Thrombocytopenia is defined as a platelet count below 150 x 109 / L (150 000 / mm3). It can be of central origin default production or consumption by peripheral, abnormal distribution or immunological destruction by antiplatelet antibodies in particular during the immune thrombocytopenic purpura (Fig. 1). There is no rule in clinical impact when the platelet count is greater than 50 × 109 / L. The most serious bleeding complications (gastrointestinal bleeding, hematuria and bleeding especially cérébroméningé) will usually occur if the platelet count is less than 20 × 109 / L. In the presence of thrombocytopenia, treatment modalities and the urgency of their implementation are conditioned by the thrombocytopenia mechanism and severity of hemorrhagic syndrome.
DIAGNOSTIC :
Examination:
It specifies the following data.
1) What is the impact of thrombocytopenia? severity of signs Wanted requiring immediate hospitalization: Important mucocutaneous bleeding, headache suggestive of intracerebral hemorrhage, gastrointestinal bleeding …
2) What is the length of thrombocytopenia?
It is essential to analyze any past counts for seniority of thrombocytopenia directs the diagnosis and determines in part the therapeutic indications.
Thus, the probability that ancient thrombocytopenia, without strictly isolated anomalies of other lines and without hemorrhagic manifestations is associated with severe hematologic malignancy requiring urgent treatment is low. Also look for a concept of family thrombocytopenia that moving towards exceptional congenital thrombocytopenia.
3) What are the drugs ingested by the patient? Ingestion of certain medications can typically be complicated thrombocytopenia (Box 1). A place must be made for thrombocytopenia due to heparin that is usually complicated by thrombosis, not bleeding.
4) Is there any risk of infection factors by HIV (HIV) and the hepatitis C virus (HCV)?
5) he has a flu syndrome preceded the onset of thrombocytopenia? The latter towards a postviral immune thrombocytopenia.
6) A transfusion she was done recently? It directs toward the diagnosis of post-transfusion purpura is however a rare complication.
7) Are there any signs of moving towards a connective? The following signs pointing to a connectivity and particularly lupus arthralgia, photosensitivity, Raynaud’s syndrome, alopecia, repeated false spontaneous abortion, recurrent phlebitis.
8) Is there a particular context and making a exogénose raise the possibility of liver disease?
Box 1. Major drug makers thrombocytopenia
thrombocytopenia plants
cancer chemotherapy
colchicine
Benzene Derivatives
thiazide
Radiotherapy
antivirals
Antifolates (Bactrim, Malocide®)
Thrombocytopenia peripheral (immunological or immunoallergic)
Quinine and quinidine
digitalis
Sulfa drugs (antibacterial and hypoglycemic)
antisecretory
Unfractionated heparins and fractionated
Valproic acid (Depakine ®)
Verapamil (Isoptine)
Rifampicin (Rifadine®)
Physical examination :
It is usually normal during the immune thrombocytopenic purpura, apart from any signs of bleeding. Organomegaly (hepatosplenomegaly, lymphadenopathy) towards a central thrombocytopenia, satellite hematological malignancy or to thrombocytopenia associated with HIV infection. Signs in favor of chronic liver disease (spider nevi, palmar erythrosis …) evoke hypersplenism. Finally, any serious infectious syndrome may be accompanied by sometimes severe thrombocytopenia, mainly due to a consumption mechanism.
Diagnostic tests:
The priority is to confirm the reality of thrombocytopenia eliminating false thrombocytopenia with platelet aggregation in the presence of ethylene diamine tetra-acetic acid (EDTA, Box 2).
Box 2. False thrombocytopenia associated with EDTA, a diagnostic trap to know
The “pseudothrombopénies EDTA” are due to platelet agglutination in vitro with a blood sample taken from a medium containing EDTA. This is the anticoagulant normally used to perform a complete blood count. This anticoagulant is unique to separate some complex glycoprotein platelet membrane and exposing the neo-antigens recognized by antiplatelet antibodies incapable of binding in vivo on the plate but capable in vitro to cause caking.
The clumped platelets are then counted by the automatic device as red blood cells which reflects the underestimation of the actual number of platelets. The presence of agglutinates may be identified during the analysis of the blood smear. This false thrombocytopenia is a laboratory artefact and is never accompanied by hemorrhagic syndrome. This diagnosis should always be removed when thrombocytopenia is not accompanied by bleeding. It will be confirmed numérant platelets on the capillary blood from “fingertip” or taking the samples on a tube containing another anticoagulant, such as citrate.
Necessary exams:
First line:
The blood typing, looking for irregular antibodies and anti-HLA antibodies should be systematic when thrombocytopenia is severe and may require transfusions.
Complete blood count (CBC) with a careful analysis of blood smear by haemobiologist is the key diagnostic. The presence of qualitative abnormalities and / or quantitative other lines towards a central thrombocytopenia. Search schistocytes must be systematic, as well as an account of reticulocytes in cases of anemia. The presence of large numbers schistocytes towards a thrombotic microangiopathy is a hematologic emergency that warrants immediate hospitalization in hematological intensive care unit.
The study of hemostasis includes a measurement of prothrombin time (PT), activated partial thromboplastin time (aPTT) and fibrinogen. It is supplemented by a measurement of D-dimer and a research fibrin degradation products when it is suspected disseminated intravascular coagulation (DIC).
The presence of abnormal liver function tests (transaminases, bilirubin, γ-GT, alkaline phosphatase) evokes thrombocytopenia due to hypersplenism associated with portal hypertension and / or a viral infection.
HIV serology will be performed after informing the patient and with his consent.
Myelogram:
At this stage, it is often possible to have an orientation on the central or peripheral mechanism of thrombocytopenia.The existence of an abnormality of the other lines or tumor syndrome towards a central thrombocytopenia and performing a bone marrow aspirate is essential.
The marrow is collected by sternal puncture can be carried out without special precautions, even in cases of severe thrombocytopenia.
If central thrombocytopenia, bone marrow aspiration shows a decrease or absence of megakaryocytes, possibly associated in case of dysplasia morphological abnormalities indicating a maturation of megakaryocytes disorder. It may also reveal the presence of abnormal cells, leukemia or metastatic. In case of peripheral thrombocytopenia, bone marrow is normal and rich in megakaryocytes.
The myelogram is however not essential that the following criteria are met:
– Age less than 60 years;
– Isolated thrombocytopenia without abnormality of other lines after a careful analysis of blood smear by haemobiologist;
– No anomaly of hemostasis;
– Absence of tumor syndrome.
In this situation, a test is justified to corticosteroids in adults if thrombocytopenia is less than 50 × 109 / L. A significant increase in platelet count greater than 50 × 109 / L with an initial figure of doubling strongly advocates the nature of immunological peripheral thrombocytopenia and may postpone the implementation of the myelogram.
In the absence of response to steroid therapy, bone marrow aspiration should be performed. This strategy is discussed in children because some teams consider that the creation of bone marrow aspiration is essential before any steroid in order not to hide acute leukemia.
Second-line examinations:
They are justified only when previous examinations inconclusive.
The presence of antiplatelet antibodies detected by techniques immunocapture reserved for specialized laboratories directed towards the diagnosis of autoimmune thrombocytopenic purpura.
Thyroid function tests will be offered before any sign suggestive of thyroid dysfunction that may be associated with the occurrence of immune thrombocytopenia.
Viral serology will be performed only in the clinical context: Epstein-Barr virus, cytomegalovirus, hepatitis …
The search for a connectivity includes antinuclear antibodies and anti-Ro (SSA) complemented by the implementation of a direct Coombs test Hemolytic anemia (Evans syndrome). It may be coupled with the search for antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant research of lupus) whose presence is an occurrence of thrombosis and risk factor of progression to lupus.
The duration of isotopic pad life is to mark the patient’s platelets with an isotope and measuring the decay of radioactivity. If central thrombocytopenia, the lifetime of platelets is normal (about 6 to 8 days), while it is shortened in peripheral thrombocytopenia (maximum 2 days). In the latter case, the examination can determine the location of platelet destruction (spleen and / or liver) which may, for some, guide therapeutic indications. This exam is especially indicated in situations where there is diagnostic uncertainty.
The dosage of thrombopoietin is currently restricted to research laboratories. This growth factor is negatively regulated by the megakaryocytic mass. Low levels of thrombopoietin is for the diagnosis of immune thrombocytopenic purpura while high levels towards a central thrombocytopenia.
ETIOLOGY:
Thrombocytopenia plants:
They are characterized by a poor marrow megakaryocytes and frequent involvement of other hematopoietic lineages.The main causes are malignant blood diseases, medullary aplasia, the encroachments by metastatic cells. It however must not overlook benign causes such as acute folate deficiency, or acute alcohol intoxication.
Treatment consists of treating the cause and platelet transfusion when thrombocytopenia is deep or when there is a hemorrhagic syndrome.
Consumption by peripheral thrombocytopenia:
This is hematological emergency warranting immediate hospitalization in a specialized environment.
DIC:
It is accompanied by a lowering of the PT and fibrinogen levels. The diagnosis is confirmed by the presence of degradation products of fibrin and by an increase in the rate of D-dimer. The main causes are severe sepsis, spinal metastases (especially prostate), obstetric pathologies, acute promyelocytic leukemia in particular, transfusion accidents.
Thrombotic microangiopathy:
These are rare but serious conditions that include thrombotic thrombocytopenic purpura, also called Moschcowitz syndrome, and hemolytic uremic syndrome. It approaches the hemolytic uremic syndrome HELLP syndrome is a severe form of pre-eclampsia involving eclampsia, hemolytic anemia, thrombocytopenia and liver damage.
Thrombotic thrombocytopenic purpura associated with varying degrees of fever, central fluctuating neurological signs and usually moderate hemorrhagic syndrome. Biologically, thrombocytopenia is associated with kidney failure and hemolytic anemia associated with the presence of many schistocytes reflecting its mechanical character. The presence schistocytes is the key element of diagnosis.
Thrombotic thrombocytopenic purpura is related to the presence of polymers with von Willebrand factors of high molecular weight due to a congenital or acquired deficiency of a protease called ADAMTS-13 whose function is to cleave the polymeric von Willebrand factor. During the thrombotic thrombocytopenic purpura, the activity of ADAMTS-13 protease is usually collapsed (<5%) while it rises under the effect of the treatment.
During the hemolytic uremic syndrome, the table is close but renal involvement is in the foreground. Treatment consists of plasma exchange made using plasma virally inactivated. Infusions of anti-CD20 monoclonal antibody are most often very effective and are indicated for severe cases.
Insist again on the severity of the prognosis and the need to immediately transfer the patient to an ICU specialist as soon as the diagnosis is suspected.
Thrombocytopenia distribution anomaly devices:
They are due to hypersplenism and are then related splenomegaly most often due to portal hypertension.
Thrombocytopenia is usually moderate and is often accompanied by neutropenia and moderate anemia. It does not directly lead to bleeding complications.
Thrombocytopenia devices immunological destruction:
They may be due to the presence:
– An auto-antibodies (immune thrombocytopenic purpura);
– An antibody recognizing the platelets in the presence of a drug (immunoallergic mechanism);
– An exceptionally allo-antibodies (thrombocytopenia
Neonatal alloimmune and posttransfusionnel purpura).
Purpura thrombocytopenic purpura:
It may be isolated or complicate the development of a lupus, a lymphoid blood disease or acute or chronic viral infections, particularly HIV. Diagnosis is based on the following:
– Isolated thrombocytopenia without abnormality of other lines;
– Absence of tumor syndrome and organomegaly;
– Lack of drug involved;
– No anomaly of hemostasis;
– Bone marrow aspiration when it is made (see paragraph
diagnostic tests) shows a normal, rich marrow megakaryocytes.
In children, autoimmune thrombocytopenic purpura often occurs with the waning of a viral infection and healing in a few weeks was observed in 80% of cases. In adults, a chronic course is rather the rule and only 20 to 30% of patients recover within six months, spontaneously or following treatment with corticosteroids and / or intravenous immunoglobulin. Mortality hemorrhage is less than 2%.
Thrombocytopenia immunoallergic:
Drug-induced (Box 1)
They are secondary to the presence of an antibody capable of binding to the platelet membrane only in the presence of the offending drug. They occur suddenly and are often severe. They heal rule within 10 days after stopping the offending drug. Diagnosis is based on clinical context (seek a change in treatment in the days preceding the onset of thrombocytopenia). Accountability is rarely demonstrated with certainty in the laboratory.
Rechallenge is against inappropriate.
Thrombocytopenia Heparin is also immunoallergic. It can be observed regardless of the type of heparin used but the risk is higher in case of unfractionated heparin use. It usually occurs 10 to 25 days after initiation of treatment which justifies médicolégalement to monitor platelet regularly during this period, even when using low molecular weight prophylactic dose heparin. Thrombocytopenia may be complicated by arterial or venous thrombosis while bleeding complications are rare. She quickly corrected after stopping treatment.
Diagnosis is based on the context but diagnostic confirmation can be provided by the laboratory where different techniques used to highlight the presence of heparin-dependent antiplatelet antibodies (antibody dependent PF4).Treatment is the immediate discontinuation of heparin and the use of danaparoid (OrgaranR).
Thrombocytopenia due to alloantibodies:
They are exceptional and can be observed during pregnancy (neonatal thrombocytopenia) or after transfusion (posttransfusionnel purpura).
TREATMENT :
Severe bleeding (intracerebral hemorrhage, gastrointestinal bleeding) does usually observed when thrombocytopenia is less than 20 × 109 / L. The importance of thrombocytopenia does not allow itself to assess the risk of serious bleeding visceral, especially cérébroméningé or digestive, and to determine the degree of urgency.
Other factors to be considered are the importance of mucocutaneous hemorrhagic syndrome, the terrain, the association with other disorders of hemostasis and coagulation, and the clinical context (need for a surgical procedure such ) (Box 3). Signs to be feared the occurrence of severe bleeding is the existence of a purpura and / or extensive bruising worsening rapidly and the existence of significant bleeding mucous membranes (uterine bleeding, spontaneous epistaxis, especially if they are bilateral spontaneous gingival bleeding, hemorrhagic blisters in the mouth). The land is also an element which determines the degree of urgency. The bleeding risk is higher in the elderly or otherwise in infants and the association with visceral tare such as poorly controlled hypertension or active peptic ulceration increases the risk of serious bleeding; must finally take account of the possible medications that can alter hemostasis or promote the appearance of a gastrointestinal bleeding (anticoagulants, aspirin, nonsteroidal anti-inflammatory drugs), association with other disorders hemostasis or coagulation (liver failure, deficiency of clotting factor …).
The hospitalization in a specialized emergency is the rule when there is signs of severity (see Box 3).
Box 3. Criteria for severity of thrombocytopenia
Importance of thrombocytopenia
The platelet count is insufficient him alone to assess the risk of bleeding.
Importance of hemorrhagic syndrome
Severe visceral bleeding (intracerebral, digestive)
major bleeding mucocutaneous:
– Purpura extensive ecchymotic
– Bilateral epistaxis or menorrhagia important
– Hemorrhagic blisters in the mouth
Related field
Elderly, infants
Tare associated visceral (hypertension, peptic ulcer …)
Taking medication altering primary hemostasis or promoting bleeding (anticoagulants, nonsteroidal anti-inflammatory drugs, aspirin)
Combination with other abnormalities of haemostasis or coagulation
Need for even minor traumatic gesture
Mechanism of thrombocytopenia
The risk is increased in case of central thrombocytopenia
Special case of immune thrombocytopenic purpura:
In the autoimmune thrombocytopenic purpura, we must distinguish the acute phase, which corresponds to the first month of evolution, and the chronic phase defi ned by a disease duration greater than 6 months. It is indeed exceptional observed spontaneous healing beyond this period which then justifies the use of invasive treatments when the severity of thrombocytopenia requires.
Treatment during the acute phase:
The goal of treatment in this phase of the disease is to prevent the occurrence of a severe hemorrhagic syndrome by allowing only treatments whose side effects are minor because a spontaneous correction is possible in the early months of evolution. If moderate ulcerative syndrome, corticosteroids are used at a dose of 1 mg / kg / day of prednisone equivalent (Cortancyl®) for a period of 3 to 6 weeks depending on the teams.
There should be no prolonged use of corticosteroids as the potential side effects are then too large and there is evidence that steroids have no effect on the long term evolution of the disease. When there is a greater mucocutaneous hemorrhagic syndrome, urgency justifies using intravenous immunoglobulin treatment and / or corticosteroids at high doses. IVIG are used in the total dose of 1 to 2 g / kg given in 48 hours.
Their high cost and their very transient effects limit their use only for emergencies characterized by the presence of a major hemorrhagic syndrome. The high-dose corticosteroids administered as a three intravenous bolus of 15 mg / kg methylprednisolone (Solumedrol®) are a cheaper alternative but less effective. Platelet transfusions are reserved for exceptional situations where the prognosis is immediately involved (mainly cerebromeningeal bleeding). Apart from these very rare cases, insist they have no place in the treatment of immune thrombocytopenic purpura as the transfused platelets are destroyed immediately.
These treatments can increase temporarily the number of platelets in the majority of patients but this effect is usually transient in adults when the immune thrombocytopenic purpura becomes chronic in 70% of cases. In case of recurrence of thrombocytopenia, no treatment (or for some treatment with dapsone or Danatrol) may be proposed if the hemorrhagic syndrome is absent or weak. Otherwise, it will renew the initially effective treatments (corticosteroids and / or intravenous immunoglobulin) and avoid offering early (that is to say at least six months of evolution) splenectomy in a patient with yet chance to heal “spontaneously”.
Treatment of chronic forms:
The management depends on the assessment of risk of bleeding (intensity of thrombocytopenia, bleeding complications of existence, land …). No treatment is the rule when the platelet count is greater than 50 × 109 / L and there is no bleeding complications. Between 30 and 50 × 109 / L platelets, the therapeutic approach depends on the terrain and the existence of haemorrhagic signs.
When the platelet count is less than 30 × 109 / L, splenectomy remains the best treatment and provides a cure or a significant increase in platelet count in 80% of cases.
Penicillin V socket for several years with the waning of splenectomy is justified because of the risk of serious pneumococcal infection.
Similarly, vaccination against encapsulated bacteria infections (pneumococci, Haemophilus influenzae,meningococcus) must be raised before splenectomy. The splenectomized patient should be advised of the need to take immediate pneumococcal antibiotic therapy and to consult a doctor before febrile episodes. In case of failure of splenectomy, dapsone and / or danazol may be indicated. It is only when these treatments often inexpensive and well tolerated are ineffective, as heavier treatments such as immunosuppressants or monoclonal anti-CD20 antibody (rituximab, MabThera) will be offered after expert advice, remembering that treatments which proved ineffective before splenectomy may become after. Studies are underway to determine whether rituximab could represent an alternative to splenectomy. New therapeutic approaches based on the use of platelet growth factors and in particular molecules stimulating the thrombopoietin receptor are also in development.
Preliminary results are encouraging, but we must emphasize that these molecules have a suspensive effect and the absence of toxicity in prolonged use has not been demonstrated.
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