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Coagulation Disorders

Learning Objectives At the end of the lecture students should be able to: Know the normal pathophysiological pathway of hemostasis. Know the clinical presentation of different bleeding & coagulation disorders. Should be able to investigate the patient. Should know the treatment of common bleeding and coagulation disorders. Should know the long term management of these disorders. Coagulation, or clotting, is a complex process (called the coagulation cascade) that involves 12 coagulation factors (designated by Roman numerals as factors I through XII) found in blood plasma and several other blood components. Besides the factors, which are all proteins, plasma carries a number of other proteins that regulate bleeding.

Platelets initiate contraction of damaged blood vessels so that less blood is lost. They also help plug damaged blood vessels and work with other constituents in plasma to accelerate blood clotting. A deficiency in clotting factors or a disorder that affects platelet production or one of the many steps in the entire process can disrupt clotting and severely complicate blood loss from injury, surgery, and specific diseases or conditions in which bleeding can occur.

Clinical manifestations of Bleeding Disorders Type of bleeding indicates which component of the hemostatic system is Defects in primary hemostasis

Easy bruising, petechiae (small dots), purpura (bleeding into the skin), ecchymoses (large superficial hemorrhaging), and spontaneous bleeding, especially from mucosal surfaces Defects in secondary hemostasis Prolonged deep bleeding into joints/muscles or hematomas: With these disorders can see spontaneous bleeding (severe factor deficiency) or post-injury (mild factor deficiency) Combination Multiple site bleeding occurs in severe combined defects (DIC). Platelet activity and coag proteins are related so disorders of one can affect the other since platelets provide phospholipid binding sites for clotting factor interaction.

Evaluation of Potential Bleeding Disorder Obtain Medical history Age of onset Symptoms Family history Drug history Exposure to toxins Physical exam Type and sites of bleeding Spontaneous/ result of trauma Order and interpret lab screening tests Platelet count PT PTT BT or PFA Vascular System Disorders Defects may be due to abnormalities in the endothelial cell lining of the blood vessel(acquired) or the connective tissue supporting the vessels(hereditary) Symptoms Superficial bleeding Hemostatic testing is normal Vascular Disorders Inherited Rare Bleeding is a common symptom Conditions

Marfan syndrome Ehlers-Danlos syndrome Vascular Disorders: Acquired Patient exhibits bruising and petechiae In all acquired disorders, the patient exhibits purpura. Defects in vasculature is caused by: Conditions that decrease the supportive connective tissue in the blood vessel walls Presence of abnormal proteins in the vascular tissues Infections or allergic conditions Mechanical stress Vascular Disorders: acquired Classification Purpura due to decreased connective tissue Collagen and elastin fibers, which form the support for blood vessels, are lost, causing fragility Senile purpura( elderly people) Scurvy ( deficiency of vitamin C) Purpura associated with paraprotein disorders Purpura due to vasculitis Inflammation of small blood vessels due to complement activation on subendothelium drugs and infectious agents

Platelet disorders Platelet disorders are the most common cause of abnormal bleeding. Qualitative: abnormalities of platelet function Quantitative: platelet count is below or above reference range Hallmarks Petechiae Excess bleeding from superficial sites Mucous membranes, skin Platelet Abnormalities

Quantitative Disorders- Its All About the Numbers..

Thrombocytopenia Decrease in the number of circulating platelets- below 100,000/L Symptom of underlying disease Bleeding time is prolonged Quantitative Disorders: Thrombocytopenia Increased destruction : bone marrow function is normal Immune Mediated Destruction Immune Thrombocytopenic Purpura (ITP): Caused by antibodies that cover the platelets Acute and chronic forms Resulting from an unknown cause (Idiopathic) Often follows a viral infection Believed to be antibody mediated, may produce a specific platelet autoantibody, specifically IgG. Spontaneous remission occurs in approximately 80% of the cases Alloimmune Thrombocytopenia Alloantibodies stimulated by foreign antigens cause destruction

Quantitative Disorders: Thrombocytopenia (Cont) Drugs HIT: Heparin Induced Thrombocytopenia Heparin causes platelets to activate which eventually causes antibodies to target the heparin/PF4 complex Results in thrombocytopenia Other Diseases Collagen disorders LE, RA Infections Infectious Mononucleosis HIV Quantitative Disorders: Thrombocytopenia

Nonimmune: excessive consumption Platelets are activated without the cascade activating TTP: Thrombotic Thrombocytopenic Purpura DIC: Disseminated intravascular coagulation HUS: Hemolytic uremic syndrome Mechanical destruction by artificial heart valves Inherited Disorders of Platelet Function Disorders of adhesion Defects in platelet-vessel wall interaction Disorders of aggregation Defects in platelet-platelet interaction Disorders of platelet secretion and abnormalities of granules Disorders of platelet secretion and signal transduction Disorders of platelet coagulant-protein interaction Qualitative (Functional) Disorders: Inherited Disorders of Platelet Adhesion: platelet to vessel wall interaction Bernard-Soulier syndrome Deficiency of a membrane glycoprotein (GPIb/IX) Giant platelets with coarse granulation and vacules may be seen. Platelet adhesion, aggregation and bleeding time/ PFA-100 are abnormal No treatment available, only supportive measures Von Willebrands disease Deficiency of the von Willebrand factor(vWF) OR production of a dysfunctional protein Abnormal platelet adhesion and bleeding time/PFA-100 as well as abnormal PTT ( due to VIII defect) Bernard-Soulier syndrome

Qualitative (Functional) Disorders: Inherited Disorders of Platelet Aggregation: platelet to platelet interaction Glanzmanns thrombasthenia Deficiency of thrombasthenin Lack the GPIIb/IIIa complex, which is where fibrinogen attaches to platelet surface Abnormal platelet aggregation, clot retraction and bleeding time

Qualitative (Functional) Disorders: Inherited Disorders of Platelet Procoagulant Activity Scott syndrome Activated platelets secrete and aggregate normally but fail to bind coagulation factors

Qualitative Disorders: Acquired Uremia Due to toxin or waste products affect on the platelets Alcohol: mechanism unclear Hematologic Disorders Myeloproliferative Disorders, Acute leukemias, myelodysplasia, multiple myeloma and macroglobulinemia Drugs Aspirin: prevents the release of thromboxane A2, thus decreasing platelet secretion. Those platelets affected by aspirin still circulate but are nonfunctional Antibiotics: penicillins & cephalosporins. Drug coats the platelet membrane blocking ADP and epinephrine receptors, so platelet can not respond to agonist.

Haemophila Inherited Bleeding Disorder Factor VIII/FIX deficiency X-Linked Inheritance Carrier XX may have low levels Spontaneous mutation

Inheritance of Haemophilia

Severe: FVIII/FIX < 1 % Repeated and severe hemarthroses and spontaneous bleeding, crippling common. Moderate: FVIII/FIX: 1-5 % Spontaneous bleeding and hemarthroses infrequent. Serious bleeding from trivial injuries. Milde: FVIII/FIX: 5-40 % Spontaneous bleeding manifestations may be absent, although serious bleeding may follow surgical procedures or traumatic injury.

Bleeding problems in Haemophilia

Factor Level <1%

Type of Bleed

Spontaneous/severe occasionally spontaneous

2%-5% Mild trauma/ >5% Trauma/Surgery

Complications Intracranial Bleeds At Birth Injury Admission Factor Concentrate Scanning Observation Neurosurgery.

Joint bleeding As blood fills the capsule, the joint swells and becomes painful and hard to move. The most common joint bleeds happen in ankles, knees, and elbows. Bleeds into other joints can also happen.

Joint bleed Synovial inflammation and hyperaemia Synovial overgrowth and Bone resorption Further Bleed

Joint Destruction Factor replacement 1 u/kg raises FVIII levels 2% 1/2 life : 12 hrs 1 u/kg raises FIX levels 1 % 1/2 life 20-24 hrs Minor Bleeding Episodes Early joint bleeds Soft tissue & muscle bleeds Nose & gum bleeding not responding to local measures Treatment of minor bleeding episodes 40 - 50% correction FVIII : 25 units / kg FIX : 50 units / kg Major Bleeding Episodes Advanced soft tissue & muscle bleeds Head & neck injuries Gastrointestinal bleeding Advanced joint bleeding Treatment of major bleeding episodes 80 100 % correction FVIII : 50 units / kg FIX : 100 units / kg Basis for Comprehensive Care Hematologist Assumes overall care Musculoskeletal Orthopedic Surgeon, Physical therapist Nursing Coordination of home/clinic care for rapid treatment at the earliest symptoms suggestive of a bleed Dental Genetic Counseling Infectious Disease Psychosocial social worker

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