chronic bleeding and attacks of life-threatening hemorrhage.

S. Levit. Werlhof's disease in children. The main symptoms of Werlhof's disease are hemorrhages into the skin and mucous membranes and bleeding from the latter. On the skin, along with petechiae, larger spots and bruises are noted, with an infiltrate in the depth of some of them. The elements are not elevated above the skin level, often erupt in groups, their coloring is diverse, and the entire skin has a very mottled appearance. As an exception, itching and swelling of the skin occur. The rash is localized without definite regularity, mostly on the legs (especially on their extensor surfaces); the palms, soles, and face are more often free of the rash. Slight traumas cause hemorrhages. Sooner or later, sometimes at the beginning of the disease and as the first symptom, hemorrhages into the mucous membranes and bleeding from them appear. Blood extravasations are most often noticeable on the mucous membranes of the mouth, less often on the conjunctiva, sclera, auditory canal, and in the area of the genitalia. Bleeding from the mucous membranes (of which the most frequent are from the nose and gums) can be very strong. Bloody stools are quite frequent, hematuria is rarer; hemoptysis is observed very rarely, uterine bleeding in girls under 13 years of age—almost never; there are descriptions of hemorrhages into the brain and spinal cord (Henoch, Mautner). Children of all ages fall ill with Werlhof's disease, but mainly after 5 years. There are a number of descriptions of Werlhof's disease in young children, even in newborns. Girls fall ill with Werlhof's disease significantly more often than boys. The disease sometimes arises acutely, in most cases gradually. Sometimes an enlargement of the spleen is observed. Other organs are without characteristic changes. The acute form is common for children, proceeding like an infectious disease, in waves and cycles, with one or several attacks of symptoms, and ending, on average, in 2–6 weeks. The prognosis of this form of Werlhof's disease is generally favorable, although cases with a severe course and significant bleeding ending fatally are not very rare. A chronic course is observed much less frequently in children. Caution is necessary in the prognosis of this form, as a series of successfully endured attacks does not guarantee against sudden profuse hemorrhage threatening the patient's life. Good results of splenectomy in children have been described (Kaznelson—operation on a 12-year-old girl).