Thrombocytopenia

Thrombocytopenia
Synonyms	Thrombopenia
A picture of the blood under a microscope showing thrombocytopenia
Specialty	Hematology

Thrombocytopenia is a disorder characterized by abnormally low levels of thrombocytes, also known as platelets, in the blood.^[1]

A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood.^[2] These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia requiring emergency treatment is a platelet count below 50,000 per microliter.^[3]

Signs and symptoms

Right upper limb with purpura caused by thrombocytopenia in patient with septic shock.

Thrombocytopenia usually has no symptoms and is picked up on a routine full blood count (or complete blood count). Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, and/or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin.^[4][5]

Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. It is also important to ensure that the other blood cell types, such as red blood cells and white blood cells, are not also suppressed.^[4] Painless, round and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body.^[4]

A person with this disease may also complain of malaise, fatigue and general weakness (with or without accompanying blood loss). Acquired thrombocytopenia may be associated with a history of drug use. Inspection typically reveals evidence of bleeding (petechiae or ecchymoses), along with slow, continuous bleeding from any injuries or wounds. Adults may have large, blood-filled bullae in the mouth.^[6] If the person's platelet count is between 30,000 and 50,000/mm³, bruising with minor trauma may be expected; if it is between 15,000 and 30,000/mm³, spontaneous bruising will be seen (mostly on the arms and legs).^[7]

Causes

Thrombocytopenia can be inherited or acquired.^[8]

Decreased production

Abnormally low platelet production may be caused by:^[9]

• Dehydration, Vitamin B₁₂ or folic acid deficiency
• Leukemia or myelodysplastic syndrome or aplastic anemia
• Decreased production of thrombopoietin by the liver in liver failure
• Sepsis, systemic viral or bacterial infection
• Leptospirosis
• Hereditary syndromes
  • Congenital amegakaryocytic thrombocytopenia
  • Thrombocytopenia absent radius syndrome
  • Fanconi anemia
  • Bernard-Soulier syndrome, (associated with large platelets)
  • May-Hegglin anomaly,
  • Grey platelet syndrome
  • Alport syndrome
  • Wiskott–Aldrich syndrome

Increased destruction

TTP

Abnormally high rates of platelet destruction may be due to immune or non-immune conditions, including:^[10]

• Idiopathic thrombocytopenic purpura
• Thrombotic thrombocytopenic purpura
• Hemolytic-uremic syndrome
• Disseminated intravascular coagulation
• Paroxysmal nocturnal hemoglobinuria
• Antiphospholipid syndrome
• Systemic lupus erythematosus
• Post-transfusion purpura
• Neonatal alloimmune thrombocytopenia
• Hypersplenism
• Dengue fever
• Gaucher's disease
• Zika virus^[11]

Medication-induced

The following medications can induce thrombocytopenia through direct myelosuppression.^[12]

• Valproic acid
• Methotrexate
• Carboplatin
• Interferon
• Isotretinoin
• Panobinostat
• H₂ blockers and proton-pump inhibitors

Other causes

• Snakebite^[13]
• Niacin toxicity^[14]
• Lyme disease^[15]
• Thrombocytapheresis (also called Plateletpheresis)

Diagnosis

Laboratory tests for thrombocytopenia might include full blood count, liver enzymes, kidney function, vitamin B₁₂ levels, folic acid levels, erythrocyte sedimentation rate, and peripheral blood smear. If the cause for the low platelet count remains unclear, a bone marrow biopsy is usually recommended to differentiate cases of decreased platelet production from cases of peripheral platelet destruction.^[16]

Thrombocytopenia in hospitalized alcoholics may be caused by spleen enlargement, folate deficiency, and, most frequently, the direct toxic effect of alcohol on production, survival time, and function of platelets.^[17] Platelet count begins to rise after 2 to 5 days' abstinence from alcohol. The condition is generally benign, and clinically significant hemorrhage is rare.

In severe thrombocytopenia, a bone marrow study can determine the number, size and maturity of the megakaryocytes. This information may identify ineffective platelet production as the cause of thrombocytopenia and rule out a malignant disease process at the same time.^[18]

Treatment

Treatment is guided by the severity and specific cause of the disease. Treatment focuses on eliminating the underlying problem, whether that means discontinuing drugs suspected to cause it or treating underlying sepsis. Diagnosis and treatment of serious thrombocytopenia is usually directed by a hematologist. Corticosteroids may be used to increase platelet production. Lithium carbonate or folate may also be used to stimulate platelet production in the bone marrow.^[19]

Thrombotic thrombocytopenic purpura

Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency, since the associated hemolytic anemia and platelet activation can lead to renal failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis, ^[20] this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.^[21]

Idiopathic thrombocytopenic purpura

Oral petechiae/purpura - Idiopathic thrombocytopenic purpura

Many cases of ITP can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts of under 50,000 are usually monitored with regular blood tests, and those with counts of under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such a low platelet count. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although there are documented exceptions to this observation.^[22][23]

Thrombopoetin analogues have been tested extensively for the treatment of ITP. These agents had previously shown promise but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.^[24]

Heparin-induced thrombocytopenia

Discontinuation of heparin is critical in a case of HITT. Beyond that, however, clinicians generally treat to avoid a thrombosis, often by starting patients directly on warfarin. ^[25] For this reason, patients are usually treated with a direct thrombin inhibitor, such as lepirudin or argatroban, which are approved by the FDA for this use. Other blood thinners sometimes used in this setting that are not FDA-approved for treatment of HITT include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HITT because thrombosis, not bleeding, is the primary problem.^[26]

Congenital amegakaryocytic thrombocytopenia

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.^[27]

Neonatal thrombocytopenia

Thrombocytopenia affects a few percent of newborns, and its prevalence in neonatal intensive care units (NICU) is high. Normally, it is mild and resolves without consequences. Most cases affect preterm birth infants and result from placental insufficiency and/or fetal hypoxia. Other causes, such as alloimmunity, genetics, autoimmunity, and infection, are less frequent.^[28]

Thrombocytopenia that starts after the first 72 hours since birth is often the result of underlying sepsis or necrotizing enterocolitis (NEC).^[28] In the case of infection, PCR tests may be useful for rapid pathogen identification and detection of antibiotic resistance genes. Possible pathogens include viruses (e.g. Cytomegalovirus (CMV),^[28] rubella virus,^[28] HIV^[28]), bacteria (e.g. Staphylococcus sp.,^[29] Enterococcus sp.,^[29] Streptococcus agalactiae (GBS),^[28] Listeria monocytogenes,^[28] Escherichia coli,^[28][29] Haemophilus influenzae,^[28] Klebsiella pneumoniae,^[29] Pseudomonas aeruginosa,^[29][30] Yersinia enterocolitica^[30]), fungi (e.g. Candida sp.^[29]), and Toxoplasma gondii.^[28] The severity of thrombocytopenia may be correlated with pathogen type; some research indicates that the most severe cases are related to fungal or gram-negative bacterial infection.^[29] The pathogen may be transmitted during^[31] or before birth, by breast feeding,^[32][33][34] or during transfusion.^[35] Interleukin-11 is being investigated as a drug for managing thrombocytopenia, especially in cases of sepsis or necrotizing enterocolitis (NEC).^[28]

References

External links

• 11-133b. at Merck Manual of Diagnosis and Therapy Professional Edition
• Thrombocytopenia Forum
• Fluorouracil/5-FU Toxicity & DPD Deficiency Education - DPD-Deficiency.com