Immunology

October 2014

Clinical

Incidentally detected thrombocytopaenia in adults

Volume 43, No.10, October 2014 Pages 700-704

Shweta Sharma

Hannah Rose

Background

With the advent of automated counters, low platelet counts are a common incidental finding. The list of possible aetiologies is long and exhaustive (Figure 1, available online only). Platelet abnormalities range from having no clinical relevance to being the only initial manifestation of a serious underlying disorder.1,2

Objective/s

This article provides general practitioners with an approach to differentiating the benign from the life-threatening causes of thrombocytopenia using routine pathology testing in adults.

Discussion

There are no specific laboratory tests that can conclusively identify the mechanism of thrombocytopenia – a thorough history, clinical examination, and blood results remain the initial means of diagnosis.

Clinical-Sharma-FIG2.jpg
Figure 1. Aetiology of thrombocytopaenia5
*Less likely to result in isolated thrombocytopenia

Proposed approach to thrombocytopenia

Is it real?

Artefactual thrombocytopenia is found in about 1 in 1000 blood test results and can be a result of platelet aggregation, collection errors and/or platelet satellitism. An unexpected result, therefore, warrants a repeat test.3 In vitro clumping of platelets can occur when EDTA is used as an anticoagulant in the test tubes used for blood collection. This is thought to result from alteration of the platelet surface glycoproteins when incubated with a calcium chelator such as EDTA. As neither citrate nor heparins produce this phenomenon when used as anticoagulants, simultaneous collection of repeat blood in EDTA (used for full blood evaluation) as well as citrated test tubes (coagulation tubes) will confirm pseudo-thrombocytopenia.4 Alternatively, the platelet count can be determined by the laboratory haematologist using automated CD61 immunoplatelet analysis. A peripheral blood film is also vital in ruling out the possibility of clots for alternative reasons.

Is it new?

The previous blood results should be reassessed. A low platelet count may be normal for the patient and not represent illness. By definition, reference ranges would encompass only 95% of the population.5 In addition, a chronically mildly low platelet count (50–100 x 109/L) in a stable/asymptomatic patient with no other cytopaenias could be safely monitored. For example, slowly reducing platelet counts in a patient with chronic liver disease does not warrant an urgent referral.

Is it isolated?

Confirm that thrombocytopenia is isolated (ie. the full blood evaluation is otherwise normal and there are no red or white blood cell abnormalities on a peripheral blood film. An abnormal blood film with the presence of blast cells and/or any dysplastic changes warrants urgent referral (Table 1).

Table 1. Red flags

Red flags

Differential diagnoses

Clinical/laboratory findings

Management

Presence of bleeding

  • Thrombocytopenia due to any cause
  • Coagulation disorder

Mucosal or cutaneous bleeding
Easy bruising, profuse bleeding from superficial trauma, menorrhagia, metorrhagia, or melena

Urgent haematologist/emergency department referral

Presence of blasts on peripheral blood film

  • Haematological malignancy

May be none
Lymphadenopathy and/or splenomegaly raise suspicion

Urgent haematologist referral

Evidence of haemolysis with the presence of neurological findings and renal dysfunction

  • TTP
  • HUS
The classic pentad:
  • (MAHA)
  • thrombocytopenia
  • fever
  • neurological findings*
  • renal dysfunction**
(all five of these may not always be present).
Haemolysis screen includes:
  • FBE and film
  • reticulocyte count
  • direct and indirect antibody test (Coombs)
  • lactate dehydrogenase
  • haptoglobin
  • urinary haemosiderin
  • haemoglobin11,34
HUS most commonly occurs after colitis resulting from Escherichia coli O157:H735

Early diagnosis and referral for plasmapheresis

Recent use of heparin or presence of skin necrosis on examination

  • HIT

HIT screen:
FBE
heparin-dependent platelet antibody, including assessing for cross-reactivity of the patients antibody with heparins and heparinoids11
Higher risk of HIT with previous exposure to unfractionated heparin, recent surgery and if the patient is female36

Cease heparin and avoid subsequent heparin therapy

Associated coagulation abnormalities

  • DIC

Platelets, fibrinogen and coagulation factors are being consumed. Hence these would be reduced
D-dimer, a marker for clot breakdown, would be elevated along with INR and PTT33

Urgent referral to the emergency department

Age >60 years and dysplastic features on peripheral film

  • MDS
  • Leukaemia

More common for patients to present with anaemia and/or leukopaenia, but isolated thrombocytopenia may be the sole manifestation.

Referral of patients >60 years to a haematologist may be warranted

*Neurological signs: seizures, headaches, blurred vision, ataxia, change in mental status/fluctuating focal signs (ie motor deficits, diplopia, or aphasia)37
**Reduced urinary output or serum creatinine rise
DIC, disseminated intravascular coagulopathy; FBE, full blood evaluation; HIT, heparin-induced thrombocytopenia; HUS, haemolytic uraemic syndrome; INR, international normalised ratio; MAHA, microangiopathic haemolytic anaemia; MDS, myelodysplastic disorder; PTT, partical thromboplastin time; TTP, thrombotic thrombocytopenia

Is the patient pregnant?

Thrombocytopenia in pregnancy deserves special consideration because, rarely, it may have disastrous consequences for the fetus.6 Gestational thrombocytopenia is a common cause of mild thrombocytopenia (100–150 x 109/L). It is seen in up to 9% of pregnancies but must be differentiated from immune-mediated thrombocytopenia, which has a similar presentation (Table 2).6,7,9 At this stage, however, there is little information in the literature to guide the frequency of platelet counts in such patients. Non-urgent review by a haematologist is prudent.

Table 2. General guidelines for thrombocytopenia in pregnancy

Gestational thrombocytopenia

Immune thrombocytopenia

  • No past history of thrombocytopenia
  • Asymptomatic
  • Mild (platelet count (100–150 x 109/L)
  • Occurs late in the pregnancy or at term
  • Not associated with significant bleeding risk
  • No association with fetal thrombocytopenia
  • Self-resolves following delivery
  • Occurs early in the pregnancy
  • May have a history of chronically low platelets
  • Low platelet count (<50 x 109/L)
  • Severe thrombocytopenia may develop in the infant in the first few days following delivery

It is important to keep in mind that serious obstetric emergencies such as the HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and disseminated intravascular coagulopathy (DIC), may be underlying, albeit rare, causes of thrombocytopenia (Table 1).8

Medication review

There is a wide range of medications associated with thrombocytopenia (Table 3). Although the most common presentation of drug-induced thrombocytopenia is severe symptomatic haemorrhage, an abnormal platelet count may be the first evidence of potential problems. Changes in medications over the past 10 days should be assessed. Normally it takes at least 5 days of drug exposure to develop thrombocytopenia, but as little as a few hours may be all that is required for fibrans and abciximab, or if the patient has been exposed to the drug previously.10

Table 3. Medications/mechanisms associated with thrombocytopenia10
  • Immune-mediated mechanism (eg quinine, consumed through tonic water)
  • Drug–hapten-induced haemolysis (eg penicillin, cephalosporins, tetracytcline, tolbutamide, semi-synthetic penicillins)
  • Fiban-dependent antibodies (eg tirofiban)
  • Monoclonal antibodies (eg abciximab)
  • Autoantibody formation (eg gold)
  • Immune complex formation (eg heparin)

The most commonly implicated drugs are quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin and chemotherapy drugs10

The gold standard for confirming this diagnosis is a drug re-challenge but this is rather impractical. A common pitfall is to refer to a haematologist without ceasing the suspected medications. As a general rule, cease the drug if suspicious. Investigations such as an indirect Coombs test, ELISA and flow cytometry may aid in the diagnosis and can be discussed with the laboratory haematologist.10,11

Presence of risk factors for chronic liver disease

Thrombocytopenia may be seen in up to 76% of patients with chronic liver disease (CLD).12 If there is clinical suspicion of high alcohol use, hepatitis, intrinsic liver disease or obstruction, clinical assessment for stigmata of CLD followed by formal liver function tests are warranted. Further assessment of cirrhosis by ultrasonography or other modality may also be indicated, but an urgent referral to the haematologist may not be required.

Distributional thrombocytopenia

The spleen normally sequesters 30–35% of the body’s platelets, but this can rise to 80–90% when it is enlarged, causing thrombocytopenia.13 Routine assessment of splenomegaly on clinical examination is important.

Concurrent B12 and folic acid deficiency

About 20% of patients with megaloblastic anaemia due to vitamin B12 and folic acid deficiency also have thrombocytopenia. These deficiencies should be suspected in patients with excess alcohol use or malnourishment, and the elderly with poor oral intake.14,15

Risk factors for HIV, hepatitis C and/or recent infections or live vaccinations

Infections or live vaccinations may cause thrombocytopenia by direct bone marrow suppression or increased peripheral consumption. An isolated low platelet count may be the initial manifestation of disease in as many as 10% of patients with HIV.16,17 Some of the other commonly associated viruses include Epstein-Barr virus, cytomegalovirus, rubella virus, parvovirus B19 and mumps.18

Suspected systemic autoimmune disorder

There is an association between systemic autoimmune disorders such as systemic lupus erythematosus (SLE) and the antiphospholipid syndrome and thrombocytopenia.19 One study found that 29 out of 50 patients (58%) diagnosed with SLE had thrombocytopenia at the time of diagnosis and this was associated with higher morbidity, affecting overall prognosis.20 Thus, investigations for antibodies may be warranted in the presence of suggestive symptoms; however, routine testing does not need to be performed as there is no gold standard diagnostic test. Additionally, false positives as well as weak true positive results are not uncommon.21

Consider congenital thrombocytopenia

Congenital conditions that cause thrombocytopenia are quite heterogenous and uncommon. They usually present in the paediatric age group with bleeding diathesis. Mild cases, however, may remain undiagnosed until older age. This group may remain completely asymptomatic or may have only sporadic thrombocytopenia during times of haemostatic stress (eg. surgery, trauma, etc); careful history taking is key.

Previous history of easy bruising, prolonged bleeding or petechiae and a family history raise suspicion. The diagnosis may be narrowed further if ‘giant platelets’ or microthrombytes are found in a peripheral blood smear.22 If congenital aetiology is highly suspected, a haematologist referral is indicated.

Immune thrombocytopenic purpura (ITP)

ITP is an immune disorder characterised by isolated thrombocytopenia and is strictly a diagnosis of exclusion. The incidence is estimated at approximately 1.6–3.9 per 100,000 person years.23 It is caused by increased platelet clearance and decreased production, but the details of how these develop are complex and for the most part remain undetermined.

The primary treatment goal is to prevent severe bleeding rather than achieve normal platelet counts. In general, almost half of the new diagnoses of primary ITP do not require treatment and there is also no gold standard investigation.25 Response to ITP-specific therapy is supportive of the diagnosis.26 It is important to mention that the prevalence of thyroid disorders is greater in people with ITP than the general population. Testing thyroid function in patients with ITP may be beneficial.

Red flags – when is immediate referral required?

Presence of blasts on a blood film

Presence of blast cells and/or any dysplastic changes is likely to be the first presentation of a haematological malignancy.27

Evidence of haemolysis with or without neurological findings and renal dysfunction

Thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are multi-system disorders characterised by thrombocytopenia and microangiopathic haemolytic anaemia (MAHA) (Table 1). TTP and HUS are life-threatening illnesses; TTP has a mortality rate of >90% without appropriate treatment.28

Recent use of heparin or presence of skin necrosis on examination

Heparin-induced thrombocytopenia (HIT) is a hypersensitivity reaction to unfractionated heparin and low molecular weight heparin mediated by an IgG antibody.29 One study found that the risk of HIT with low molecular weight heparin was lower (0.2%), compared with unfractionated heparin (2.6%).30 There are two forms of HIT, type I and type II. Type I HIT occurs more frequently and does not require cessation of therapy. Type II is immune-mediated and can cause venous or arterial thrombosis, which may be fatal or require limb amputation. In general, about half of the patients with HIT also have thrombosis.31 In a critical situation, there is no test that can be performed with sufficient speed, sensitivity and specificity; therefore, the diagnosis is primarily clinical.31 This is a medical emergency. The in-patient mortality for HIT is up to 20%.32

Associated coagulation abnormalities

Acute or chronic disseminated intravascular coagulopathy is a consumptive coagulopathy associated with end-organ damage. It may present with a background of many conditions including pregnancy, malignancies and systemic infections.33 Essentially clotting and clot breakdown are occurring simultaneously. There is no single laboratory test for diagnosis (Table 4).

Table 4. Investigations for thrombocytopenia in an asymptomatic patient

First-line investigations

Not routine/ordered by specialist

FBE and peripheral blood film
Platelet indices (size and volume): limited value
Fibrinogen, D-dimer, clotting factors
Haemolysis screen (see Table 3)
Vitamin B12 and folic acid levels
Liver function tests
HIV and hepatitis serology1
Stool for occult blood
Renal function (deranged in TTP/HUS)

Anti-platelet antibody test39
Tests for SLE, anti-phospholipid syndrome
Quantitative immunoglobulin level
Bone marrow biopsy
Helicobacter pylori (ITP refractory to treatment)
Thyroid function tests

FBE, full blood evaluation; HUS, haemolytic uraemic syndrome; ITP, immune thrombocytopenic purpura; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura

Older age (>60 years) and dysplastic features on peripheral film

Myelodysplasia describes the abnormal development of one or more of the three major haematopoietic lineages (ie. red blood cells, while blood cells, platelets). These are pre-leukaemic disorders, more common in people older than 60 years and warrant particular attention as they may manifest solely as isolated thrombocytopenia with subtle changes on peripheral film. They should be considered in all patients >60 years of age with progressive or significant thrombocytopenia (<50 x 109/L). As a guide, bone marrow tests are appropriate people aged over 60 years who have thrombocytopenia but are otherwise asymptomatic.1

Suggested management in the absence of red flags

Clinical-Sharma-FIG1.jpg

After excluding red flags and other common causes listed above, patients with modest decreases (50–100 x 109/L) but are asymptomatic may have a repeat test in 1–2 weeks. Broad clinical referral guidelines based on the ranges of laboratory values can be useful (Figure 2, available online only). With minimum degrees of asymptomatic thrombocytopenia (100–150 x 109/L), the tests may be repeated in 1 or more months.17 Patients with symptomatic thrombocytopenia but otherwise healthy may require no activity restriction, but all patients need to be advised regarding symptoms and signs suggestive of severe thrombocytopenia, such as mucosal bleeding, petechiae and easy bruising.

Key points

  • Thrombocytopenia is a common finding and has a wide range of aetiologies. A systematic approach to identifying the underlying causes is essential (Figure 3, available online only).
  • Due to lack of specific tests, careful history, examination and blood evaluation remain the initial means of diagnosis.
  • A list of common benign causes of isolated thrombocytopenia and red flags can help the general practitioner triage those at high risk.

Clinical-Sharma-FIG3.jpg

Competing Interests: Hannah Rose received an honorarium from Amgen for the development and presentation of lectures to nurses in May 2014.
She has also been provided with accommodation by Novartis and Roche for attendance at educational meetings in Melbourne over the past 12 months, although no money was received directly in relation to this.

Provenance and peer review: Not commissioned; externally peer reviewed.

References

  1. Houwerzijl EJ, Blom NR, van der Want JJL, Vellenga E, de Wolf JTM. Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia 2006;20:1937–42.
  2. Shavit L, Grenader T. Delayed diagnosis of HIV-associated thrombocytopenia in a man of 70. J Royal Soc Med 2005;98:515.
  3. Veneri D, Franchini M, Randon F, Nichele I, Pizzolo G, Ambrosetti A. Thrombocytopenias: a clinical point of view. Blood Transfus 2009;7:75.
  4. Bain BJ. Diagnosis from the blood smear. New Engl J of Med 2005;353:498–507.
  5. Sekhon SS, Roy V. Thrombocytopenia in adults: a practical approach to evaluation and management. South Med J 2006;99:491–98.
  6. Federici L, Serraj K, Maloisel F, Andrès E. Thrombocytopenia during pregnancy: from etiologic diagnosis to therapeutic management. Presse Med 2008;37:1299–307.
  7. Boehlen F, Hohlfeld P, Extermann P, Perneger TV, De Moerloose P. Platelet count at term pregnancy: a reappraisal of the threshold. Obstet Gynecol 2000;95:29–33.
  8. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A review. BMC Pregnancy Childbirth 2009;9:8.
  9. McCrae KR, Samuels P, Schreiber AD. Pregnancy-associated thrombocytopenia: pathogenesis and management. Blood 1992;80:2697–714.
  10. Arnold DM, Nazi I, Warkentin TE, et al. Approach to the Diagnosis and Management of Drug-Induced Immune Thrombocytopenia. Transfus Med Rev 2013;27:137–45.
  11. Australia TRCoPo. RCPA Manual 2013. Available at www.rcpamanual.edu.au/index.php?option=com_clinical&task=show_clinical&id=74&Itemid=27 [Accessed 3 August 2013].
  12. Afdhal N, McHutchison J, Brown R, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008;48:1000–07.
  13. Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of ‘hypersplenic’ thrombocytopenia. J Clin Invest 1966;45:645–57.
  14. Bain BJ. Blood cells: a practical guide. 4th edn. Oxford: Blackwell Publishing, 2007.
  15. Erkurt MA, Kaya E, Berber I, Koroglu M, Kuku I. Thrombocytopenia in adults: review article. J Hematol 2012;1:44–53.
  16. Nagamine T, Ohtuka T, Takehara K, Arai T, Takagi H, Mori M. Thrombocytopenia associated with hepatitis C viral infection. J Hepatol 1996;24:135–40.
  17. Stasi R, Amadori S, Osborn J, Newland AC, Provan D. Long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia. PLoS Med 2006;3:e24.
  18. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009. New Engl J Med 2009;361:1935–44.
  19. Schmugge M, Revel-Vilk S, Hiraki L, Rand ML, Blanchette VS, Silverman ED. Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus. J Pediatr 2003;143:666–69.
  20. Ziakas P, Giannouli S, Zintzaras E, Tzioufas A, Voulgarelis M. Lupus thrombocytopenia: clinical implications and prognostic significance. Ann Rheum Dis 2005;64:1366–69.
  21. Egner W. The use of laboratory tests in the diagnosis of SLE. J Clin Pathol 2000;53:424–32.
  22. Drachman JG. Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood 2004;103:390–98.
  23. Bradbury C, Murray J. Investigating an incidental finding of thrombocytopenia. BMJ 2013;346:f11.
  24. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003;120:574–96.
  25. Choi P, Gordon J, Harvey M, Chong B. Presentation and outcome of idiopathic thrombocytopenic purpura in a single Australian centre. Intern Med J 2012;42:841–45.
  26. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168–86.
  27. Scott MA, Erber WN. The integrated approach to the diagnosis of hematological malignancies. In: Erber WN, ed Diagnostic Techniques in Hematological Malignancies. 1st ed. Cambridge: Cambridge University Press, 2010;111–26.
  28. Veyradier A, Meyer D. Thrombotic thrombocytopenic purpura and its diagnosis. J Thromb Haemost 2005;3:2420–27.
  29. Newman PM, Chong BH. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4–heparin antibodies to platelets and the resultant platelet activation. Blood 2000;96:182–87.
  30. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710–15.
  31. Chong BH, Isaacs A. Heparin-induced thrombocytopenia: what clinicians need to know. Thromb Haemost 2009;101:279–83.
  32. Baroletti S, Piovella C, Fanikos J, Labreche M, Lin J, Goldhaber SZ. Heparin-induced thrombocytopenia (HIT): clinical and economic outcomes. Thromb Haemost 2008;100:1130–35.
  33. Levi M. Disseminated intravascular coagulation. Crit Care Med 2007;35:2191–95.
  34. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin. JAMA 2005;293:1653–62.
  35. Wong LN, Yeung RSD. A case presentation of haemolytic uraemic syndrome presenting as gastroenteritis. Hong Kong J Emerg Medi 2003;10:54–56.
  36. Greinacher A, Althaus K, Krauel K, Selleng S. Heparin-induced thrombocytopenia. Thromb Haemost 2008;99:759–66.
  37. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003;102:60–68.
  38. Liebman HA. Viral-associated immune thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2008; 2008:212–18.
  39. Tosetto A, Ruggeri M, Schiavotto C, Pellizzari G, Rodeghiero F. The clinical significance of the antiplatelet antibody test based on results for 265 thrombocytopenic patients. Haematologica 1993;78(Suppl 2):41–46.

Correspondence afp@racgp.org.au

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