Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes, which in turn shed platelets from their cytoplasm. Thrombopoietin is produced in the liver at a constant rate; its circulating level is determined by how much is bound to circulating platelets and possibly to bone marrow megakaryocytes and the extent to which circulating platelets are cleared. Platelets circulate for 7 to 10 days. About one third are always transiently sequestered in the spleen.
The platelet count is normally 140,000 to 440,000/mcL (140 to 440 × 109/L). However, the count can vary slightly according to menstrual cycle phase, decrease during near-term pregnancy (gestational thrombocytopenia), and increase in response to inflammatory cytokines (secondary, or reactive, thrombocytosis). Platelets are eventually destroyed by apoptosis, a process independent of the spleen.
Platelet disorders include
An abnormal increase in platelets (thrombocythemia and reactive thrombocytosis)
A decrease in platelets (thrombocytopenia)
Platelet dysfunction
Any of these conditions, even those in which platelets are markedly increased, may cause defective formation of hemostatic plugs and bleeding.
The risk of bleeding is inversely proportional to the platelet count and platelet function (see table Platelet Count and Bleeding Risk). When platelet function is reduced (eg, as a result of uremia or the use of a nonsteroidal anti-inflammatory drug [NSAID], aspirin, or another medication), the risk of bleeding increases.
Table
Platelet Count and Bleeding Risk
Table
Platelet Count and Bleeding Risk
Platelet Count | Risk of Bleeding* |
|---|---|
≥ 50,000/mcL (≥ 50 × 109/L) | Minimal |
20,000–50,000/mcL (20–50 × 109/L) | Minor bleeding after trauma |
< 20,000/mcL (< 20 × 109/L) | Spontaneous bleeding |
< 5000/mcL (< 5 × 109/L) | Severe, possibly life-threatening spontaneous bleeding |
* Reduced platelet function (eg, due to uremia or the use of a nonsteroidal anti-inflammatory drug [NSAID], aspirin, or another medication) adds to risk of bleeding in each platelet count range. | |
Etiology of Platelet Disorders
Thrombocythemia and thrombocytosis
Essential thrombocythemia is a myeloproliferative neoplasm (previously called a myeloproliferative disorder) involving overproduction of platelets because of a clonal abnormality of a hematopoietic stem cell. There is no correlation between the platelet count and risk of thrombosis, but some patients with extreme thrombocytosis (ie, > 1,000,000/mcL [> 1000 × 109/L]) develop bleeding due to loss of high molecular weight von Willebrand factor multimers (acquired type 2B von Willebrand disease).
Reactive thrombocytosis is platelet overproduction in response to another disorder. There are many causes, including acute infection, chronic inflammatory disorders (eg, rheumatoid arthritis, inflammatory bowel disease, tuberculosis, sarcoidosis), iron deficiency, and certain cancers. Reactive thrombocytosis is not typically associated with an increased risk of thrombosis or bleeding.
Thrombocytopenia
Causes of thrombocytopenia can be classified by mechanism (see table Classification of Thrombocytopenia) and include
Decreased platelet production
Increased splenic sequestration of platelets with normal platelet survival
Increased platelet destruction or consumption (both immunologic and nonimmunologic causes)
Dilution of platelets
Table
Classification of Thrombocytopenia
Table
Classification of Thrombocytopenia
Cause | Conditions |
|---|---|
Diminished or absent megakaryocytes in bone marrow | Aplastic anemia Leukemia Paroxysmal nocturnal hemoglobinuria (some patients) |
Diminished platelet production despite the presence of megakaryocytes in bone marrow | Alcohol-induced thrombocytopenia HIV-associated thrombocytopenia Myelodysplastic syndromes (some) Vitamin B12 deficiency or |
Platelet sequestration in enlarged spleen | Cirrhosis with congestive splenomegaly Gaucher disease Primary myelofibrosis Sarcoidosis |
Immunologic destruction | Antiphospholipid syndrome Systemic rheumatic diseases Drug-induced thrombocytopenia Hepatitis B-associated thrombocytopenia (uncommon) Hepatitis C-associated thrombocytopenia HIV-associated thrombocytopenia Immune thrombocytopenia Lymphoproliferative disorders (eg, chronic lymphocytic leukemia) Neonatal alloimmune thrombocytopenia Posttransfusion purpura Sarcoidosis |
Nonimmunologic destruction | Certain systemic infections (eg, hepatitis [any], infectious mononucleosis, cytomegalovirus infection, or dengue) Disseminated intravascular coagulation Hemolytic-uremic syndrome Sepsis Thrombocytopenia in acute respiratory distress syndrome Thrombotic thrombocytopenic purpura |
Dilution | Massive red blood cell replacement or exchange transfusion (most RBC transfusions use stored RBCs that do not contain many viable platelets) |
Unknown cause | Pregnancy (eg, gestational thrombocytopenia, HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets])* † |
* Possible mechanisms may include increased destruction, decreased production, and placental sequestration. | |
† Additional information in Fogerty AE, Kuter DJ. How I Treat Thrombocytopenia in Pregnancy.Blood Published online November 22, 2023. doi:10.1182/blood.2023020726 | |
A large number of medications may cause thrombocytopenia, typically by triggering immunologic destruction.
Overall, the most common specific causes of thrombocytopenia include
Pregnancy (gestational thrombocytopenia; HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets]) (1)
Medications that cause immune-mediated platelet destruction (commonly, heparin, trimethoprim/sulfamethoxazole, rarely quinine [cocktail purpura] or abciximab), and rarely vaccinations (eg, influenza; shingles; measles, mumps, and rubella; COVID-19)
Medications and substances that cause dose-dependent bone marrow suppression (eg, chemotherapeutic agents, ethanol)
Systemic infection
Immune disorders (eg, immune thrombocytopenia [ITP], antiphospholipid syndrome, systemic lupus erythematosus)
Platelet dysfunction
Platelet dysfunction may stem from an intrinsic platelet defect or from an extrinsic factor that alters the function of normal platelets. Dysfunction may be hereditary or acquired. Hereditary disorders of platelet function consist of von Willebrand disease, the most common hereditary hemorrhagic disease, and inherited platelet function disorders, which are much less common. Acquired disorders of platelet dysfunction are commonly due to diseases (eg, renal failure) as well as to aspirin and other medications such as NSAIDs.
Etiology reference
1. Fogerty AE, Kuter DJ. How I Treat Thrombocytopenia in Pregnancy.Blood Published online November 22, 2023. doi:10.1182/blood.2023020726
Symptoms and Signs of Platelet Disorders
Platelet disorders result in a typical pattern of bleeding:
Multiple petechiae in the skin (typically most evident on the lower legs)
Scattered small ecchymoses at sites of minor trauma or venipuncture sites
Mucosal bleeding (oropharyngeal, nasal, gastrointestinal, genitourinary)
Excessive bleeding after surgery
Extensive menstrual bleeding
Manifestations of Platelet Disorders
Petechiae in Immune Thrombocytopenia (ITP)
By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
Ecchymoses in Immune Thrombocytopenia
By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
Ecchymoses
Ecchymoses are the large purple bruises seen on the leg of this patient.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
Petechiae (Hard Palate)
Petechiae are characterized by small red spots as seen here on the palate of this patient.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
Petechiae in Immune Thrombocytopenia (ITP)
By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
Ecchymoses in Immune Thrombocytopenia
By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
Ecchymoses
Ecchymoses are the large purple bruises seen on the leg of this patient.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
Petechiae (Hard Palate)
Petechiae are characterized by small red spots as seen here on the palate of this patient.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
Heavy gastrointestinal bleeding and bleeding into the central nervous system are rare but may be life threatening. However, bleeding into tissues (eg, deep visceral hematomas or hemarthroses) rarely occurs with thrombocytopenia; instead, patients usually have immediate and superficial bleeding following an injury. Bleeding into the tissues (often delayed for up to a day after trauma) suggests a coagulation disorder (eg, hemophilia).
Diagnosis of Platelet Disorders
Clinical presentation of petechiae and mucosal bleeding
Complete blood count (CBC) with platelets, coagulation studies, peripheral blood smear
Sometimes bone marrow aspiration
Sometimes von Willebrand antigen, platelet-binding activity, and multimer studies
Platelet disorders are suspected in patients with petechiae and mucosal bleeding. A CBC with platelet count, coagulation studies, and a peripheral blood smear are obtained. Excessive platelets and thrombocytopenia are diagnosed based on the platelet count. Coagulation studies are normal unless there is a simultaneous coagulopathy. In patients with a normal CBC, platelet count, international normalized ratio (INR), and partial thromboplastin time (PTT), platelet or vessel wall dysfunction is suspected.
Pearls & Pitfalls
Suspect platelet or vessel wall dysfunction in patients with petechiae and/or hemorrhage but with normal platelet count and coagulation test results.
Thrombocytopenia
Peripheral smear examination is important in patients with thrombocytopenia because automated platelet counts sometimes show pseudothrombocytopenia due to platelet clumping caused by the ethylenediaminetetraacetic acid (EDTA) reagent present in most blood collection tubes. Also, schistocytes may be seen, which can indicate valvular hemolysis, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), or disseminated intravascular coagulation (DIC—see table Peripheral Blood Findings in Thrombocytopenic Disorders).
Bone marrow aspiration is often indicated if the smear shows abnormalities other than thrombocytopenia, such as nucleated red blood cells (RBCs) or abnormal or immature white blood cells (WBCs). Bone marrow aspiration reveals the number and appearance of megakaryocytes and is the definitive test for many disorders that cause bone marrow failure. If the bone marrow is normal but the spleen is enlarged, increased splenic sequestration is the likely cause of thrombocytopenia. If the bone marrow is normal and the spleen is not enlarged, excess platelet destruction is the likely cause.
However, normal number and appearance of megakaryocytes does not always indicate normal platelet production. For example, in many patients with immune thrombocytopenia (ITP), platelet production may be decreased despite the normal appearance and increased number of megakaryocytes. In fact, bone marrow examination is rarely required in patients who present with typical features of immune thrombocytopenia.
The immature platelet fraction (IPF) in peripheral blood is sometimes a useful measure in patients with thrombocytopenia, since it is elevated when the bone marrow is producing platelets and not increased when bone marrow platelet production is reduced, similar to the reticulocyte count in anemia.
Measurement of antiplatelet antibodies may be clinically useful in some patients to distinguish ITP from other causes of thrombocytopenia (1). HIV testing is done in patients with or at risk of HIV infection, hepatitis B or hepatitis C infection, or HIV and hepatitis coinfection.
Table
Peripheral Blood Findings in Thrombocytopenic Disorders
Table
Peripheral Blood Findings in Thrombocytopenic Disorders
Normal red blood cells (RBCs) and white blood cells (WBCs) | Drug-induced thrombocytopenia Gestational thrombocytopenia Hepatitis C–related thrombocytopenia HIV-related thrombocytopenia Immune thrombocytopenia Posttransfusion purpura |
RBC fragmentation (schistocytes) | Disseminated intravascular coagulation (DIC) HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelets) Hemolytic-uremic syndrome Metastatic cancer Preeclampsia with DIC Thrombotic thrombocytopenic purpura Valvular hemolysis |
WBC abnormalities | Hypersegmented polymorphonuclear leukocytes in megaloblastic anemias Immature cells in large granular lymphocyte leukemia or increased mature lymphocytes in chronic lymphocytic leukemia Markedly diminished granulocytes in aplastic anemia |
Frequent giant platelets (approaching the size of RBCs) | Bernard-Soulier syndrome Disorders related to the myosin heavy chain 9, non-muscle gene (MYH9) Other congenital thrombocytopenias |
RBC abnormalities, nucleated RBCs, and immature granulocytes | Myelodysplastic syndrome |
Platelet clumping | Pseudothrombocytopenia |
Schistocytes (Red Blood Cell Fragments)
Image
By permission of the publisher. From Tefferi A, Li C. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
Suspected platelet dysfunction
A hereditary cause is suspected if there is a lifelong history of easy bruising; bleeding after tooth extractions, surgery, childbirth, or circumcision; or heavy menstruation. In the case of a suspected hereditary cause, von Willebrand factor (VWF) antigen and VWF activity studies are routinely done.
In patients with suspected hereditary dysfunction, platelet aggregation tests may identify a defect in how the platelet responds to various platelet agonists (adenosine diphosphate [ADP], collagen, thrombin) and thereby demonstrate the type of platelet defect.
Platelet dysfunction caused by most systemic disorders is typically mild and of minor clinical importance; in these patients, the causative systemic disorder is the clinical concern, and hematologic tests are unnecessary. However, patients with renal failure may develop significant bleeding.
Diagnosis reference
1. Al-Samkari H,RosovskyRP,Karp LeafRS: A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia. Blood Adv 4(1):9–18, 2020.doi: 10.1182/bloodadvances.2019000868
Treatment of Platelet Disorders
Stopping medications that impair platelet function
Thrombopoietin receptor agonists (TPO-RA)
Rarely platelet transfusions
Rarely antifibrinolytic agents
Patients may require platelet transfusion, but transfusions are given only in limited situations. For example, platelet transfusion is the mainstay of therapy for patients with platelet dysfunction and active bleeding or for those in need of an invasive procedure. Prophylactic transfusions are used sparingly because they may lose their effectiveness with repeated use due to the development of platelet alloantibodies.
If decreased production
Active bleeding
Severe thrombocytopenia (eg, platelet count < 10,000/mcL [< 10 × 109/L)
A need for an invasive procedure
If platelet destruction
