In Morning Report on December 7th, we discussed a fictional case of a patient presenting with epistaxis and gum bleeding for one month and platelet count of 19. We discussed an approach to thrombocytopenia which I’ve summarized below as well as some pearls on how to distinguish between the causes. Ultimately, our patient was diagnosed with immune thrombocytopenia (ITP) and we reviewed some pearls around this and tips on management.

1. Approach to Thrombocytopenia

This can be divided into three main categories, decreased production, sequestration, and increased destruction, see below:

Drug-induced thrombocytopenia can be related to marrow suppression, for instance examples would be linezolid, valproid acid, daptomycin, or gold compounds.

Drug-induced immune thrombocytopenia can be caused by several drugs, common examples include acetaminophen, amiodarone, carbamazepine, ceftriaxone, furosemide, ethambutol, rifampin, quinines, phenytoin, piperacillin, sulfonamides, vancomycin, Septra, among others.

Remember to also exclude pseudo-thrombocytopenia i.e. a falsely low platelet count which can occur in the setting of incompletely/inadequately anti-coagulated samples that may form a clot that traps platelets in the tube. In a small proportion of patients, this occurs when blood samples are exposed to EDTA anticoagulant leading to platelet clumping. A solution is to repeat using heparin or sodium citrate as an anticoagulant in the collection tube.

2. History and Physical Examination

Important elements on history to inquire about are:

• Prior platelet counts
• Bleeding history (petechiae, ecchymoses, epistaxis, gingival bleeding, hematemesis, melena, heavy menstrual bleeding)
• Family history of bleeding disorders
• Diet that could impact nutritional deficiencies
• Recent heparin exposures
• Medication history (see list above)
• Infectious exposures and assessing risk factors for HIV infection
• Other chronic medical conditions

On examination, the type of bleeding disorder that one may have can impact the physical examination manifestations. For instance, platelet function defects or thrombocytopenia will manifest differently on physical examination compared to clotting factor deficiencies:

Bleeding characteristics	Low platelets or platelet function defects	Clotting factor deficiencies or inhibitors
Sites bleeding	Epistaxis, gingival bleeding, GI/GU tract, menstrual bleeding	Joints, muscles, soft tissue hematomas
Types of bleeding	Common to get petechiae Generally small and superficial ecchymoses (depends on plt count)	Uncommon to get petechiae Large ecchymoses may develop
Other features	Excessive bleeding after small cuts Often immediate bleeding with surgery/invasive procedures (varies with the plt count and cause of dysfunction)	Don’t usually have excessive bleeding after small cuts Often have bleeding during invasive procedures (some experience delayed bleeding)

Assessment of neurologic status is important given TTP as a potential cause of thrombocytopenia. Examination should also include cardiac examination for prosthetic valve/murmurs, as well as lymph node examination, and assessment for organomegaly.

3. Investigations and How to Differentiate Between Causes

For heparin-induced thrombocytopenia (HIT), the 4T score is a common tool used to determine probability of heparin-induced thrombocytopenia. A score of ≤3 points: low probability for HIT, 4-5 points: intermediate probability, 6-8 points: high probability.

	2 points	1 point	0 points
Thrombocytopenia	> 50% fall or nadir >= 20 x 10^9/L	30-50% fall or nadir of platelets 10-19	< 30% fall or nadir < 10 x 10^9/L
Timing of decrease in platelet count	Days 5 to 10, or <= 1 day with recent heparin (in the past 30 days)	> Day 10 or timing unclear, or < day 1 if heparin exposure within past 30-100 days	< Day 4 (no recent heparin)
Thrombosis or other sequelae	Proven thrombosis, skin necrosis, or acute systemic reaction after heparin bolus	Progressive, recurrent, or silent thrombosis; erythematous skin lesions	None
Other causes of thrombocytopenia	None evident	Possible	Definite

In the references below, I have included an article from the American Society of Hematology (ASH) on the management of HIT.

In terms of other causes, one important distinction to be made is whether or not there are features of hemolysis. There are a few disorders that fall within the category of microangiopathic hemolytic anemia (MAHA) which are important to know.

Within the umbrella term of MAHA, are a group of disorders can thrombotic microangiopathies (or TMAs). TMAs are characterized by red blood cell destruction within the micro-vessels, thrombocytopenia and microthrombi leading to ischemic tissue injury.

An example of a TMA is thrombotic thrombocytopenic purpura (TTP) characterized by the pentad of hemolytic anemia, thrombocytopenia, renal impairment, neurologic deficits, and fever. There are various scoring tools that can be used, one of the main ones being the PLASMIC score. If TTP is the suspected diagnosis, the management of TTP is plasma exchange (you can send the ADAMTS13 level but this should not delay treatment).

Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia and renal damage in a patient with a history of diarrhea in the preceding two weeks. The causative agent is E coli O157:H7.

There is a scoring tool used for disseminated intravascular coagulation (DIC) which is called the ISTH (International Society of Thrombosis and Hemostasis) scoring tool can be found at this link.

4. ITP (Immune Thrombocytopenia)

The diagnosis of ITP relies on the fact that the platelet count is less than 100 in the absence of other causes.

This disorder is mediated by platelet antibodies that speed up platelet destruction and inhibit their production.

This is a diagnosis of exclusion, i.e. causes above including exposure to drugs, medications, or other disorders including causes of secondary ITP have been excluded.

The presentation involves mucosal bleeding, petechiae, wet purpura. In terms of investigations, testing for HIV or hepatitis C (or both) is indicated in at-risk populations. H. pylori testing should only be done if eradication therapy will be used – and testing is usually considered in chronic cases and those with gastrointestinal symptoms. The international guidelines state that H. pylori testing should be done in the initial work-up in appropriate geographical areas.

A small fraction of patients (~1%) coexisting autoimmune hemolytic anemia (Evans’ syndrome) and a smaller group have immune neutropenia. Immunoglobulin levels are measured if is a history of infection or allergy, or reaction to transfusions or IVIG, or if specific diagnoses are suspected such as common variable immunodeficiency or IgA deficiency.

If there is persistent fatigue and prior to splenectomy, TSH is checked. Anti-phospholipid antibodies are checked if there is a history of recurrent or T2/T3 pregnancy loss, thrombosis, or prolonged aPTT.

Testing for causes such as SLE would occur in patients with other findings that are suggestive of the diagnosis.

A bone marrow evaluation is not necessary to make a diagnosis of ITP.

5. Management of ITP

If platelet count is > 30 and the patient is asymptomatic or has minor mucocutaneous bleeding –> usually watch and wait approach. If someone has platelet count < 30 and is asymptomatic or has minor mucocutaneous bleeding, treatment includes:

• Glucocorticoids prednisone 0.5-2 mg/kg OR dexamethasone 40 mg x 4 days (glucocorticoids are the preferred initial therapy) or IVIG or anti-D therapy
• Other second line therapies include: splenectomy, rituximab, TPO-r agonists

In terms of admission to hospital, patients with profound mucocutaneous or internal bleeding, those presenting with platelet counts < 20, those in whom there is a question about compliance, or if responsiveness to therapy has not been established –> they should be admitted to hospital.

If there is critical bleeding, i.e. bleeding into a critical anatomical site or bleeding that causes hemodynamic instability or respiratory compromise –> treatment includes platelet transfusion, IVIG, steroids, and other treatments as needed (such as tranexamic acid).

If you have any questions or comments, please email me at cmr@wchospital.ca. Thanks for reading! 🙂

References:

1. Thrombocytopenia – Arnold, D. M. and Cuker, A. May 18, 2021. Diagnostic approach to the adult with unexplained thrombocytopenia. UpToDate article.
2. ITP – Douglas B. Cines, James B. Bussel, Howard A. Liebman, Eline T. Luning Prak; The ITP syndrome: pathogenic and clinical diversity. Blood 2009; 113 (26): 6511–6521. doi: https://doi.org/10.1182/blood-2009-01-129155. Accessed at https://ashpublications.org/blood/article/113/26/6511/26188/The-ITP-syndrome-pathogenic-and-clinical-diversity
3. ITP – Douglas B. Cines, James B. Bussel; How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005; 106 (7): 2244–2251. doi: https://doi.org/10.1182/blood-2004-12-4598 Accessed at https://ashpublications.org/blood/article/106/7/2244/21649/How-I-treat-idiopathic-thrombocytopenic-purpura
4. TMAs – Arnold DM, Patriquin CJ, Nazy I. Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ. 2017;189(4):E153-E159. doi:10.1503/cmaj.160142 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266569/
5. Heparin Induced Thrombocytopenia: Adam Cuker, Gowthami M. Arepally, Beng H. Chong, Douglas B. Cines, Andreas Greinacher, Yves Gruel, Lori A. Linkins, Stephen B. Rodner, Sixten Selleng, Theodore E. Warkentin, Ashleigh Wex, Reem A. Mustafa, Rebecca L. Morgan, Nancy Santesso; American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018; 2 (22): 3360–3392. doi: https://doi.org/10.1182/bloodadvances.2018024489 – https://ashpublications.org/bloodadvances/article/2/22/3360/16129/American-Society-of-Hematology-2018-guidelines-for
6. ITP International Guidelines – https://www-ncbi-nlm-nih-gov.myaccess.library.utoronto.ca/pmc/articles/PMC6880896/
7. 2019 ASH ITP Guidelines – https://www-ncbi-nlm-nih-gov.myaccess.library.utoronto.ca/pmc/articles/PMC6963252/