Hemorrhagic Diathesis and DIC Lecture Notes PDF

HEMORRHAGIC DIATHESIS And DISSEMINATED INTRAVASCULAR COAGULATION (DIC)  Intended learning objectives  Summarize clotting factors and clotting mechanism.  Describe various reasons for excessive bleeding.  Describe hemorrhagic diathesis related to abnormalitie...

HEMORRHAGIC DIATHESIS And DISSEMINATED INTRAVASCULAR COAGULATION (DIC)  Intended learning objectives  Summarize clotting factors and clotting mechanism.  Describe various reasons for excessive bleeding.  Describe hemorrhagic diathesis related to abnormalities in clotting factors.  Describe etiology, pathophysiology, clinical manifestations and investigations for Hemophilia A.  Describe etiology, pathophysiology, clinical manifestations and investigations for Hemophilia B.  Describe etiology, pathophysiology, clinical manifestations and investigations for von-Willebrand disease.  Describe etiology, pathophysiology, clinical manifestations and investigations for DIC. Introduction-Coagulation system Coagulation Pathway  Clotting mechanism Initiated by either of two pathways: (1) the extrinsic pathway - triggered by the release of tissue factor (“tissue thromboplastin”); and (2) the intrinsic pathway - activation of factor XII by surface contact with collagen or other negatively charged substances.  Both pathways result in the generation of thrombin, which in turn converts fibrinogen to fibrin.  Bleeding disorders / Hemorrhagic Diatheses Excessive bleeding can result from (1) increased fragility of vessels- Vit C deficiency (2) platelet deficiency or dysfunction, and (3) derangement of coagulation. Hemorrhagic diatheses related to abnormalities in clotting factors  Types  Inherited deficiency of clotting factor/s  Acquired deficiency of clotting factor/s Inherited Hereditary deficiencies typically affect a single clotting factor. Most common types 1. Hemophilia A (Deficiency of factor VIII ). 2. von-Willebrand disease and 3. Hemophilia B (Deficiency of factor IX ).  Acquired deficiencies  Deficiency of multiple coagulation factors.  Decreased protein synthesis or a shortened half-life. Common examples  Vitamin K deficiency - impaired synthesis of factors II, VII, IX, and X and protein C.  Severe liver disease- many factors are made in liver  DIC - multiple coagulation factors are consumed and are therefore deficient.  von Willebrand factor  Stabilizes factor VIII.  Most important function is to promote the adhesion of platelets to the subendothelial matrix. von Willebrand Disease  Deficiency of vWF  Most common inherited bleeding disorder of humans.  Defect in platelet function despite a normal platelet count.  Pathogenesis  Deficiency of vWF gives rise to a secondary decrease in factor VIII levels. Most common symptoms  Spontaneous bleeding from mucous membranes (e.g., epistaxis);  Excessive bleeding from wounds;  Menorrhagia;  Common types  Type 1, 2 and 3 Type 1 vWD  70% of all cases ( most common)  Autosomal dominant.  Mild disease.  Hemophilia A (Factor VIII Deficiency)  Most common hereditary disease associated with life-threatening bleeding.  Caused by mutations in factor VIII, which is an essential cofactor for factor IX in the coagulation cascade.  X-linked recessive trait- affects males and homozygous females.  30% of patients have no family history( new mutations).  Clinical manifestations  Easy bruising.  Massive hemorrhage after trauma or operative procedures.  “Spontaneous” hemorrhages - eg. joints- ’’Hemarthroses.’’.  Investigations Factor VIII assays - must for diagnosis. Treatment  Infusions of recombinant factor VIII.  Efforts to develop somatic gene therapy for hemophilia are continuing.  Hemophilia B (Christmas Disease, Factor IX Deficiency)  Severe factor IX deficiency  Clinically indistinguishable from factor VIII deficiency (hemophilia A).  Factors VIII and IX function together to activate factor X.  X-linked recessive.  Diagnosis Assay of the factor IX levels Treatment Infusions of recombinant factor IX. DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Definition  Thrombohemorrhagic disorder  Characterized by the excessive activation of coagulation,  Leads to the formation of thrombi in the microvasculature of the body.  Not a primary disease.  Itis a coagulopathy observed in a variety of clinical conditions.  Etiology and Pathogenesis Two major mechanisms that trigger DIC 1. Release of tissue factor or thromboplastic substances into the circulation, and 2. Widespread injury to the endothelial cells. Pathophysiology of DIC  Consequences of DIC Two fold. 1. First, there is widespread deposition of fibrin within the microcirculation  This leads to ischemia of the organs and  Microangiopathic hemolytic anemia, (fragmentation of red cells as they squeeze through the narrowed microvasculature.) 2. Secondly, consumption of platelets and clotting factors leads to a hemorrhagic diathesis.  Important clinical conditions in which DIC is observed 1. Malignant neoplasms  Acute myeloblastic leukemia (Cytoplasmic granules- thromboplastic substance)  Adenocarcinomas of the lung  Adenocarcinomas of pancreas, Mucin acts as a thromboplastic substance.  Adenocarcinomas of colon,  Adenocarcinomas of the stomach 2. Sepsis (bacterial infections- meningococcemia) 3. Major trauma 4. Extensive surgery release of tissue thromboplastins. 5. Severe burns, 6. Hypoxia, 7. Acidosis, widespread endothelial injury 8. Shock,  Patho-morphology Thrombi are found in decreasing order of frequency  Brain,  Heart,  Lungs,  Kidneys,  Adrenals,  Spleen,  Liver,  Any tissue can be affected.  Kidneys Small thrombi in the glomeruli leads to 1. Microinfarcts or 2. Bilateral renal cortical necrosis. Lungs Thrombi in alveolar capillaries, pulmonary edema and fibrin, create “hyaline membranes.” ( like acute respiratory distress syndrome). Central nervous system Thrombi can cause microinfarcts - neurological deficits.  REFERENCES  Robbins and Cotran Pathologic Basis of Disease, 9th edition, 2014 ( Kumar, Abbas, Aster)  Robbins Basic Pathology 10th edition, 2017 ( Kumar, Abbas, Aster) AMBOSS https://next.amboss.com/us/article/io0JbS? q=disseminated+intravascular+coagulation #Zfe7e3ae8c22fecf85e6b257def2f006b THANK YOU