Immune Thrombocytopenic Purpura and Paradoxical Thrombosis: A Systematic Review of Case Reports

Background and Aims: Immune thrombocytopenic purpura (ITP) is an acquired bleeding disorder characterized by autoantibodies against platelets. The clinical presentation is variable; the main symptom is bleeding, and many patients are asymptomatic; others have nonspecific symptoms like fatigue. Uncommonly, ITP can present with paradoxical thrombosis. The risk of thrombosis in ITP may be higher than expected, which makes the management of ITP more challenging. This review aims to evaluate patients with ITP who develop thrombosis and identify potential risk factors related to thrombosis in this category of patients. Materials and Methods: English literature was searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for adults above 18 years with primary ITP who had infarctions or thrombotic events. Patients with secondary ITP were excluded. The search included articles published up to 20th October 2021. Results: A total of 73 articles were included. Seventy-seven patients with ITP had developed infarctions and various thrombotic events. Sixty-three patients had arterial events, and 14 patients developed venous thrombotic events. Conclusion: Patients with ITP have low platelets, which predispose them to bleed; despite that, serious thrombotic complications can happen in these patients and are difficult to predict. Therefore, it is critical for physicians to understand that ITP is paradoxically a prothrombotic condition and to address preventive thromboembolic measures whenever possible.


Introduction And Background
Immune thrombocytopenic purpura (ITP), previously known as Werlhof's Disease, is a hematological disorder [1] characterized by immune-mediated destruction of platelets and persistently decreased platelet count (PLT); hence, the bleeding tendency is the hallmark of the disease. ITP can be either primary or secondary to another disease such as autoimmune disease, malignancies like chronic lymphocytic leukemia, or infections like human immunodeficiency virus (HIV) and hepatitis C virus (HCV) or post-vaccine [2]. The underlying mechanism for thrombocytopenia in ITP is not fully understood. The possible mechanism is autoantibodies targeting platelet surface glycoproteins, such as GPIIb/IIIa and GPIb/IX complexes [3]. The diagnosis of ITP is usually made after secondary causes have been ruled out by a thorough history, physical examination, and investigations. ITP usually presents with bleeding, which is seen in up to two-thirds of patients, but a significant number of patients are asymptomatic. Patients with significant bleeding usually have PLTs below 20,000/mL; however, the relation between the plate count and bleeding risk is unclear [3]. Recently, thromboembolic events have been increasingly reported in patients with ITP despite the low PLT [4]. The presence of thrombosis and infarction in patients with ITP is an unexpected finding that can change the concept of ITP and fill the gaps in our understanding of the disease. In this review, we tried to study the reported cases of the thromboembolic phenomenon in patients with ITP with respect to patient characteristics, disease, and hematologic parameters at the time of thrombosis to understand the risk factors and underlying mechanisms.

Study Selection
Two independent reviewers examined the titles and abstracts of the records, excluding papers that did not meet our inclusion criteria. Inter-rater conflicts were settled with the help of a third reviewer and a discussion among the reviewers.

Data Extraction
Two reviewers extracted the date of publication, patient characteristics, treatment received, and the outcome.

Results
A total of 73 articles (Figure 1) reported 77 patients with ITP who developed thrombotic events or infarctions identified in Tables 1-2. Some 63 patients were with arterial events and 14 patients were with venous thrombotic events . Some 44 patients had chronic ITP, one with persistent ITP, and 18 with a new diagnosis (less than three months), one patient with a recent diagnosis with no duration was specified, and others had ITP with no clear mention of onset or time of diagnosis. Some 38 patients were females, and 40 were males. The youngest patient was 18 years old, and the most senior was 83 years old. The mean age at the time of the event was 55.4 years, The mean age of venous thrombosis patients was 44.5 years, and the mean age of arterial thrombosis patients was 57.8 years. Thrombotic events affected different organs and locations; 14 patients had a stroke (infarction), 48 patients had coronary artery disease (ACS MI 3VD), one patient with cutaneous infarction, and one with mural aortic thrombus ( Table 1). Some 14 patients had venous thrombotic events, including venous thrombosis in the central nervous system (venous sinus thrombosis) as well as thrombosis in the portal vein axillary brachial and jugular veins and intracardiac thrombus ( Table 2). Treatment modalities used for ITP include patients, not on medication n=8, steroids n=39, danazol n=3, splenectomy n=10, one patient with splenic artery embolization, intravenous immune globulin (IVIG) n=13, platelet transfusion n=3, a thrombopoietin receptor agonist eltrombopag n=9, romiplostim n=3, rituximab n=1, and 17 patients with no mention of previous treatment.   Among patients with ITP with known duration (n=47), the mean duration of ITP to thrombotic events was 7.58 years, with the most prolonged duration being 30 years. The mean time for the development of venous thrombosis was 4.9 years, while for arterial thrombosis was 8.12 years. The mean PLT count during the time of thrombosis was 90.2 x 109/L in 75 patients, the mean PLT for patients with venous thrombosis was 156.7 x 109/L, while those with arterial thrombosis were 77.1 x 109/L. The lowest PLT associated with thrombosis was 1 x 109/L, and the highest PLT was 658 x 109/L. However, most patients (n=66) had thrombosis with a PLT below 100 x 109/L, and 50 patients had PLT below 50 x 109/L. Seven events happened while being treated with IVIG, five were arterial events, and two were venous thrombotic events.

Reference
Regarding comorbidities, 32 patients had no significant past medical history (PMH) or were not reported. The most commonly reported medical condition was hypertension in 23 patients, followed by diabetes mellitus in 16 patients and prediabetes in one patient, and dyslipidemia in eight patients. Cardiac valve defects in four patients and asthma in one patient, smoking in nine patients, and coronary artery disease in seven patients. Among all patients, mortality was reported in five patients from complications related to thrombosis or infarction. Some 12 patients had developed another complication after admission; another thrombotic event or infarction. Among them, seven had cardiac thrombotic events, including ischemia and stent thrombosis, three cerebrovascular events, and one had venous thromboses.

Discussion
Thrombosis is a process characterized by complex pathophysiology. Generally, thrombosis occurs when one or more of Virchow's triads are present; blood stasis, endothelial injury, or hypercoagulable states. In arterial thrombosis, the main culprit is endothelial injury, while in venous thrombosis, the etiology can be explained by the stasis of blood in veins and procoagulant states are the underlying factors favoring thrombosis. ITP commonly presents with bleeding and paradoxically sometimes it presents with thrombosis [3]. To understand the link between the two paradoxical processes, the existing data and evidence suggest an increased incidence of thromboembolism in patients with ITP [79]. However, the role of patient characteristics including age, gender, duration of ITP, and treatments used and the hematological parameters at the time of the event, was not mentioned before in previous systematic reviews [80] and other studies included patients based on diagnosis from the code without elaborating the inclusion and exclusion criteria [81].
Although there is a slightly higher incidence of ITP in young females [82]. Our review found out that among the patients with ITP, both genders are prone to develop paradoxical thromboembolic complications with slightly higher numbers in males. But considering that coronary artery disease is more common in males, it is expected to have males being more affected by cardiac events [83] including patients with ITP ( Table 3). This supports that gender has no significant role in the pathogenesis of thrombosis.

ITP, immune thrombocytopenic purpura
It is clear that in ITP, a low PLT is not protective against thrombosis and infarction. In this review, the data show that thrombosis can occur in all stages of ITP, including patients with a new diagnosis, persistent, and chronic ITP (with the persistent stage being the least risky phase); this includes both patients on treatment and patients who were managed expectantly. This suggests that the ITP itself has the potential for being a prothrombotic state. Additionally, among ITP patients who developed thrombosis, a large percentage of them had developed a second thrombotic event after admission or discharge. This suggests that ITP is a disease that carries not only a prothrombotic state but with a significant risk of recurrence or complications as 13/78 patients develop a second event. Additionally, many patients had both arterial and venous thrombotic events making ITP a rare cause of arterial and venous thrombosis as in patients number [63,76]. Although most patients who had events had PLT above 100, there is no clear-cut number of platelets that are safe to prevent thrombosis in patients with ITP; as thrombosis was observed in patients with low PLT as well low as 1 x 109/L. However, the presence of other factors predisposing to infarction and thrombosis, including age-advanced atherosclerosis, uncontrolled blood pressure, and diabetes, could have marked effects [84].
Patients with ITP have low platelets and most guidelines recommend avoiding the use of antiplatelet agents or anticoagulation when PLT is less than 50,000 x 109/L. The major difficulty is that there is no anticoagulant that can treat thrombosis without also increasing the chance of bleeding. Therefore, patients with ITP with thrombosis are difficult to manage and there is no unified treatment plan in such a situation; although, many experts recommend platelet transfusion to increase PLT to a safe level and then to give anticoagulation or antiplatelet.

Limitations
This review focuses on studying the impact of patient characteristics, disease course, and treatment modalities on the incidence of thromboembolism in patients with ITP. As such events are rare; mainly case reports have been studied with no control population and a very small sample size of 73 articles.

Theory
There are many theories that can explain unexpected thrombosis and infarction in patients with ITP. First, persistent activation of the immune system leads to accelerated atherosclerosis as in other autoimmune conditions, predisposing the patient to arterial thrombotic events [85]. Interestingly, platelet microparticles (PMPs) have been found to play a significant role in thrombus development in ITP. Platelet microparticles are minute vesicles formed by platelet membranes that are undetectable during routine platelet counting and are usually produced in association with platelet activation [86]. PMP levels were found to be higher in ITP patients compared to a control population without ITP in many studies, and they were also proven to be protective against hemorrhage. PMPs, in excess, can increase the synthesis of thrombin. They are hypothesized to play a function in clot formation as a result [87]. At the moment there is no specific treatment that can target the platelet microparticles. The treatment used is another probable cause for thrombus development in ITP. First, IVIGs can cause thrombosis by raising blood viscosity [88] and thrombin generation, as well as by directly influencing the vascular endothelium, which results in higher amounts of von Willebrand factor (vWF) antigen. Some studies showed elevated levels of vWF in ITP patients, particularly patients with long-standing diseases. Additionally, thromboelastography showed a relatively higher thrombotic tendency correlating to elevated levels of the vWF antigen levels [89]. Thrombopoietin receptor agonists are newer agents added to ITP treatment almost in the last decade. These are platelet growth factors that act on megakaryocytes and megakaryocyte precursors in the same way that endogenous thyroid peroxidase (TPO) does, boosting their growth, differentiation, and enhancing platelet production [90]. Elevated PLT beyond the target level is an expected side effect that probably plays a pivotal role in raising the risk of thrombotic events in patients treated with thrombopoietin receptor agonists. Despite that, thrombotic events have been reported with PLT that is lower than normal in patients treated with TPO-Ras, favoring the fact that megakaryocyte activation itself leads to an increased risk of thrombosis prior to the rise in PLT [91]. Additionally, manufacturers recommend using the lowest minimal dose to keep PLT above 50 x 109/L and not to aim for normal PLT. This supports that platelets in ITP are active, and patients rarely report bleeding compared to patients with the same count in other diseases [92]; this may be related to younger platelets with more hemostatic effect. Observational studies of ITP patients treated with thrombopoietin receptor agonists have revealed a modestly higher rate of thrombosis [90,93]. The data showed that nine patients had treatment with eltrombopag; all of them had PLT above 100 x 109/L at the time of the thrombosis except one patient who had a PLT of 22 x 109/L. This emphasizes the need for frequent monitoring of PLT in patients on TPO-Ras to avoid the rise of PLT above the target and subsequent development of thrombosis. However, it is important to note that three of the nine patients who were on TPO-Ras had a splenectomy because splenectomy can result in an increase in the number of active circulating platelets and prolong their lifespan which can contribute to thrombosis.

Conclusions
Although patients with ITP are prone to life-threatening bleeding, it is crucial to know that ITP patients are susceptible to thromboembolic phenomenon. These events can occur at any stage of the disease in both patients on active treatment and those not on medications and with various PLT. All patients with chronic active ITP treated with IVIG or TPO-RA should be observed closely for any thromboembolic events. The question of thromboprophylaxis use despite low PLT, especially if no active bleeding, is yet to be answered and needs further studies and trials. We recommend, ITP patients to be evaluated for the risk of thrombosis and atherosclerotic disease to avoid difficult situation where patient has low PLT and he or she requires anticoagulation.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.