Bleeding PDF

BLEEDING HISTORY & PHYSICAL EXAM We have to take history of the patient: - We would like if the patient is taking medication that a ect bleeding - Have a medical condition that a ects bleeding. - If the patient has a previous history, will ask them if they have bleeding while doing a surgery - supp...

BLEEDING HISTORY & PHYSICAL EXAM We have to take history of the patient: - We would like if the patient is taking medication that a ect bleeding - Have a medical condition that a ects bleeding. - If the patient has a previous history, will ask them if they have bleeding while doing a surgery - supplements also can cause bleeding, for example garlic, ginger, ginseng. - We’ll follow the SOAP Steps of hemostasis: 1. vasoconstriction, giving signals to the blood 2. Temporary platelet plug —> 1st hemostasis (primary) 3. Coagulation —> secondary hemostasis 4. Fibrinolysis (factor 13 prevent brinolysis and stabilize the clot) 5. Regeneration (repair) HEMOSTASIS: REVIEW (Broken down into 4 stages) 1) Vascular phase Vasoconst. Retraction of vess. Press. on vess 2) Platelet Plug/Aggregation 3) Coagulation (Cascade) 4)Fibrinolytic stage 1) VASOCONSTRICTION Vascular Spasm Vasoconstriction by smooth muscle cells Helps reduce the amount of blood ow and limits blood loss. Exposed collagen at the site promotes platelet adherence. First response to injury. Controlled by vascular endothelium that releases intravascular signals. Platelets release granules, which will a ect vasoconstriction containing the following: ADP attracts more platelets to the a ected site. Serotonin is a vasoconstrictor. Thromboxane A2 assists aggregation, vasoconstriction, and degranulation. 1 of 19 fi fl ff ff ff ff 2) PLATELET PLUG A. Primary Hemostasis B. Platelets 1. Adhere (vWBF & GpIb) 2. Activate (ADP & Gp2b/3a) 3. Aggregate Platelets adhere to the damaged endothelium to form a platelet plug & then degranulate. Activated by Von Willebrand factor (vWF). Made by Megakaryocytes (Alpha granules Pr.) Endothelial cells (Weibel-Palade bodies). When platelets come across damaged endothelium they become activated. Release ADP, Serotonin, Thromboxane A2. Activated platelets become sticky causing aggregation and adhesion. PLATELET ACTIVATION A nuclear (notcells) produced in the bone marrow by Megakaryocytes 9 days circulating life Platelet adhesion mediated by membrane GPs which act as receptors for vWBF, ADP, other molecules With injury to the endothelium, platelets adhere to the underlying tissues via membrane glycoprotein receptors & vWF. Platelet becomes spherical & immediately degranulates, promoting adhesion of further platelets to the forming platelet plug. Vasoconstriction & formation of the initial platelet plug is su cient for Primary Hemostasis. Hemorrhage will resume if secondary hemostasis/coagulation does not occur. Secondary hemostasis or coagulation is dependent on the plasma components (Liver): Contact clotting pathway (Intrinsic pathway). Tissue factor (III) (Extrinsic pathway). 3)COAGULATION AKA secondary hemostasis. Intrinsic, extrinsic, and common pathway. Eventually leads to brin mesh (clot) which reinforces the platelet plug & is stabilized by FXIIIa. Prothrombin II → Thrombin IIa. Fibrinogen I → Fibrin Ia. ***Protein C and proteins S are working from the extrinsic pathway Series of reactions involving Zymogens. Majority are produced in the liver. Zymogens → active enzymes once cleaved by enzymes further up the chain. 2 of 19 fi ffi  Mainly divided into 2 distinct pathways: The intrinsic & extrinsic pathways. The Common FXa pathway. ***Protein C and proteins S are working from the extrinsic pathway Activation is almost instantaneous following damage to the endothelium and exposure of tissues that express TF III. After the initial thrombin burst, this pathway is turned o by tissue factor pathway inhibitor (TFPI). ***Plasmin works on brinogen TISSUE FACTOR (TF III) PATHWAY→EXTRINSIC Generate a thrombin burst Fast pathway FVIIa circulates in higher amounts than any other coagulation factor Following damage: FVII leaves the circulation and comes in contact with tissue factor (TF) forming an activated complex TF-FVIIa —> Activates FIX and FX FVII is activated by thrombin, FXIa, FXII and FXa. The activation of FXa is immediately inhibited by tissue factor pathway inhibitor Prothrombin II is activated to thrombin IIa Activates FV Activates/releases FVIII: vWVF complex INTRINSIC PATHWAY Contact activation pathway. Begins with formation of a primary complex on collagen by HMWK, prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes activated. Converts FXI, IX to their active form & nally X. 3 of 19 fi fi ff  THE COMMON PATHWAY Thrombin functions Conversion of brinogen 1 to brin 1a (The building block of the 2nd hemostatic plug) Goes back & activates FVIII, FV, protein C and FXIII FXIII Fibrin stabilizing factor Forms covalent bonds that crosslinks the brin Stabilize the Fibrin mesh The cascade is maintained in a prothrombic state by the continued activation of FVIII and FIX. Down regulated by anticoagulant pathways. REGULATORS Protein C Major physiologic anticoagulant It is a Vit-K dependant serine protease activated by thrombin. The activated form of protein C along with protein S and a phospholipid→degrade FVa and FVIIIa Antithrombin Serine protease inhibitor Degrades Thrombin (IIa), FIXa, FXIa, FXIIa Antithrombin antibodies is seen in SLE (Coagulopathy) Tissue factor pathway inhibitor (TFPI) —> (inhibit VII conversion) Plasmin Generated by proteolytic cleavage of plasminogen Catalyzed by tissue plasminogen activator which is synthesized and secreted by endothelium. Causes brin degradation/inhibits excessive brin formation Inhibited by Tranexamic acid & Aminocaproic acid (Amicar) LABS PT/INR re ects the integrity of the TF/extrinsic pathway. PTT/aPTT re ects the integrity of the intrinsic pathway. TT re ects the common pathway. Special factor assays. FDP/FSP, D-Dimers further activities and speci c indications. PT for messing extrinsic pathway. 4 of 19 fl fl fi fl fi fi fi fi fi  Warfarin works on the extrinsic pathway, and works on protein C and protein S. VITAMIN K Vitamin K-dependent factors: II, VII, IX, X, Protein C & Protein S. Absorption requires gut bacteria. Causes of vitamin K de ciency: Diet. Alcoholism. Liver disease. Bile obstruction as Vitamin K is a fat-soluble vitamin. Malnutrition. Warfarin inhibits reactivation of vitamin K. Malabsorption. Wide spectrum antibiotic use, which suppresses normal GI ora necessary for vitamin K synthesis. Exogenous Vitamin K is contraindicated in G6PD-de cient patients. IV replacement carries a considerable risk of anaphylaxis LAB VALUES 1. Platelet count (quantitative) – used to evaluate thrombocytopenia < 150,000 Normal is 150,000 - 400,000 2. Bleeding time (BT) (function & quan.) – time between in iction of wound to moment the bleeding stops Normal 2-5mins Platelets assay 3. Prothrombin Time (PT) (extrinsic pathway) Addition of TF to citrate anti-coagulated plasma, recalci cation of the plasma, & measurement of clotting time; May demonstrate de ciency of factors in the extrinsic pathway & common pathway Normal time 11 - 15 sec INR: used to standardize values from di ering labs 4. Activated Partial Thromboplastin Time (aPTT) - addition of activating agent (Kaolin) and phospholipid to citrate-anticoagulated plasma, which is incubated to allow activation of contact factors and then re-calci ed and clotting time recorded; de ciency of factors in the Contact activation /Intrinsic and common pathways will prolong this time Normal time 25 – 35 sec 5. Thrombin Time (TT) – monitors the last step in the common pathway. Addition of a diluted thrombin solution to anticoagulated plasma and measurement of clotting time; will be prolonged when plasma brinogen is low, or brinolytic split products are high Normally 12 – 14 sec BLEEDING DISORDERS Bleeding diathesis (primary , 2nd or both) can cause VonWillebrand disease (a ect both primary and secondary) Coagulopathies Idiopathic Medications Autoimmune Hereditary disorders Infections Hemophilia A, B, C Neoplasms VonWillebrand disease 5 of 19 fi fi fi fi fi ff fl fi fi fi fl ff HEMOPHILIA Inherited bleeding disorder characterized by de ciency in a coagulation factor a ecting the cascade. A – Factor VIII X-linked. B – Factor IX X-linked (Christmas). C – Factor XI Autosomal recessive (Rosenthal). Also have acquired de ciencies that are possible. A. Hemophilia A 2nd most common after vWBD 1/5k – 1/10k 2/3 will have severe disease Often considered a X-linked disorder occurring primarily in males, but spontaneous mutation or variable expression of alleles may result in female cases B. Hemophilia B 3rd most common after vWBD X-linked Christmas disease 50% have severe disease 1/30k C. Hemophilia C 4th most common after vWBD Ashkenazi Jews Rosenthal syndrome 1/100k The majority of patients have a known family member with the disease or family history. The severity is based on the level of factors circulating compared to the normal population. Has a direct correlation to the symptoms. Mild: 5–49%. Moderate: 1-5%. Severe: Same as Factor VIII. HOW MUCH TO REPLACE? Early joint or muscle bleed: 30-40%. Severe muscle hematoma or dental surgery (extractions no wound healing B. OPTION 2: DESMOPRESSIN (DDAVP) Synthetic analogue of Vasopressin or ADH (Minimal pressor activity) vWBF: VIII complex. Stimulates the release of vWBF (carrier of FVIII). Can increase levels of factor VIII 2-4x above baseline. Will be the treatment of choice for: vWBD, hemophilia A carriers. mild hemophiliacs 8 of 19 ff fi fi  Not recommended for vWBD subtype 2B (not to activate the already mutant vWBF). DDAVP Multiple Routes of administration IV intranasal. Subcutanous IV or subcutaneous prophylaxis or acute bleed..3 mcg/kg (max of 20 mcg) → avg adult 70 kg. Dilute in 50 mL of NS infused over 20-30 minutes. Factor level should increase 30-60 minutes after infusion. Should work for 6-12 hours. Able to repeat dose in 12 hr prn. Intranasal spray (less predictable) —> 300 mcg. DDAVP SIDE EFFECTS Vasodilation: facial ushing peripheral tingling. headache Rare to have changes in BP. Tachyphylaxis after repeated administration (sudden decrease in e ectiveness) Water retention – hyponatremia. Watch H2O intake, possible restriction. Monitor lytes (especially Na). 3RD OPTION: ANTIFIBRINOLYTICS A. Tranexamic acid (Fibrin degradation products). B. Aminocaproic acid. Inhibit Plasminogen conversion to Plasmin which dissolves the brin clot → FDP. Inhibition of brinolysis. Both inhibit plasminogen activation in brin/platelet clot. Therefore longer retention of clot. A. AMINOCAPROIC ACID 75–100 mg/kg q6h. Available in both PO or IV. If PO, then q6h due to shorter half-life. May be required for 10-14 days after initial infusion. Tabs or syrups. Can cause gastric upset, terrible taste. B. TRANEXAMIC ACID Inhibits brinolysis through competitive inhibition of the activation of plasminogen to plasmin. Disrupts plasmin formation. More potent than Amicar, longer half-life. Dose: 10 mg/kg IV q6-8h. 25 mg/kg po q6-8h. A 500mg tab can be crushed and mixed with 10 ml of saline/water. Also available as syrup/solution (5%), but expensive. Can be given IV 9 of 19 fl fi fi fi fi ff  ACQUIRED HEMOPHILIA Produces an antibody to factors. Normal platelets. Di ering presentation than hemophilia. Normal PT. Elevated aPTT. Normal bleeding time. INHIBITORY ANTIBODY Autoantibodies to the transfused factor that cross-react with endogenous or transfused products. IgG antibodies that neutralize clotting factors. More often in Hemophilia A than B. Incidence: 25-30% in severe Hemophilia A (lifetime risk). In mild: 5-10%. Much less common in Hemophilia B. More likely to develop in: Elderly. Factor replacement > 9 days. Severe hemophilia. INHIBITORS Should be suspected in any patient who fails to respond clinically to clotting factors. Prevention of bleeding at the time of surgery in patients with inhibitors to FVIII or FIX requires careful planning. TESTING FOR INHIBITORS: BETHESDA ASSAY Serially dilute patient plasma into normal plasma Incubation period of 2 hours Assay the residual factors 1 BethSeda unit: Neutralization of 50% of factor in equivalent volume of normal plasma INHIBITOR TREATMENT Recombinant Factor VIIa —> Enhances tissue factor driven thrombin formation Factor Eight Inhibitor Bypassing Agent (FEIBA)—>Vitamin K dependant clotting factor proteases Factor VII If low titer inhibitor (low besthesda units) Tolerance may develop FACTOR VIIA DOSING Hemophilia A or B WITH inhibitors: Bleeding: 90 mcg/kg q2h Surgical 90 mcg/kg prior to surgery Minor: q2h for 2 days Major: q2h for 5 days Acquired hemophila —> Bleeding/Surgical: 70 - 90 mcg/kg q2 3 h until hemostasis. SEVERE HEMORRHAGE Maintain factor level > 50% if life-threatening. Head injuries: First rule out bleeding with CT or MRI. Late bleeding can occur 3-4 weeks later. Instruct of neurological signs/symptoms of bleeds. All head/neck injuries are transfused unless clearly insigni cant. 10 of 19 ff fi VON WILLEBRAND DISEASE AD. (autosomal dominant inherited) 1% population. Most common inherited bleeding disorder. Lack or malfunction of von Willebrand factor. M=F WHAT IS VWBF? vWF is a large adhesive alpha granules Pr. Synthesized at two sites: endothelial cells & megakaryocytes Stored in endothelium and platelet alpha granules Composed of variable multimers —> HMW multimers can cause TTP vWF gene is located on the short arm of chromosome 12 FACTOR VIII AND VWF vWF stabilizes FVIII. Inhibits factor VIII binding to phospholipids. Increases the half-life of FVIII. Ratio of vWF to FVIII is maintained at 50:1. An increase or decrease in plasma vWF level results in a corresponding change in the level of FVIII. THE FUNCTIONS OF VWF Primary Hemostasis: Mediates platelet adhesion to injured blood vessel sites. Promotes platelet aggregation at sites of vessel injury. Secondary Hemostasis: Stabilization of coagulation factor VIII in the circulation. Protects circulating factor VIII from inactivation or degradation. Increases half-life of FVIII from may be the rst recognizable symptom of vWBD! Signi cant bleeding with oropharyngeal surgery. LAB FINDINGS Normal platelet count except for 2B. Normal PT. Normal to elevated aPTT. (Depends on the level of factor VIII) Screening: Plasma vWF antigen (vWF:Ag). Plasma vWF activity. Factor VIII activity. TREATMENTS OF VWD 1. DDAVP: Used for Type 1 and Type II (Not Type 2B). Ine ective in Type 3. Acquired vWBD – therapeutic trial when the patient is bleeding. Reassess response. 2. Replacement therapy for VWF concentrates. 3. Anti brinolytics. 4. Topical thrombin or brin. 13 of 19 ff fi fi fi fi OTHERS Most common congenital disorder: Hereditary hemorrhagic telangiectasia (HHT)/Osler-Weber-Rendu disease. AD. Characterized by spontaneous bleeding from telangiectasias (malformed walls of small dilated vessels). Ehlers-Danlos syndrome, osteogenesis imperfecta result in congenital defects in collagen formation, leading to augmented vessel fragility. Diagnostic tests will be normal. Marfan syndrome, issues with Elastin. Acquired disorders: Idiopathic purpura (purpura simplex) probably caused by increased fragility of skin vessels. Primarily a cosmetic problem. Easy bruising of the trunk and lower extremities, with no abnormalities of platelets. Senile Purpura (progressive loss of dermis and vascular wall with age). Common on the dorsal side of hands and wrists. Large, demarcated purpura often caused by venipuncture. HYPERCOAGULABLITY AND OTHER COAGULOPATHY Factor V Leiden Homocystinurea Throwing mutation Thrombohemorrhagic events Antiprothrombin def TTP large vWBF multimers Pr. C def DIC trigger that activates put and CFs til Pr. S def they are depleted PLATELET DISORDERS May be grouped into quantitative (Thrombocytopenia) & qualitative Thrombasthenia. Reduced platelet production may be caused by: Aplastic anemia. Radiation. Leukemia. Drugs, ethanol, viruses, chemicals. Increased platelet destruction may have immune causes: Idiopathic Thrombocytopenic purpura. Infection: HIV, malaria. Lymphoma. Post-transfusion. Drug-induced HIT. Liver disease → portal HTN → splenomegaly → TCP. THROMBASTHENIAS Thrombasthenia common diseases: vWBD vWBF/GPIb complex de ciency or malfunction. Bernard Soulier syndrome GPIb de ciency. Glanzmann’s thrombasthenia GPIIb/IIIa de ciency. IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) 5:1 ratio F:M. Peak age of incidence between 20-40 years. Acute Pediatric ITP is equally prevalent in both sexes, with peak incidence 2-4 years. Remission generally occurs in 2-4 weeks. Most commonly discovered due to epistaxis, petechiae, or purpura. Normal white cell count and hemoglobin unless bleeding has caused secondary anemia. 14 of 19 fi fi fi  Platelet antibody tests have largely been abandoned due to low sensitivity and speci city. ITP TREATMENT Treatment generally occurs only if severe thrombocytopenia is present ( Idarucizumab (Praxbind) injection. Andexanet alpha (Andexxa) is a reversal agent for factor Xa inhibitor anticoagulants Rivaroxaban & Apixaban. 19 of 19 ff fl fi