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John George, PA-C
Key Words: bruising, thrombocytopenia, ITP, petechiae, purpura, spontaneous bleeding
Introduction
Patients commonly present to Urgent Care with concerns of unexpected bleeding, bruising, and rashes that may be petechiae or purpura. Laboratory testing should be performed if suspicion is high for thrombocytopenia or other bleeding disorders, and if abnormal or if bleeding is severe, patients should be referred to the emergency department.
History
A 36-year-old female presents to Urgent Care with a complaint of bruising on her body for the past 3 days. She also complained of fatigue and myalgia. She stated she had some nasal congestion a week ago that had since resolved. She states she scratched herself in the chest area 3 days ago and subsequently noticed a big bruise in the area. This resolved, but now she has scattered bruising to her arms and legs. The patient notes a past medical history of anxiety and depression, an episode of optic neuritis of unknown etiology about 10 years ago. She also notes she is 6 months postpartum and presently breastfeeding. According to the patient, there were no complications in the last pregnancy. She has had three prior miscarriages prior to 12 weeks gestation. She denies OCP use, any new medications, current pregnancy, personal or family history of thrombocytopenia or autoimmune disease, mucosal, vaginal, rectal, or urinary bleeding, recent trauma, chest pain, shortness of breath, abdominal pain, UTI symptoms, fever, chills, cough, sore throat, any new exposures, insect bites, recent travel, hiking or camping, blurry vision, headaches, dizziness, nausea, vomiting, numbness, or tingling. She voiced no other complaints. She has never had COVID-19 as far as she is aware; her last COVID-19 vaccine was >1 year prior. She had an influenza vaccine approximately 3 months ago. She has been taking sertraline for the last 6 months. She is allergic to sulfa and moxifloxacin.
Clinical Findings
T: 98.7 *F HR: 84 BP:124/78 RR:16 Spo2: 98%
Physical exam: A basic exam was grossly normal. Examination of the skin revealed a few scattered ecchymoses and petechial rashes on the bilateral arms and legs. The face and trunk were spared.
Assessment
The initial impression was that of a previously healthy postpartum female with possible inappropriate bruising, rash, and fatigue after a suspected viral upper respiratory infection. Although this could be nothing more than normal trauma, there was concern for more serious illness such as an acquired bleeding disorder.
The in-house pregnancy test was negative, and a urinalysis was unremarkable.
A STAT complete blood count (CBC) and comprehensive metabolic profile (CMP) were sent to the laboratory. The platelet count was 5,000/microL [Normal: 150,000-450,000/microliter]. The remainder of the CBC and CMP were unremarkable.
Therapeutic intervention
The patient was called about the abnormal platelet count and was advised to proceed immediately to the emergency department for further evaluation and treatment.
Follow-up
At the hospital, a respiratory virus panel was positive for entero/rhinovirus, and negative for COVID-19. HIV, RPR, Hepatitis panel, ANA, and Parvovirus Antibody were all negative.
Hematology was consulted, and the patient was started on 40 mg IV dexamethasone daily for 3 days and pantoprazole 40 mg. She was admitted to the hospital. Breastfeeding was discontinued. The patient was hospitalized for three days and discharged on oral prednisone and was advised outpatient follow-up with hematology. No platelet transfusion was required. Upon discharge, her platelet count had increased to 19,000/microL.
Discussion
Idiopathic thrombocytopenia purpura (ITP) is an acquired thrombocytopenia, which is caused by the destruction of platelets in the reticuloendothelial system due to platelet autoantibodies. This results in destruction as well as underproduction of platelets. (Song) It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults. The lack of a sensitive or specific diagnostic test for ITP and the large number of other potential causes of thrombocytopenia (e.g. drug-induced thrombocytopenia, hereditary thrombocytopenia) also contribute to the challenges in diagnosing ITP.
Primary ITP is an acquired immune thrombocytopenia due to autoimmune mechanisms, which leads to platelet destruction and platelet underproduction. Primary ITP is not triggered by an associated condition.
Secondary ITP however is precipitated by another condition. The list is long and comprises immunologic, hematologic, and infectious conditions. (See Figure 1) Drug-induced immune thrombocytopenia (DITP) is thrombocytopenia due to drug-dependent platelet antibodies that cause platelet destruction. This syndrome should be distinguished from drug-induced bone marrow suppression, a non- immune phenomenon. See Figure 2 for a list of common offending drugs.
The interval between initiation of a new drug taken daily and drug induced ITP (DITP) is usually less than two weeks. A drug taken daily for several months or longer is rarely associated with DITP. Drugs taken only intermittently may cause DITP even if it has been many years since the initial exposure.
COVID-19 vaccines were initially suspected of causing ITP and exacerbating existing ITP, however, there is no current evidence to support this. (Pishko) ITP rates after a COVID-19 vaccination are no higher than in the general population. Thrombocytopenia may be mistaken for ITP when due to chronic liver disease, hypersplenism, bone marrow suppression, transient drops in platelet counts from infection, or hereditary thrombocytopenia.
ITP may be seen in otherwise healthy pregnant women on their initial pregnancy lab testing. However, pregnancy is also associated with other causes of thrombocytopenia including gestational thrombocytopenia (a physiologic condition) and pregnancy-associated microangiopathic syndromes.
ITP in children, especially in children younger than age 10, is a clinically distinct condition compared to that in adults, with a higher likelihood of spontaneous remission, a lower incidence of underlying diseases and comorbidities, and often a lower risk of bleeding. During adolescence, ITP may be similar to typical childhood ITP or to ITP in adults.
ITP is further categorized into the time elapsed since diagnosis. ITP is newly diagnosed as ITP in the first 3 months and persistent if lasting three months to 12 months and chronic if more than 12 months.
The pathogenesis of ITP is likely multifactorial. Reduced platelet lifespan due to clearance is the predominant cause of thrombocytopenia. The principal mechanism is thought to involve specific autoantibodies (typically, IgG) most often directed against platelet membrane glycoproteins such as GPIIb/IIIa. (Cines) The primary site of platelet clearance for most patients is the spleen, which removes opsonized (antibody coated) cells including platelets. Other mechanisms that may play a role include autoreactive cytotoxic T cells as well as humoral and cellular autoimmunity directed at megakaryocytes which causes impaired platelet production.
In the US, the prevalence of ITP is approximately 8 per 100,000 in children and 12 per 100,000 in adults. (Terrell) In younger patients, it is felt that ITP is more common in females, however, there is some debate about this. There is a similar incidence in males and females over age 60.
Clinical manifestations
Patients with ITP can be expected to have normal WBC and RBC counts as there is no effect on these cell lines. Coagulation parameters are also typically normal. Abnormal results of WBC, RBC, or coagulation should prompt an urgent evaluation for conditions other than ITP such as leukemia, thrombotic thrombocytopenia purpura (TTP), disseminated intravascular coagulation (DIC), or aplastic anemia.
Diagnosis
ITP is a diagnosis of exclusion that is made in patients with isolated thrombocytopenia with other cell lines remaining normal. Other possible causes of thrombocytopenia should be ruled out, and conditions that may be responsible for secondary ITP should be considered. Many potential causes will be apparent from the history, physical examination, and review of the complete blood count (CBC). Keep in mind that thrombocytopenia caused by a medication or previous illness may require specific questioning or review of the medical record to identify the responsible agent. The history should be focused on recent infections, medications, underlying conditions such as rheumatologic disorders and liver disease, beverages such as tonic water, herbal remedies, and foods.
The physical examination should be focused on signs of bleeding, specifically on the skin and oral mucous membranes, which would suggest the need for more urgent evaluation and therapy; and the presence of lymphadenopathy or hepatosplenomegaly, which could suggest an underlying condition responsible for the thrombocytopenia.
All patients should have a peripheral smear as platelet clumping may give an erroneous low platelet count. HIV and HCV testing should be performed. Liver function testing should be performed. Coagulation studies such as PT and PTT should be done in any patient with clinically significant bleeding. Testing for H. pylori and thyroid testing may also be reasonable in evaluation for secondary causes of ITP. Bone marrow biopsies are no longer recommended. (Neunert) Immunologic studies, such as ANA, etc. are also not routinely recommended, except if there is a suspicion of an underlying immunologic disorder. Antiplatelet antibody testing has a low sensitivity and has no correlation with clinical outcomes and is not recommended.
Treatment
For patients with presumed or known ITP who have severe bleeding, urgent hospitalization with early involvement of a hematologist is necessary to confirm the diagnosis, exclude other potential causes of bleeding, and assist with appropriate therapies. Bleeding should be controlled in traditional ways with direct pressure, nasal packing, etc. Individuals with thrombocytopenia with platelet counts > 20,000/microL that are stable without bleeding may be managed as outpatients if there is close hematologic monitoring and a plan for urgent management of bleeding. Patient education and expedited follow up with a hematologist should be arranged. Patients with platelet counts < 20,000/microL, whether bleeding or not, should be evaluated in the hospital due to the increased risk of bleeding. (Neunert). Long term management of ITP is aimed at preventing significant bleeding, not necessarily to normalize the platelet count. Any secondary causes should be eliminated, if possible, such as drugs and infections. Corticosteroids are often used as initial treatment and in cases of minor bleeding, followed by intravenous immune globulin (IVIG). Anti-D immune globulin may be an alternative to IVIG. Platelet transfusions are reserved for severe or refractory bleeding. TPO-RA’s and rituximab may also be considered. Definitive care may require splenectomy. Generally, patients who do not improve within 1 year are considered for splenectomy.
Informed Consent
Consent for publication of this case was not obtained as the patient was unable to be reached.
References
Song F, Al-Samkari H, Management of Adult Patients with Immune Thrombocytopenia (ITP): A Review on Current Guidance and Experience from Clinical Practice, Journal of Blood Medicine, 2021 12:, 653-664, DOI: 10.2147/JBM.S259101
Pishko AM, Bussel JB, Cines DB. COVID-19 vaccination and immune thrombocytopenia. Nat Med. 2021 Jul;27(7):1145-1146. doi: 10.1038/s41591-021-01419-1. PMID: 34108715.
Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002 Mar 28;346(13):995-1008. doi: 10.1056/NEJMra010501. PMID: 11919310.
Terrell DR, Beebe LA, Neas BR, Vesely SK, Segal JB, George JN. Prevalence of primary immune thrombocytopenia in Oklahoma. Am J Hematol. 2012 Sep;87(9):848-52. doi: 10.1002/ajh.23262. Epub 2012 Jun 5. PMID: 22674643; PMCID: PMC3429719.
Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, George JN, Grace RF, Kühne T, Kuter DJ, Lim W, McCrae KR, Pruitt B, Shimanek H, Vesely SK. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum in: Blood Adv. 2020 Jan 28;4(2):252. PMID: 31794604; PMCID: PMC69632