The normal platelet count is usually between 150,000 to 400,000/µL. The number represents the balance between platelet production, storage/pooling and degradation. Thrombocytopenia is generally defined as a platelet count of less than 150,000/µL.
Platelet counts are regulated by thrombopoietin, a hormone produced by the liver. This hormone acts on hematopoietic cells to differentiate and mature into megakaryocytes, contributing to the production of platelets. Thrombopoietin generally binds to c-Mpl receptor on platelets. In cases of low platelet counts, free thrombopoietin is more prevalent, and the free hormone increases megakaryocyte and platelet production. Conversely, free thrombopoietin levels decrease with higher platelet counts due to increased binding of thrombopoietin with platelet receptors, with subsequent clearance from circulation. Hence, platelet production decreases.
Since platelets help in hemostasis, coagulation and clot formation, the concern in patients with thrombocytopenia is a greater risk of bleeding. Risk of bleeding is higher with counts less than 50,000 and risk of spontaneous bleeding is greatest with counts less than 10,000. Risk of bleeding is also higher in cases of decreased platelet production when compared to consumptive reasons.
Platelet counts can be determined by examination of a blood sample. Platelets generally have a lifespan of about 7-10 days in peripheral blood, and can be lower in cases of thrombocytopenia.
II. Diagnostic Approach.
A. What is the differential diagnosis for this problem?
Etiologies of thrombocytopenia can be organized into three broad mechanisms:
Decreased platelet production
Myeloproliferative or lymphoproliferative disorders (acute or chronic leukemias, myelofibrosis).
Aplasia or hypoplasia (idiopathic, radiation, alcohol, or drugs – for example, chemotherapy, thiazide diuretics, and certain antibiotics).
Ineffective hematopoiesis (MDS, severe megaloblastic anemia in the setting of B12 or folate deficiency).
Increased platelet destruction or utilization
Immune Destruction: Idiopathic thrombocytopenic purpura (ITP), medication induced (caused by dozens, if not hundreds of medications; for example, heparin, quinidine, sulfonamides), infection (HIV, hepatitis, CMV, EBV), Evans syndrome.
Non-immune destruction: Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), preeclampsia/HELLP syndrome, IABP, hemangiomas, infection (bacterial, viral, malarial, tick-borne illnesses), sepsis.
Abnormal pooling or distribution
Splenomegaly, massive transfusion.
B. Describe a diagnostic approach/method to the patient with this problem.
The workup of thrombocytopenia begins with a detailed history and physical examination to help assess for possible etiologies, as well as manifestations of bleeding.
1. Historical information important in the diagnosis of this problem.
a. History of mucocutaneous bleeding – Since platelets are very important in hemostasis, a decrease in platelet count will predispose to mucosal bleeding. Epistaxis, gingival bleeding, rash or bruising on the skin, menorrhagia or abnormal vaginal bleeding in women, rectal bleeding (hematochezia or melena), hematuria, bleeding after surgeries, or dental procedures.
b. History of substance abuse – especially alcohol use that can contribute to low platelet count.
c. History of any recent infections or live virus vaccinations. History of recent travel, animal contacts, or insect bites.
d. History of liver disease and/or splenomegaly – including history of cirrhosis, jaundice, enlarged abdomen.
e. History of recent medications – including prescription, over-the-counter, and herbal medication and supplements.
f. History of malignancy – any treatment with chemotherapy or radiation.
g. Family history of bleeding or low platelet counts.
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
There are clues in the physical examination that may prompt an evaluation of platelet count or suggest other diseases commonly associated with thrombocytopenia.
a. General – pallor (especially if has had bleeding episodes or associated with anemia)
b. Dermatologic – petechiae, purpura, bruising, ecchymoses or skin rashes
c. Oral cavity – gingival bleeding, hemorrhagic blisters
d. Eyes – conjunctival or retinal bleeding
e. Abdomen – Splenomegaly – in some cases of thrombocytopenia, signs of liver disease including ascites, portal hypertension in cases of cirrhosis or in cases of lymphoma
f. Lymphadenopathy – in some cases of infection, lymphoma, etc.,
g. Neurological – neurological findings suggestive of CNS hemorrhage/stroke
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem
Thrombocytopenia may occasionally be a spurious finding, often as a result of platelet clumping. Sending a separate platelet count in a tube containing a non-EDTA anticoagulant (i.e., citrate) can avoid this problem. If thrombocytopenia is significant and out of context with the patient’s clinical picture, a repeat CBC is warranted before embarking on an extensive workup.
It is important to note whether the thrombocytopenia is occurring in isolation or if the CBC reveals involvement of other cell lines.
A peripheral smear should be examined both for platelet morphology and to assess for abnormalities in other cell lineages. Large platelets may raise suspicion for a destructive etiology. Similarly, schistocytes are associated with a microangiopathic process such as TTP/HUS or DIC. Blasts or other immature whites blood cells, as well as dysplastic cells, may indicate leukemia or myelodysplasia; leukoerythroblastic findings can indicate myelophthisis; while spherocytes point to hypersplenism related to hereditary spherocytosis.
HIV and HCV testing is appropriate if there has not been a recent evaluation.
Other laboratory tests should be obtained based on the initial workup and history. For example, presence of schistocytes or hemolytic anemia might prompt further workup with PT, PTT, fibrinogen, fibrin split products, LDH, and creatinine to elucidate if there is underlying DIC, HUS, or TTP. Similarly, a clinical picture consistent with an auto-immune disorder might be worked up with ANA or antiphospholipid antibodies.
In unexplained cases, bone marrow aspiration and biopsy may be useful. It will establish etiology of bone marrow processes as well as malignancies, iron deficiency, and can also indicate infections.
Ultrasound of the abdomen can help determine if splenomegaly is present. Ultrasound can also show presence of ascites and suggest cirrhosis in cases of liver disorders with portal hypertension.
Computed tomography (CT) Scan of the abdomen – can also characterize presence/features/size of splenomegaly, changes of portal hypertension, lymphadenopathy, and evidence of malignancy.
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Idiopathic thrombocytopenic purpura
Primary ITP is mediated by platelet autoantibodies that accelerate destruction. Secondary ITP is related to an underlying condition: common culprits include HIV, HCV, SLE and CLL. The clinical presentation is one of insidious mucocutaneous bleeding. CBC reveals an isolated thrombocytopenia with platelet count <100,000/µL. Primary ITP is a diagnosis of exclusion, made after other potential etiologies have been ruled out. There are no specific associated laboratory findings. Anti-platelet antibodies are neither sensitive nor specific, and are not required for diagnosis.
Hemolytic uremic syndrome/Thrombotic thrombocytopenic purpura
Both HUS and TTP fall in the spectrum of thrombotic microangiopathies, a pathological entity of abnormal arteriolar and capillary vessel walls, leading to microvascular thrombosis and thrombocytopenia with hemolytic anemia. In the case of TTP, this is due to a decrease in ADAMTS13 protease activity, leading to large von Willebrand Factor multimers on endothelial surfaces, which in turn cause platelet aggregation and thrombosis. In HUS, shiga toxin produced by Shigella and certain strains of E. Coli (classically, O157:H7) damages renal and vascular endothelial cells.
The full TTP pentad of thrombocytopenia, hemolytic anemia, changes in mental status, renal failure, and fever is rare, so suspicion should be raised when significant thrombocytopenia (generally <20,000 µL) occurs in the setting of hemolytic anemia. The peripheral smear may show schistocytes in both TTP and HUS. Presence of ADAMTS13 deficiency or inhibitor can be suggestive of TTP in the appropriate clinical context; however, the results are often not available in time to assist with immediate clinical decision making.
Clinical manifestations and laboratory findings for HUS are similar to TTP, often occurring in children and associated with a prodrome of bloody diarrhea secondary to enterohemorrhagic E. Coli.
Two forms of heparin-induced thrombocytopenia (HIT) exist. HIT Type 1 is related to a direct effect of heparin on platelets and has little clinical significance. It occurs within 1-4 days from the initiation of heparin therapy and is characterised by a platelet nadir of >100,000/µL. Heparin can generally be continued while the patient is observed.
In contrast, HIT Type 2 is mediated by IgG antibodies against platelet factor 4. Clinical manifestations include both thrombocytopenia and a propensity for thrombosis. The onset is typically after 4-10 days but can occur within 24 hours if there has been prior heparin exposure in the past 100 days. Platelet nadir is usually ~60,000/µL, or a decrease in platelet count of >50%.
The 4Ts score has been suggested as a tool to assess the probability of HIT (see Table I). A low score has a negative predictive value of 99.8%; intermediate and high probability scores have positive predictive values of 14% and 64% respectively. When HIT Type 2 is suspected, antibodies to heparin-PF4 should be sent. While this test is sensitive (>95%), false positives are not uncommon (specificity 50-89%). If diagnostic ambiguity remains or there is a discrepancy between clinical and laboratory findings, confirmatory testing with a functional assay (i.e., serotonin release assay) may be obtained (sensitivity 90-98%, specificity 90-95%), though the test must frequently be sent to an external laboratory for processing.
Disseminated intravascular coagulation
DIC is addressed in another chapter.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
Antiplatelet antibodies have a low sensitivity and specificity for ITP. Demonstration of antibodies is not required for establishing the diagnosis of ITP.
Antibodies to heparin-PF4 are unlikely to be helpful if pretest probability of HIT Type 2 is low, based on the 4Ts calculation.
III. Management while the Diagnostic Process is Proceeding.
A. Management of Clinical Problem Thrombocytopenia.
Platelet transfusion should be considered in patients with active bleeding and a platelet count <50,000/µL; it should also be considered in non-bleeding patients with platelets <10,000/µL to prevent spontaneous bleeding. Platelet transfusion is rarely required if platelets are over 50,000/µL.
Review of the patient’s medications is essential and culprit medications should be held or substituted with an alternative if possible. Most drug induced thrombocytopenia requires no specific treatment other than discontinuation of the offending medication. There is no high quality evidence for the role of glucocorticoids.
If clinical suspicion is high for HIT Type 2, heparin should be discontinued whilst the diagnostic workup unfolds. Platelet transfusions may increase the risk of thrombotic events and should be reserved unless there is active bleeding. Given the risk of thrombosis, the patient should be anticoagulated with a non-heparin anticoagulant (i.e., argatroban or bivalirudin) and started on warfarin when platelets have risen above 150,000/µL. An overlap of at least 5 days is recommended.
If TTP is highly suspected, consultation with a hematologist is helpful in determining the need for urgent plasma exchange, in addition to administration of glucocorticoids.
First line therapies for ITP include glucocorticoids and IVIG.
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.
Spurious thrombocytopenia is not uncommon. Clinicians should repeat a CBC and consider sending a platelet count in a non-EDTA collection tube before pursuing an extensive workup.
Cuker, A, Gimotty, PA, Crowther, MA. “Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis”. Blood. vol. 120. 15 November 2012.
Aster, RH, Bougie, DW.. “Drug-Induced Immune Thrombocytopenia”. N Engl J Med. vol. 357. 2007. pp. 580-587.
George, JN.. “Thrombotic Thrombocytopenic Purpura”. N Engl J Med. vol. 354. 2006. pp. 1927-1935.
Neunert, C, Lim, W, Crowther, M. “The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia”. Blood. vol. 117. 2011. pp. 4190
Kumar, A, Mhaskar, R, Grossman, BJ. “Platelet transfusion: a systematic review of the clinical evidence”. Transfusion. vol. 55. 2015. pp. 1116
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- I. Problem/Condition.
- II. Diagnostic Approach.
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem.
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding.
- A. Management of Clinical Problem Thrombocytopenia.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.