Essentials for Oncologists and Haematologists

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Case Report International Journal of Hematology and Blood Disorders Open Access

Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists Piyush Vyas* *Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw Hospital, Warsaw, Poland

Received: 8 October, 2017; Accepted: 26 October, 2017; Published: 16 November, 2017

*Corresponding author: Piyush Vyas, Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw Hospital, Warsaw, Poland; email: [email protected]

Abstract primarycongenital, ITP or can systemic only be (autoimmune diagnosed by diseases thoroughly like for examining example aSLE) patient and which a platelet would count include of less detailed 100 G/l. history Thus taking, a diagnosis physical of An in depth knowledge is essential about the pathology of immune thrombocytopenias before we start managing these aetiologyautoimmune is known, disorders. we try It’s to important eliminate to the differentiate antigen which whether triggers the patient has primary or secondary immune thrombocytopenia. If the thrombocytopeniaexamination, full blood except count the andprimary a bone ITP.Secondary marrow biopsy. ITP Thecan secondary ITP broadly include all the other forms of immune aetiology is unknown then as per international working group criteria, wefurther diagnose formation such immune of autoantibodies thrombocytopenia directed as against primary platelets. immune If thrombocytopenias. Primary immune thrombocytopenias are be H. Pylori related, drug related, HIV related, related with managed primarily by administering intravenous immunoglobulins autoimmune disorders like SLE etc..(1) thrombocytopenia with secondary immune thrombocytopenia drugs like azathioprine, cyclosporine, rituximab, vinca alkaloids like Of prime importance here is to differentiate primary immune vincristine,or steroids ascyclophosphamide first line treatment. or other In second drugs line like immunosuppressiveandrogens- danazol, are managed differently thus it should be assured that the patient relapsed ITP splenectomy remains as an important surgical option be screened for HIV or HCV. A bone marrow aspiration and a TPO mimetics etc. are administered. And of course for refractory or however now-a-days less popular. trephine biopsy are further advised for all patients ( especially Keywords: ITP- immune thrombocytopenia; ALPS – Autoimmune elderly patients >60 years) to rule of myelodysplastic syndromes as(MDS) their and initial haematological stages thus such malignancies diseases should .Of course also autoimmunebe excluded. VZV- Varicella zoster virus; APS – Antiphospholipid syndrome; CVID diseases like SLE also can present as isolated thrombocytopenias lymphoproliferative Syndrome; SLE –Systemic lupus erythematosis; If patient has autoimmune haemolytic anaemia (AIHA), always – Intravenous Common variable immunoglobulins; immune deficiency; TPO- Thrombopoeitin MMR- Measles, mimetics; mumps, can be suspected (2). rubella.; MDS –Myelodysplastic syndrome; GP- Glycoprotein; i.v.Ig Evans syndrome along with thrombocytopenic Evans syndrome Definition of different phases of ITP NK-natural killer; MHC- Major histocompability Complex; APC- insulinantigen dependent presenting diabetes cells; TCR mellitus – T cell ;CTL- recerptor; cytotoxic Tregs T lymphocyte. –T relulatory The International working group recommended the use Lymphocytes ;IL-interleukin ; TGF-transforming growth factor; IDDM-

Introduction of “newly diagnosed ITP” for all cases at diagnosis. The term “persistent ITP,” was introduced for patients with ITP to define Immune thrombocytopenia (ITP) are autoimmune disorders category includes patients not achieving spontaneous remission the period lasting between 3 and 12 months from diagnosis. This which characterize that autoantibody mediated platelet destruction, suboptimal platelet production and T cell mediated or not maintaining their response after stopping treatment platelet lysis occurs leading to decrease in platelet count. between 3 and 12 months from diagnosis. The term “chronic Clinical Definition of primary and secondary immune ITP” was suggested for patients with ITP lasting for more than 12 months. Term ”severe” ITP was reserved for ITP with “clinically thrombocytopenias relevant bleeding” which was defined by the presence of bleeding As per the International working group criteria, primary ITP symptoms at presentation sufficient to mandate treatment, or by agentthe occurrence or an increased of new dose. bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing is clinically defined by the presence of thrombocytopenia in the absence of demonstrable causes be it be pathogenic, therapeutic,

Immune thrombocytopenias and solid tumours There have been isolated case studies or isolates case series Opinions are very conflicting, some authors advocate that these are paraneoplastic phenomena of cancers {Krauth et.al. tumours with immune thrombocytopenias. Our group was 2012(17)}, others are of the opinion that no correlation exists reported of incidences of co-existent cancers especially solid between these 2 diseases if they coexist. Whether there exists duodenal cancer with coexistent immune thrombocytopenia some significant correlation between immune thrombocytopenias the first to publish a case report of a patient with metastatic and cancers remains still is a topic of further research. patients with coexistent immune thrombocytopenias are that (P.Vyas et.al.) (7). In this case we first treated the immune Some of the proposals about treating these solid tumour thrombocytopenia and when the platelet count of more than 75 like cyclophosphamide, vincristine, vinblastine, cyclosporine, theG/l cancer was achieved, responded we to treated treatment, this the patient platelet with count chemotherapy increased. procarbazine,of using protocols etoposide with ,steroids combined in chemotherapytheir regimens. drugs In cases (21) without any episodes of bleeding. Our observation showed as where radical resection is possible (ovarian cancers, breast coexistent immune thrombocytopenia{P.Vyas et.al. (9)} where cancers, lung cancers etc.) it is advised to resect radically the initiallyAfterwards the againpatient we was reported treated awith case endocrine of breast therapies, cancer withand

casestumour splenectomy after attaining is an an optionoptimal now-a-days platelet count less from popular ITP directed among when the disease got endocrine refractory, chemotherapy was physicianstherapies and (steroids/immunoglobulins patients too.Since endocrine etc.). therapies In referactory can be treatedadministered with steroids successfully and immunoglobulins, achieving long periodswhen the of immune stable disease. As far as ITP is concerned our patient was initially steroids , treatment with rituximab, vincristine, danazol was administered safely in thrombocytopenias ,we recommend thrombocytopenia got refractory to immunoglobulins and to start treatment with endocrine therapies for example in breast cancer (ER/PR + patients), prostate cancer patients. Sinceadministered these 2 withdisease good entities(immune effects , attaining thrombocytopenia satisfactory levels and of patients.Our observations Protocols found like thatAC (Doxorubicine, protocols like FOLFOX/Cyclophosphamide) FOLFIRI / solidplatelet tumours) counts occur to further rarely treat or rarely the patient are diagnosed with chemotherapy. as immune Capecitabine can be safely administered in gastrointestinal cancer

to conduct prospective randomised clinical trials .Thus we treat cancer/Docetaxel patients monotherapy with coexistent /Cyclophosphamide immune thrombocytopenias. monotherapy / thrombocytopenias with coexistent solid tumours , it is difficult InVincristine a situation monotherapy when no guidelines can be exists, safely we administered recommend in to breast treat .It seems that many patients with immune thrombocytopenias withthese coexistent patients on solid the tumours basis of availableare not diagnosed knowledge by in oncologists literature , as chronic thrombocytopenia in these cases is misunderstood patients as have been done the world over based on case studies/ caseImmune series asthrombocytopenias far as solid tumors with coexistentand Haematological ITP is concerned. malignancies as massive tumour infiltration to the bone marrow. Many a times trephine biopsy is not done to find out the reason of occur with haematological malignancies. In chronic lymphocytic thrombocytopenia / cytopenias. Isolated thrombocytopenia Certain protocols are advised if immune thrombocytopenias if it occurs in a patient should not be understood a priori as diseases is high, among others autoimmune haemolytic anaemia , withinfiltration coexistent by tumour chronic unless thrombocytopenia we find massive have tumour chronic infiltration immune leukaemia where the incidence of coexisting autoimmune in bone marrow biopsy. Many of these patients with solid tumours some authors have suggested administering protocols like autoimmune immune thrombocytopenia and of Evan’s syndrome thrombocytopenia which get resolved with effective treatment surgeryof immune or chemotherapy thrombocytopenias or other with treatment steroids modalities or intravenous .Case Rituximab-Cyclophosphamide-Dexamethasone combination immunoglobulins and with effective anti cancer therapies, be it in the management of autoimmune cytopenias associated with inchronic certain lymphocytic autoimmune leukemia disorders (18). as shown It has in been pooled noted analysis that studies have shown remission of immune thrombocytopenias by there exists an increases incidence of non Hodgkin lymphomas effective treatments. Not every patient with thrombocytopenia should be disqualified from potential curative or life prolonging within the InterLymph Consortium (19). In various case studies palliative therapies. In our e-poster at Polish Association of splenectomy or steroids was advised for the treatment of Hodgkin Haematologists and transfusion medicine specialists Conference, lymphoma patients (20). In haematological malignancies Warsaw , 2017{P.Vyas et.at.(16)} we presented case reports butespecially also immune CD20+ thrombocytopenias. B cell lymphomas multi drug protocols with of our patients who had initially immune thrombocytopenia, rituximab is a valuable option not only for treating lymphomas and after effective treatments not only the patients had Differential diagnosis effective anti-neoplastic therapy, but their platelet count too immunosuppressiveincreased to satisfactory drugs levels.like cyclophosphamide Our observation or showed vincristine, that with effective anti-neoplastic therapies especially with use of we Differentialhave so called diagnosis pseudothrombocytopenia of thrombocytopenias which includes occurs many in diseases states where thrombocytopenia occurs. Many a times immuneit is possible thrombocytopenias to effectively treat coexisted and cure/prolong with breast, lifelung of cancers, cancer patients with coexistent thrombocytopenias. Most of the cases of renal cancers, with prostate cancer even rarely. 1:1000 individuals, in about 15% of ambulatory patients with Citation: Int J Page 2 7 Hematol Blo Dis Piyush Vyas (2017) Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists. of 2(2). 1-7. Immunopathology of Immune thrombocytopenia: Essentials for Copyright: oncologists and haematologists © 2017 Vyas P.

thrombocytopenia. In pseudothrombocytopenia –platelet platelets are produced. Thrombopoetin regulates megakaryopoeisis11 and produce several thousand platelets. Daily 2 x10 clumping occurs where EDTA dependent IgG plays a role .Occurs orwhen heparins platelets will with give neoepitope the actual are count. exposed Another in presence condition of EDTA. like restthrombopoiesis. remains in splenic Under circulation. normal conditions two third of total dilutionalOccurs in thrombocytopenia EDTA containing tubes. occurs In in such patients cases who use get of massive citrates platelet mass is circulating at concentration of 150 to 400G/l, the

Under physiological conditions platelets survive, have a amounts of crystalloids or colloids. lifespan of 7 to 10 days, after which are sequestrated in spleen. Thrombocytopenia can be congenital or acquired. In However liver and accessory spleens also play role in platelet associatedcongenital with thrombocytopenias, skeletal abnormalities, patients change have in a platelet family size history and destruction. Under conditions where destruction of platelets of thrombocytopenia, may present in adulthood, often are occur for example by autoantibody the mean life span of platelets Plateletis significantly membrane reduced. glycoproteins change in platelet function. Isolated acquired hypoproliferative thrombocytopenia can be caused by infections like HIV, HBV, thrombocytopenia).IsolatedCMV; with drugs like linezolid, thrombocytopenias bortezomib; bycan alcohol occur anddue GP IIb IIIa and GP Ib IX complexes are the most also in MDS(5-10% of thrombocytopenia in MDS is isolated immunogenic of the platelet glycoproteins, carrying some like immune or non immune thrombocytopenias .Immune recognized autoepitomes. GP IIb IIIa complex is a member of to processes which involve increased destruction of platelets thrombocytopenias can be alloimmune thrombocytopenia which earlythe superfamily at promegakaryocyte of integrins.GP stage IIb and IIIa complexis considered is required as early for normal platelet aggregation .GP IIB IIIa complex appears very neonatal thrombocytopenia. Autoimmune thrombocytopenia can beoccurs primary in for ITP example or secondary post transfusion ITP. purpura or in isoimmune marker of megakaryocytic lineage. When activated GP IIaIIIA clustering occurs .GP Ib IX V complex plays an important role in the adhesion of platelets to exposed vascular subendothelium. induced thrombocytopenias or other drug induced immune Other causes of thrombocytopenias are for example heparin Along with Von Willebrand factor, this complex causes platelet activation which promotes the recruitment of additional platelets .GP Ia IIa complex is also a member of integrin superfamily of etc.).thrombocytopenias, now classified as secondary immune thrombocytopenias( for example after therapy with quinine , gold adhesion receptors (alpha2beta1). GP Ia IIa complex functions as Non immune thrombocytopenias due to increased destruction a receptor for collagen, and mediates as a significant portion of Fcthe gamma adherence receptors of platelets to the subendothelium.

of platelets occur in diseases like disseminated intravascular coagulation,sepsis,may occur in the use of extracorporal phagocytes, monocytes, macrophages, neutrophils, eosinophils Fc Fragment of IgG receptors are probably the binding sites for circulation , can occur in post operative periods after surgery and also in patients with large clot burden for example in pulmonary and also platelets .Activation of FcR receptors induces activation embolismThrombocytopenia , in thrombotic may microangiopathies occur in disease (TTP,HUS). states with of phagocytes which further causes release of inflammatory mediators.Fc Gamma R type I, FcGamma R type II, Fc Gamma R III peripheralincreased blood. sequestration.In In states where normal splenomegaly conditions occurs only increased 1/3 of are the 3 different subclasses of this receptor. The only Fc Gamma platelets are stored in spleen and 2/3 of platelets is circulating in AutoimmuneR expressed on plateletThrombocytopenia is Fc Gamma R IIA.

sequestration of platelets occurs. Splenomegaly occurs in various disease states for example in chronic liver disease. autoimmune disease occurs. Autoimmune disease may be organ If our body’s own antigen is recognized as foreign entity, As far as immune thrombocytopeni are concerned 80% of cases are primary ITP and 20% of cases are secondary ITP. specific or can manifest as a systemic disorder. Lymphocytes T and Secondary ITP occurs in various disease states like SLE, APS, in versionlymphocytes would B playbe thatan important lymphocytes role inT autoimmuneespecially T disorders.regulator rubella)limphoproliferative vaccination. disorders like CLL, H.Pylori and also seen The mechanism is very complex, however an oversimplified after vaccinations for example after MMR (Measles mumps Platelet Physiology autoantibodiescells influence the are productionproduced against of autoantibodies platelets resulting being inproduced platelet by lymphocyte B cells. In autoimmune thrombocytopenia ITP is much common, in other populations the disease is rare, as sequestration mainly in spleen. It seems that in some populations an Toimportant understand role in pathogenesis haemostasis, of they ITP, prevent a clinician and shouldarrest have good understanding of platelet physiology. Platelets play HLA molecules too play a role in autoimmunity. Different HLA physiological receptors and play a role in interacting between hemorrhage. Platelet membrane Glycoproteins (GP) act as molecules have different peptide binding properties and are vascular subendothelium and the platelets (adhesion) and platelet selective for particular T cells. Thus in certain populations with platelet interaction (aggregation). A single megakaryocyte can a particular HLA setup, certain autoimmune diseases are much more manifested. Citation: Int J Page 3 7 Hematol Blo Dis Piyush Vyas (2017) Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists. of 2(2). 1-7. Immunopathology of Immune thrombocytopenia: Essentials for Copyright: oncologists and haematologists © 2017 Vyas P.

Immunology of autoimmune disorders Our body has 2 immune systems, the innate immunity and the By and large, T regs cause immunosuppression by(a) cellsreleasing (b) by inhibitory causing cytolysis cytokines – where for examplegranzyme TGF A or beta(mostgranzyme immunosuppressive), IL35, IL10 which then act on effector T adaptive immunity. Innate immunity is very ancient, found in a ie. the neutrophils, macrophages, etc..Other components like (c)by metabolic disruption caused by contact inhibition where lot of vertebrates. It consists of epithelial barriers, the phagocytes B attack porforin pore thus causing apoptosis of effector T cells cytokine deprivation (d)and lastly by targeting dendritic cells complement system and NK cells take part in first line of defence CD39 ;CD73;IL-2 ;CD25 proteins take part causing death due to ie. through innate immunity. Innate immunity actively defends our body mostly for 1st 12 hours after infection, then comes the role via inhibition od DC maturation and function. In this process of the so called “adaptive immunity”. In adaptive immunity the B as a result the dendritic cells cannot present antigen and are inactivated.CTLA-4; CD80/CD86; LAG3; MHC class II proteins take part. And tolymphocytes plasmocytes and and T lymphocytesproduce antibodies, take part and and the defend T lymphocytes our body against various infections. The B lymphocytes then transform

ofcourse orchestrate the whole adaptive immunity for example Thus “autoimmunity” is immune reactivity against our own immunityvia effector is T the cells. most In importanthumans, it immuneseems this system “adaptive in the immunity” hierarchy multiplebody. Autoimmunity sclerosis(brain), can be pernicious organ specific anaemia(stomach),thyroid or systemic (non organ plays much more important role in fighting pathogens. Adaptive specific). Examples of organ specific autoimmune diseases are thyrotoxicosis; adrenal gland diseases like Addison’s disease; of immune systems in our body. diseases like Hashimoto thyroiditis, primary myxoedema,

T cells bind to MHC class I molecules expressed on most diseases like IDDM(pancreas autoimmune disorder)or nucleated cells and platelets (CD8+T cells) and the CD4+T cells cells and on activated Tcells. T cells become activated by antigen dermatomyositis.autoimmune disorders like ITP. Examples of non organ specific presentingbind to MHC cells II moleculeslike macrophages, expressed dendritic on APCs, cells macrophages, etc.. In this B autoimmune disorders are RA (joints),SLE, scleroderma,

process the first incident is the binding of the peptide on for For development of autoimmune disease certain example mature dendritic cell (APC) –MHC II molecule with T cellsrequirements are some are pathological to be met. immune Immune processes dysregulation; going abnormalon in the cell receptor (TCR) and binding of B7 peptide of mature dendritic activation of dendritic cells, abnormal activity of T cells and B cells to CD28 proteins of activated T helper cells. The process is much complex involving co-stimulatory signals, antigen specific autoimmune disorders. Also genetic and environmental factors TCR signals, CD28, CD80, CD86 , CD40 ligand , CD40 proteins, like exposures to infectious agents too play an important role. CD3, alpha, beta TCR peptide antigen and MHC class II molecules. Since our topic is pathogenesis of ITP, we would talk in CD40 ligand and CD28 have to interact with their appropriate tolerancemore detail induction about organ mechanism specific ie. autoimmunity. the ability to Organ eliminate specific or receptors on the antigen presenting cells surface. In autoimmune autoimmunity is deficiency of central or /and peripheral diseases the T cells have to be activated by this synapse. For autoreactive T cells to be activated, all of these synapses should Cytokine driven T cell activation also plays an important role autoimmunedeactivate self diseases reactive the lymphocytes. T cells cannot The be CD4+CD25+FoxP3 suppressed and be formed within our body. regulatory T cells suppress T cell functions. And in many

in our body’s immune system. After the two signals are met at thus the disorder is manifested. In ITP, the autoantibodies are the interface of T cell and antigen presenting cells, then the next primarily IgG directed against epitopes on GP IIbIIIa (CD41) most important processes which occurs afterwards is through and/or GP IbIX(CD42). The complex immunopathology involves cytokine network. The Th1 generates interferon gamma, Th2 opsonisation of platelets, after which the platelets interacts with generates IL4 resulting in good anti-inflammatory responses. Fc gamma receptor of the macrophage which allow phagocytosis Thus it is the interaction between Th1 and Th2 which would of the platelets. After phagocytosis of platelets, some of the tell us amount of particular response to a particular antigen. proteins of the platelets are reprocessed and expressed on MHC decades,The processes play a very involve important IL-4, interferon role in the gamma, whole process IL-12, IL-18,too. They IL- type II proteins, which turns on autoreactive B cells, which then 10, TGF-beta. Regulatory T cells have gained attention in last 2 turn on other autoreactive B cells to generate more and more antibodies. At last this vicious cycle continues causing further are part od CD4 positive repertoire. Cytokines produced by Th1 platelet destruction .In some cases of ITP, we cannot demonstrate cells and Th2 cells can downregulate each other for example IFN the formation of autoantibodies, the mechanism proposed gamma and IL12 downregulate Th2 cells while IL10 inhibits Th1 here is that such patients have CD8+cytotoxic T cells and cause cells CD4+CD25+Foxp3 T regulator cells mediate suppression destruction of platelets by binding to megakaryocytes via CTL allergicby cell cellresponses contact occur and byin our releasing body. These cytokines T regs (IL10 are andproduced TGF). andmediated not a singlemechanism. mechanism. Thus a lot of heterogeneity of autoimmune inThus thymus in regulatory (natural TTregs) cell deficiencies or in peripheral , autoimmune blood in responsediseases orto pathogenesis are probably the cause of platelet destruction in ITP (induced Tregs) during immune responses. B cells play a central role in inducing autoimmunity. B cells differentiate to mature plasma cells which produce Citation: Int J Page 7 Hematol Blo Dis Piyush Vyas (2017) Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists. 4 of 2(2). 1-7. Immunopathology of Immune thrombocytopenia: Essentials for Copyright: oncologists and haematologists © 2017 Vyas P.

autoantibodies. Antibodies have heavy chains and light chains. Pathogenesis of Immune Trombocytopenias

chains –kappa and lambda chains also have various types. There About 6000 types of heavy chains can be produced. The light patients with primary ITP into compatible healthy volunteers leadingIn the in markedyear 1951, reduction Harrington in platelet et. al. counts (3) injected within hours.blood Thusfrom exist about 200 kappa chains and 120 possible lambda chains, put together it comes out to be about 320 different types of light chains. Thus when we combine the probable combinations of these authors hypothesized existence of an anti platelet factor in the globulin fraction of plasma of patients diagnosed with diversitylight and heavywith splicing chains ie variations 6000 heavy due chains to addition and 320 and light deletions chains, that comes out to be 1.9 million antibodies. Moreover, more primary ITP. Afterwards Mc Milan et al. Dixon et al. successfully described this factor as antiplatelet antibodies. Basically these of nucleotide bases of DNA is possible with additional 30 million are autoantibodies to platelet glycoproteins (GP)IIb/IIIa and GP types of various antibodies produced. Now if we have 1.9 million Ib/IX; but autoantibodies to platelet glycoprotein GP Ia/IIa; GPIV, antibodies combination of heavy and light chains; and 30 million GPV have also been observed. The chief class of these antibodies variations of antibodies due to addition or deletion of nucleotide leadingis immunoglobulin to these autoantibody (Ig)G, the complement production, fixing but it IgG1 is likely and IGg3that bases, then we can probably have 60 trillion probable antibodies isotypes. Researchers still do not know the underlying defect types which can be produced in1327 our body. Further, somatic mimicry and epitome spread; also to a lower extend hereditability various possible antibodies more than one aetiology is involved. Infections causing molecular inmutations a human canbody. introduce 3 x 10 various types of antibodies which together makes about 2x 10 Thus our body under normal regulatory mechanisms like (as shown in PARC – ITP study; about 2, 3% of children with clonal deletion (apoptosis), receptor editing, anergy (reduced ITP have family history of ITP) seems to be the autoantibody production triggering factors.

membrane IgM) and clonal ignorance (normal phenotype, no ITP with infectious aetiology have been reported by many antibody secretion) makes these B cells dormant / inactive to authors .For example Murphy et.al. (1987) reported incidence of avoid self reactivity. ITP among 10, 5% of HIV patients. Similarly Kaslow et. al. (1987) reported 6, 7%; Rossi et.al.(1990) reported 10, 9%; Sullivan et.al. Autoantigens stimulate “ignorant” cells. The B cells with (1987) reported 8, 7% and Mientjes et.al. (1992) reported an specificity for DNA bind soluble fragments of DNA, sending a incidence of 23, 5% of ITP among HIV positive patients. Thus a signal through B cell receptor. Then the cross linked B cell receptor clear increase of incidence of ITP among HIV patients has been inis internalizedan endosomal with compartment, the bound DNA sending molecule. a co-stimulatory After which thesignal. GP observed. Most of these patients have platelet counts less than rich fragments from the DNA which is internalized bind to TLR-9 50G/l. In HIV associated ITP, a particular autoantibody is produced in these patients to a very specific aminoacids aa49-46 of GP IIIa And thus these “ignorant” B cells are then activated and produce molecule. And when these very specific autoantibodies touch “autoantibodies”. Different mechanisms are suggested for the GP IIIa molecules , they turn on 12 lipoxygenase which in turn APC,formation so these of cells autoantibodies. can directly ingest One mechanisma platelet, process is formation it , present of generate reactive oxygen radicals via NADPH oxidase particularly autoantibodies directly which occurs probably in ITP.B cells are superoxides .And at last, as a result platelet “suicide” occurs via ROS (reactive oxygen species)mediated platelet destruction. Thus platelet antigen peptides on it’s surface which further causes these HIV infected patients have peroxide mediated platelet lysis. clonal production of T cells. And these T cells further orchestrate Immune thrombocytopenia post infection is also reported stimulatenext B cells dendritic to produce cells autoantibodies. which enhance Thistheir mechanism antigen penetration is called epitope spreading. Also B cells secrete cytokines; they can in HCV positive patients without overt liver disease ranged from 10% (Pawlotsky) upto 36% (Pivetti,1996).Garcia Suarez (2002) vicious cycle starts when normal immune regulatory mechanisms again to next B cells. And thus in autoimmune disorders this reported an incidence of 23% of ITP among HIV positive patients .These ITP patients with HCV positive patients. These ITP patients fail. increasewith HCV viral infection reproduction manifest among generally these bleeding patients. at higher platelet counts, may respond to interferon gamma. Corticosteroids may (collagen In ITP, receptor) autoantibodies etc. are specificproduced. to Since GP IIb/IIIa serological (Fibrinogen assays receptor), GP Ib/IX (Von Willebrand receptor), GP Ia/IIa H. Pylori and ITP have an association, a fact well established have low specificity and sensitivity, these tests do not have a from years. Many centres have published multiple single centre definitive role in making the diagnosis which till date as per the studies where an effect of eradication therapy on platelet counts definition of International working group definition remains in Helicobacter Pylori infected patients with primary ITP has one of exclusion as far as primary immune thrombocytopenia been noted. Some studies showed an increase of platelet count is concerned. Thus in ITP, loss of self tolerance occurs. This upto 100G/l and more in about 40% patients ie a complete can be due to immunodeficiency states like CVID, APLS; due to response was achieved using triple therapy for Helicobacter Pylori eradication. In about 50% of patients with H.Pylori autoantigenmolecular mimicry presentation, (cross reactive epitope antibodies spreading, to decreased HIV, HCV,VZV) T regs, or was achieved and at least double the baseline platelet level was /and due to disturbances in our immune repertoire like increased infection and ITP, a satisfactory platelet count of 30 G/l or more cytokines by exogenous antigens. decreased TGF beta cytokines, production of proinflammatory achieved after triple therapy of H.Pylori. Some patients have good Citation: Int J Page 7 Hematol Blo Dis Piyush Vyas (2017) Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists. 5 of 2(2). 1-7. Immunopathology of Immune thrombocytopenia: Essentials for Copyright: oncologists and haematologists © 2017 Vyas P.

response to triple therapy, others don’t. What is the explanation Conclusion

to this heterogeneity in ITP response to eradication of H.Pylori? Understanding of immunopathology of ITP is important to generationWell some authorsantibody have production suggested in theearly mutability stages, in of later ITP. Clonalstages further manage these patients. Many patients with secondary 2ndevolution, and even epitome 3rd generation spread modify autoantibody natural historyproduction of ITP. occurs 1st ITP or even primary ITP can have long lasting remission from the which leads to non responsive to triple therapy disease. Thus in disease if treated adequately. Elimination of antigen (if known for ITP,example long Helicobactercomplete durations Pylori) can can be cause achieved complete by administering remission of the disease / durable remissions of the disease. And in primary associatedH.Pylori associated ITP treatment ITP if the by treatment triple therapy is initiated is good. at the At time later of production of primary autoantibodies, the response to H.Pylori eliminatesteroids, intravenousthe antigen immunoglobulinstriggering the autoimmune etc.. The process. meat of List the matter here is to stop the production of autoantibodies / to stages of H.Pylori associated IT, when secondary and tertiary autoantibodies are formed, the disease then do not respond to of “secondary immune thrombocytopenias” will increase due to shouldtriple therapy be treated of with H.Pylori immunosuppressive eradication. H.Pylori agents associated like steroids, ITP our better understanding of the disease, and less frequently will cyclophosphamidewith “secondary” or etc. “tertiary along “autoantibody with triple therapy production to eliminateprobably be these immune thrombocytopenias be categorized as “primary immune thrombocytopenias” in future. Disease specific therapies for secondary immune thrombocytopenias, and for primary monoclonalthe primary autoantibodyautoantibodies production too if they will remain command still in treatmentadvanced immune thrombocytopenias - steroids and/or intravenous ITP associated with H.Pylori. Thus polyclonal, oligoclonal or primaryimmunoglobulins immune thrombocytopenias are first line options, is manydone by a timesTPO mimetics resulting steroids etc. or their combination can prevent clonal evolution in complete remissions. Second and further line management of of ITP. Early immunosuppression from drugs like Rituximab, like eltrombopag or romiplostim, androgens - danazol, or by other and epitome spread in ITP patients. immunosuppressive drugs like cyclophosphamide, vincristine, rituximab etc.

80% of ITP is “primary” and the rest 20% is “secondary”. References Causes of secondary ITP are varied , to mention a few -SLE(5%),APS(2%),CVID (1%),EVAN syndrome(2%), ALPS(1%),Hepatitis C(2%), H.Pylori(1%), ITP post vaccination 1. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, especially MMR(1%) and various systemic infections(2%). Since in primary ITP the cause is unknown, thus we lack specific et al. Standardization of terminology, definitions and outcome criteria treatment and in many patients we see the development of a in immune thrombocytopenic purpura of adults and children: report “refractory adult ITP”. In secondary ITP excellent responses withdrawn. Such good response to treatments with complete from an international working group. Blood 2009;113(11): 2386- are shown if the antigen triggering autoantibody production is 2. 2393. doi:10.1182/blood-2008-07-162503 remission/ durable responses have been in secondary ITP like Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: MMR, H. Pylori, CMV, VZV, Hepatitis C virus related ITP if the pathogenic and clinical diversity. Blood 2009;113(26):6511- 6521. APS,underlying ALPS. diseaseAn intermediate has been responsetreated well. to treatment Response isis observedworse in 3. amongITP related immunosupressed, to autoimmune diseasespost transplantation like EVANS syndrome, patients SLE,and doi: 10.1182/blood-2009-01-129155 in patients with CLL and CVID. ITP patients have antinuclear William J. Harrington, Virginia Minnich, James W. Hollingsworth, Carl V. Moore. Demonstration of a thrombocytopenic factor in the antibodies(incidence 15-25%), antithyroid antibodies (incidence blood if patients with thrombocytopenic purpura. J lab.Clin.Med. 25-50%), antiphospholipid antibodies (incidence upto 30-40%)- suggestingCertain furthersecondary immune immune relation thrombocytopenias to the disease. are drug 1951;38(1):1-10 induced. In drug induced thrombocytopenia, the platelet 4. Immune thrombocytopenia post infection: Molecular mimicry GP IIIa Nardis Met.al.PNAS(1997);94:7589 Zhang et. Al .Blood count decreases after ingestion of the drug and generally (2009);113:4086 immunestarts to related reverse thrombocytopenia. shortly after cessation Sulphonamides of the drug. cause Quinidine, early quinine, gold, heparin, sulphonamides can cause drug induced 5. Antonio Gasbarrini, Francesco Franceschi, Raffaele Tartaglione, gold salts. The mechanism proposed here is that the drug may Raffaele Landolfi, Paolo Pola, Giovanni Gasbarrini. Regression of thrombocytopenia, whereas a long induction period is typical of autoimmune thrombocytopenia after eradication of Helicobactor

wouldconjugate later with be recognized a platelet membraneby circulating and antibodies trigger production only in the of Pylori. The Lancet. 1998;35:878. doi: 10.1016/S0140- hapten-dependent antibodies, or induction of a neoantigen which 6736(05)60004-9

presence of a drug. 6. Heterogeneity in ITP response to eradication of H.Pylori.Stasi et.al. Blood(2009)113:1231-1240 Citation: Int J Page 6 7 Hematol Blo Dis Piyush Vyas (2017) Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists. of 2(2). 1-7. Immunopathology of Immune thrombocytopenia: Essentials for Copyright: oncologists and haematologists © 2017 Vyas P.

7. Vyas Piyush, et al. Chemotherapy in a patient with metastatic .

15 Piyush Vyas, Krzysztof Wózniak, Marta Dudek, Ewa Zurawiska duodenal cancer and idiopathic thrombocytopenic purpura: A case Grzelka,thrombocytopenia Mateusz (ITP) Cieslak, and Anna breast Dryja. cancer. et Case al. report Primary and immune review report and review of literature. J Cancer Prev Curr Res;4(6):00140. Int J Hematol Blo Dis. 2017;2(2):1-5. doi:10.15406/jcpcr.2016.04.00140 16. of literature. 2017) 8. Czy maloplytkowosc moze byc przyczyna dyskwalifikacji od leczenia Czy maloplytkowosc moze byc przyczyna dyskwalifikacji od leczenia guzow litych.(Can thrombocytopenia be a reason to disqualify guzow litych?Eng.transplation: Can thrombocytopenia be a reason patients with solid tumours from treatments”).e-poster presented to disqualify patients with solid tumours from treating?(ePoster at Polish Society of Haematologists and Transfusion medicine Annual conference of Polish society of haematologists and specialists 27TH Annual Conference. Vyas Piyush et al. .Acta transfusion medicine specialists-2017.).Piyush Vyas et.al. Acta 9. Hematologica Polonica Elservier ;Suppl.1;Volume 48.2017 Hematologica Polonica Suppl1/Volume48-2017:35-36 Piyush Vyas, Krzysztof Wózniak, Marta Dudek, Ewa Zurawiska 17. Krauth MT, Puthenparambil J, Lechner K . Paraneoplastic Grzelka,thrombocytopenia Mateusz (ITP) Cieslak, and Anna breast Dryja. cancer. et Case al. report Primary and immune review autoimmune thrombocytopenia in solid tumors. Crit Rev Oncol Int J Hematol Blo Dis. 2017;2(2):1-5. Hematol. 2012;81(1):75-81. doi:10.1016/j.critrevonc.2011.02.004 of literature. 2017) 18. Rossignol J, Michallet AS, Oberic L, Picard M, Garon A, Willekens 10. Semple JW. Immune pathophysiology of autoimmune C. et al. Rituximab-cyclophosphamide –dexamethasone(RCD) thrombocytopenic purpura. Blood Rev.2002;16(1):9-12. doi: combinationassociated with in thechronic management lymphocytic of autoimmuneleukemia. cytopeniasLeukemia. 10.1054/blre.2001.0172 11. Sakakura M, Wada H, Tawara I, Nobori T, Sugiyama T, Sagawa 2011;16:2451. doi: 10.1038/leu.2010.278 N. Reduced CD4+CD25+ T cells in patients with idiopathic 19. Ekström Smedby K, Vajdic CM, Falster M, Engels EA, Martínez-Maza thrombocytopenic purpura .Thromb. Res. 2007;120(2):187-193. O, Turner J. et al. Autoimmune disorders and risk of non Hodgkin doi: 10.1016/j.thromres.2006.09.008 lymphoma subtypes :a pooled analysis within the InterLymph 12. Circulating dendritic cells subsets and CD4+FoxP3+ regulatory Consortium. Karin Ekstrom Smedby et.al .Blood. 2008;111(8):4029- T cells in adult patients with chronic ITP before and after 4038. doi: 10.1182/blood-2007-10-119974 treatment with high dose dexamethasone .Yun Ling et.al.Eur J 20. Jeffrey J.Kirshner, Kenneth W.Zamkoff, Arlan J.Gottlieb. Case report Haematol.2007:79(4):310-316 Idiopathic thrombocytopenic purpura and Hodgkin’s disease:report 13. John W Semple. et al. ITP three ‘R’s: regulation, routing, rituximab. of two cases and a review of the literature.Jeffrey J .Kirshner et.al.The Blood .2008;112:927-928. American Journal of the Medical Sciences. 1980;280(1):21-28. doi: 14. Piyush Vyas, Krzysztof Wózniak, Marta Dudek, Ewa Zurawińska 10.1097/00000441-198007000-00004 Grzelak,with metastatic Leszek duodenal Kraj, Mateusz cancer Cieślak. and idiopathic Chemotherapy Thrombocytopenic in a patient 21. LawrenceMichael Figueroa, Piro, Talisman Jane Gehlsen, Pomeroy. Denis Hammond,Combination Sharon chemotherapy Ondreyco,

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Citation: Int J Page 7 7 Hematol Blo Dis Piyush Vyas (2017) Immunopathology of Immune thrombocytopenia: Essentials for oncologists and haematologists. of 2(2). 1-7.