Drug-induced platelet dysfunction

Table II.

Drug class	Drug
Drugs used in cardiovascular diseases
Antihypertensive agents	Terazosin, amlodipine, verapamilAngiotensin converting enzyme (ACE) inhibitors: ramipril, Captopril, carvedilol, propranolol, losartan, valsartan
Vasodilators	Nitroglycerine, isosorbide dinitrate, isosorbide-5-mononitrate
Phosphodiesterase inhibitors	Milrinone
Other drugs	Statins, fish oil
Anticoagulants	Heparin
Antibiotics	Beta-lactams, penicillins and cephalosporins
HIV protease inhibitors	Tipranavir/ritonavir
Antidepressants and antipsychotics	Selective serotonin reuptake inhibitors, tricyclic antidepressants
Drugs used in labor and delivery	Misoprostol (prostaglandin E1 analogue)
Phosphodiesterase inhibitors	Sildenafil, tadalafil, pentoxyfylline
Drugs that inhibit adenosine receptors and increase cyclic adenosine monophosphate levels	Methylxanthines (caffeine, theophylline, theobromine)
Anesthetic agents	Etomidate, thiopental
Drugs used in cancer	Vincristine, mithramycinTyrosine kinase inhibitors (dasatinib, imatinib)
Miscellaneous
Herbal supplements	Ginkgo bilboa, saw palmetto, ginger, garlic, ginseng
Foods	Grape juice
Other agents	Vitamin C, Vitamin E, ethanol

Platelet function testing with light transmission aggregometry (LTA), the platelet function analyzer (PFA-100), or a template bleeding time may reveal abnormalities that support the diagnosis.

Treatment requires stopping the offending agent and depending upon the severity of bleeding, platelet transfusion.

What features of the presentation will guide me toward possible causes and next treatment steps:

The following features will guide you toward possible causes and next treatment steps:

• History of bleeding

– A thorough personal and family history of bleeding is needed to assess whether the bleeding is congenital or acquired.

• Medical history

– A detailed medication history is essential, and it is critical to attempt to establish a temporal link of drug use with bleeding.

• Mucocutaneous bleeding

– In the outpatient setting, patients may be referred to a hematologist for the evaluation of mucocutaneous bleeding, such as epistaxis, easy bruising, petechiae, purpura, menorrhagia, or gastrointestinal bleeding. A careful personal and family history usually excludes a congenital bleeding disorder.

• Previous diagnosis of a congenital bleeding disorder

– Patients with a previous diagnosis of a congenital bleeding disorder can have a change in their bleeding pattern when they are on drugs that interfere with platelet function (for example, aspirin use in von Willebrand disease [vWD]).

• Other acquired conditions that put the patient at higher risk of bleeding

– Patients with other acquired conditions that put them at higher risk of bleeding (uremia, liver disease, thrombocytopenia) often have an increased bleeding or change in the pattern of the bleeding when initiating drugs that interfere with platelet function.

• Patients undergoing surgeries

– Patients undergoing surgeries can have increased blood loss during the intra-and postoperative period.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory testing provides supporting information, but cannot substitute for a thorough personal and family history of bleeding as well as a detailed medication history.

Screening tests:

• The platelet count, PT and aPTT are normal in the setting of an isolated drug-induced platelet dysfunction

• A comprehensive metabolic panel is needed to assess renal and hepatic function

• Von Willebrand disease must be considered even in the setting of normal screening tests

– We recommend testing von Willebrand factor (VWF) activity, VWF antigen and either a PFA-100 or bleeding time. The VWF activity and antigen are normal in isolated drug-induced platelet dysfunction.

Platelet function assays:

• Assays of platelet function include light transmission aggregometry (LTA), the PFA-100 and the bleeding time

– These assays have variable sensitivity to the platelet-inhibiting effects of various anti-platelet agents.

• PFA-100 and the bleeding time

– The PFA-100 and the bleeding time are usually able to be performed with fairly rapid turnaround time, but have only modest sensitivity for drug-induced platelet dysfunction. The PFA-100 uses citrated whole blood and two different cartridges with membranes coated with collagen and either epinephrine (EPI) or adenosine diphosphate (ADP). The blood flows through an aperture in the membrane under high shear stress condition and the time taken for the platelets to aggregate and occlude the aperture (closure time) is the read out. Patients with vWD or platelet function defects can have prolonged PFA-100 closure times (CT). Patients on aspirin or NSAIDs usually have abnormal results (prolonged CTs) in the PFA-100 EPI cartridge and a normal result with the PFA-100 ADP cartridge. The PFA-100 assay has poor sensitivity to the effects of thienopyridines (e.g., clopidogrel). The GP IIb/IIIa receptor inhibitors (e.g., abciximab and eptifibatide) result in the prolongation of both the EPI and ADP PFA-100 cartridges.

• Some of the other drugs mentioned in Table I can also result in abnormalities of PFA-100 (for example, high doses of fish oil)

– A diagnosis of drug-induced platelet dysfunction can be made with reasonable confidence if the PFA-100 is prolonged and the result normalizes after the discontinuation of the suspected offending drug. However, the most important point to remember is that a patient could still have drug-induced platelet dysfunction despite having a normal PFA-100 result.

• The bleeding time (BT) measures platelet function and platelet vessel wall interactions

– The BT may be prolonged with numerous drugs shown in Table I and Table II. In practice, the BT has grown out of favor because operator technique and patient dependent factors reduce the reproducibility and predictive value of the test.

In most instances the best evidence of drug-induced platelet dysfunction comes not from the laboratory tests but with improvement in the bleeding pattern after discontinuation of the offending agent.

In an acute care setting, if the patient is bleeding and is on a medication that can interfere with platelet function, it is prudent to assume that the patient has drug-induced platelet dysfunction and treat accordingly, without waiting for a test to assess platelet function.

What conditions can underlie drug-induced platelet dysfunction:

The differential diagnosis includes uremic platelet dysfunction, paraproteinemias, myeloproliferative disorders, myelodysplastic syndrome, acute leukemias, hepatic dysfunction and antiplatelet antibodies. Most of these disorders can be assessed with a good history and physical examination, simple complete blood count, comprehensive metabolic panel and serum protein electrophoresis with immunofixation. Though antiplatelet antibodies may need specialized testing, most of these patients will have concomitant thrombocytopenia. (Table I, Table II)

When do you need to get more aggressive tests?

N/A

What imaging studies (if any) will be helpful?

N/A

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

If the patient is acutely bleeding, we recommend discontinuing the suspected drugs and considering a platelet transfusion. The decision regarding the transfusion of platelets is based on the severity and location of the bleeding. Platelet transfusion may not be needed if the bleeding is minor and hemostasis can be achieved by local measures. Some drugs may have active metabolites in the circulation for days after their discontinuation and this may necessitate repeated platelet transfusions every 8-12 hours until the patient has achieved hemostasis.

What other therapies are helpful for reducing complications?

Desmopressin (DDAVP) increases the VWF levels and may enhance platelet function and help achieve hemostasis. DDAVP may be a good agent to use in a bleeding patient with drug-induced platelet dysfunction while waiting for the platelet transfusion or in conjunction with platelets. DDAVP can increase the risk of cardiovascular events and strokes in high risk patients, and it should be used cautiously in patients at high risk of recurrent thrombotic events. DDAVP is administered intravenously at a dose of 0.3 mcg/kg in normal saline over 15-30 minutes. The dose can be repeated every 6-12 hours for a total of up to four doses. Patient’s fluid intake and sodium need to be carefully monitored due to the risk of hyponatremia.

Antifibrinolytic agents like aminocaproic acid and tranexamic acid may be used in addition to the above measures. We would avoid using these agents in upper urinary tract bleed, due to the possibility of clots in the ureters causing obstruction.

Packed red blood cell transfusion can be considered in a bleeding or hemodynamically unstable patient with a hematocrit less than 30%.

If the platelet dysfunction and bleeding was cause by drugs used for indications other than for their antiplatelet properties, then we would recommend finding an alternative agent. In patients who are taking antiplatelet agents, once hemostasis is achieved, we recommend reducing the intensity of their antithrombotic therapy at least for a few weeks after the bleed. This may mean changing to a single agent from dual therapy. However, these decisions need to be made after an extensive discussion with the patient, the appropriate consultant and after weighing the risks and benefits of changing the existing therapy.

What should you tell the patient and the family about prognosis?

Platelet function will improve within 7-10 days of discontinuing the offending drug in almost all patients.

“What if” scenarios.

N/A

Pathophysiology

Drugs causing predictable platelet inhibition:

• Aspirin

– Aspirin irreversibly acetylates platelet cyclooxygenase COX), thereby inhibiting the synthesis of thromboxane A2 (TxA2), which plays an important feedback role in platelet aggregation. The antiplatelet effect of aspirin lasts for the lifetime of a platelet, which is 7-10 days.

• Non-steroidalanti-inflammatory drugs (NSAIDS) reversibly inhibit COX

– Complete platelet function is usually restored within 2-3 days of discontinuing these agents.

• ADP receptor P2Y12 antagonists (clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor) cause platelet dysfunction by preventing the binding of ADP to the P2Y12 receptor

– Clopidogrel, ticlopidine, and prasugrel or their active metabolites irreversibly bind to the platelet P2Y12 receptors. The antiplatelet effect of these agents lasts for 7-10 days. Ticagrelor and cangrelor reversibly bind to the platelet P2Y12 receptor.

• Dipyridamole and cilostazole

– Dipyridamole and cilostazole inhibit phosphodiesterase and increase the levels of cyclic AMP adenosine monophosphate in platelets, thereby inhibiting platelet aggregation.

• GP IIb/IIIa receptor blockers (abciximab, eptifibatide, tirofiban) block the binding of fibrinogen to the platelet GP IIb/IIIa receptors

– Since the binding of fibrinogen is the final step in platelet aggregation, these agents cause severe platelet dysfunction. The antiplatelet effect of these agents usually lasts only a few hours after their discontinuation.

• Vorapaxar inhibits thrombin-induced platelet aggregation by blocking the protease-activated receptor-1 (PAR-1) on the surface of platelets

– Vorapaxar is an irreversible antagonist of PAR-1. Its antiplatelet effect lasts for 7-10 days.

Drugs used for other indications with anti-platelet properties

The mechanism of platelet inhibition of some of the drugs in this category (Table I and Table II) is not clear. Furthermore, some of these drugs have very weak antiplatelet effects, but can potentiate the antiplatelet effects of other drugs and cause increased bleeding in patients with other risk factors for bleeding.

• Antihypertensive agents

– Some of the antihypertensive agents like beta-blockers and ACE inhibitors may cause platelet dysfunction by inhibiting the production of TxA2 and Thromboxane B2 (TxB2). Nitric oxide can increase platelet cyclic granule membrane protein (GMP) levels through the activation of guanylate cyclase.

• Beta-lactam antibiotics

– Beta-lactam antibiotics like penicillin may cause platelet dysfunction by preventing the binding of agonists to their receptors on platelets, inhibiting production of thromboxane B2, and affecting signal transduction after an agonist binds to the receptor. The platelet dysfunction is time and dose dependent.

• Chemotherapeutic agents

– Some chemotherapeutic agents like mithramycin are associated with depleted platelet ADP stores and platelet dysfunction. Anesthetic agents like etomidate, affect thromboxane production, resulting in platelet dysfunction.

• Kinase inhibitors

– BCR-ABL inhibitors like imatinib and dasatinib can cause platelet dysfunction. Dasatinib increases the PFA-100 epinephrine/collagen closure time but not the ADP/collagen closure time. Patients on dasatinib have an abnormal platelet aggregation response to arachidonic acid and epinephrine. Imatinib causes abnormal arachidonic acid-induced platelet aggregation. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, affects collagen-induced platelet aggregation as measured by LTA.

• Fish oil (rich in omega-3 fatty acids)

– This can cause platelet dysfunction by changing the platelet membrane structure and surface charge.

What other clinical manifestations may help me to diagnose drug-induced platelet dysfunction?

N/A

What other additional laboratory studies may be ordered?

LTA can be useful in the evaluation of drug-induced platelet dysfunction. Platelet rich plasma is used in LTA with different concentrations of agonists that act on various platelet receptors. The agonists most commonly used are EPI, ADP, collagen, ristocetin, AA and thrombin. While evaluating other congenital and acquired causes of platelet dysfunction, we recommend that patients stop all medications that can interfere with platelet function. While evaluating drug-induced platelet dysfunction however, it will be prudent to perform the test while the patient is on the drug and then repeat it 7-10 days after discontinuing the drug.

LTA is most useful in the out-patient setting because of the challenges with interpreting the results in acutely ill patients on multiple drugs.

Patients on NSAIDs have reduced or absent aggregation to AA and EPI.

Patients on thienopyridines have reduced or absent aggregation to ADP.

A variety of LTA abnormalities have been noted with the agents listed in Table I and Table II.

What’s the Evidence?

Hassan, AA, Kroll, MH.. “Acquired disorders of platelet function”. Hematology Am Soc Hematol Educ Program. 2005. pp. 403-408. (A good review of the causes, testing and management of all acquired platelet function disorders, including drug-induced platelet dysfunction.)

Scharf, RE, Rahman, MM, Seidel, H.. “The impact and management of acquired platelet dysfunction”. Hamostaseologie. vol. 31. 2011. pp. 28-40. (A section of this review article covers the various drugs that cause platelet dysfunction and the management of it.)

Balduini, CL, Noris, P, Belletti, S, Spedini, P, Gamba, G.. “In vitro and in vivo effects of desmopressin on platelet function”. Haematologica.. vol. 84. 1999. pp. 891-896. (This study addresses the mechanism of action of DDAVP for use in platelet dysfunction.)

Burroughs, SF, Johnson, GJ.. “Beta-lactam antibiotic-induced platelet dysfunction: evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin”. Blood.. vol. 75. 1990. pp. 1473-1480. (This study addresses the mechanism of action of beta-lactam-induced platelet dysfunction.)

Gresele, P, Momi, S, Falcinelli, E.. “Anti-platelet therapy: Phosphodiesterase inhibitors”. Br J Clin Pharmacol.. vol. 72. 2011 Oct. pp. 634-46. (This paper discusses the anti-platelet effects of phosphodiesterase inhibitors.)

Hernandez, R, Angeli-Greaves, M, Carvajal, AR, Guerrero Pajuelo, J, Armas Padilla, MC, Armas-Hernandez, MJ.. “Terazosin: ex vivo and in vitro platelet aggregation effects in patients with arterial hypertension”. Am J Hypertens.. vol. 9. 1996. pp. 437-444. (This paper discusses the effects on platelet aggregation by the anti-hypertensive agent terazosin.)

Quintas-Cardama, A, Han, X, Kantarjian, H, Cortes, J.. “Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia”. Blood.. vol. 114. 2009. pp. 261-263. (This study demonstrates the anti-platelet effects of tyrosine kinase inhibitors used in CML.)

Szapary, L, Horvath, B, Marton, Z. “Short-term effect of low-dose atorvastatin on haemorrheological parameters, platelet aggregation and endothelial function in patients with cerebrovascular disease and hyperlipidaemia”. CNS Drugs.. vol. 18. 2004. pp. 165-172. (This study demonstrates the anti-platelet effects of statins.)

Weber, CF, Gorlinger, K, Byhahn, C. “Tranexamic acid partially improves platelet function in patients treated with dual antiplatelet therapy”. Eur J Anaesthesiol.. vol. 28. 2011. pp. 57-62. (Provides some rationale for the use of antifibrinolytic agents in the management of drug-induced platelet dysfunction and bleeding.)

Levade, M, Severin, S, Gratacap, MP, Ysebaert, L, Payrastre, B.. “Targeting kinases in cancer therapies: adverse effects on blood platelets”. Curr Pharm Des. 2016. (The review article discusses the platelet dysfunction caused by various kinase inhibitors.)

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