Thrombocytopenia

Overview
Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood.

Generally speaking a normal platelet count ranges from 150,000 and 450,000 per mm3. These limits, however, are determined by the 2.5th lower and upper percentile, and a deviation does not necessarily imply any form of disease. The number of platelets in a blood sample also decreases rather quickly with time and a low platelet count may be caused by a delay between sampling and analysis.

Signs and symptoms
Often, low platelet levels do not lead to clinical problems; rather, they are picked up on a routine full blood count (or CBC, complete blood count ). Occasionally, there may be bruising, particularly purpura in the forearms, nosebleeds and/or bleeding gums.

It is vital that a full medical history is elicited, to ensure the low platelet count is not due to a secondary process. It is also important to ensure that the other blood cell types red blood cells, and white blood cells, are not also suppressed.

Diagnosis
Laboratory tests might include: full blood count, liver enzymes, renal function, vitamin B12 levels, folic acid levels, erythrocyte sedimentation rate, and peripheral blood smear.

If the cause for the low platelet count remains unclear, bone marrow biopsy is often undertaken, to differentiate whether the low platelet count is due to decreased production or peripheral destruction.

Causes
There are two broad mechanisms of thrombocytopenia: reduced platelet production and increased platelet destruction. Thormbocytopenia is seen in a variety of infectious and genetic disorders as well as a side effect of a large list of phramacotherapies.

Vitamin deficiencies

 * Vitamin B12 deficiency
 * Folic acid deficiency
 * Iron deficiency

Hematologic disorders

 * Pancytopenia
 * Aplastic anemia
 * Acute lymphoblastic leukemia
 * Acute myeloid leukemia
 * Chronic lymphocytic leukaemia
 * Chronic myeloid leukaemia
 * Hairy cell leukaemia
 * Myeloma
 * Non-Hodgkin lymphoma
 * Myelodysplastic syndrome
 * Myelofibrosis

Reduced thrombopoiesis due to reduced thrombopoietin production

 * Decreased production of thrombopoietin by the liver in liver failure.

Infectious etiologies

 * Sepsis, systemic viral or bacterial infection
 * Dengue fever can cause thrombocytopenia by direct infection of bone marrow megakaryocytes as well as immunological shortened platelet survival
 * Protozoa and protozoal conditions
 * Visceral leishmaniasis
 * Human granulocytic ehrlichiosis
 * Human monocytotropic ehrlichiosis
 * Mycoplasma pneumonia
 * Staphylococcal toxic shock syndrome
 * Epstein-Barr virus
 * Hantavirus
 * HIV-1 disease
 * Infectious mononucleosis
 * Lassa fever
 * Measles
 * Mumps
 * Oklahoma tick fever
 * Rubella
 * Severe acute respiratory distress syndrome
 * Tick born encephalitis

Intrauterine acquired conditions

 * Neonatal alloimmune thrombocytopenia
 * Rubella, congenital
 * Syphilis, congenital

Hereditary syndromes

 * Congenital Amegakaryocytic Thrombocytopenia (CAMT)
 * Bernard-Soulier syndrome, associated with large platelets
 * May-Hegglin anomaly, the combination of thrombocytopenia, pale-blue leuckocyte inclusions, and giant platelets
 * Grey platelet syndrome
 * Alport syndrome

Chromosomal abnormalities

 * Jacobsen syndrome

Mendelian inherited conditions

 * Autoimmune lymphoproliferative syndrome type 1
 * Autoimmune lymphoproliferative syndrome type 2
 * Radial aplasia-thrombocytopenia syndrome or Thrombocytopenia absent radius syndrome
 * von Willebrand disease, platelet type

Autosomal dominant conditions

 * Arias oculootoradial syndrome
 * Complement factor H deficiency
 * Fechtner syndrome
 * May-Hegglin anomaly
 * Platelet glycoprotein 4 deficiency
 * Sebastian platelet syndrome

Autosomal recessive conditions

 * Chediak-Higashi disease
 * Dibasic aminoaciduria type 2
 * Familial histiocytic reticulosis
 * Fanconi anaemia
 * Folate malabsorption hereditary
 * Gaucher disease
 * Griscelli syndrome type 1
 * Histiocytosis X
 * Holocarboxylase synthase deficiency
 * Iminodipeptiduria
 * Isovaleric acidaemia
 * Methylmalonic aciduria type 2
 * Neuroectodermal melanolysosomal disease
 * Niemann-Pick disease type B
 * Omenn syndrome
 * Platelet glycoprotein Ib deficiency
 * Propionyl-CoA carboxylase deficiency PCCA type
 * Sea blue histiocytosis
 * Shwachman-Diamond syndrome

X-linked inherited conditions

 * GATA1-related cytopenia
 * Immunodysregulation polyendocrinopathy and enteropathy, X-linked
 * Wiskott-Aldrich syndrome
 * X-linked hyperimmunoglobulin M syndrome
 * Mitochondrial genome inherited conditions
 * MELAS

Chemical exposure
Strontium-89

Zinc

Hematologic Disorders

 * Idiopathic thrombocytopenic purpura (ITP)
 * Thrombotic thrombocytopenic purpura (TTP)
 * Hemolytic-uremic syndrome (HUS)
 * Disseminated intravascular coagulation (DIC)
 * Paroxysmal nocturnal hemoglobinuria (PNH)
 * Neonatal alloimmune thrombocytopenia (NAITP)
 * Following transfusion or post transfusion alloimmune thrombocytopenia
 * Evans syndrome
 * Macrophage activation syndrome

Cardiovascular causes

 * Cholesterol embolism
 * Intraaortic balloon pump placement
 * Endocarditis

Obstetric disorders

 * Eclampsia
 * HELLP syndrome
 * Pre-eclampsia

Autoimmunde Disorders

 * Antiphospholipid syndrome
 * Systemic lupus erythematosus (SLE)
 * post transfusion purpura

Infectious Disorders

 * Dengue fever has been shown to cause shortened platelet survival and immunological platelet destruction
 * HIV

Other disorders

 * Splenic sequestration of platelets due to hypersplenism

Medication-induced
Thrombocytopenia associated with medications can be due to either a reduction in production of platelets or increased destruction.

Direct myelosuppression

 * Valproic acid
 * Methotrexate
 * Carboplatin
 * Interferon
 * Other chemotherapy drugs

Immunological platelet destruction

 * Drug binds Fab portion of an antibody. The classic example of this mechanism is the quinidine group of drugs.  The Fc portion of the antibody molecule is not involved in the binding process.
 * Drug binds to Fc, and drug-antibody complex binds and activates platelets. Heparin induced thrombocytopenia  (HIT) is the classic example of this phenomenon. In HIT, the heparin-antibody-platelet factor 4 (PF4) complex binds to Fc receptors on the surface of the platelet.  Since Fc portion of the antibody is bound to the platelets, they are not available to the Fc receptors of the reticulo-endothelial cells, so therefore this system cannot destroy platelets as usual. This may explain why severe thrombocytopenia is not a common feature of HIT.

Heparin-induced thrombocytopenia
(HIT or white clot syndrome): this is a rare but serious condition that may occur in a hospitalized population. The most common clinical setting for HIT is in postoperative coronary artery bypass graft recipients, who may receive large quantities of heparin during surgery. HIT typically occurs about a week after exposure to heparin. The heparin-PF4 antibody complex will activate the platelets, and this can often lead to thrombosis. The term HITT, where the last T stands for thrombosis, denotes the concept that heparin-induced thrombocytopenia often is associated with thrombosis.

List of potential etiologies:
Low molecular weight heparins

Sulphonamides

Drugs, hormones and mediators

5-Azacytidine

Abciximab

Aclarubicin

Actinomycin D

Aggrastat

Albendazole

Alemtuzumab

Altretamine

Amiodarone

Amrinone

Anagrelide

Anazolene

Antithymocyte globulin

Ardeparin

Arsenic trioxide

Azathioprine

Bendamustine

Benoxaprofen

Bortezomib

Captopril

Caspofungin

Chloramphenicol

Cilazapril

Cimetidine

Cladribine

Clofarabine

Dasatinib

Decitabine

Desferrioxamine

Doxorubicin

Efalizumab

Eflornithine

Epirubicin

Eptifibatide

Ethanol

Flucytosine

Fondaparinux

Ganciclovir

Gemcitabine

Gemtuzumab ozogamicin

Gold salts

Guanidinium

Haem arginate

Heparin

Ibritumomab tiuxetan

Idarubicin

Imatinib mesylate

Indomethacin

Integrilin

Interferon alpha

Interleukin 10

Interleukin 2

Irinotecan

Ixabepilone

Lenalidomide

Lomustine

Melphalan

Mercaptopurine

Methyldopa

Methyldopate

Mithramycin

Nelarabine

Nilotinib

Nitisinone

Oxaliplatin

Para-amino salicylic acid

Pemetrexed

Penicillamine

Pentamidine

Phenylbutazone

Pyrimethamine

Quinidine

Quinine

Ranitidine

ReoPro

Rifampicin

Sirolimus

Sorafenib

Stiripentol

Sulphasalazine

Sunitinib malate

Temozolomide

Ticlopidine

Tirofiban

Topotecan

Trabectedin

Trimetrexate

Valganciclovir

Valproic acid

Vancomycin

Vinorelbine

Vorinostat


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Epiphenomenon
Kasabach-Merritt syndrome Paraneoplastic syndrome

Treatment
Treatment is guided by etiology and disease severity. The main concept in treating thrombocytopenia is to eliminate the underlying problem, whether that means discontinuing suspected drugs that cause thrombocytopenia, or treating underlying sepsis. Diagnosis and treatment of serious thrombocytopenia is usually directed by a hematologist.

Specific treatment plans often depend on the underlying etiology of the thrombocytopenia.

Thrombotic thrombocytopenic purpura (TTP)
Treatment of thrombotic thrombocytopenic purpura is a medical emergency, since the 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 , this treatment theoretically works by removing antibodies directed against the von Willebrand factor cleaving protease, ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a more physiological state 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 the how plasmapheresis treats TTP.

ITP
In many cases, ITP is self-limited, and does not require treatment. Platelet counts less than ten thousand per mm3 usually require treatment(less than fifty thousand requires treatment, less than ten thousand is a potentially dangerous situation) and patients with significant bleeding and thrombocytopenia due to ITP are also usually treated. The threshold for treating ITP has decreased since the 1990s, and hematologists recognize that patients rarely bleed with platelet counts greater than ten thousand, though there are documented exceptions to this observation. Treatments for ITP include:
 * Prednisone and other corticosteroids
 * Intravenous gamma globulin
 * Splenectomy
 * Danazol
 * Rituximab

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 thrombopoeitin or lead to thrombosis.

A medication known as AMG 531 was found to be safe and effective for the treatment of ITP in refractory patients. AMG 531 is a peptide that bears no sequence homology with endogenous human thrombopoeitin, so it is not as likely to lead to neutralizing antibodies as previous peptide thrombopoeitin analogues.

Heparin-induced thrombocytopenia and thrombosis (HITT)
Discontinuation of heparin is critical in a case of HITT. Beyond that, however, care must be taken to avoid a thrombosis, and patients started directly on warfarin after a diagnosis of HITT are at excess risk of venous limb gangrene. For this reason, patients are usually treated with a type of blood thinner called a direct thrombin inhibitor such as the FDA-approved lepirudin or argatroban. 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 a routine component of the treatment of HITT, since thrombosis, not bleeding, is the usual associated problem in this illness.

Congenital amegakaryocytic thrombocytopenia (CAMT)
Bone Marrow/Stem Cell Transplant is the only thing that ultimately cures this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death until transplant is done.

Prognosis and Clinical Significance
In acute coronary syndrome trials and ST elevation MI trials, thrombocytipenia has been associated with an increase risk of major bleeding, transfusion, recurrent MI, stroke and both in-hosptial and 30 day mortality