Pathological Hemostasis PDF

Pathological hemostasis Sef lucrari Dr Mihaela Andreescu UTM – Facultatea de Medicina Pathological hemostasis  PATHOLOGY OF VASCULAR HEMOSTASIS Hemorrhagic syndrome due to vascular wall damage is characterized by VASCULAR PURPURA The diagnosis is mainly CLI...

Pathological hemostasis Sef lucrari Dr Mihaela Andreescu UTM – Facultatea de Medicina Pathological hemostasis  PATHOLOGY OF VASCULAR HEMOSTASIS Hemorrhagic syndrome due to vascular wall damage is characterized by VASCULAR PURPURA The diagnosis is mainly CLINICAL, based on the characteristic aspects of purpuric skin lesions: PETECHIAE - purpuric lesions with a diameter below 3 mm, which do not disappear at vitreous depression ECCHYMOSES -skin lesions larger than 3 mm, whose color varies depending on the metabolism of extravased haemoglobin VASCULAR ECTASIAS ( telangiectasias ) - pathological dilations of blood vessels as a result of supporting tissue alterations; they disappear at in vitropressure PALPABLE PURPURA – extravasation of blood into tissues is associated with an inflammation of the structures of the vascular wall WET PURPURA – mucos hemorrhagic syndrome (epistaxis, menorrhagia, hemoptysis, gastrointestinal bleeding) Paraclinical diagnosis disposes of few laboratory tests that are less sensitive and not specific to this pathology (can also be modified in platelet disorders), they are not standardied and depend very much on the operator and its interpreting ability The diagnosis of these diseases is actually one of EXCLUSION (exclusion of platelet dusorder or other coagulation disorder). CLASSIFICATION OF VASCULAR PURPUA I. Vascular purpura secondary to connective tissue abnormality: Collagen abnormalities Ehlers – Danlos syndrome, Osteogenesis imperfecta, Marfan syndrome Elastic fibers abnormalities: Elastic pseudoxanthoma Acquired connective tissue abnormalities: Vascular purpura in scurvy, Casectic vascular purpura, Senile vascular purpura, Vascular purpura in corticoids excess, Vascular purpura in amyloidosis II. Vascular purpura secondary to subendothelium abnormality: Hereditary hemorrhagic telangiectasia (Rendu-Osler disease), Cavernous hemangioma III. Vascular purpura secondary to endothelium damage: Henoch-Schonlein purpura Dysglobulinemic vascular purpurae (cryoglobulinemias, Waldenstrom disease,multiple myeloma), Mechanical vascular purpura, Vasculitis.  PLATELET DISORDERS Quantitative disorders - decreased platelet number = THROMBOCYTOPENIA - increased platelet number = THROMBOCYTOSIS Qualitative disorders = THROMBOPATHIA THROMBOCYTOPENIC PURPURAE CLINICAL - CUTANEOUS-MUCOUS HEMORRHAGIC SYNDROME occurs post-traumatic when platelets are > 30.000/mmc and spontaneously when platelets are low (often < 10.000/mm3) and according to the patient's tolerance. PARACLINICAL: - Bleeding time, capillary fragility test = altered - Low platelet number - Normal/altered platelet function in thrombopathies - The rest of the hemostasis exploration tests are normal.  PLATELET PURPURAS CLASSIFICATION PRODUCTION DEFICIT - Decrease number of megakaryocytes in the bone marrow ( aplasia, infiltration of the marrow from oncological diseases, congenital); - Ineffective thrombopoesis (B12 deficiency, folic acid, hereditary forms - Alport syndrome, May- Hegglin anomaly), - Thrombopoetine deficiency ACCELERATED DESTRUCTION - Immune mechanism (autoantibodies - ITP or secondary autoimmune purpura, alloantibodies - posttransfusion, neonatal, drugs) - Consumption (TTP, HUS,DIC, vasculitis, vascular prostheses) ABNORMAL DISTRIBUTION - Splenomegaly (congestive, neoplastic, infiltrative, infectious) - Hypothermic anesthesia DILUTION/IRREPLACED LOSSES - Massive transfusions - Extracorporeal circulation  IDIOPATHIC AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ITP)/ PRIMARY IMMUNE THROMBOCYTOPENIA Immune thrombocytopenia produced by the presence of antithrombocytic auto-antibodies (IgG type, less often IgM) that are responsible for the destruction of platelets at in the splenic/hepatic monocyto-macrophage system, in the absence of a known condition, exposure to toxics / consumption of drugs (exclusion diagnosis) Acute ITP - frequently in children (maximum incidence 2 - 6 years), both sexes are equally affected, in 90% of cases, there is a history of respiratory viral infections / recent vaccinations. Brutal onset with serious bleeding in the oral cavity, nose bleeding, hematuria or digestive bleeding. The prognosis is good, in 85% of cases obtain spontaneous remission in 3-6 weeks when the platelet count returns to normal. Chronic ITP more frequent in adults (maximum incidence 20 - 40 years), slightly increased incidence in women (2-3:1). Onset - insidious, with hemorrhagic syndrome of lesser intensity, characterized by petechiae, ecchymosis, repetitive epistaxis, gingivorrhagia, metrorrhagia and rarely digestive hemorrhages. Chronic evolution, over several years, with periodic exacerbations. - NEWLY DIAGNOSED PTI/ITP= within the first 3 months after diagnosis - PTI / PERSISTENT ITP = 3-12 months - CHRONIC PTI/ITP= with evolution over 12 months Paraclinical: low platelet count, bone marrow smear with rich megakaryocytic series, platelet survival time - 1-2 days, bleeding time is prolonged, coagulation and fibrinolysis tests - within normal limits, Antiplatelet antibodies - highlighted by different immunological methods or flow cytometry.  IDIOPATHIC AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ITP) TREATMENT Acute ITP - TREATMENT ALGORITHM => Symptomatic treatment (rest, avoiding trauma) => Palliative treatment - care of hemorrhagic lesions of the mucous membranes (oral hygiene, antibiotics, antifungals) => Short-term corticosteroid therapy (Prednisone 1-2 mg/kg) - in severe cases; good response to treatment => Substitution - platelet transfusion in severe hemorrhages => Gamma-globulin (400 mg/kgv, iv, 5 days) - cerebral hemorrhages => Splenectomy - increased risk; it is only practiced as an emergency measure for cases that do not respond to treatment => Plasmapheresis - in severe cases, that do not respond to previous treatments Chronic ITP – TREATMENT ALGORITHM => Corticotherapy (Prednisone 1.5-2mg/kg per os, Dexamethasone 40mg/day, 4 days, Methyl prednisol pulse therapy) => IV immunoglobulins (corticosteroid therapy can be associated, preferably in major emergencies) => Splenectomy (indicated in corticosteroid-resistant PTI/contraindications for corticosteroid therapy, good response in 70-80% of cases) => Immunosuppressive therapy (Azathioprine, Cyclophosphamide, Cyclosporine, Vincristine), => Androgenic hormones (Danazol - preferably for postmenopausal women and splenectomized women), => Monoclonal antibodies against CD20 – Rituximab;  THROMBOTIC THROMBOCYTOPENIC PURPURA Syndrome of platelet intravascular aggregation, forming blood clots in the small blood vessels and is characterized by the following manifestations: Thrombocytopenic purpura + Microangiopathic hemolytic anemia + Neurological damage + Renal imparment + Fever Physiopathology: lesions of the vascular endothelium through direct immune/toxic mediated mechanisms => increased release of multimers with high GM of FvW => hyperaggregatibility; disorders of FvW proteolysis by congenital/acquired deficiency of serum metalloprotease (ADAMTS 13) responsible for the proteolysis of multimers with very high molecular weights => disseminated microthrombi in circulation => circulation disorders in vital organs Clinical: neurological syndrome (headache, vertigo, convulsions, paresis, aphasia up to coma); kidney damage (hematuria, proteinuria, nitrogen retention up to acute renal failure); hemorrhagic syndrome (petechiae, ecchymosis, hematuria, gastrointestinal bleeding); fever Paraclinical: Thrombocytopenia below 50,000/mmc; ADAMTS 13 low; Megakaryocytes - normal or even increased in the marrow; Platelet survival time - 24 hours; Microangiopathic hemolytic anemia (Hb HEMORGAPIPAR SYNDROME Hemorrhagic syndrome due to fibrinolysis disorders are characterized by the occurrence of hemorrhages in two phases (new bleeding occurs a few hours after venous punctures, biopsies, surgical interventions, as a result of premature lysis of the hemostatic plug). DECREASED fibrinolysis => THROMBOTIC MANIFESTATION Congenital anomalies that predispose to bleeding: Acquired anomalies leading to bleeding (fibrinolysis activation) deficiency of α2 - antiplasmin liver cirrhosis, PAI deficit Acute promyelocytic leukemia Familial increased t-PA Amyloidosis Nephrotic syndrome Congenital anomalies that predispose to thrombosis: DIC and primary fibrinolysis Decreased t-PA activity Acquired anomalies leading to thrombosis (decreased fibrinolysis) Quantitative and qualitative abnormalities of plasminogen Postoperative status, Familial increased PAI vasculitis, malignancies  PRIMARY FIBRINOLYSIS Spontaneous, systemic activation of fibrinolysis, independent of coagulation activation, followed by an exaggerated proteolytic degradation of fibrinogen and other proteins (FV, FVIII, FXIII, complement) and the appearance of a hemorrhagic event ETIOPATHOGENY: Severe liver diseases (liver cirrhosis) Urogenital neoplasms (prostate metastatic carcinoma) Surgical interventions on the uro-genital system, pancreas, lung, cardio-vascular bypass Acute promyelocytic leukemia (AML3) Overdose of thrombolytic therapy (steptokinase) Hypoxia Thermal shock (severe burn) Electrocution  Fibrinoliza primară CID Număr trombocite Normal Scăzut PT,PTT Normale/uşor prelungite Prelungite FV, FVIII, FXIII Scăzuţi Normali/scazuţi Fibrinogen Scăzut Scăzut ATIII Normală Scăzută TMF Negativ Pozitiv TLCE Scăzut Mult scăzut PDF Intens pozitiv Intens pozitiv Plasminogen Scăzut Scăzut D-Dimeri Normali Crescuţi Frotiul periferic Relativ normal Anemie microangiopatică 37  PRIMARY FIBRINOLYSIS TREATMENT: Antifibrinolytic agents epsilon amino-caproic acid (EACA) tranexamic acid which is not administered unless the diagnosis of DIC is ruled out, especially by the D-Dimer test Substitute therapy HEMOSTASIS  HEMOSTASIS I Platelet count= 165000/mmc ( VN= 150000- 400000/mmc) Prothrombin time (PT)= 15.7 seconds (VN= 12-15 seconds) 1. What diagnoses does this hemostasis Prothrombin activity (AP)= 67% (VN= 70-100%) investigation suggest? INR= 1.38 2. What other tests do you need for Cephalin time (APTT)= ( APTT)= 35.1 sec ( VN= 24-34 sec) diagnosis? Fibrinogen= 1.09 g/L ( VN= 2-4 g/L)  HEMOSTASIS I ANSWER Primary fibrinolysis, chronic DIC, hepatopathy, vitamin k deficiency Peripheral blood smear, TLC, PDF, D-Dimers, ATIII, specific diagnostic markers for DIC: fibrinopeptides A and B, liver function 42 42  HEMOSTASIS II Prothrombin time (PT)= 12.8 seconds (VN= 12-15 seconds) 1. What additional paraclinical Prothrombin activity (AP)= 97% (VN= 70-100%) explorations do you need for diagnosis? INR= 1.09 2. What are the differential Cephalin time (APTT)= 70.6 seconds (VN= 24-34 seconds) diagnoses? Fibrinogen= 2.89 g/L (VN= 2-4 g/L) 43  HEMOSTASIS II ANSWER Dosing FVIII, FIX, FvW, ristocetin aggregation , BT, ristocetin cofactor, lupus anticoagulant, heparinemia, other factors from the intrinsic pathway - FXII, FXI Hemophilia A and B, von Willebrand disease, antiphospholipid syndrome, heparin therapy, deficiency of other intrinsic factor FXII, FXI 44  HEMOSTASIS III Bleeding time (BTS = 10 minutes 35 seconds (Duke method = 2-4 sec) Prothrombin time (PT)= 12.7 seconds (VN= 12-15 seconds) Prothrombin activity (AP)= 96% (VN= 70-100%) INR=1.13 Cephalin time (APTT)= 32.2 seconds (VN= 24-34 seconds) Fibrinogen= 3.12 g/L (VN= 2-4 g/L) 1. What are the differential diagnoses in this case ? 2. What additional explorations are necessary for the diagnosis?  HEMOSTASIS III ANSWER Thrombocytopenic purpura, thrombopathy, vascular purpura, von Willebrand's disease Platelet count, platelet aggregation tests, FvW, FvWAg, ristocetin cofactor HEMOSTASIS IV Platelet count= 85000/mmc (VN= 150000- 400000/mmc) Prothrombin time (PT)= 27.9 seconds (VN= 12-15 seconds) Prothrombin activity (AP)= 34% (VN= 70-100%) INR= 2.98 Cephalin time (APTT)= 42.6 seconds (VN= 24-34 seconds) Fibrinogen= 1.85 g/L (VN= 2-4 g/L) 1.What diagnoses does this hemostasis investigation suggest? 2. What other paraclinical tests do you need for diagnosis?  HEMOSTASIS IV ANSWER 1. DIC 2. Peripheral blood smear, D-Dimers, TLCE, liver function  HEMOSTASIS V Bleeding time (BT) = 7 minutes 45 seconds (Duke VN method = 2-4 sec) Prothrombin time (PT)= 13.5 seconds (VN= 12-15 seconds) 1. What diagnoses does this hemostasis Prothrombin activity (AP)= 88% (VN= 70-100%) investigation suggest? INR= 1.19 2. What other paraclinical tests do you need for diagnosis? Cephalin time (APTT)= 39.1 seconds (VN= 24-34 seconds) Fibrinogen= 3.12 g/L (VN= 2-4 g/L) Answer 1. Von Willebrand disease 2. Ristocetin aggregation, AgFvW, ristocetin cofactor