ITP-Immune Thrombocytopenic Purpura

Etiology

Immune thrombocytopenic purpura can occur with infections (e.g., human immunodeficiency virus), malignancy (e.g., adenocarcinoma and lymphoma), and common variable immunodeficiency and autoimmune diseases (e.g., systemic lupus erythematosus, autoimmune hepatitis, and thyroid disease).[4] 

In these diseases, anti-platelet antibodies form, leading to platelet destruction. Drugs such as acetazolamide, aspirin, aminosalicylic acid, carbamazepine, cephalothin, digitoxin, phenytoin, meprobamate, methyldopa, quinidine, rifampin, and sulfamethazine may also cause autoimmune thrombocytopenia,  Autoantibody production against platelets is advocated as one etiology for ITP.[5] The modern theory also considers the possibility of a failure of the self-tolerance mechanism. 

Epidemiology

Immune thrombocytopenic purpura can be divided into two classifications: acute and chronic. The acute form presents in childhood, affects both sexes and may be prefaced by a viral infection. Most children (85%) have a benign course and do not require treatment. They can spontaneously recover within three months. The chronic form affects individuals between ages 20 to 50 years; there is a female/male ratio of 3 to 1, and It is usually not preceded by a viral infection. The female preponderance is thought to have some relationship to the increased prevalence of autoimmune disease in women.[3] It may present with bleeding episodes for months or years; during that time, the platelet counts are close to normal. Fewer than 10% of children develop chronic ITP.

Pathophysiology

The spleen is an important site of autoantibody production. Sequestration of anti-platelet IgG antibodies occurs in the spleen's red pulp, where sensitized platelet removal occurs by phagocytosis. Research showed that radiolabeled-IgG sensitized platelet removal occurs in a few hours compared with a normal platelet half-life of 8 to 9 days.[2]

In contrast to maternal ITP, gestational thrombocytopenia rarely brings the count below 70,000/dL, typically does not cause bleeding, and has its origins in a dilutional, not consumptive, mechanism.[3]

Neonatal alloimmune thrombocytopenia may occur in pregnant women who are negative for the platelet antigen PL a1 but were sensitized in prior pregnancies by infants who were PL a1 positive or by blood transfusion. The condition has also involved other platelet antigens.[6] Pregnant women with ITP have an increased incidence of fetal loss, a low fetal birth rate, and a higher incidence of premature births.[3]

In drug-induced ITP, the drug absorbs the platelet cell membrane. The immune system makes antibodies to the target drug-platelet complex, which results in the removal of the sensitized platelet by phagocytes residing in the spleen and liver. The activation of the complement system by the classical pathway is another effector mechanism of platelet cell damage (thrombocytopenia).[7] 

Childhood immune thrombocytopenic purpura often occurs within a few weeks following a viral infection, suggesting a possible cross-immunization between viral and platelet antigens, the absorption of immune complexes, or a hapten mechanism.

Many other platelet antigens are a target of autoantibodies, including GPIIb/IIIA and GP V (after chickenpox). However, their exact role in diagnostic testing is dubious at best.[3]

Histopathology

Histopathology of immune thrombocytopenic purpura can often reveal the increased production of megakaryocytes in the bone marrow.[8] This finding suggests that thrombocytopenia is secondary to increased platelet destruction rather than decreased platelet formation. Harrington and coworkers first showed in 1951 that the plasma from a patient with immune thrombocytopenic purpura caused thrombocytopenia when transfused into a healthy subject.

History and Physical

There may be a history of drug use, a viral infection, or immunization. Acute immune thrombocytopenic purpura can be characterized by generalized purpura in a previously healthy child or, less commonly in an adult, bruises following minor trauma, the presence of oral hemorrhagic bullae, epistaxis, gastrointestinal bleeding, conjunctival hemorrhage, and hematuria. More commonly, the illness is gradual in onset but chronic. Severe bleeding has been noted in as many as 9.5% of adults.[9]

Chronic immune thrombocytopenic purpura may be characterized by insidious onset or suddenly become acute. It is seen more commonly in females and presents with scattered petechiae, epistaxis, and menorrhagia, episodes of bleeding separated by an extended period. Occasionally, these clinical findings can be due to HIV-related illness.

Evaluation

The laboratory tests will show the following:

• Low platelet count, usually less than 40x10⁹/L for over three months.
• Blood film: It shows large platelets and tiny platelet fragments.
• Bone marrow examination: It shows an increased number of megakaryocytes.
• Platelet Coomb's test: Detects anti-platelet antibodies fixed on the patient's platelets. However, it should also be noted that antibody analysis focal to the platelet glycoproteins IIb/IIIa, Ib/IX, and Ia/IIa are of low sensitivity and seldom efficacious.[3]
• Indirect test: Uses a pool of normal donor platelets to detect free serum antibodies against platelets, usually anti-glycoprotein IIb/IIIa antibodies. 
• Various other tests can detect anti-platelet antibodies, including lymphocyte activation by autologous platelets, lymphocyte activation by platelet-antibody immune complexes, phagocytosis of platelet-associated IgG by competitive binding assays, radiolabeled Coombs antiglobulin test, fluorescein-labeled Coombs antiglobulin, and ELISA. 

Testing for systemic lupus erythematosus (presenting with ITP):

• Antinuclear antibodies (ANA) can be performed using indirect immunofluorescence. Most cases of SLE show positive ANA results. There is clinical data to suggest that ITP patients are at high risk of developing SLE [10]. It was noted in one study that 12.8% of patients with SLE were initially diagnosed with ITP. The search for one should press consideration of the other.   
• Testing for auto-antibodies: This includes testing for anti-double-stranded DNA (anti-dsDNA), anti-Smith, ENA, anti-cardiolipin, and anti-beta2 GP-I antibodies. A high serum level of anti-dsDNA and anti-Smith antibodies suggests SLE.   
• Additionally, detection of C3 and C4, immunoglobulins (IgM, IgG, and IgA), serum protein electrophoresis, and cryoglobulins (if Raynaud is present) may be performed.
• Biopsies (lupus band test): Shows IgG and C3/C4 deposits along the dermo-epidermal junction in a lumpy-bumpy distribution. A renal biopsy may be helpful. It shows the deposition of immunocomplexes in the glomeruli. 

Testing for HIV and Hepatitis C is advocated as these are treatable causes of thrombocytopenia.[3]

Treatment / Management

The management of ITP involves several goals and concepts.[11][1][12] These include the following:

• Aim to bring the platelet count to normal.  
• Indication for active therapy is only when there is acute bleeding or if emergent surgery is forthcoming. If there is no significant bleeding and the platelet count is > 30,000 /dL, then transfusion may be withheld.[3]  In a recent analysis, severe bleeding was seen in about 20% of children and about 10% of adults. Bleeding usually does not occur until the platelet count decreases to below 30,000 /dL. Cutaneous and mucosal bleeding may occur below 20,000 /dL, and life-threatening hemorrhage (e.g., intracranial) typically occurs with counts below 10,000 /dL. It is preferred to give one apheresis unit; 4 to 6 pooled platelet units may also be given. 
• The vast majority of children recover spontaneously without sequelae. In severe cases, the treatment of choice is intravenous immunoglobulin (IV IgG). A 5-day course of 400 mg/kg/d is given. Responses occur in more than 70% in 1 to 4 days, but only for a short period; many patients respond, and repeated courses may be necessary.   
• Patients (children and adults) with active bleeding require corticosteroids to stop further destruction of platelets (about 60% of patients respond well within two weeks). Steroid use in pregnant women during the first trimester carries a small risk of cleft palate.[13] Dexamethasone use in pregnancy can cause an increased risk of abruptio placenta as well as premature rupture of fetal membranes. 
• Patients who do not respond adequately and have active bleeding after a month of being treated with corticosteroids may need splenectomy after using intravenous immunoglobulins to raise the platelet count. Therefore, splenectomy is the treatment of choice for adult patients with ITP who have persistent symptomatic thrombocytopenia. It is recommended that patients be screened for COVID-19 prior to splenectomy.[13] Splenectomy results in upwards of a 70% long-term response rate; it is important to give vaccinations > 15 days prior to surgery. 
• In adult patients with ITP, the corticosteroid preferred is prednisone 1 to 2 mg/kg/d. The response rate for a seven-day course is about 56%, with a long overall remission rate.[9] Steroid administration beyond a 6-week course is not advocated.[13] 
• It reserves plasmapheresis for cases of fulminant ITP.[14]
• Neonatal thrombocytopenia is treatable with intravenous immunoglobulin, which raises the platelet count. IV-IgG is favored over Anti-D immune globulin due to the increased risk of severe hemolytic transfusion reactions in the latter.[3]
• Platelets increase after three months in untreated ITP neonates due to the catabolism of maternal anti-platelet antibodies transferred during birth.  
• Vincristine (VCR) seems to be a valuable drug in adult patients who do not respond to splenectomy. However, VCR can cause neuropathy, and it is contraindicated in pregnancy.[9]
• Hemostaticxs such as tranexamic acid and Epsilon Aminocaproic Acid are not favored in treating ITP.[3]
• Rituximab use in ITP appears limited to second-line deployment, likely as combination therapy.[13] While it carries a > 50% response rate, its use is fraught with potential difficulties. A hepatitis panel must be checked prior to use in case of possible Hepatitis B reactivation. There is a small risk of progressive Multifocal Leukoencephalopathy (PML). With rituximab administration, COVID vaccinations cannot be given for 6 to 12 months. There is also a possible (20%) risk of hypogammaglobulinemia (requiring IV-IgG replacement) if rituximab is coadministered with dexamethasone. Rituximab can also cross the placenta leading to neonatal B-cell depletion. 
• Anti-RhD globulin is immunoglobulin directed against the D-antigen of the Rh blood group.[15] It inhibits the destruction of antibody-coated platelets. Its utility is limited to Rh+ patients with a spleen. The response rate is approximately 70%, with almost all being complete responses (CR), and 26% of these had sustained responses beyond six months.[16] The use of anti-RhD in pregnant women is tempered by the increased risk of neonatal jaundice and anemia.[13]
• Fostamatinib is a splenic tyrosine kinase inhibitor that decreases antibody-dependent phagocytosis of platelets.[5][17] The overall response rate was 43% within 12 weeks of therapy, and 18% had stable disease.[13][18] Responses can occur despite prior failures with thrombopoietins, rituximab, or splenectomy. 
• Efgartigimod and rozanolixizumab are compounds undergoing testing for use in myasthenia gravis as well as in ITP.[5][19] They are antibody fragments that target the neonatal Fc-receptor (FcRn), thereby inhibiting IgG recycling. They decrease the half-life of IgG, reducing it to normal or subpathogenic levels. Investigators have found response rates of 38% with efgartigimod and 50% with Rozanolixizumab. 
• Sutimlimab is a humanized monoclonal antibody against C1s, a complement pathway inhibitor.[20] In ITP, it decreases complement-dependent cytotoxicity, thereby decreasing platelet destruction.[5] Studies have revealed responses of 33%, many within days. However, their overall sample sizes were small. 
• Rilzabrutinib is a Bruton Tyrosine kinase inhibitor (BTKI) with efficacy in the treatment of ITP.[5][18] It inhibits Fc (gamma) signal transduction causing a decrease in platelet phagocytosis and auto-antibody production. Studies have shown a response rate of about 40 to 50%, with minimal toxicity and a time to respond of about a week. 
• Azathioprine may take several months of therapy to exert an effect on ITP.[9] Although deemed safe in pregnancy, there are reports of an increased rate of prematurity as well as a decreased birth rate.[13] In general, vaccinations must be withheld for six months after the total cessation of immunosuppressive therapy to allow for the restoration of immunity. 
• Thrombopoietins (eltrombopag, romiplostin, and avatrombopag) have been shown in ITP to have upwards of an 80% response rate.[13] These medicines stimulate the JAK-STAT pathway with subsequent megakaryocytic proliferation and platelet production.[5] There is an inherent risk of thrombosis, which increases substantially if the patient is on oral contraceptives, has an underlying antiphospholipid antibody, or has other prothrombotic issues. Problems typically occur within a year of use. In recent clinical trials in children with ITP treated with Romiplostin, about half demonstrated a positive platelet response within the first 6 months [21]. Bone marrow biopsies obtained during therapy revealed that reticulin deposition had no correlative effect with the positive platelet response. Clinically significant fibrosis occurred rarely with prolonged therapy. The Korean Society of Hematology recommended using thrombopoietins (TPO) after steroid failure but before considering splenectomy.[9] It was felt that the shortcomings of surgery outweighed those of this medical management.  
• Recent opinion appears to support the use of combined agents in the therapeutic approach to ITP.[18][21][22] A common format involves giving steroids along with IV-IgG and adding platelets should the patient be bleeding.[3] The combination of mycophenolate mofetil or cyclosporine with thrombopoietin and IV-IgG has been seen to have a response rate of 72% in severe refractory ITP. Studies combining Dexamethasone, Cyclosporine, and low-dose rituximab revealed a response rate of 60%, often with a long-term (> 7 months) remission. Rituximab with thrombopoietin has fared better than rituximab alone. The overall response rate ()RR) was about 79% for the combination compared to about 71% for monotherapy. The combination did carry a shorter response time but no long-term advantage. 
(B2)

Differential Diagnosis

One should consider the following in the differential thrombocytopenias due to increased platelet destruction and those due to decreased platelet production.[1][23][24]

Thrombocytopenias due to increased platelet destruction include:

Immune thrombocytopenia

• Idiopathic thrombocytopenic purpura
• Secondary autoimmune thrombocytopenias
• Drug-induced immune thrombocytopenias
• Posttransfusion purpura (PTP) is a transfusion-associated reaction about a week after the transfusion. It is an amnestic response to platelet antigens, resulting in the destruction of native and transfused platelets.[25] It occurs in multiparous women due to alloimmunization against platelet antigens.[26] It is treated with IV-IgG. 
• Neonatal immune thrombocytopenias
• Viral infection often is the presage for thrombocytopenia. The HIV-associated disease is now the most common cause of thrombocytopenic purpura, especially in males between 20 and 50. Testing for HIV antibodies is a critical part of the assessment of ITP.[27][28] Zidovudine effectively raises platelet counts in individuals with HIV-associated immune thrombocytopenic purpura. Data has also shown that COVID is a cause of thrombocytopenia, with 71% of COVID-induced ITP occurring in elderly patients and three-quarters of these having moderate to severe infections.[3] Typically, the platelet count does not drop below 100,000 /dL, severe bleeding is uncommon, and the overall prognosis is deemed relatively favorable. Incidentally, COVID-19 vaccines have been implicated in causing and exacerbating ITP [29]. Hepatitis C can cause significant thrombocytopenia, which can resolve with antiviral treatment.[30][31] 

Consumptive thrombocytopenias

• Thrombotic thrombocytopenic purpura (TTP): Of special note is that TTP and ITP, though thought of as distinct hematopoietic maladies, both subset autoimmune disorders [30]. Clinical examples exist of concurrent or sequential presentations. A phenotypic distinction can sometimes be difficult but a necessity in terms of selecting the proper treatment (eg. plasm exchange, steroids, etc.). 
• Disseminated intravascular coagulation (DIC) 
• Hemolytic-uremic syndrome (HUS)

Microangiopathic hemolytic anemias such as TTP, DIC, and HUS can manifest thrombocytopenias as blood flow is disrupted and erythrocytes are destroyed as platelets are consumed.[32][33]

• Sepsis causes thrombocytopenia via various mechanisms, such as complement activation, histone release, and coagulation activation.[34]

Hypersplenism; sequestration mechanism. 

Thrombocytopenias, due to decreased platelet production, colloquially described as "the first to go and the last to grow back," platelet production and survival are affected by a myriad of factors, sometimes with long-term results.[34]  

• Bone marrow suppression by drugs, alcohol, toxins, and infections 
• Aplastic anemia manifests as pancytopenia, typically from a damaged marrow manifesting marrow failure.[35]
• Leukemias and other bone marrow cancers; the patient may present with thrombocytopenia within a myelophthisic picture or with leukoerythroblastocic.[36]  
• Megaloblastic anemia and thrombocytopenia can appear in B12 deficiency, especially as this disease can mimic TTP.[37]  
• Refractory anemias, preleukemia, and hematopoietic dysplasia typically have cellular dysmorphism evident on bone marrow exams and often present as lineage cytopenias.[38]

Prognosis

The prognosis is good for acute ITP since most patients make a spontaneous recovery. Patients with chronic ITP almost always require treatment, and relapse commonly occurs. A complete response to the first-line steroid can occur in about 20% of the patients, and about 60% have a partial response. Vincristine is used in adult patients who do not respond to splenectomy.

Complications

The most severe complication of ITP is hemorrhage, especially the rare complication of bleeding into the brain that may prove fatal.