Platelet destruction can develop because of immunologic causes (viral infection, medications, systemic rheumatic or lymphoproliferative disorders, blood transfusions) or nonimmunologic causes (sepsis, vascular malformations, acute respiratory distress syndrome). Manifestations are petechiae, purpura, and mucosal bleeding. Laboratory findings depend on the cause. The history may be the only suggestion of the diagnosis. Treatment is correction of the underlying disorder.
Acute respiratory distress syndrome
Patients with acute respiratory distress syndrome may develop nonimmunologic thrombocytopenia, possibly secondary to deposition of platelets in the pulmonary capillary bed.
Blood transfusions
Posttransfusion purpura involves immunologic platelet destruction indistinguishable from immune thrombocytopenia (ITP), except for a history of a blood transfusion within the preceding 7 to 10 days. The patient, usually a female, lacks a platelet antigen (PLA-1) present in most people. Transfusion with PLA-1–positive platelets stimulates formation of anti–PLA-1 antibodies, which (by an unknown mechanism) can react with the patient’s PLA-1–negative platelets. Severe thrombocytopenia results, taking 2 to 6 weeks to subside. Treatment with IV immune globulin (IVIG) is usually successful.
Systemic rheumatic and lymphoproliferative disorders
Systemic rheumatic disorders (eg, systemic lupus erythematosus, antiphospholipid syndrome) or lymphoproliferative disorders (eg, chronic lymphocytic leukemia [CLL]) can cause secondary ITP. Glucocorticoids and the usual treatments for immune thrombocytopenia are often effective; treating the underlying disorder does not always lengthen remission.
Medication-induced platelet destruction
Commonly used medications that occasionally induce thrombocytopenia include:
Carbamazepine
Chlorpropamide
Glycoprotein IIb/IIIa inhibitors (eg, abciximab, eptifibatide, tirofiban)
Heparin
Hydrochlorothiazide
Quinine
Ranitidine
Rifampin
Sulfamethoxazole/trimethoprim
Vancomycin
Except for heparin, medication-induced thrombocytopenia occurs typically when a medication bound to the platelet or a carrier protein creates a new and “foreign” antigen, causing an immune reaction. This disorder is indistinguishable from ITP except for the history of medication use. When the medication is stopped, the platelet count typically begins to increase within 1 to 2 days and recovers to normal within 7 days.
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) occurs in up to 2.4% of patients receiving unfractionated heparin (1). Heparin-induced thrombocytopenia may occur even when very-low-dose heparin (eg, used in flushes to keep IV or arterial lines open) is used. The mechanism is usually immunologic.
Bleeding rarely occurs, but more commonly platelets clump excessively, causing vessel obstruction, leading to paradoxical arterial and venous thromboses, which may be life threatening (eg, thromboembolic occlusion of limb arteries, stroke, acute myocardial infarction).
Heparin should be stopped immediately in any patient who becomes thrombocytopenic and develops a new thrombosis or whose platelet count decreases by more than 50% pending results of tests done to detect antibodies to heparin bound to platelet factor 4.
Anticoagulation with a nonheparin anticoagulant (eg, argatroban, bivalirudin, apixaban, rivaroxaban, fondaparinux) should be substituted at least until platelet recovery.
Low-molecular-weight heparin (LMWH) is ten-fold less immunogenic than unfractionated heparin but cannot be used to anticoagulate patients with heparin-induced thrombocytopenia because most HIT antibodies cross-react with LMWH. Fondaparinux is an acceptable alternative in many patients, but, given its long 17-hour half-life, it is not appropriate in those patients who may soon need a procedure or have a high bleeding risk. Warfarin should not be substituted for heparin in patients with heparin-induced thrombocytopenia. In patients who require subsequent warfarin anticoagulation, warfarin should be started only after the platelet count has recovered.
The 4-T score may be helpful in estimating the pretest probability that a patient is at risk for HIT and requires testing or empirical anticoagulation. Scores of 0 to 3 suggest a very low risk for HIT while intermediate (4 to 5) or high (6 to 8) scores indicate that HIT is possible with a subsequent need to stop heparin, obtain diagnostic testing, and start alternative anticoagulation (2).
Infections
HIV infection may cause immunologic thrombocytopenia indistinguishable from immune thrombocytopenia except for the association with HIV. The platelet count may increase when glucocorticoids are given. However, glucocorticoids are often withheld unless the platelet count falls to < 20,000/mcL (< 20 × 109/L) because glucocorticoids may further depress immune function. The platelet count also usually increases after treatment with antiviral medications.
Hepatitis C infection is commonly associated with thrombocytopenia. Active infection can create a thrombocytopenia that is indistinguishable from immune thrombocytopenia with platelets < 10,000/mcL (< 10 × 109/L). Milder degrees of thrombocytopenia (platelet count 40,000 to 70,000/mcL [40 to 70 × 109/L]) may be due to liver damage that reduced production of thrombopoietin, the hematopoietic growth factor that regulates megakaryocyte growth and platelet production. Hepatitis C-induced thrombocytopenia responds to the same treatments as does immune thrombocytopenia.
Other infections, such as systemic viral infections (eg, Epstein-Barr virus, cytomegalovirus, influenza A, dengue), rickettsial infections (eg, Rocky Mountain spotted fever), and bacterial sepsis, often cause thrombocytopenia.
Pregnancy
Thrombocytopenia, typically asymptomatic, occurs late in gestation in approximately 5% of normal pregnancies (gestational thrombocytopenia); it is not autoimmune-mediated and is usually mild (platelet counts < 70,000/mcL [< 70 × 109/L] are rare), requires no treatment, and resolves after delivery. However, severe thrombocytopenia may develop in pregnant patients with preeclampsia and the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets); such patients typically require immediate delivery, and platelet transfusion is considered if platelet count is < 20,000/mcL (< 20 × 109/L), or < 50,000/mcL (< 50 × 109/L) if delivery is to be cesarean (3, 4).
Sepsis
Sepsis often causes nonimmunologic thrombocytopenia that parallels the severity of the infection. The thrombocytopenia has multiple causes:
Activation of complement
Deposition of platelets on damaged endothelial surfaces
Formation of immune complexes that can associate with platelets
Platelet apoptosis
Removal of the platelet surface sialic acid, resulting in increased platelet clearance by the liver mediated by hepatocyte Ashwell-Morell or Kupffer cell CLEC4F receptors
(See also Overview of Platelet Disorders.)
References
1. Miller E, Norwood C, Giles JB, et al. PharmGKB summary: heparin-induced thrombocytopenia pathway, adverse drug reaction. Pharmacogenet Genomics. 2022;32(3):117-124. doi:10.1097/FPC.0000000000000465
2. Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360-3392. doi:10.1182/bloodadvances.2018024489
3. ACOG Practice Bulletin No. 207: Thrombocytopenia in Pregnancy.Obstet Gynecol. 2019;133(3):e181-e193. doi:10.1097/AOG.0000000000003100
4. Fogerty AE, Kuter DJ. How I Treat Thrombocytopenia in Pregnancy. Blood. 2024;143(9):747-756. doi:10.1182/blood.2023020726
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