Werlhof's disease: what it is and how it manifests itself

Werlhof's disease, now known as immune thrombocytopenia, is an autoimmune disorder in which the immune system destroys platelets and simultaneously disrupts their production in the bone marrow. The primary clinical symptom is isolated thrombocytopenia below 100×10^9/L without other causes, which increases the risk of bleeding, primarily mucocutaneous. In severe cases, life-threatening bleeding is possible, including intracranial bleeding, requiring emergency treatment. [1]

The historical term "idiopathic thrombocytopenic purpura" has been replaced by "immune thrombocytopenia": the cause is most often immune, and purpura is not always present. In 2009, an international working group standardized definitions and stages: "newly diagnosed" up to 3 months, "persistent" 3-12 months, and "chronic" over 12 months. These criteria have become the basis for current guidelines. [2]

The diagnosis remains one of exclusion: it is confirmed by typical clinical and laboratory findings after ruling out other causes of thrombocytopenia—medicinal, infectious, oncohematological, obstetric, and others. It is important to check for pseudothrombocytopenia, when the counter "loses" platelets due to agglutination in a test tube containing ethylenediaminetetraacetic acid. This is a rare laboratory pitfall, but without excluding it, it is easy to misdiagnose. [3]

Treatment has become more personalized in recent years. First-line therapy is a short course of glucocorticoids (prednisolone or dexamethasone) with a targeted short duration; in life-threatening cases, a combination of intravenous immunoglobulin, high-dose steroids, and platelet transfusions is used. Second-line therapy in adults includes thrombopoietin receptor agonists (romiplostim, eltrombopag, avatrombopag), rituximab, and delayed splenectomy; a new class of drugs, Bruton's tyrosine kinase inhibitor (rilzuratinib), will be registered in the United States in 2025. [4]

Code according to ICD-10 and ICD-11

In the International Classification of Diseases, Tenth Revision, immune thrombocytopenia is coded as D69.3 "Immune thrombocytopenic purpura." Calculation versions (e.g., ICD-10-CM) provide clarifications, but the basic code remains D69.3. This is important for patient routing and statistics. [5]

In the International Classification of Diseases, Eleventh Revision, the disease is classified under the "Thrombocytopenia" section: 3B64.10 "Immune thrombocytopenic purpura." ICD-11 allows for post-coordination—expanding criteria for cause and severity are added, which helps to more accurately capture the clinical picture. [6]

Table 1. Coding of immune thrombocytopenia

Classifier	Main code	Notes
ICD-10	D69.3	Immune thrombocytopenic purpura
ICD-11	3B64.10	"Immune thrombocytopenic purpura" in section 3B64.1 "Acquired thrombocytopenias"
Sources: Official Code Browsers. [7]

Epidemiology

Immune thrombocytopenia in adults is a rare disease with an annual incidence of approximately 2-10 cases per 100,000 people and a prevalence of 9-20 cases per 100,000. The incidence increases with age, with a peak at 50-70 years of age. In adults, the disease is often chronic. [8]

In children, the annual incidence ranges from 1.6 to 6.4 per 100,000, with some series reporting rates as high as 8-10 per 100,000; most childhood cases are acute and resolve spontaneously within months. The peak incidence in children is 2-5 years; in adolescents, manifestations are less common, but often develop into a persistent form. [9]

Gender differences vary by age: young boys are slightly more likely to be affected, while women are more likely to be affected in adults. Registry estimates vary between countries due to methodology (outpatient cases are often underreported), so the ranges are wide. [10]

The economic and clinical burden is associated not only with bleeding but also with prolonged steroid use and multiple lines of therapy. Modern strategies (early thrombopoietin receptor agonists, targeted therapy) improve disease control and quality of life. [11]

Table 2. Epidemiological landmarks

Indicator	Meaning
Incidence in adults	2-10 per 100,000 per year
Prevalence in adults	9-20 per 100,000
Morbidity in children	1.6-10 per 100,000 per year
Age peaks	Children 2-5 years old; adults 50-70 years old
Chronicity in adults	Prevails
Sources: reviews and registry data. [12]

Reasons

Primary immune thrombocytopenia is an autoimmune condition with no identifiable external cause; the key is the formation of antibodies to platelet glycoproteins. The secondary form develops against the background of other conditions: systemic lupus erythematosus, chronic infections (including human immunodeficiency virus and hepatitis C virus), lymphoproliferative diseases, and medication use. This distinction is critical for management. [13]

In some patients, a link to Helicobacter pylori infection has been identified: eradication can increase platelet levels, especially in regions with a high prevalence of infection. This approach is considered a "find and treat" approach when there are no other causes of thrombocytopenia. [14]

Drug-induced immune thrombocytopenia can mimic Werlhof's disease. Classic triggers include quinidine, sulfonamides, some antibiotics, and biologics; discontinuation of the offending drug is key. In questionable cases, the chronology and dynamics after discontinuation are used as a guide. [15]

Nutritional deficiencies (vitamin B12 and folate deficiency) do not in themselves trigger the immune mechanism, but they exacerbate the decrease in platelet production and must be corrected in parallel. This is especially important in cancer patients and in cases of malabsorption. [16]

Risk factors

No reliable modifiable risk factors for primary immune thrombocytopenia have been identified: the disease remains rare and has multiple etiologies. The risk increases with age, and women of reproductive age and older are more commonly affected. In children, the disease most often occurs after viral infections. [17]

Risk factors for an unfavorable outcome include the combination of severe thrombocytopenia with clinically significant bleeding, steroid dependence, the ineffectiveness of multiple lines of therapy, and comorbidities (hypertension, peptic ulcer, antiplatelet therapy). These parameters are taken into account when choosing a second-line treatment. [18]

During pregnancy, gestational age and neuraxial anesthesia planning are important factors: target platelet levels are increased at the time of delivery to reduce obstetric risks. A collaborative approach between the obstetrician, hematologist, and anesthesiologist is essential. [19]

Helicobacter pylori infection is a potential modifiable factor in some patients: if infection is confirmed and there are no other causes, eradication with outcome monitoring is recommended, because in a significant proportion of patients this leads to an increase in platelets. [20]

Pathogenesis

The classic mechanism is the production of antibodies to platelets (most often to glycoproteins IIb/IIIa and Ib/IX/V), followed by their opsonization and subsequent destruction by macrophages via Fc-γ receptors, primarily in the spleen. Concurrently, antibodies and cellular mechanisms suppress megakaryocytes and thrombopoiesis, which reduces production. The result is both accelerated destruction and insufficient production. [21]

Immune imbalance involves changes in the T-cell system (including regulatory T cells and CD8+ cells), complement activation, and cytokine profile changes. These mechanisms explain the effectiveness of targeted immunotherapy, such as Bruton's tyrosine kinase inhibitors, which reduce antibody production and macrophage phagocytosis. [22]

The modern concept emphasizes the dual nature of "increased destruction + decreased production." This leads to two strategic treatment approaches: suppression of the autoimmune process and stimulation of thrombopoietin receptor agonists. Individualized combinations of these approaches allow for reduced steroid dosages and avoidance of early splenectomy. [23]

Not all patients have detectable platelet antibodies using standard methods (up to 40% may be "seronegative"), reflecting the limited sensitivity of tests and the multicomponent immune mechanism. In such cases, the diagnosis remains clinical, "by exclusion." [24]

Symptoms

The most common manifestations are petechiae, bruises, bleeding gums, nosebleeds, and, in women, heavy menstrual bleeding. With very low platelet levels, bleeding from the gastrointestinal and urinary tracts is possible. The severity of symptoms does not always strictly correlate with the platelet count, but the risk increases at levels below 20-30×10^9/L. [25]

General well-being may worsen due to anemia associated with chronic blood loss and the side effects of long-term steroid therapy. Fever is absent in uncomplicated immune thrombocytopenia; its occurrence requires a search for another cause. Examination excludes hepatosplenomegaly and lymphadenopathy, as their presence suggests another pathology. [26]

In children, the disease often begins acutely following an infection, with bleeding typically mild and self-limiting. In adults, the onset is gradual and the course more protracted, with relapses occurring when attempts are made to discontinue therapy. This determines the differences in approaches between pediatricians and adult physicians. [27]

Rare, but most dangerous, events include intracranial hemorrhage and massive gastrointestinal bleeding. If signs of threatening bleeding are present, emergency care protocols are implemented: a combination of intravenous immunoglobulin, pulse steroids, platelet transfusions, and supportive measures. [28]

Classification, forms and stages

Based on their origin, immune thrombocytopenia is classified as primary (idiopathic) and secondary. Secondary thrombocytopenia is associated with infections (human immunodeficiency virus, hepatitis C virus), systemic autoimmune diseases, lymphoproliferations, and medications. This is important because treatment of secondary forms depends on correcting the underlying process. [29]

By duration of disease progression (IWG, 2009): "newly diagnosed" - up to 3 months, "persistent" - 3-12 months, "chronic" - more than 12 months. The term "refractory" is also used when the disease is ineffective after splenectomy or multiple lines of therapy. This staging helps plan the second line of treatment. [30]

In adults, clinical decisions are often based on the presence/absence of bleeding, platelet count, and quality of life. In children, in the absence of significant bleeding, observation is preferred: most cases resolve without aggressive therapy, as reflected in the recommendations. [31]

Table 3. Working classification

Base	Categories	Practical significance
Etiology	Primary, secondary	Finding and treating the cause
Duration	Newly diagnosed, persistent, chronic	Selecting the second line
Clinic	Without bleeding / with bleeding	Duration and intensity of therapy
Sources: IWG and ASH guidelines. [32]

Complications and consequences

The main threat is bleeding, ranging from mild to life-threatening. The risk increases with platelet levels below 20-30×10^9/L and with associated factors (anticoagulants, peptic ulcer, uncontrolled hypertension). Early recognition and targeted prevention reduce the severity of complications. [33]

Long-term steroid therapy is associated with metabolic and psychiatric side effects, so current guidelines advocate short courses (up to 6 weeks in adults) with early transition to other classes. This reduces complications without sacrificing effective bleeding control. [34]

Thrombopoietin agonists improve bleeding control but are associated with a small increased risk of thrombosis, particularly in patients with risk factors; therefore, a strategy of "minimally sufficient" target platelet levels (often 30-50×10^9/L for daily use) remains reasonable. Maintenance therapy should be personalized. [35]

Pregnancy complicates management: by the time of delivery, the target platelet level is increased to 50×10^9/L and above (to reduce the risk of postpartum hemorrhage), while for neuraxial anesthesia, most experts aim for 70×10^9/L and above. The decision is made interdisciplinary. [36]

When to see a doctor

Immediately - if there are signs of massive bleeding: black stool, vomit that looks like coffee grounds, sudden severe headache, neurological symptoms, blood in the urine, prolonged nosebleeds that do not stop with normal methods. These are reasons for emergency care. [37]

Urgently - if multiple petechiae and bruises appear "out of nowhere," or if bleeding gums occur, especially if the platelet count is low, or if invasive procedures or surgeries are planned. In these cases, rapid blood testing and therapy adjustments are necessary. [38]

Scheduled - for recurring minor bleeding, fatigue associated with possible anemia, and at the start or discontinuation of steroids to monitor side effects. Regular visits and quality-of-life monitoring are part of standard care. [39]

Pregnant women - discuss delivery plan, target platelet levels, and the possibility of neuraxial anesthesia in advance; treatment is initiated when clinically significant bleeding occurs or when platelets are below 30×10^9/L in the first half of pregnancy. [40]

Diagnostics

Step 1. Confirm thrombocytopenia and exclude laboratory artifact: complete blood count with manual smear verification and, if pseudothrombocytopenia is suspected, repeat analysis in a citrate/heparin tube. Detection of platelet aggregates in the ethylenediaminetetraacetic acid test confirms the artifact. [41]

Step 2. Assess the clinical picture and identify any red flags: lymphadenopathy, splenomegaly, significant cytopenias of other lineages, and systemic symptoms require an expanded search for an alternative diagnosis (oncohematology, bone marrow failure). In typical cases in adults and children, routine bone marrow biopsy is not indicated. [42]

Step 3. Minimum laboratory tests to exclude secondary causes: tests for human immunodeficiency virus and hepatitis C virus; if indicated, testing for Helicobacter pylori (especially in regions with high prevalence) with subsequent eradication if detected. Vitamin B12 and folates are also assessed. [43]

Step 4. Assess the severity and need for immediate therapy: presence of bleeding, upcoming procedures, platelet count. If bleeding is imminent, therapy is initiated immediately, without waiting for a full diagnostic "set." Further stratification determines the choice of second-line treatment in the following weeks and months. [44]

Table 4. Diagnostic matrix for suspected immune thrombocytopenia

Question	What to do	What does this give?
Is there a lab error?	Repeated general analysis in citrate sample, smear	Exclusion of pseudothrombocytopenia
Are there any red flags?	Examination, differential blood, reticulocytes	Bone marrow/advanced search decision
Secondary causes?	Human immunodeficiency virus, hepatitis C virus, Helicobacter pylori	Etiological correction
Is emergency treatment needed?	Bleeding Clinic + Platelet Level	Immediate start of treatment
Sources: IWG/ASH and contemporary reviews. [45]

Differential diagnosis

Thrombotic thrombocytopenic purpura and disseminated intravascular coagulation: in these cases, thrombocytopenia is combined with hemolysis, organ dysfunction, and altered coagulograms. These are emergency conditions and require completely different protocols (plasma exchange, correction of coagulopathy). [46]

For drug-induced immune thrombocytopenia: a strong temporal relationship with drug initiation and rapid recovery after discontinuation; a chronological causal assessment tool is useful. Examples include quinidine, some antibiotics, and biologics. [47]

Bone marrow invasions and aplasia: these are usually accompanied by anemia and/or neutropenia, and atypical cells are present in the smear; a trephine biopsy is indicated. The presence of hepatosplenomegaly and lymphadenopathy shifts the diagnosis from immune thrombocytopenia to lymphoproliferations. [48]

For obstetric thrombocytopenia (gestational thrombocytopenia, preeclampsia/HELLP): the pregnancy period, associated symptoms, and laboratory indicators of hemolysis are taken into account. In doubtful cases, the decision is made in consultation with the obstetricians. [49]

Treatment

The first-line treatment for adults with newly diagnosed disease is a short course of glucocorticoids: prednisolone 0.5-2.0 mg/kg/day for up to 6 weeks followed by tapering, or dexamethasone 40 mg/day for 4 days (often 1-4 pulses). Recommendations emphasize avoiding "long" courses longer than 6 weeks due to side effects, with comparable efficacy of short regimens. The choice between prednisolone and dexamethasone depends on the desired response rate and the patient profile. [50]

In cases of life-threatening bleeding, treatment begins immediately with combination therapy: intravenous immunoglobulin 1 g/kg for 1-2 days, pulse dexamethasone, and platelet transfusions, plus hemostasis support (tranexamic acid, local measures). This strategy allows for a rapid increase in platelet levels and gains time for basic therapy. After stabilization, second-line therapy is initiated if necessary. [51]

In the second line, three equally valid approaches are considered in adults with persistent/chronic steroid-dependent disease: thrombopoietin receptor agonists (romiplostim, eltrombopag, avatrombopag), rituximab, and splenectomy. The choice is individualized based on the patient's preferences: avoid surgery, avoid long-term medications, or achieve the most durable remission. Splenectomy, if possible, is delayed for 12 months after onset due to the chance of spontaneous remission. [52]

Thrombopoietin receptor agonists stimulate platelet production and exhibit a high efficacy profile with good tolerability. Romiplostim is administered subcutaneously weekly, while eltrombopag and avatrombopag are administered orally. During therapy, liver function tests (for eltrombopag) are monitored, the risk of thrombosis is assessed, and a "sufficient" level (usually 30-50×10^9/L) is achieved without striving for normalization. [53]

Rituximab (anti-CD20) reduces antibody production and can lead to long-term remissions, especially in patients wishing to avoid surgery or long-term drug therapy. The decision is balanced against the risk of infections and hypogammaglobulinemia; vaccination and prophylaxis are part of the plan. Rituximab is particularly useful in secondary autoimmune phenotypes. [54]

Fostamatinib, an oral Syk kinase inhibitor, is an option for adults with an inadequate response to previous lines of therapy; it reduces the phagocytosis of opsonized platelets. It is useful in cases of intolerance to or contraindications to thrombopoietin receptor agonists/rituximab. Side effects include diarrhea and increased blood pressure; monitoring is necessary. [55]

A new class of drugs are Bruton's tyrosine kinase inhibitors. In August 2025, the US Food and Drug Administration approved rilzuratinib (Wayrilz) for adults with persistent/chronic immune thrombocytopenia after an inadequate response to previous therapies. The mechanism is blockade of B-cell signaling and reduction of macrophage platelet uptake; this expands steroid-free and non-surgical strategies. [56]

Pregnancy: If the platelet count is 30×10^9/L or higher and there is no bleeding in the second trimester, observation is often sufficient. If treatment is necessary, prednisolone/prednisolone-like agents or intravenous immunoglobulin are used as first-line therapy; at delivery, the target is ≥50×10^9/L, and for neuraxial anesthesia, many experts use a threshold of ≥70×10^9/L. The choice is repeated dynamically. [57]

Helicobacter pylori eradication is recommended when infection is detected and no other causes are present: in some patients, it increases platelet counts and reduces the intensity of immunosuppression. Confirmation of eradication is mandatory, and regimens are selected based on local antibiotic resistance (e.g., bismuth-containing quadruple regimens). [58]

Treatment discontinuation tactics and "minimally sufficient" goals: the focus should be on the clinical picture and risks, not the "number at any cost"; most patients will benefit from a daily dose of 30-50×10^9/L without bleeding. This reduces the drug burden and complications. In some patients with sustained remission on thrombopoietin receptor agonists, a trial of discontinuation with observation is possible, as discussed in recent reviews. [59]

Table 5. Key second-line options in adults

Situation	Preferred approach	Alternatives
Steroid dependent, no bleeding	Thrombopoietin receptor agonist	Rituximab; delayed splenectomy
Reluctance to long-term drug therapy	Splenectomy (after ≥12 months)	Rituximab
Multi-line pretreatment, comorbidities	Fostamatinib/rilzuratinib	Another thrombopoietin receptor agonist
Pregnancy	Prednisolone/intravenous immunoglobulin	Individually, together with the obstetrician
Sources: ASH guidelines/regulatory reviews and news. [60]

Prevention

There is no specific primary prevention for primary immune thrombocytopenia. Prevention of complications relies on patient education: recognizing warning signs of bleeding, avoiding nonsteroidal anti-inflammatory drugs and antiplatelet agents unless indicated, and coordinating invasive procedures with the healthcare team. [61]

In secondary forms, prevention and treatment of the underlying cause are important—for example, eradication of Helicobacter pylori when infection is confirmed. Vaccination prior to immunosuppressive therapy reduces the risk of infection; after splenectomy, vaccinations against pneumococcus, meningococcus, and Haemophilus influenzae are mandatory. [62]

Steroid reduction is a separate "complication prevention" strategy: short courses and early transition to steroid-sparing strategies are consistent with current recommendations and reduce metabolic risks. The monitoring plan includes quality-of-life assessment and monitoring of side effects. [63]

Table 6. Mini-reminder for the patient

Situation	What to do
Multiple petechiae/bleeding appeared	Contact a doctor and get a blood test.
Dentistry/surgery planned	Discuss target platelet levels and preparation
New drugs	Check safety with a hematologist
Pregnancy/planning	Early joint plan with an obstetrician and hematologist
Based on ASH/international consensus recommendations. [64]

Forecast

Most adults achieve bleeding control and a satisfactory quality of life with short courses of steroids and timely second-line therapy. A significant proportion of patients treated with thrombopoietin receptor agonists achieve long-term remission; the choice of strategy is personalized. [65]

In children, the prognosis is generally favorable: most cases are acute and self-limiting. When the disease becomes chronic, the availability of thrombopoietin receptor agonists and well-designed regimens allows for outpatient care with minimal restrictions. [66]

The emergence of new classes, such as Bruton's tyrosine kinase inhibitors, expands treatment options for refractory forms and allows for a reduction in steroid load. Expert algorithms are increasingly based on the patient's goals and risk profile, rather than universal "rigid" corridors. [67]

With proper routing and patient education, threatening bleeding is rare. The key is knowing when to escalate therapy and not overusing glucocorticoids. [68]

FAQ

Is it always "life-threatening"? No. Most patients live full lives; it's not the "number" that's being treated, but the risk of bleeding. Maintaining platelet counts at 30-50×10^9/L without symptoms is often sufficient. [69]

Are steroids always necessary? For adults, initially, yes, but only for a short course of up to 6 weeks. In children, in the absence of significant bleeding, observation is often sufficient. Then, they switch to steroid-sparing regimens. [70]

What to do if severe bleeding occurs? Seek emergency care immediately. Inpatient treatment includes intravenous immunoglobulin, high-dose steroids, platelet transfusions, and supportive measures. [71]

Does it make sense to search for Helicobacter pylori? Yes, especially in regions with high prevalence. Eradication in some patients increases platelet levels and reduces the need for immunosuppression. [72]

What new drugs have emerged? In the US, rilzuratinib, an oral Bruton's tyrosine kinase inhibitor, was approved in 2025 for adults after previous treatments failed. It complements the arsenal of thrombopoietin receptor agonists, rituximab, fostamatinib, and delayed splenectomy. [73]

Additional tables

Table 7. Platelet threshold levels for practical decisions (guidelines)

Situation	Target/threshold (landmark)
Everyday life without bleeding	≥30-50×10^9/l
Elective invasive procedure	Individually; more often ≥50×10^9/l
Childbirth (reducing the risk of postpartum hemorrhage)	≥50×10^9/l
Neuraxial anesthesia during childbirth	≥70×10^9/L (expert consensus)
Sources: international reviews and obstetric guidelines. [74]