Introduction Diagnostic Challenge Assessment and Treatment Conclusion References
 
 
 
  TABLE OF CONTENTS
  Introduction
  Diagnostic Challenge
  Assessment and Treatment
  Conclusion
  References



Table 1

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Drug-Induced Thrombocytopenia: New Options and Treatment Strategies
October 30, 2009
Patricia A. Ford, MD

Introduction

More than 140 years have passed since W. H. Vipan first described the clinical manifestations of drug-induced thrombocytopenia (DIT).1 In that landmark article, published in The Lancet, Vipan noted the onset of purpura in patients treated with quinine for malaria. In the years that have followed, hundreds of new drugs have entered the marketplace, and many have been implicated in DIT.2 It is perhaps not surprising that the occurrence of DIT is becoming an increasingly common phenomenon. Quite simply, more drugs equal more potential offenders, and this in turn gives rise to increased complexity of diagnosis and treatment.2,3

Our understanding of the pathogenesis of DIT is still evolving. At least 6 different mechanisms have been proposed by which drug-induced antibodies can promote platelet destruction (see Table 1 ).4 While identification of the offending agent or agents is possible in many cases, the testing required is technically demanding, time-consuming, and not widely available.4 Therefore, clinicians must often make the initial decision on whether to discontinue an implicated medication in a patient suspected of having DIT based on clinical manifestations, just as Vipan did more than a century ago.1,2,4 A high index of suspicion and a careful history of drug exposure in any patient who presents with acute, often severe thrombocytopenia remain the most important elements of effective assessment and management.4

The clinical presentation of DIT ranges from mild to life-threatening bleeding.4 Exposure to the offending agent normally occurs 1 week before thrombocytopenia becomes clinically evident, although this can vary depending on the offending agent.4 Petechiae, bruising, and epistaxis are common early clinical manifestations.2 The majority of patients with DIT experience moderate to severe thrombocytopenia, defined as platelet counts <50,000/µL, with most of these reaching nadir levels <20,000 µL.2 However, platelet counts can be profoundly reduced in some cases, and an acute drop to a level that places patients at risk for spontaneous hemorrhage can quickly occur.2 In all cases, DIT should be viewed as a serious condition requiring prompt attention.2

 


Diagnostic Challenge


  

As noted, a wide range of medications have been implicated in the onset of DIT (Table 2).5 Moreover, patients may be exposed to multiple implicated medications, particularly critically ill patients in whom thrombocytopenia often occurs, creating a diagnostic challenge for the clinician.3

Both immune and nonimmune processes have been linked to the development of DIT (Table 3).2,3 In cases involving immune-mediated DIT, it is imperative that the offending agent be identified and discontinued as quickly as possible, preferably immediately whenever feasible.2



Table 2

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Table 3

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Figure 1

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Table 4

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Table 5

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Nonimmune DIT

Platelet production is dependent on adequate marrow function, as well as a sufficient megakaryocyte population.2 Numerous antineoplastic medications induce marrow suppression, including myeloablative chemotherapeutic compounds, certain antiviral agents, tolbutamide, and thiazide diuretics.2 In most cases, a dose-dependent decrease in platelet count can be observed.2

Myeloablative chemotherapeutic compounds represent the most commonly cited agents responsible for the onset of nonimmune DIT.2 Thrombocytopenia is usually an anticipated consequence of therapy with myelosuppressive agents and can be cumulative with subsequent cycles; diagnosis in these cases is therefore typically straightforward, and treatment is usually easily managed with platelet transfusion2 and sometimes a dose reduction of chemotherapy. There is normally a slow time course for DIT related to marrow suppression, a reflection of the time required to deplete megakaryocyte production (Figure 1).2


Immune-Mediated DIT

Immune-mediated DIT is by far the more common and more problematic form of DIT to diagnose.2 As the literature has noted, platelets appear to be affected by immune-mediated, drug-dependent destruction more than other marrow-derived cell types.2,6 The mean delay in the onset of immune-mediated thrombocytopenia is reported to be 1 to 2 weeks following a patient's exposure to the offending drug, but this can range in individual patients, which may further complicate diagnosis.2

The proposed mechanisms of action involved in immune-mediated DIT are varied and just partly understood. Only a small percentage of patients are affected by this disorder, and no predisposing genetic or environmental factors have been identified.5 The mechanisms believed to be involved in DIT are summarized in Table 4.5


Heparin-Induced Thrombocytopenia

Heparin remains the most common offending agent involved in drug-induced, antibody-mediated thrombocytopenia.7 Heparin-induced thrombocytopenia (HIT) is a life-threatening disorder that occurs in susceptible individuals following exposure to unfractionated or, less commonly, low-molecular-weight heparin.8 The classic presentation of HIT includes platelet count <150,000 per cubic millimeter or a relative decrease in platelet count of  ≥30% from baseline.8-10 As in other cases of DIT, diagnosis can be challenging, particularly in patients with complicated medical conditions and/or in those who have recently undergone cardiac surgery.8 Table 5 summarizes the clinical populations at risk for HIT, and provides recommendations for monitoring platelet count.8

Two types of HIT have been noted in the literature. There is the more common type I form, which occurs in 10% to 20% of patients and is not associated with hemorrhagic or thrombotic sequelae, and the type II form, in which 30% to 80% of patients experience thrombotic sequelae.3 Importantly, the immune mechanism behind HIT initially results in platelet activation before platelet consumption.2 Early recognition is therefore pivotal for preventing thrombosis, limb loss, and even death.11

For further discussion on the incidence, diagnosis, and treatment of HIT, CLICK HERE.



Assessment and Treatment

  

Decreasing serum fibrinogen levels and increasing TTs, PTs, aPTTs, and fibrin degradation products demonstrate the presence of a consumptive coagulopathy in the setting of thrombocytopenia (Table 6).3 An inverse relationship between bleeding severity and platelet count has been noted, although there have been reports of patients with profound thrombocytopenia who have no bleeding symptoms.4 Patients with platelets <10,000 µL often present with extensive purpuric lesions on the skin and mucosal surfaces, hematuria, and gastrointestinal hemorrhage (“wet purpura”).4

Treatment of DIT and related coagulopathies begins with identification and discontinuation, when feasible, of offending agent(s).2,4 Clinicians are advised to consider the distinctive aspects of each patient's clinical presentation, as well as the potential advantages and disadvantages of various treatment approaches, when making treatment decisions for their patients.11

The following treatment options may be considered:





Table 6

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Red Blood Cell Transfusions

Red blood cell (RBC) transfusions may be useful in cases in which hemoglobin is ≤7 g/dL in patients older than 65 years and patients with chronic cardiovascular or respiratory disease. Transfusion is also recommended for patients with acute blood loss >1500 mL or >30% of blood volume.12 Other indications include patients with preoperative anemia and hemoglobin <9 g/dL with impending major blood loss.13


Platelet Transfusions

Platelet transfusions are the standard treatment for DIT associated with the use of myelosuppressive agents, but they may also be employed in other cases of DIT.2 Because platelets play an instrumental role in managing patients who are bleeding or at risk for bleeding, prophylactic use of platelet transfusions to prevent bleeding in the patient with thrombocytopenia may be considered.3 Other indications for platelet transfusions include the following:


  • Platelet count ≤10,000 per microliter blood
  • Platelet counts ≤50,000 per microliter blood and bleeding due to thrombocytopenia or platelet dysfunction
  • Platelet counts ≤50,000 per microliter blood and potential for bleeding from an invasive procedure (surgery, placement of subclavian venous access, lumbar spinal puncture, etc)
  • Platelet counts >100,000 and evidence of bleeding due to platelet dysfunction intractable to DDAVP or cryoprecipitate
Plasma Product Transfusions

Plasma product transfusions are the treatment of choice when bleeding arises due to malfunction, consumption, or underproduction of plasma coagulation proteins.3 As with platelet transfusion, plasma product transfusions may be used prophylactically in the critical care setting to correct coagulopathies prior to invasive or surgical procedures. In cases involving active bleeding, clinicians should administer plasma products until bleeding stops or coagulopathy ceases.3


The choice of plasma product is dependent upon the patient's clinical circumstances. Fresh frozen plasma (FFP) is the most common plasma product used to correct clotting factor deficiencies, including coagulopathies related to DIT.3


Find out why you should be concerned about perioperative anemia in your patient base.

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Recombinant Factor VIIa

Recombinant factor VIIa (rVIIa) enhances coagulation at the site of injury, apparently by enhancing platelet-surface thrombin generation independently of its usual cofactor, tissue factor.3 It is indicated for the treatment of factor VIII or IX deficiency and inhibitors in patients with hemophilia A and B, but it has been gaining widespread use in off-label applications as well, including the treatment of DIT. Reported off-label applications include the following:


  • Trauma
  • Hepatic failure
  • Postprocedural bleeding (tooth extraction)
  • Prior to liver transplantation
  • Prior to invasive procedures, such as liver biopsy, GI endoscopy, or ethanol injection
  • Reversal of warfarin effect
  • Upper GI bleeding
  • Platelet dysfunction
  • Cardiac surgery
  • Intracranial hemorrhage
  • rVIIa may be used for rapid reversal of warfarin anticoagulation when vitamin K administration is insufficient14

Is perioperative anemia placing your surgical patients at risk?

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New and Upcoming Treatments: Thrombopoietin Agents

Two new thrombopoietin agents are the newest agents for the treatment of thrombocytopenia.

Eltrombopag is the first nonpeptide, thrombopoietin-receptor agonist to be developed as a treatment for thrombocytopenia of various etiologies.15 It was approved by the FDA in November 2008 for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who are refractory to first-line treatments. Eltrombopag stimulates thrombopoiesis, leading to increased platelet production.16,17

Romiplostim is a thrombopoietin (TPO) peptide mimetic given by subcutaneous injection that activates the TPO receptor by binding to the distal hematopoietic receptor domain just like TPO.17 It was approved by the FDA in August 2008, also for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who are refractory to alternative treatments.18

Both eltrombopag and romiplostim increase platelet count in healthy humans as well as in >80% of patients with immune thrombocytopenic purpura (ITP).17 Although initially restricted to the second-line treatment of ITP, these agents could potentially help treat many thrombocytopenic disorders in the future.17



Conclusion

  

DIT is a common, serious condition with increasing prevalence. Clinicians should include DIT consideration as an important component of the differential diagnosis of patients with thrombocytopenia. Once a diagnosis of DIT has been made, the offending agent(s) should be identified and removed, with appropriate treatment initiated.



References

  
     
  1. Vipan WH. Quinine as a cause of purpura. Lancet. 1865;2:37.
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  2. Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab Med. 2009;133:309-314.
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  3. Drews RE. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. Clin Chest Med. 2003;24:607-622.
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  4. Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost. 2009;7:911-918.
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  5. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 2007;357:580-587.
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  6. Aster RH. Drug-induced immune cytopenias. Toxicology. 2005;209:149-153.
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  7. McCrae KR, Bussel JB, Mannucci PM, Remuzzi G, Cines DB. Platelets: an update on the diagnosis and management of thrombocytopenic disorders. Hematology Am Soc Hematol Educ Program. 2001; 287-305.
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  8. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809-817.
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  9. Greinacher A, Eichler P, Lietz T, Warkentin TE. Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia. Blood. 2005;106:2921-2922.
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  10. Tardy B, Lecompte T, Boelhen F, et al, for the GEHT-HIT study group. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006;108:1492-1496.
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  11. Dager WE, Dougherty JA, Mguyen PH, Miritello MA, Smythe MA. Heparin-induced thrombocytopenia: treatment options and special considerations. Pharmacotherapy. 2007;27:564-587.
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  12. Ferraris VA, Ferraris SP, Saha SP, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Clinical Practice Guideline. Ann Thorac Surg. 2007;83:S27-S86.
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  13. American Red Cross. Transfusion Guidelines for Blood Components. Available at: http://www.newenglandblood.org. Accessed October 14, 2009.
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  14. Ingerslev J, Vanek T, Cilic S. Use of recombinant factor VIIa for emergency reversal of anticoagulation. J Postgrad Med. 2007;53:17-22.
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  15. Fogarty PF, Bussel JB, Cheng G, et al. Oral eltrombopag treatment reduces the need for concomitant medications in patients with chronic idiopathic thrombocytopenic purpura. Blood. 2008;112:abstract 3424.
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  16. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641-648.
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  17. Kuter DJ. Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193-206.
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  18. Jamali F, Lemery S, Ayalew K, et al. Romiplostim for the treatment of chronic immune (idiopathic) thrombocytopenic purpura. Oncology. 2009;23:704-709.

Additional contributing author: Kathleen Casey Krafton
The authors of this article have no real or apparent conflicts of interest to report.


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