Thrombocytopenia

Infobox_Disease
Name = Thrombocytopenia


Caption =
DiseasesDB = 27522
ICD10 = ICD10|D|69|6|d|65, ICD10|P|61|0|p|50
ICD9 = ICD9|287.3, ICD9|287.4, ICD9|287.5
ICDO =
OMIM = 188000
OMIM_mult = OMIM2|313900
MedlinePlus = 000586
eMedicineSubj =
eMedicineTopic =
MeshID = D013921

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

Generally speaking, in humans, a normal platelet count ranges from 150,000 and 450,000 per mm³ (microlitre).Cite web
url=http://www.labtestsonline.org.uk/understanding/analytes/platelet/test.html
title=Platelet count aka thrombocyte count
publisher=Lab Tests Online UK
accessdate=2008-05-22
date=2004-05-28] 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.

igns 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

Decreased platelet counts can be due to a number of disease processes:

Decreased production

**vitamin B12 or folic acid deficiency
**leukemia or myelodysplastic syndrome
**Decreased production of thrombopoietin by the liver in liver failure.
**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
**Hereditary syndromes
***Congenital Amegakaryocytic Thrombocytopenia (CAMT)
***Thrombocytopenia absent radius syndrome
***Fanconi anemia
***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

Increased destruction

**idiopathic thrombocytopenic purpura (ITP)
**thrombotic thrombocytopenic purpura (TTP)
**hemolytic-uremic syndrome (HUS)
**disseminated intravascular coagulation (DIC)
**paroxysmal nocturnal hemoglobinuria (PNH)
**antiphospholipid syndrome
**systemic lupus erythematosus (SLE)
**post transfusion purpura
**neonatal alloimmune thrombocytopenia (NAITP)
**Splenic sequestration of platelets due to hypersplenism
**Dengue fever has been shown to cause shortened platelet survival and immunological platelet destruction
**HIV cite journal |author=Scaradavou A |title=HIV-related thrombocytopenia |journal=Blood Rev. |volume=16 |issue=1 |pages=73–6 |year=2002 |pmid=11914001 |doi=10.1054/blre.2001.0188 |url=http://linkinghub.elsevier.com/retrieve/pii/S0268960X01901882

Medication-induced

The most comprehensive list of thrombocytopenia-inducing medications is maintained by Dr. James George at Ohio State University [http://moon.ouhsc.edu/jgeorge/drug%20ITP_single04.htm at this website, though last updated in 2004] . A small subset of drug-induced thrombocytopenia culprits:

*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.

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 [cite journal |author=Furlan M, Lämmle B |title=Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease |journal=Best Pract Res Clin Haematol |volume=14 |issue=2 |pages=437–54 |year=2001 |pmid=11686108 |doi=10.1053/beha.2001.0142] [cite journal |author=Tsai H |title=Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura |journal=J Am Soc Nephrol |volume=14 |issue=4 |pages=1072–81 |year=2003 |pmid=12660343 |doi=10.1097/01.ASN.0000060805.04118.4C] , 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.

Idiopathic thrombocytopenic purpura (ITP)

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 monitiored 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 a platelet count this low. Any patient experiencing severe bleeding symptoms is 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 Immune 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 investigational medication known as AMG 531 (Romiplostim, trade name Nplate) was found, in early studies, to be safe and effective for the treatment of ITP in refractory patients. [cite journal |author=Bussel J, Kuter D, George J, McMillan R, Aledort L, Conklin G, Lichtin A, Lyons R, Nieva J, Wasser J, Wiznitzer I, Kelly R, Chen C, Nichol J |title=AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP |journal=N Engl J Med |volume=355 |issue=16 |pages=1672–81 |year=2006 |pmid=17050891 |doi=10.1056/NEJMoa054626] [Cite news
author=AMGEN
publisher=Business Wire via drugs.com
accessdate=2008-05-22
date=2008-03-12
title=Press release: Amgen Statement on Successful Outcome of Romiplostim Panel Meeting
url=http://www.drugs.com/nda/romiplostim_080313.html] [Cite news
author=
publisher=Reuters
accessdate=2008-05-22
date=2008-03-12
title=US FDA panel backs Amgen's Nplate against ITP
url=http://www.reuters.com/article/rbssHealthcareNews/idUSWAT00911720080312] 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. [cite journal |author=Broudy V, Lin N |title=AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl |journal=Cytokine |volume=25 |issue=2 |pages=52–60 |year=2004 |pmid=14693160 |doi=10.1016/j.cyto.2003.05.001]

Heparin-induced thrombocytopenia and thrombosis (HITT)

Discontinuation of heparin is critical in a case of HITT. Beyond that, however, clinicians generally treat 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)

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder. The primary manifestations are thrombocytopenia and megakaryocytopenia, or low numbers of platelets and megakaryocytes. There is an absence of megakaryocytes in the bone marrow with no associated physical abnormalities.cite journal | author=Freedman MH, Estrov Z| title= Congenital amegakaryocytic thrombocytopenia: an intrinsic hematopoietic stem cell defect | date=1990 |journal=Am. J. Pediatr. Hematol. Oncol. |volume=12 | pages=225–230] The cause for this disorder appears to be a mutation in the gene for the TPO receptor, "c-mpl", despite high levels of serum TPO.cite journal | author=Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T |title=Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia |journal=Proc. Natl. Acad. Sci. |date=1999 |volume=96 |pages=3133–6 | doi=10.1073/pnas.96.6.3132 |pmid=10077649] cite journal | author=Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, Krukemeier S, Eilers M, Strauss G, Welte K | title=C-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia |journal=Blood. |date=2001 |volume=97|pages=139–46 | doi=10.1182/blood.V97.1.139 | pmid=11133753] In addition, there may be abnormalities with the central nervous system including the cerebrum and cerebellum which could cause symptoms. The primary treatment for CAMT is bone marrow transplantation.

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, although this is not always the case.

One of the few non Medical Research related sources on the web with some information on CAMT is;

* [http://www.haleysgiggle.com/ CAMT Specific Infant Bone Marrow Transplant Journal]

There appears to be no generic resource for CAMT patients on the web, and this is potentially due to the rariety of the disease.

References

External links

*
* [http://www.thrombocytopenia.info Thrombocytopenia Forum]