It is the combination of clinical (examination and questioning) and biological examinations which allows better assess risk or seek an etiology. Note that the interrogation in search of a bleeding tendency is difficult in the patient (whose young age can never having set real risk situation, or whose seniority of pathology may have did get used …)This is to emphasize the unreliability when asked about his family history. These screening tests thus play a role either in addition to a failed examination, either at the beginning of characterization in a suggestive questioning.Neither exams can not avoid questioning or interrogation can not replace exams. This assessment (bleeding time, prothrombin time, activated partial thromboplastin time) is therefore carried out under two different conditions, either during a routine preoperative looking for a bleeding risk in a patient with no history of bleeding or staff, or family, or in the exploration of a spontaneous or induced hemorrhagic incident (Fig. 1). In both cases, the patient interview is fundamental: search all sense of abnormal bleeding incident, spontaneous or induced particularly benign even after surgical intervention like tooth extraction, tonsillectomy, and specify the type of bleeding – the anomaly primary hemostasis (mucosa, bleeding purpura), bleeding disorder (deep hematoma, hemarthrosis) – and the time to onset (over the wound, injury …). The balance sheet of usual screening – bleeding time to study primary hemostasis (it should to involve blood count including platelet count), prothrombin time and activated partial thromboplastin time to study the coagulation – it is strongly advisable to associate a fibrinogen assay functional technology. Some anomalies escape this assessment screening that will specifically investigate whether the clinic is evocative.
Prolonged bleeding time:
Primary hemostasis violations are characterized by mucocutaneous bleeding with the questioning specify: congenital or acquired character (since when and under what conditions) and the existence of a similar pathology in the family, conditions triggering especially taking nonsteroidal anti-inflammatory drugs (aspirin) to clarify if it worsens or reveal hemorrhagic syndrome.
From a schematic point of view, the prolongation of bleeding time corresponds to a disorder of the interaction of platelets with the connective tissues to which they are exposed during vascular breach, which should be responsible for the hemostatic reaction . The anomaly can therefore be at 3 levels (fig. 2):
• platelets may be deficient: in number, they are then diagnosed by thrombocytopenia platelet count; as it is the thrombopathies that can affect every interaction and reactivity function of platelets with the connective between themselves and with the coagulation. Note that the number does not replace quality, for example, thrombocythemia myeloproliferative disorders where platelets that are functionally deficient toggle thrombotic risk (increased number and hyperactivation) and bleeding risk (consecutive functional deficit) and that platelets act with their environment in optimal conditions and hémorrhéologiques that when they are seriously disturbed (severe anemia, monoclonal peak …), this can lead to prolonged bleeding time and bleeding risk;
• plasma cofactors platelet interaction are primarily von Willebrand factor and to a lesser extent fibrinogen whose deficit causes a disorder of primary hemostasis in cases of major hypofibrinogenemia even afibrinogenaemia (which is exceptional);
• the structure of the connective which interact platelets.
Their mechanism is detailed in Table I.
• The discovery of a platelet count decreased platelet count involves checking that it is a true thrombocytopenia and not a technical artefact due to platelet clumping in the commonly used anticoagulant, EDTA (ethylene diamine tetra-acetic acid). This control is achieved by a blood smear examination and platelet count on another anticoagulant or capillary blood collected without anticoagulant.
• The diagnosis of thrombocytopenia is confirmed, then it is to search for the mechanism of thrombocytopenia.Schematically, there are two mechanisms: either defective platelet production or destruction of excess and (or) distribution anomaly of platelets. To distinguish the production anomalies, it is mainly associated with bone marrow examination blood count that determines if it is a purely mégacaryocytoplaquettaire reached or an overall achievement of one or more lines . The development, family studies and additional examinations distinguish and clarify the congenital forms of acquired forms.
• Platelets may be consumed, either as part of a coagulation syndrome or reaction to thrombogenic surfaces such as are disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, intravascular coagulation localized in angioma (Kassabach-Merritt syndrome), on surfaces or in an artificial organ (especially cardiovascular prosthesis or bypass) or as part of an immunological destruction autoimmune thrombocytopenia, thrombocytopenia posttransfusionnelles, neonatal thrombocytopenia isoimmunes, thrombocytopenia immuno-allergic drug. We close, or the trappings in major vascular masses thrombocytopenia kind of splenomegaly or mixed forms associating consumption and hemodilution as in thrombocytopenia resuscitation or massive transfusions, or thrombocytopenia in the third trimester of pregnancy.
2- normal platelet turnover or less modified than would be the prolongation of bleeding time and hemorrhagic syndrome:
The prolongation of bleeding time can then depend on four mechanisms: an intrinsic abnormality of platelets and these are thrombopathies; an abnormality of plasma cofactors of platelet function: Willebrand disease, afibrinogenaemia; abnormal reactivity of connective tissue (especially collagen); a platelet interaction with the anomaly formed elements (hémorrhéologie); severe anemia or polycythemia induce platelet reactivity disorder. • Extension of the bleeding time by thrombopathies All functional and metabolic steps platelets can be achieved. The main hereditary thrombopathies are summarized in Figure 3. Their specific diagnosis is performed in specialized laboratories or highly specialized, in which front-line tests at present are the tests of platelet aggregation at various inductors and flow cytometry to quantify the membrane glycoproteins and granular contents. The acquired thrombopathies are much more common that constitutional thrombopathies. The most common cause is drug especially by antiagrégeants platelet plug which reproduce various constitutional thrombopathies. Many other drugs work more or less specifically on platelets (non-steroidal anti-inflammatory, … penicillins and cephalosporins), numerous pathologies induce thrombopathies and more or less thrombocytopenia (or thrombocytosis) with often integrated mechanisms: haematological diseases myeloproliferative disorders (combined risk of bleeding and thrombosis), acute leukemia and pre-leukemia statements; chronic renal failure; Alcoholism often associated with thrombocytopenia and thrombopathy complex mechanisms at the stage of cirrhosis.
• Extending the achievement of plasma cofactors by bleeding time: an effective cessation of bleeding (measured by bleeding time) requires interaction of platelets with exposed connective tissue and platelet interaction between them.Both mechanisms involve plasma cofactors, in particular fibrinogen and von Willebrand factor. Congenital afibrinogenemia: small amounts of fibrinogen (0.10 g / L) are sufficient to allow platelet reactivity. In deficits fibrinogen, only afibrinogenemia induces a prolonged bleeding time. Willebrand disease: one must say Willebrand disease because there are several subtypes. Type 1 von Willebrand disease is the constitutional haemorrhagic disease with the highest prevalence because biological abnormalities are found in type I 1-2% of the general population. The precise dosage of von Willebrand factor is difficult because the plasma is variable in nycthémère, modified by external stimuli (adrenergic stimulation, inflammatory syndromes, hormonal stimulation (intrinsic: cycle in women; extrinsic: contraception), influenced by the group Blood: O group of subjects have Von Willebrand factor levels on average 20% less than non O. group of subjects The determination of von Willebrand factor demand to measure the various components of the complex: VIIIc factor (clotting) which, in the circulation is bound to von Willebrand factor that stabilizes, the quantitative determination of the latter, which takes place by an immunological technique (von Willebrand factor antigen), the qualitative determination of von Willebrand factor which is done by inducing the von Willebrand interaction with platelets (hence platelet aggregation) by a reagent, ristocetin (von Willebrand factor ristocetin cofactor). These three routine tests are supplemented as appropriate if the Willebrand disease diagnosis is suspected by varying: the search for a sensitivity of platelets to clump together to very low doses of ristocetin; the study of the distribution of multimeric von Willebrand factor by electrophoresis on agarose gel;factor von Willebrand assay intraplatelet; the study of the binding of von Willebrand factor to collagen, the binding of von Willebrand factor VIII or the search for gene mutations as those responsible for major forms of Type 2 VWD are quite localized. There are 3 types of schematically Willebrand disease (Table II): the most common form (type 1) is a form with a moderate quantitative deficit. 3 The activities of FVIII-von Willebrand factor are parallel decreased around 30%, which is due to heterozygous anomaly; 2 types are forms of qualitative abnormalities; 3 types, the rarest, are homozygous severe deficits.
Besides the platelet-shaped due to an abnormality derived binding glycoproteins of von Willebrand factor to platelets (GPIb), there are acquired forms of von Willebrand disease due to consumption of von Willebrand factor (usually in an immunoassay process ).
• Extending the default responsiveness bleeding time and connective particularly collagen: it is a diagnosis that is suggested by the elongations “idiopathic” bleeding time, that is to say, not all the causes of unexplained reviewed earlier. There is no convincing evidence of their existence.
Lengthening of prothrombin time and activated partial thromboplastin:
While bleeding time overall explores primary hemostasis, coagulation abnormalities are detected by a lengthening of prothrombin time and activated partial thromboplastin time, tests that explore all plasma clotting factors (apart factor XIII) (fig. 4).
1- Quick Time:
Prothrombin time of adding thromboplastin and calcium to plasma anticoagulated citrate (calcium chelator).Thromboplastin is tissue extract (and now a biotechnology product) that combines the initiator coagulation factor: tissue factor, and phospholipids that form the molecular surfaces necessary for efficiently assembling complexes of coagulation factors. This pathway is called now tissue factor pathway (formerly extrinsic or exogenously) is the only effective. You can have trouble understanding that this test is not sensitive to deficiencies in factors VIII and IX which are necessary factors and whose deficits (hemophilia A and B) drive the bleeding disorders that we know. This is due to the fact that the large quantity of thromboplastin reagent added to the test plasma, causes a sudden complex formation (the normal prothrombin time is 11 to 13 seconds depending on the reactants) that bypasses the prothrombinase complex (that is directly factor VIIa activates factor X to Xa). While in vivo, because the relative concentrations and flow conditions, this complex prothrombinase plays a major role.
Prothrombin time (PT) is a way of expressing the prothrombin time either in absolute time but a percentage of normal. Normal values of the prothrombin time is 70 to 120%. His expression percentage is very easy to understand and follow anticoagulant therapy with vitamin K antagonists was understood how the thromboplastin reagent affects prothrombin time, and that is to avoid this technical variability that the test was standardized as form of the INR (international normalized ratio) to now follow the treatment with vitamin K antagonists (VKA). The INR is the ratio of prothrombin time at the patient prothrombin time the witness corrected by a factor dependent on the sensitivity of the reagent to lower factors dependent on vitamin K (INR therefore makes sense only in anticoagulated patients with vitamin K antagonists). In general, the reduction of a coagulation factor carries a high risk of bleeding when the factor is less than 30% and more then the factor is decreased, the more the risk of hemorrhage is high. This is why a prothrombin time between 50 and 60% reflects only a moderate anomaly while a lower rate of prothrombin to 30% means an elongated prothrombin time and a major risk of bleeding. The only exception to this rule is the deficit due to an inhibitor, acquired against a specific factor prothrombin time. The most common example (although it is generally rare and it affects the activated partial thromboplastin time and prothrombin not) is antifactor VIII; Indeed, the factor inhibitor + retains activity in coagulation tests but has lost its effectiveness in vivo. A relatively moderate decrease (about 30%) by an inhibitor comprises a major risk of bleeding. Note that from a technical point of view, the reagent prothrombin time further contains an inactivating heparin which makes it insensitive test to therapeutic concentrations of heparin.
2- activator thromboplastin time:
Formerly called partial thromboplastin time, the activated partial thromboplastin time is to add an activation surface of the contact phase of coagulation (which was once as kaolin and now can be silica, ellagic acid … ). The thromboplastin is a phospholipid which forms the molecular surface needed for assemble complex clotting factor and calcium to plasma anticoagulated citrate. This test explores the so-called intrinsic or endogenous coagulation pathway. Activation of the contact phase activates the coagulation cascade. It is therefore particularly sensitive to the contact phase so that this phase does not play a significant role in the physiological coagulation (and whose deficits do not carry risk of bleeding). But slowly activating coagulation (times are 3 times as long as prothrombin time), it is sensitive to anomalies in the prothrombinase complex and in particular deficits in factor VIII and IX which it effectively ensures screening. In practice these two tests (prothrombin time and activated partial thromboplastin time), 4 schematically possibilities can arise: results are normal, then we can reasonably eliminate hémorragipare coagulation abnormality (outside of special cases of deficits Total Factor XIII already mentioned); is only the prothrombin time is extended; either only the activated partial thromboplastin time is extended; either the activated partial thromboplastin time and prothrombin time are elongated.
B- isolated Elongation prothrombin time:
In theory, only the deficit in factor VII prolong prothrombin time and no time activated partial thromboplastin.Heterozygous constitutional deficits (50%) are rare and exceptional homozygotes. It has recently been described polymorphisms that affect the level of factor VII and the association of several genetic polymorphisms may lead to actual losses (up to 30%). Factor VII is the factor dependent on vitamin K for the shortest life span in the induction of a therapy with vitamin K (or in the case of vitamin K deficiency), the factor VII which fall the first. In practice, the activated partial thromboplastin time is much less sensitive to factors dependent on vitamin K as prothrombin time (prothrombin time 50% may be associated with an activated partial thromboplastin time still within the normal ). So a seemingly isolated lengthening of prothrombin time should be dosed all the prothrombin complex factors (V, VII + X complex II), except in special cases, the dosage of the VII and X is made only after a Charging test for vitamin K.
C- Extension of activated partial thromboplastin time, without significant prolongation of prothrombin time:
Must then complete the examinations by the fibrinogen assay and a thrombin time (TT).
1- extended thrombin time:
A thrombin time lying with normal fibrinogen evokes primarily the action of antithrombin, typically unfractionated heparin and, for some time, direct antithrombin in particuhémolier hirudin. If the patient does not receive and if the harvest could not be defiled (coagulation tube removed after a heparin collection tube), it may be a disorder fibrinogénoformation (dysfibrinogenemia) or constitutional or acquired either by synthesis of abnormality (cirrhosis) or by external interference (sharp increase in fibrin degradation products, paraprotein, exceptional antithrombin autoantibodies).
2- normal thrombin time:
If the thrombin time and prothrombin time are normal, then it is the case of an isolated prolongation of activated partial thromboplastin time, which may correspond to either a coagulation inhibitor or a deficit in an unexplored factor by prothrombin time. The distinction between the two is based on the correction test of time prolonged activated partial thromboplastin patient with normal control plasma. But be aware that for moderate elongation (10-15 s) that can match some potent inhibitor, the test may be inconclusive forcing, where the context requires, to be quantified individually all factors and if normal to seek arguments for an inhibitor of other specialized techniques. • If the extension is significant in the absence of correction, the diagnosis of inhibitor is assumed and confirmed by specific tests demonstrating the specificity of antiphospholipid inhibitor. Antiphospholipid do not bleed but if there is not an antiphospholipid let alone if there is a deficit on the isolated coagulation factors explored by the activated partial thromboplastin time, a neutralizing inhibitor must be mentioned. That explains why exploration can not stop looking for circulating lupus anticoagulant but must include an individual dosage of all factors concerning a potential risk hémorragipare particularly factors VIII and IX. • If correction of activated partial thromboplastin time the patient by the plasma of the witness: a deficiency of clotting factor is probable. Prothrombin time is normal, so this deficit relates to one or more of the following factors: VIII, IX, XI, XII or another factor of the contact phase (prekallikrein, high molecular weight kininogen). It is the individual combination of these factors which allows for the accurate diagnosis.Be aware that some low-affinity antibodies against any of the coagulation factors can appear as corrected after a short incubation. Incubation must be prolonged (at least until 2 am) and when there is doubt, special techniques must be used. Factor XII deficiency is usually congenital (sometimes as acquired over the massive leak protein nephrotic syndrome). This deficit causes no bleeding tendency (although it extends significantly the activated partial thromboplastin time). We even raised the possibility that this factor, which plays a role in one of the ways of activation of fibrinolysis, may cause a risk of thrombosis (the concept is much discussed today). When the extension is explained for any classic deficits VIII, IX, XI, XII, it evokes a deficiency of prekallikrein or high molecular weight kininogen whose confirmation should be provided by a highly specialized laboratory. Deficits as factor XII deficiency are not accompanied by any bleeding tendency, confirming the subsidiary role of the contact factors in physiological hemostasis. Hemophilia is the result of a deficiency of factor VIII for hemophilia A and factor IX for hemophilia B. Clinically, in practice nothing distinguishes these two deficits. Hemophilia A (5 times more common than B) has an estimated frequency of 1 in 5 000. Hemophilia is a sex-linked recessive disease. The boys and girls are affected are generally free from clinical disorders. A hemophiliac gives rise to free boys and girls to conductive. Biological diagnosis is simple, it is a lengthening of partial thromboplastin time + normal prothrombin time activator: the specific dosage factor specifies the type of hemophilia and severity. A factor VIII or IX undetectable or less than 2% defines a severe hemophilia characterized by numerous and spontaneous bleeding episodes. A rate of factor VIII or IX between 2 and 5% which defines a moderate hemophilia hemorrhagic stroke is less common but equally worrying.The moderate hemophilia is so only in the collapse of factor levels, not in the severity of accidents. Above 5%, which is the minor hemophilia hemorrhagic stroke are usually caused. When the rate is between 15 and 30%, hemophilia can be ignored and not be apparent until late in life eg postoperative hemorrhage. He must know the risk of these forms called minor but revealing more or less belatedly by a very serious hemorrhagic stroke. Five to ten percent with severe haemophilia (so substituted on numerous occasions) can be immunized against the factor they do not.This immunization that poses serious therapeutic problems should be systematically sought by careful monitoring.These antibodies occur more often if factor VIIIc indosable but not exclusively. This may be of molecular variants justifying the use of molecular biology. Should be compared 2N Willebrand disease (factor levels VIIIc by connecting to its default stabilizing molecule abnormal von Willebrand factor in this form of Willebrand) of hemophilia A; Indeed, if we think it more easily in women, the forms of man have, for some, was initially diagnosed as minor or moderate haemophilia. Hemophiliacs should be treated in a specialized structure (hemophilia treatment center) which alone can provide the multidisciplinary approach adapted both the management of hemophilia, that of his family for all the specific problems biological monitoring, transfusion, orthopedic, social and genetic counseling. The Factor XI deficiency carries a risk of bleeding for rates below 30%. The bleeding risk is constantly in severe deficits (homozygous deficits below 1%), but is variable for rates between a few and 30% percentiles from one subject to another without clear whether this variability depends on type of molecular defect and (or) the type of factor XI deficiency of the contents of platelet granules.
D- combined elongation of prothrombin time and activated partial thromboplastin time:
For decreases in fibrinogen, be aware that rates as low as 0.5 g / L of fibrinogen alter neither the PT nor the activated partial thromboplastin time. In contrast, very large increases (> 10 g / L) extend these tests. Decreases may correspond to hypo- or dysfibrinogénémies and can be constitutional or acquired. If several results of these two first-line tests, prothrombin time and activated partial thromboplastin time, are abnormal, it may be several different diseases including coagulation tests associated with clinical presentation and other laboratory tests enable diagnosis specifically: liver disease, consumptive coagulopathy, hypovitaminosis K, isolated constitutional or acquired deficiency in factor involved in both prothrombin time and activated partial thromboplastin time, which must be added some forms of powerful anti-phospholipid which may also act on prothrombin time. When the prothrombin time is elongated, the individual analysis of the prothrombin complex factors directs one of the following diagnoses proposed that it is the combination of hepatic synthesis of factors deficits (II, V, VII, X) consumed during clotting (V, II), dependent on vitamin K (VII, X, II). A hypofibrinogenemia often complete the first two tables. Thrombocytopenia and significant increase in soluble fibrin complexes and fibrin degradation products are part of the full picture of consumption coagulopathy. In fact, organic paintings are often separated because the pathogenic mechanisms are frequently entangled or because you have to have technical knowledge: Quick time commercial reagents possess an inhibitor that antagonizes heparin up to 2 U / mL, so the prothrombin time is apparently insensitive to therapeutic doses of heparin. Congenital deficits inducing a lengthening of activated partial thromboplastin time and prothrombin time are deficits fibrinogen II, V, and X. The most serious deficits in factor V are also accompanied by an increase in bleeding time which is due to a defect of platelet procoagulant activity. For partial deficiencies in Factor V, the intensity of the bleeding disorder is also connected to the content in platelet factor V which is stored in the granules. The final point to remember is that the lengthening of activated partial thromboplastin time was not proportional indication of the risk of bleeding. The low molecular weight heparins in potentially hémorragipare dose not little or lengthen the activated partial thromboplastin time. With direct antithrombin as hirudin, the risk of bleeding occurs for elongations thromboplastin time + more moderate enhancer with unfractionated heparin.
Highlights to include:
• Hemostasis, in the broad sense of the term, involves stopping bleeding or primary hemostasis involving platelets and cofactors, stabilizing the clot by plasma coagulation and the formation of a fibrin network and the remodeling the clot by the fibrinolytic system.
• A fault on one of these systems is to wear a risk of bleeding.
• The guidance tests in search of a bleeding risk before a risky situation (as an operative act), or to search the etiology of hemorrhagic condition therefore combine the bleeding time (BT) to explore the primary hemostasis, the prothrombin time (PT) and activated partial thromboplastin (APTT) to explore coagulation.
• Two types of anomalies escape:
– Deficiency of factor stabilizing the fibrin (Factor XIII) which only the total deficits bleed. These are exceptional deficits of particular symptoms (association for healing disorders);
– The hyperfibrinolyses, not the generalized forms (as they affect circulating factors in particular fibrinogen) but the forms localized in particular tissues (eg uterus).
* The ACT (Activated partial thromboplastin time) is called in the text: activated partial thromboplastin time.
Strong Points to remember:
• The overall balance screening: bleeding time, prothrombin time, activated partial thromboplastin time theoretically explores the key components of hemostasis in a broad sense but bleeding time is very dependent on the technician, poor sensitivity and specificity.
• The activated partial thromboplastin time is very sensitive to reductions factors of the contact phase, to transient circulating anticoagulant activities (especially in children) who do not cause increased bleeding risk.
• If the value of routine screening, preoperative particular, is questioned by some, particularly in a logical cost / efficiency, provided they are replaced by a clinical examination and a rigorous examination, this attitude can not not be accepted because the clinical exam and examination did not consistently this rigorous nature and because even well done, it is not always possible or contributory (young age, intercurrent disease or therapeutic …).
• If the data of the interrogation suggests uncertainty, the balance is then triggered, which acts as initial screening tests: bleeding time, platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen dosage and behavior is geared clinical and errors encountered.