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Overview of Platelet Disorders

By

David J. Kuter

, MD, DPhil, Harvard Medical School

Last full review/revision Jun 2020| Content last modified Jun 2020
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Topic Resources

Platelets are 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 and its circulating level is determined by the extent to which circulating platelets are cleared, and possibly by bone marrow megakaryocytes. 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. 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

Any of these conditions, even those in which platelets are 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 use of nonsteroidal anti-inflammatory drug [NSAID] or aspirin), the risk of bleeding increases.

Table
icon

Platelet Count and Bleeding Risk

Platelet Count

Risk of Bleeding*

≥ 50,000/mcL

Minimal

20,000–50,000/mcL

Minor bleeding after trauma

< 20,000/mcL

Spontaneous bleeding

< 5000/mcL

Severe, possibly life-threatening spontaneous bleeding

* Reduced platelet function (eg, due to uremia, or use of nonsteroidal anti-inflammatory drug [NSAID] or aspirin) adds to risk of bleeding in each platelet count range.

Etiology

Thrombocythemia and thrombocytosis

Essential thrombocythemia is a myeloproliferative neoplasm (previously 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) develop bleeding due to loss of high molecular weight von Willebrand factor multimers.

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 Thrombocythemia) 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
icon

Classification of Thrombocytopenia

Cause

Conditions

Diminished or absent megakaryocytes in bone marrow

Myelosuppressive drugs (eg, hydroxyurea, interferon alfa-2b, chemotherapy drugs)

Diminished platelet production despite the presence of megakaryocytes in bone marrow

Alcohol-induced thrombocytopenia

Bortezomib use

Platelet sequestration in enlarged spleen

Cirrhosis with congestive splenomegaly

Myelofibrosis with myeloid metaplasia

Immunologic destruction

Connective tissue disorders

HIV-associated thrombocytopenia

Lymphoproliferative disorders

Neonatal alloimmune thrombocytopenia

Posttransfusion purpura

Sarcoidosis

Nonimmunologic destruction

Certain systemic infections (eg, hepatitis, infectious mononucleosis, cytomegalovirus infection, or dengue)

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

A large number of drugs 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])

  • Drugs that cause immune-mediated platelet destruction (commonly, heparin, trimethoprim/sulfamethoxazole, rarely quinine [cocktail purpura] or abciximab)

  • Drugs that cause dose-dependent bone marrow suppression (eg, chemotherapeutic agents, ethanol)

  • Systemic infection

  • Immune disorders (eg, immune thrombocytopenia [ITP])

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 hereditary intrinsic platelet 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 drugs.

Symptoms and Signs

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

Manifestations of Platelet Disorders

Heavy gastrointestinal bleeding and bleeding into the central nervous system 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

  • 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 and activity 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 a reaction with the ethylenediaminetetraacetic acid (EDTA) reagent present in some blood collection tubes. Also, schistocytes may be seen, which can indicate 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 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 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 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 at risk of HIV infection.

Table
icon

Peripheral Blood Findings in Thrombocytopenic Disorders

Normal red blood cells (RBCs) and white blood cells (WBCs)

Drug-induced thrombocytopenia

HIV-related thrombocytopenia

Posttransfusion purpura

RBC fragmentation (schistocytes)

Metastatic cancer

Preeclampsia with DIC

HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelets)

WBC abnormalities

Hypersegmented polymorphonuclear leukocytes in megaloblastic anemias

Immature cells or increased mature lymphocytes in 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

Myelodysplasia

Platelet clumping

Pseudothrombocytopenia

Suspected platelet dysfunction

In patients with platelet dysfunction, a drug cause is suspected if symptoms began only after the patient started taking a potentially causative drug (eg, ticarcillin, prasugrel, clopidogrel, ticagrelor, abciximab). Platelet dysfunction caused by drugs may be severe, but specialized tests are rarely needed.

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 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.

Diagnosis reference

  • Al-Samkari H, Rosovsky RP, Karp Leaf RS: A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia. Blood Adv 14;4(1):9–18, 2020. doi: 10.1182/bloodadvances.2019000868.

Treatment

  • Stopping drugs that impair platelet function

  • Rarely platelet transfusions

  • Rarely antifibrinolytic drugs

In patients with thrombocytopenia or platelet dysfunction, drugs that further impair platelet function, particularly aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), should not be given. Patients who are already taking such drugs should consider alternative drugs, such as acetaminophen, or simply stop using them.

Patients may require platelet transfusion, but transfusions are given only in limited situations. Prophylactic transfusions are used sparingly because they may lose their effectiveness with repeated use due to the development of platelet alloantibodies.

In platelet dysfunction or thrombocytopenia caused by decreased production, transfusions, thrombopoietin (TPO)-receptor agonists (eg, romiplostim, eltrombopag, avatrombopag), or antifibrinolytic drugs (eg, aminocaproic acid, tranexamic acid) are reserved for patients with

  • Active bleeding

  • Severe thrombocytopenia (eg, platelet count < 10,000/mcL)

  • A need for an invasive procedure

In thrombocytopenia caused by platelet destruction, transfusions are reserved for life-threatening or central nervous system bleeding.

Drugs Mentioned In This Article

Drug Name Select Trade
AMICAR
CYKLOKAPRON
TYLENOL
No US brand name
PLAVIX
PROMACTA
NPLATE
HYDREA
VELCADE
BRILINTA
REOPRO
EFFIENT
QUALAQUIN
PANHEPRIN
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