The hemorrhagic stroke may be the warning sign of a more serious condition, with sometimes tragic consequences.So some bruises benign appearance or occurrence of spontaneous bruising can be early signs of a life-threatening emergency such as disseminated intravascular coagulation (DIC) or the existence of a specific inhibitor antifactor VIII.
After careful analysis of the clinical history, it is important to establish the precise diagnosis with targeted biological tests to define therapeutic strategy best suited promptly.
PROCEDURE FOR ESTABLISHING THE DIAGNOSIS:
Examination and clinical examination:
The etiological investigation depends largely on the quality of the examination.
In addition to age and sex, it must also specify:
– Location: repetition bleeding in the territory rather evokes a local lesion, while appearing in different territories towards a constitutional bleeding diathesis;
– Assessing the importance of bleeding;
– Appearance mode: spontaneous bleeding or triggered by minor trauma (shock, intramuscular injection, tooth extraction, etc.); existence of a cause-effect relationship between the bleeding and the therapeutic context (aspirin, anti-inflammatory, anticoagulant, antidepressants, etc.);
– The possible association to organic disease responsible for hemostasis problems and / or increased risk of bleeding (blood disease, liver failure, etc.);
– The recurrent character, which actually motivates consultation and sign the persistence of a possible alteration of hemostasis;
– Knowledge of results of previous laboratory tests (blood count, hemostasis tests, etc.);
– The existence of a family history that moving towards a constitutional anomaly of hemostasis.
Inbreeding should be sought during the interrogation, and it is often useful to establish a family tree.
Clinical examination assesses the intensity of the anomaly and the urgency of the situation, and directs the biological exploration. It can distinguish a simple episodic bleeding caused an authentic persistent alteration of hemostasis.
He must :
– Search petechiae, purpura, telangiectasia (language, fingertips); include consideration of the conjunctiva and mucous membranes (gums, tongue), after removing any removable dental prosthesis;
– Note the existence of hemorrhagic blisters, bruises, joint deformities;
– Insist on palpation of the lymph nodes, liver and spleen.
The examination and clinical examination behaved well enough feeling in adults to affirm the existence of hemorrhagic disease in 90% of cases (Table I). Laboratory tests should be selected after the first stage and not precede it.
Laboratory tests:
The tests of first-line biological diagnosis are: blood count with platelet count and blade examination, bleeding time, prothrombin time (or prothrombin time), partial thromboplastin activator more time (aPTT). The dosage of fibrinogen and thrombin time may be useful in secondary intention. The preanalytical phase is crucial, because the reliability of the results depends on compliance with conditions for realization of these reviews. Priority should be given to the laboratory: the quality of the blood test and the conditions of their transport to the laboratory is essential. Table II recalls the main clotting factors.
Blood count:
The risk of bleeding is described for significant thrombocytopenia with values less than 50 gigabytes / L (50,000 / mm3).
The discovery of anemia may be related to chronic ulcerative disease with iron deficiency, for example (anemia hypochromic, microcytic, aregenerative). The blood count may suggest an authentic blood disease, revealed by bleeding, myelodysplasia kind in the elderly.
Bleeding time:
Bleeding time, determined by the method of Ivy (normal: 4-8 minutes) or variants, explores the primary phase of hemostasis.
Given its invasive, operator dependent, and the lack of correlation with clinical bleeding risk, this exam is increasingly neglected by clinicians.
A PLC, PFA-100 (Platelet Function Analyzer, Dade Behring), allows the determination of a time platelet occlusion (sampling in citrated whole blood). It artificially mimics the process of primary hemostasis.
His sensitivity for the detection of deficiency Willebrand factor of thrombopathies and detection of aspirin is clearly established. It is therefore increasingly proposed instead of bleeding time because of its convenience of implementation and its noninvasive nature.
Prothrombin Time (PT):
Quick time is the clotting time exploring the “extrinsic” pathway of coagulation, that is to say, factors II, V, VII, X and fibrinogen. Normal values are between 70 and 100%. A quantitative or qualitative defi cit in one or more of these factors results in a lengthening of prothrombin time. Insensitive to heparin treatment, the recommended test for the monitoring of oral anticoagulant therapy like oral anticoagulants (vitamin K).
Activated partial thromboplastin time (aPTT)
TCA explores the “intrinsic” pathway of coagulation, and can identify a quantitative or qualitative deficiency of factor VIII, IX, XI, XII, in prekallikrein (PK) or high molecular weight kininogen (HMWK). The result is considered abnormal if the CAW report of the patient (TCAM) on ATT indicator (TCAT) exceeds 1.20.
Before all aPTT, the biologist must achieve equal parts by mixing correction test of patient plasma and a normal plasma pool: this test is called TCAM + T. It allows swivels a constitutional challenge cit or acquired a clotting factor if the TCAM + T is “corrected” or to the presence of a circulating anticoagulant if TCAM + T remains “lying.”
Thrombin Time:
Thrombin time exploring the fi brinoformation.
He is lying when hypofibrinogenemia, dysfibrinogenemia, presence of antithrombin kind inhibitory activity or during treatment with unfractionated heparin.
Determination of fibrinogen:
It is carried out in case of prolongation of PT and aPTT. Fibrinogen assay by chronometric method (Clauss method) allows to highlight hypo- (quantitative abnormality) or a dysfibrinogenemia (qualitative abnormality). The differential diagnosis can be made after measurement of the immunological fibrinogen, the latter is lowered in case of hypofibrinogenemia, but normal in case of dysfibrinogenemia.
In total, these tests allow a better assessment of healthy and pathological hemostasis, and they guide the diagnosis of hemorrhagic disease (Table III).
The exploration of fibrinolysis by specialized service can be useful, particularly in the context of a defibrination syndrome. Finally, rare hemorrhagic disorders are compatible with conventional exploration tests normal: the deficit in α2-antiplasmin (natural inhibitor of fibrinolysis) or factor XIII deficiency (factor stabilizing the fibrin).
You have to know find these alterations before clinical bleeding diathesis contrasting with normal conventional tests.
CONDITIONS OF PRIMARY HEMOSTASIS:
Congenital anomalies of primary hemostasis are rare, and acquired alterations are far the most common. They are responsible for a prolonged bleeding time and / or occlusion time of the PFA-100.
It is conventional to distinguish three groups of diseases:
– Alterations in the vascular wall;
– Quantitative disturbances and / or qualitative platelet;
– Constitutional Willebrand disease and the deficits acquired von Willebrand factor.
Alterations in the vascular wall:
Achieving the capillary wall can cause purpura in the appearance of petechiae (dots), bruises more or less widespread or vibices (elongated streaks). The origin is immunological, infectious or, most often, idiopathic. capillary fragility tests (sign of the pressure cuff or suckers) are often positive, but their interest is very limited in practice.
Different forms of purpura are described:
– Purpura by v ascularite leucocytoclastic, sitting on the lower limbs, possibly associated with myalgia, arthralgia, segmental edema, kidney disease, peripheral neuropathy. Purpura results from the deposition of immune complexes circulating in the vessels of the dermis. Cryoglobulins can be detected, most often mixed and rarely monoclonal. The HSP or syndrome-Schönlein purpura (leukocytoclastic vasculitis with IgA) occurs most often before 15 years, especially among boys.
The treatment of these vasculitis usually comprises corticosteroids (prednisone at an initial dose of 1 mg / kg) and sometimes immunosuppressants.
Where mixed cryo-globulin linked to hepatitis C, the treatment comprises interferon α and ribavirin pegylated.
– Meningococcal purpura fulminans, which should be treated urgently in intensive care;
– Purpura of various origins: septic vasculitis germs Gram + or Gram, eruptive diseases (measles, rubella, scarlet fever), Osler disease, amyloidosis, purpura capillary fragility (senile, prolonged corticosteroid scurvy).
Platelet reached:
thrombocytopenia:
Thrombocytopenia is the platelet count decreased below 120 giga / L. It must be confirmed over several examinations in order to eliminate a possible artifact. Observation of smear after staining with May-Grünwald-Giemsa (research clusters in smears of tail) and counts on different anticoagulants will eliminate a pseudo-thrombocytopenia by more frequent platelet aggregation EDTA.
Hemorrhagic risk begins below 50 gigabytes / L but is important in case of thrombocytopenia (<20 giga / L). The functional value of platelets plays a key role and explains the good clinical tolerance.
Thrombocytopenia of central origin:
They fall mostly a global myelosuppression acquired, related to a blood disease (acute leukemia, aplastic anemia, myelodysplasia, etc.) Or toxic origin (trimethoprim, for example). Deficiencies in vitamin B12 and should be mentioned folic acid, even in the absence of macrocytosis because folic acid supplement (Spéciafoldine® 5mg / day) and vitamin B12 (intramuscular whether there are intrinsic factor antibodies) is rapidly effective.
Family thrombocytopenia with MPV usually grown are reported in different syndromes:
– Gray platelet syndrome with platelet loss in their granular contents;
– May-Hegglin syndrome, an autosomal dominant, often asymptomatic and with leukocyte inclusions containing blue tapered ends shuttle (Dohle bodies);
– Epstein syndrome with thrombocytopenia due to large platelets associated with nephropathy (Alport syndrome) and conductive hearing loss;
– W iscott-Aldrich syndrome, transmission X-linked associating eczema and repeated infections by immune deficiency.In this case, the plates are small;
– Family thrombocytopenia Paris-Trousseau, characterized by a deletion of the long arm of chromosome 11, a moderate mental retardation, syndactyly and facial dysmorphia. Platelets have a melting their alpha granules.
Family thrombocytopenia autosomal dominant and normal or increased platelet volume, production disorder, often moderate, and mainly affect populations from around the Mediterranean. The diagnostic confusion with idiopathic thrombocytopenic purpura (ITP) is common. The possibility of constitutional thrombocytopenia must be considered, through careful family study, in the absence of normal platelet count in personal history and even before the inefficiency of the treatment of ITP.
Thrombocytopenia devices:
The mechanisms of peripheral thrombocytopenia are of 3 types: hyperdestruction, distribution anomaly (hypersplenism), consumerism (generalized intravascular coagulopathy). The treatment of thrombocytopenia by hyperdestruction peripheral immune-mediated (PTI) is discussed in Chapter thrombocytopenia.
thrombopathies:
Constitutional, very rare thrombopathies:
Pathologies glycoprotein receptors are:
– Dystrophy thrombocytic hémorragipare Bernard-Soulier transmission autosomal recessive, defiantly ciency glycoprotein membrane receptors (GP) Ib-IX; – T hrombasthénie Glanzmann transmission autosomal recessive disorder characterized by an absence of aggregation of platelets regardless of the agonist used due to a deficiency mooring sites fibrinogen (GPIIb-IIIa complex or integrins α2bβ3) .
Alterations in platelet signaling pathways include: various abnormalities of receptors or enzymes compromising platelet functional responses: achieving the path of prostaglandins (aspirin-like-syndrome) or deficiency cyclooxygenase inhibiting the synthesis of thromboxane A2;
– The anomaly receptor ADP (adenosine diphosphate), responsible for a similar thrombopathy to that induced by taking ticlopidine or clopidogrel (ticlopidine-like syndrome).
Pathologies of platelet granule or their secretion are:
– Diseases called storage pool delta syndrome Hermansky-Pudlack autosomal dominant, associated with albinism or Chediack-Higashi syndrome, autosomal recessive transmission, combining a partial albinism and recurrent infections;
– Deficiency content of platelet alpha granules, or disease “empty pool alpha” Gray Platelet Syndrome autosomal dominant.
The thrombopathies involving abnormalities of platelets and plasma factors are:
– Abnormality of platelet factor V or Quebec platelet disorder autosomal dominant, due to a defi cit in multimerin and exaggerated proteolysis of alpha granular constituents;
– Scott syndrome: the lining is abnormal exposure of membrane phospholipids. The mode of inheritance is autosomal recessive. The anomaly of the cytoskeleton is associated with a defi cit in scramblase (aminophospholipid translocase).
Thrombopathies acquired common:
The acquired character should be considered in the absence of personal or family history of bleeding reported during the interrogation.
Drugs are most frequently at the origin of these platelet functional alterations with, first, the non-steroidal anti-inflammatory drugs including aspirin and other anti-aggregation inhibitors. Iatrogenic thrombopathies are also due: to antibiotics (penicillin, cephalosporins), diuretics, calcium channel blockers, some chemotherapies, anesthetics, tricyclic antidepressants, to dextran, the lipid lowering, alcohol, or even to a variety of fungi Chinese black, etc.
Authentic organic pathologies can lead to secondary disturbances in platelet response:
– Significant anemia;
– Pre-leukemic and myeloproliferative disorders;
– The dysglobulinémies;
– M yélodysplasies;
– Chronic renal failure;
– Postoperative contexts especially extracorporeal circulation;
– Valvular heart disease;
– Autoimmune diseases with autoantibodies directed against the membrane glycoproteins;
– Chronic liver disease.
Thrombocythémies:
Thrombocytosis is secondary reaction and transient increase in platelet count above 500 giga / L recorded several successive laboratory tests and in different contexts: post-splenectomy, inflammatory syndrome, iron deficiency …
Platelet function are met and normal.
Thrombocythemia is the primitive increase platelet production in the context of myeloproliferative disorders: polycythemia vera, chronic myeloid leukemia, myelofibrosis and essential thrombocythemia itself.
The very high platelet counts (sometimes up to 3000 giga / L) resulting from a monoclonal achievement of the multipotent stem cell with significant dystrophies. In more than half of the essential thrombocythémies, an acquired platelet disorder is observed, resulting in alterations in aggregation.
Thus, paradoxically, the most thrombocytic forms are most at risk of bleeding (> 1500 giga / L).
The recommended treatment is aspirin at very low doses (75-100 mg / day or every 2 days), because it is very effective to prevent painful crises Erythromelalgia and arterial thrombosis.
Cytoreductive different treatments, such as hydroxyurea, may be proposed to maintain the platelet count short of 500 giga / L: Hydrea®, 2 capsules per day for 15 days and then adjust the dose with monthly blood monitoring. Nearly 25% thrombocytaemia are refractory to hydoxyurée; the proposed treatment is pipobroman (Vercyte®, 1.25 mg / kg / day, 10 weeks then reduce to half-dose maintenance therapy) or interferon á (3 MU 3 times a week) to acute indications (pregnant woman, for example). Anagrelide (Xagrid®), a phosphodiesterase inhibitor, is proposed in case of treatment failure (1 mg / d to adjust according to changes), and it would be devoid of mutagenic unlike hydroxyurea and Vercyte ®.
Willebrand factor deficiency:
Congenital deficiency:
This is the most common constitutional abnormalities of hemostasis, defi ned by quantitative or qualitative impairment of von Willebrand factor (FW) with an estimated prevalence in the general population of 1%. VWF has two essential functions in protein and cellular mechanisms of hemostasis:
– Transportation of factor VIII or antihemophilic factor
A in the circulating blood, giving it a stability of its clotting activity and protecting the early proteolytic degradation;
– The formation of molecular bridges between the injured vessel wall and specific platelet receptor glycoprotein whose IBIX.
The deficit will therefore suspected in a lengthening of bleeding time or the closure time (PFA) with or without aPTT (cit by concomitant challenge more or less profound factor VIII). The platelet count is normal except in some patients with von Willebrand disease type 2B, which have a fluctuating thrombocytopenia and variable intensity.
Table IV summarizes the laboratory diagnosis of von Willebrand disease.
Genetic inheritance is autosomal, usually dominant. The severe form (type 3) and certain molecular variants have a recessive inheritance. The quantitative challenge cit (type 1) is the most common (75% of cases).
Haemorrhages are mucous membranes (gingival bleeding, epistaxis, etc.) And skin (bruising), frequent postoperatively. In children, post-traumatic bleeding from the mouth and spontaneous tonsillar hemorrhage are characteristic. The bleeding tendency fades with age. Menorrhagia of the young woman are improved by estrogen-progestogen oral contraceptives. The therapeutic choice is guided by the characterization of the type and sub-type: type 1 (partial quantitative defi cit in FW), type 2 (qualitative anomaly and many subtypes) and type 3 (total loss).Accurate diagnosis will be established in specialized services.
The differential diagnosis should essentially eliminate hemophilia A.
Specific treatment is necessary in case of heavy bleeding caused by trauma or prevention (eg surgical setting). It aims to normalize rates Willebrand factor, and it will be defined with the assistance of a specialized center whose details are usually on the card certifying the type of von Willebrand disease.
Physical methods may be sufficient: Local compression, hemostatic biological glue or wicking.
The appropriate hormonal treatment helps reduce menorrhagia. Desmopressin (dDAVP, Minirin®), synthetic vasopressin analogue is a hormone capable of inducing the release of von Willebrand factor and factor VIII from endothelial cell compartments. This therapeutic test is performed before surgery to assess the patient’s response and ensure the importance of the correction (rate multiplied by 3 to 5) and its duration. The vector dose is 0.3 mg / kg by slow intravenous infusion over 30 minutes in 50 mL of saline.
This is usually done in day hospital, because it is necessary to monitor pulse, blood pressure during infusion (headache, hypotension, facial flushing, tachycardia possible transient reaction) and diuresis.
A restriction of fluid intake is essential during the treatment period to 750 mL / d or 20 mL / kg. The cons-indications are pregnant or breastfeeding, 2B Willebrand variants, frail patients, cardiovascular disorders with hypertension (high blood pressure).
There is a nasal form (Octim® / usable as an outpatient.
Replacement therapy is feasible in
If cons-indication or wrong answer to dDAVP with input from only Willebrand factor (Wilfactin®) or in combination with factor VIII (Wilstart®) (40 to 60 IU / kg repeated every 12 to 24 hours) . In practice, 1 IU / kg increases plasma levels of 2% Willebrand.
The information and patient education are critical: avoid situations increasing the risk of bleeding, avoid taking aspirin or anti-inflammatory.
Acquired deficiency:
Acquired deficiency in VWF are described in dysglobulinémies, lymphoproliferative or myeloproliferative disorders, autoimmune diseases, cancer, thyroid dysfunction, diabetes. The mechanisms are varied:
– Selective adsorption of VIII-FW complex on tumor cells;
– Formation of immune complexes with increased clearance (autoantibodies);
– FW accelerated proteolysis by leucocyte enzymes (leukemia).
Treatment is an indispensable etiological treatment (chemotherapy, hormone therapy, etc.). Plasmapheresis, sometimes associated with Willebrand factor concentrate infusion, can control the hemorrhagic syndrome.
The disappearance of the syndrome after treatment of the causal affection can be an excellent retrospective diagnostic element.
BLEEDING DISORDERS BY TROUBLE BLEEDING PLASMA:
We will consider the biological alterations may be responsible for a clinical hemorrhagic syndrome.
Lengthening of prothrombin time:
The isolated prolongation of PT should suggest a factor VII deficiency.
The combination of aPTT and PT, makes suspect an abnormality of fibrinogen, a deficit of the final common pathway: deficiency of factor II, V and X. This shows the interest before the TCA Association TQ + elongated, request the measurement of prothrombin complex factors: II, V, VII and X.
Acquired deficiencies:
They are common and often combined.
Their etiology is usually a K vitamin deficiency or liver damage.
The challenge of combining narratives in factors II, VII, IX and X is most often the result of a disorder of the metabolism of vitamin K acquired by cholestasis, celiac disease or intestinal resection extent. So check if the patient is receiving vitamin K antagonists, then search for biliary obstruction and malabsorption.
The recommended treatment is the intake of vitamin K1 IV slow (10 to 20 mg), which will allow the gradual correction factor levels commensurate with their half-lives.
In case of overdose of warfarin (INR> 4, INR: International normalized ratio) without hemorrhagic manifestation, no treatment for 24 to 48 hours and the recovery of the AVK at a reduced dose suffi cient to restore the INR desired therapeutic range.
If greatly increased INR (INR> 6), the oral intake of vitamin K1 (sublingual) (1 to 2.5 mg) can help shorten within hours INR without exposing the patient to a secondary resistance VKA treatment for several weeks. However, in case of hemorrhagic manifestation or threatening bleeding risk, (co-morbidity, Grandage, etc.), hospitalization is required and immediate correction by the infusion of the vitamin K dependent factors is indicated (Kaskadil®).
In poisoning by rat poison, upper and repeated doses of vitamin K1 are essential (50 mg / d) to correct hypovitaminosis K.
If liver disease, abnormalities are often complex and multiple. They result from a vascular disease or hypersplenism with portal hypertension or to hepatic insufficiency with synthesis or even consumption coagulopathy disorders leading to heterogeneous biological and tables of varying severity. The first factors are those with which the half-life is as short as factors VII and X. In case of parenchymal more important, there appears a decrease in factor V levels and fibrinogen. Qualitative abnormalities may be associated with or dysfibrinogénémies dysplasminogénémies.
Specific inhibitors of factors:
Anti-factor II were reported in systemic lupus erythematosus or lymphoproliferative disorders. Thus, almost 3/4 of patients with lupus anticoagulant have lupus-like immune complexes and sometimes authentic defi cit partner responsible prothrombin rarely a clinical hemorrhagic syndrome.
Anti-Factor VII are also described in cancer patients or infected with HIV (HIV).
An anti-Factor X is rarely reported in similar circumstances. During the early AL amyloidosis, the amyloid sequestration X factor most often in the spleen, which poses a major risk of bleeding when the X factor falls below 10%.
Constitutional deficits:
The general rule is that it is an isolated deficiency of a single coagulation factor as opposed to acquired deficiencies that involve the infringement of several coagulation factors.
The exception is the combined deficit of factors V and VIII.
The factor VII deficiency has an estimated prevalence of 1 case per 500 000. Patients often identical to those bleeding hemophiliacs with haemorrhagic signs occurring early: risk of bleeding from the umbilical cord at birth or cerebral hematoma. However, some patients remain asymptomatic despite very low rates.
The diagnosis of defi cit factor VII is suspected in a hemorrhagic syndrome combining a prolongation of PT and normal APTT.
The differential diagnosis is actually the acquired deficiency of factor VII as it may be at the beginning of anticoagulant treatment, hypovitaminoses K, or during severe sepsis.
The factor X deficiency, in its severe form, would prevalence 1 to 1 million. Hemorrhagic disease is then often very severe with bruises, hemarthroses but sometimes gastrointestinal bleeding and hematuria. The defi cit is suspected in a hemorrhagic syndrome and the association of aPTT and PT.
The challenge cit factor II, in its severe form, have a prevalence of 1 to 2 million. Patients homozygous or compound heterozygous usually have rates between 2 and 20%. The lack of factor II would be lethal.
Heterozygotes are usually asymptomatic, but it was described nosebleeds and bleeding after tooth extractions. Severe deficits have serious bleeding cord at birth, paintings evoking haemophilia with hemarthroses. Other events are described: muscle hematoma, spontaneous ecchymosis, epistaxis, menorrhagia, postpartum hemorrhage. There are also dysprothrombinemias resulting in a mismatch between the immunoassays and functional assays of factor II.
The diagnosis of defi cit factor II should be considered in a prolongation of PT associated with an aPTT. Differential diagnoses (after eliminating an isolated defi cit fibrinogen in FX, FV) are hypovitaminosis K and liver failure.
The factor V deficiency, in its severe form, has an estimated prevalence of 1 in 1 million.
A peculiarity of factor V is its presence in the intracytoplasmic platelet granules, contributing to hemostasis.Hematomas and especially hemarthroses are quite common in case of severe challenge cit leading to talk of “para-Owren hemophilia.”
FV deficiency is suspected in a hemorrhagic syndrome combining a prolongation of PT and aPTT. The differential diagnosis is with the deficits acquired by VF, especially antifactor antibody V.
Hemorrhagic syndrome varies among subjects and the persistence of platelet factor V. pool
The combined deficit of factors V and VIII has an estimated prevalence of 1 in 1 million. It has been described in patients of this challenge cit mixed, a mutation on a gene called ERGIC, located on chromosome 18, which codes for a protein involved in intracellular transport of factors V and VIII. Patients usually have moderately lowered rate of 2 factors (between 5 and 20%). Hemorrhagic syndrome combined deficits in factors V and VIII is moderate with epistaxis, menorrhagia and bleeding after tooth extraction. The diagnosis is suspected in the association of aPTT and PT.
Deficits fibrinogen are suspected before the elongated combination TQ + TCA lying, and the isolated nature of the decrease of fibrinogen.
Thrombin time may be a guidance element to the qualitative abnormalities of fibrinogen with a relatively large elongation compared with other coagulation time.
The differential diagnosis arises with acquired anomalies of fibrinogen: liver failure, fibrinolysis, disseminated intravascular coagulation.
Prolonged activated partial thromboplastin time (aPTT)
The first cause of TCA extender is treatment with unfractionated heparin and, rarely, curative treatments of low molecular weight heparins. It is important to eliminate circulating anticoagulant that is rather associated with an increased thrombotic risk (lupus anticoagulant or anti-prothrombinase). The specific inhibitors of factors are responsible for an increased risk of bleeding in case of deep defi cit. The deficits in the so-called endogenous pathway factors to search in case of correction of the aPTT on equal parts mixture of patient plasma and control plasma.
Specific inhibitors: prohémorragiques anticoagulants:
The anti-factor VIII are most frequently found in the context dysimmun like lupus or rheumatoid arthritis, hematological malignancies, diabetes, antibiotics, postpartum. They are in half of all cases of idiopathic etiology not found. This is a therapeutic emergency. With nearly 90% of patients, ulcerative functional symptoms is severe: deep hematomas, retroperitoneal, intracerebral, with a poor prognosis (20% mortality). The diagnosis is suspected on a signifi cant lengthening isolated CAW not corrected plasma input witness in equal parts. The rate of factor VIII coagulant collapsed. The title of the inhibitor is thus determined, corresponding to the inverse of the dilution to obtain 50% of F VIII residual activity.
Therapeutically, the urgent care of these patients is reserved for specialized centers to treat bleeding complications and eliminate the autoantibodies. The choice of therapy is twofold: the porcine FVIII concentrates and recombinant activated F VII.
Porcine FVIII has the advantage of not being recognized by the autoantibody, and there is no cross-reactivity (100 U / kg). Prothrombotic complexes are also offered. They contain the activated clotting factors and phospholipids which aim to circumvent the inhibitor to activate the coagulation system directly from the factor X (FEIBA®, 50 to 200 U / kg).NovoSeven®, or recombinant activated factor VII has a remarkable efficiency, by enabling the formation of thrombin directly (90 ìg / kg bolus repeat 2 and 6 hours later). Immunotherapy with monoclonal antibody chimerized (rituximab: Mabthera®) is also available with or without associated immunosuppressive therapy (corticosteroids or cyclophosphamide: Endoxan®).
Anti-IX are rarer than the previous; they are encountered in various autoimmune diseases, viral, inflammatory, overload or even postpartum. This is usually IgG whose research and titration were performed as for the anti-VIII.
They entail the same bleeding symptoms that anti-VIII.
Inhibitors of fibrinogen and fi Brino-formation have been reported in some contexts dysimmuns lymphoproliferative disorders. They are also described in the constitutional deficits. They can prevent the polymerization of fibrin monomers (antipolymérases myeloma).
haemophilia:
The diagnosis is suggested by the isolated aPTT. Prothrombin time, thrombin time and fibrinogen are normal. The specific dosage of factor VIII and IX confirms the diagnosis of hemophilia A or B and defines the severity: severe if the clotting factor is less than 1%, moderate between 2 and 5% and unpolished or minor form between 5 and 30%.
Hemophilia A is caused by a challenge cit factor VIII, and affects about one birth in 5000 male children. Hemophilia B is a challenge cit factor IX and its incidence is 6 times lower. These two hereditary diseases are transmitted by women called this fact “conducting” recessive X-linked mechanism
In hemophiliacs suffering from a severe form of the disease (factor VIII or IX <1%), the triggering trauma can be so discreet that it can go unnoticed, thus believe in spontaneous bleeding. Conversely, the term bleeding is lower in moderate or minor haemophilia: haemarthrosis are rare or absent hematomas are the result of known injuries. The bleeding risk is very real contrast in case of surgery. The most frequent hemorrhagic manifestations are hemarthroses (70% of bleeding) and bruising subcutaneous or intramuscular (10-20% of bleeding).
Some hemorrhagic stroke can be life-threatening (gastrointestinal hemorrhage or central nervous system) or functional (orbit, anterior compartment of the forearm or axillary hollow, for example) and require emergency administration of antihemophilic suitable product.
Complications can be of several types: infectious complications, immunological and musculoskeletal.
Therapeutically, hemophilia should be supported in close cooperation with a specialized center. The treatment is based primarily on patient education (precautions, learning self-treatment) and substitution of the missing molecule (factor VIII in hemophilia A and factor IX in hemophilia B). The factors produced by genetic engineering gradually aim to offer an almost absolute security against infectious agents, but they are associated with a higher incidence of antibody inhibitors of Factor VIII. The extent of recovery is around 2 units / dL recirculated per unit and infused per kg (injection of 50 IU / kg caused an average rise of 100% of plasma factor VIII in patients with severe hemophilia). For factor IX, the recovery is only 0.5 to 1 unit / dL per infused recirculation unit per kg. The treatment of minor bleeding events requires to reach a level of circulating anti-hemophilic factor of around 30%. More severe injuries require a circulating level of around 50%, and for the heaviest surgeries, it is suggested to reach rates of at least 80%.
Curative treatment at the time of a bleeding episode consists of one or two separate injections of 8 to 12 hours to correct in general hemostasis. Prophylactic treatment is of 2 types: in small children, often from the onset of hemorrhagic stroke and temporarily to “dry” a joint target of repeated hemarthrosis. Injections of factor VIII or IX are made from infancy on a one to three weekly injections with doses of the order of 25 to 50 units / kg body weight at least until the end of the adolescence. A short prophylaxis can be initiated to prevent recurrence of bleeding into a joint “target”, seat of recurrent hemarthrosis.
Finally, desmopressin (1-deamino-8-D-arginine vasopressin or dDAVP) is used as a therapeutic alternative in the minor hemophiliac with a basal plasma level of factor VIII neighbor by 10%. It multiplies in average by 2-3 circulating levels of factor VIII.
It can not be used in hemophilia B.
Factor XI deficiency:
Prevalence is estimated at 1 per 100 000, but it is actually quite variable between populations studied: as Ashkenazi Jews, the frequency of heterozygotes varies from 6 to 10% and that of homozygotes from 0.1 to 0.3 %.
Spontaneous bleeding is exceptional even in patients with severe deficits challenge.
Most bleeding is observed after surgical procedures (ENT or in the urinary tract). postpartum hemorrhage have been described.
These locations are bleeding areas with high fibrinolytic activity, and the role of factor XI in fibrinolysis is known.
In fact, the bleeding risk varies from one subject to another. Patients with a rate of less than 40% increased risk of bleeding during surgical procedures mentioned above.
F XI deficiency should be suspected in a hemorrhagic syndrome with prolonged aPTT and normal PT. The first diagnosis included before this association are hemophilia and other challenge cits in FVIII (von Willebrand disease, antibodies antifactor VIII). In asymptomatic subjects, aPTT with normal TQ can evoke deficiency F XII (which is never hémorragipare) or lupus anticoagulant which when isolated is not responsible for hemorrhagic syndrome.
That’s why, before a longer combination of TCA and normal TQ, we must always balance the F XI.
Box 1. Other non hémorragipares deficits
Warning: some extensions TCA by constitutional deficits are not bleeding. This is in principle deficits in the contact system factors.
Deficiency Factor XII (Hageman factor) is quite common, and gives no evidence of bleeding. The only pathology associated with defi cit in F XII could be the occurrence of repeat abortions. There is no treatment because there is no need to substitute the missing F XII, including patients with a F XII indosable.
deficit discovering the circumstances prekallikrein (Fletcher factor) are the same as for the F XII deficits: sometimes significant aPTT and absence of hemorrhagic syndrome. This elongation is variable depending on the activator used to perform aPTT, and is reduced by prolonged incubation with activator. The diagnosis requires a specific dosage of prekallikrein.
The challenge of discovering circumstances cit in high molecular weight kininogen (Flaujeac factor or Fitzgerald factor) are the same as for the F XII and prekallikrein. Diagnosis requires a specifi dosage as high molecular weight kininogen
Lengthening of thrombin time:
Antithrombin:
Besides pharmacological thrombin inhibitors such as heparin, logically extending the TT (thrombin time) and TCA, acquired inhibitors have been reported in surgery suites using haemostatic glues containing bovine thrombin.
Fibrinogen deficiencies:
The prevalence of defi cit fibrinogen is difficult to estimate; must differentiate well:
– The afi brinogénémies in which there is a total absence of fibrinogen regardless of the measurement method (immunoassay or by coagulation technique). Afibrinogenemia is exceptional, of autosomal recessive inheritance. It can be mentioned in the perinatal period with easy bruising, mucocutaneous bleeding, post-surgical prolonged bleeding.The most severe forms can lead to serious bleeding neonatal cord or large subcutaneous hematoma. The diagnosis is suspected before global clotting times anticoagulated and perfectly corrected by the normal plasma intake equal parts.Fibrinogen is indosable while other cofactors are normal;
– The dysfibrinogénémies in which the usual methods of coagulation assay technique fibrinogen give cheap rates while immunological techniques are normal or subnormal levels. Dysfibrinogenemia is relatively common with hundreds of families reported in the literature. Autosomal dominant, it is in most cases asymptomatic and discovered incidentally. It is responsible, in almost 10% of cases, moderate hemorrhagic manifestations mainly caused and postoperative. In less than 20% of cases it is associated with venous or arterial thrombotic episodes without formal proof of his responsibility is established;
– The hypofibrinogénémies that are of moderate cover the real losses and non-severe dysfibrinogénémies. The hypofibrinogénémies are usually asymptomatic as the dysfibrinogénémies.
The dysfibrinogénémies with hemorrhagic syndrome mainly deal with fresh frozen plasma infusion.
PATHOLOGY FIBRINOLYSIS:
Increased fibrinolytic activity associated with hemorrhagic stroke is very rare.
Fibrinolysis hémorragipare:
It describes cits constitutional challenge
physiological fibrinolysis inhibitors: the deficit in α2-antiplasmin or Miyasato disease, discovered in Japan in the eighties, and one whose homozygous form has clinical expression made severe bleeding, even including hemarthroses. You should know thinking despite its great rarity.
Hyperfibrinolysis acquired:
There are very likely to hyperfibrinolysis acquired states, both systemic and localized, eg gastrointestinal sphere, genital, or even cerebral, more or less well identified. The best studied cases have been reported in cancers of the prostate, pancreas, liver. Vascular tumors, the promyelocytic leukemia (AML3), aneurysms and systemic lupus erythematosus can also be responsible for a hyperfibrinolysis.
Disseminated intravascular coagulation (DIC)
DIC is an acquired pathological activation of coagulation syndrome, often widespread, rarely localized (vascular tumors), resulting in intravascular fibrin formation, with excessive consumption of platelets and clotting factors.
DIC is often associated with usually moderate activation of fibrinolysis.
Diagnostic :
DIC is called “clinic” where there is ischemic or hemorrhagic manifestations, and so-called “organic” when biological anomalies characteristics are isolated.
The factors responsible for DIC induce most often an increased release of tissue factor (TF), activator of the extrinsic pathway of coagulation. It would come monocytes, vascular endothelial cells and granulocytes, in the cases described in Table V.
Clinical DIC is characterized by hemorrhagic syndrome with extensive bruising say “geography map”, a cover of bleeding points punctures, visceral bleeding (hematemesis, hematuria, hemoptysis or cerebral-life-threatening).Surgical context, there is bleeding tablecloths and bleeding into drains or catheters.
If the clinical presentation, diagnosis of DIC is confirmed by the hemostasis tests showing:
– Moderate or severe thrombocytopenia (≤ 50,000 / mm3) in half of the cases;
– Lengthening coagulation tests: PT, APTT and TT;
– Decrease of fibrinogen: absolute (<2 g / L or 0.5 g / L) or if relative rates were initially increased (infl ammation, pregnancy, etc.);
– Decrease of coagulation factors and activators especially Factor V;
– Presence of fibrin degradation products (FDP) and in particular D-dimer, which is a key argument of the positive diagnosis of DIC;
– Signs of fibrinolysis hyperfi: time euglobulins lysis is moderately hot, with a decrease of plasminogen, α2-antiplasmin.
The algorithm proposed by the International Society on Thrombosis and Hemostasis is particularly effective for determining the risk of poor outcome and death (score of sensitivity 91%, specificity 97%).
The differential diagnosis is easy to establish:
– Primary fibrinogenolysis: it differs from DIC by a lysis time much shortened euglobulins (<30 min), absence of thrombocytopenia, the absence of soluble complexes, the absence of D-dimer and a high rate of total PDF;
– Severe hepatic impairment lower coagulation factors is observed but the rate of D-dimer is normal or slightly increased, soluble complexes are absent.
Treatment :
The treatment of DIC is primarily etiological with a directed substitution: platelets when combined with a lower thrombocytopenia at 50 G / L, fresh frozen plasma (FFP) “secure” or “virus-inactivated” in case of collapse coagulation factors.
A recombinant activated protein C may be prescribed in sepsis associating organ failure.
The deficit in fibrinogen and coagulation factors is corrected by providing secure fresh frozen plasma (from a single donor). It is indicated in case of fall of TQ (<40%) with active or potential bleeding (10 to 15 mL / kg with an initial speed of 20 to 30 mL / min).
The use of low doses of heparin not factionnée (5 IU / kg / h) or low molecular weight heparin (5000 to 10 000 IU / day) was effective in some cases of DIC associated with aneurysms or major malformations angiomatous.
The fundamental basis of the therapeutic management of DIC in often difficult and prognosis with significant morbidity and mortality is early and effective etiological treatment.
Thus, in case of infectious origin, appropriate antibiotic treatment will be in the front line or in cases of major obstetric complication, surgery will be the key essential treatment.
So the treatment of this complex syndrome requires both alternative measures for clearing multiple deficits and more specific strategies depending on the origin of physiopathogenic DIC.
HAEMORRHAGIC SYNDROME CLINIC FAULT TESTS HEMOSTASIS:
Hemorrhagic syndrome is caused by a local cause bleeding, such as a gastric ulcer, a colon tumor, renal tumor, vascular malformation. This haemorrhagic syndrome is sometimes favored by taking antiplatelet agents or anticoagulants.
Thus, a gastrointestinal bleeding or hematuria occurring in vitamin K (even in overdose) must find an underlying pathology.
Factor XIII Deficiency:
It is not detected by the coagulation testing.
The stabilizer fibrin factor is a plasma protein with activity transamidasique whose cit constitutional challenge is exceptional and autosomal recessive transmission.
Only homozygotes are symptomatic with haemorrhagic phenomena since the fall of the umbilical cord and deep bruises. healing disorders are unique to this deficit.
It takes less than 5% of factor XIII to ensure physiological hemostasis.
The defi cit in F XIII is the rarest of the coagulation factor deficiencies with an estimated prevalence of 1 to 3 million.The diagnosis of this challenge cit is difficult because none of the usual hemostasis tests (PT, aPTT, fibrinogen, thrombin time) is changed. The diagnosis is based on the determination of factor XIII.
Deficits acquired F XIII were found in rheumatoid purpura or ulcerative colitis. Anti-XIII autoantibodies have been reported in the literature especially after prolonged treatment with isoniazid.
Vascular fragility without vascular anomaly
This fragility can be congenital vascular:
– Osler Rendu disease, or hereditary hemorrhagic telangiectasia and autosomal dominant disease that is sometimes only in adulthood. The two essential elements of the diagnosis are repeated nosebleeds (ENT examination is often very suggestive) and telangiectasia finding lips, oral mucosa or the fingertips. We must then verify the absence of pulmonary arteriovenous fistula (search for a lateral thoracic breath and chest CT scan with injection) and telangiectasia hepatosplenic (ultrasound). When epistaxis cause iron deficiency anemia, can be proposed in women taking the pills high dose of estradiol (50 ã / d). More or less aggressive local treatments are sometimes necessary (bioadhesives, selective arterial embolization by the external carotid);
– Dystrophy of Ehler Danlos syndrome, which includes more than 10 variants; this is the type IV is more serious because it is accompanied by vascular ruptures especially digestive.
Vascular fragility can be gained:
– Multiple bruises that occur under prolonged corticosteroid therapy, or more rarely Cushing’s syndrome;
– Vascular purpura, who must search for rheumatoid purpura, cryoglobulinemia or other vasculitis (polyarteritis nodosa, Wegener’s disease, etc.);
– Amyloidosis, which is often responsible for hemorrhagic stroke; there are sometimes acquired deficiency of factor X, fibrinolysis, but in more than half of the cases, there is no abnormality of hemostasis.
CONCLUSION:
Semiotics in case of hemorrhagic clinical setting is important because it helps to define the strategy of the laboratory diagnosis with a measure of clotting based on complementary tests. Biology can confirm the diagnosis, but it is not always standardized, with possible variations related to reagents and practicalities of implementation. Careful and cross analysis of these coagulation tests completed by the specifi dosage that factors in second intention and the use of specialized centers is essential to define the subsequent therapeutic or prophylactic attitude to biological diagnosis.
