PATHOLOGY: COAGULATION

Most Commons: MC blood goup in all pops is Group O MC infection transmitted by blood is CMV VII X V II I Clot MC hepatitis transmitted by blood is HCV MC transfusion reaction is a febrile reaction XII XI IX VIII X V II I Clot MC cause of HDN is ABO incompatibility MC cause of Rh HDN is anti D MC cause of prolonged BT is aspirin or nonsteroidal therapy (inhibit TXA2 formation) MC ordered coag tests are PT & aPTT MC genetic vascular disease is hereditary telangiectasia (Osler Weber Rendu) MC of thrombocytopenia in children is idiopathic thrombocytopenic purpura MC acquired defect of uremia is platelet dysfunction MC of hereditary qualitative platelet disorders is VWD MC of aquired qualative platelet disorders are drugs (aspirin/nonsteroidals) MC hereditary bleeding disorder is VWD MC inhibitor of coagulation used clinically is factor VIII MC cause of arterial thrombosis is endothelial injury assoc. w/atherosclerosis

(Extrinsic Pathway, MIF, PT) (Intrinsic Pathway, PTT)

BLOOD DISORDERS:
AI Hemolytic Anemia Febrile Transfusion Rxn Acute Hemolytic Transfusion Rxn ABO HDN Rh HDN Ideopathic Thrombocytopenic Purpura Viral Assoc. Immune Thrombocytopenia Drug Induced AI Thrombocytopenia Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome HS 2 where, Indirect Coombs = serum Abs and Direct Coombs = IgG &/or C3 on RBCs LAB: Perform in/direct Coombs Abs against leukocytes or platelets Intravascular: most serious, ABO mismatch Extravascular: atypical Ab in recipient against donor RBC Ag. (Ex. AntiKell against Kell Ag) O mom w/A or B fetus (25% of normal pregos) IgG crosses to fetus and attaches to RBCs for splenic removal Rarely requires transfusion, bili-lights good idea. Spherocytes in blood w/weak Coombs. Anti D Ag Circulating. Presents w/severe fetal anemia leading to ht failure, resp distress, kernicteus LAB: Kleinhauer-Betke test for HbF. Give RhIG to mom after testing. AI w/IgG against GPllb/iiia on platelets. Presents w/ URIs w/epitaxis & petechi. LAB: megakaryocytes will be found in bone marrow due to peripheral platelet destruction in spleen CMV, EBV, & HIV Quinidine, sulfa drugs, penicillin, heparin, thiazides Non immune platelet dystruction. Seen in young women who present w/fever, microangiopathic HA, severe neuro probs & few renal probs Non immune platelet destruction. Similar to TTP but with less neuron symps & more renal symps. Possible E157:H7 assoc in raw beef & w/Cyclosporin, mitomycin, cisplatin LAB: flip is seen with the LDH Only platelets get caught in thrombi so you get normal coag factors w/PT & aPTT normal Rx w/plasmapheresis Seen in pts w/recurrent abortions, venous/art occlusions or thrombocytopenia w/SLE symps Type I: Syphilis False Positives (biological) Type II: Lupus anticoag prolongs aPTT b/c of phospholipid Ab cross rxn (incr a/v thrombosis, abortion risk) Type III: anti-cardiolipin Abs directed at serum cofactor rather than phospholipids LAB: LA (lupus anticoag) & ACA (anticardiolipin Ab) present Seen where LA acts against PF3 with incr aPTT & PT Rx by adding phospholipid to correct the aPTT NOT by adding plasma which wont help aPTT Caused by fat malabsorption, broad spectrum antibiotics, congenital physiology, or coumarin anticoagulation (blocks epoxide reductase) Intravascular thrombohemorrhagic disorder. Assoc w/septicemia, pregos, ABO mismatch, massive trauma, malignancy LAB: D diamer assay, Rx w/heparin, replacement therapy, or antifibrinolytics (severe) DO NOT Rx w/heparin if antithrombin III is decr Impaired Vit K dep factor synthesis. Bad b/c of fibrinogen & probs caused by fibrin product clearance Fibrin product clearance interfere w/clot formation & platelet fxn Caused by malignancy, oral contraceptives, polycythemia, or hypergammaglobulinemia (incr IgM Waldenstroms macroglobulinemia) Bad bleeding when A2 antiplasmin is used up Sm. Vessel vasculitis 2ndary to IC deposition likely causes Umbilical cord bleeding. LAB: Abnormal 5 molar urea clot solubility test (tests for Factor 8) w/normal PT & aPTT Factor VIII: C def w/normal vWF & Ag levels. Normal bleeding time (platelets ok) XLR LAB: Detect w/RFLP AD Combo of a platelet defect & a coag def. Assoc. w/epitaxis, angiodysplasia, mitral/aortic stenosis Classical Type I: Longer BT, normal PT & aPTT. Prophylasxis w/tranexamic acid (antifibrinolytic) Rx w/desmopressin (only useful in Type I), cryoprecipitate, humate P Differentials include: Glanzmann Thrombastemia, Bernard Soulier Synd, Storage Pool Disease Differentiation by prolonged PTT & decr factor 8 levels (except hemophilia---has normal vWF) LAB: Ristocetin cofactor assay XLR Incr aPTT with normal PT & BT. Factor IX def. AD Epitaxis, telangiectasia in mouth & GI AD AD Leads to DCTs & PEs at early ages. From failure to prolong the aPTT when the pt is on heparin LAB: Test by giving heparin & noting if aPTT is not prolonged Serve as vit K dependent factors. Cant inactivated factors V & VII to enhance fibrinolysis Leads to DVTs & PEs at early ages.

Primary Antiphospholipid Ab Syndrome

Acquired Vit K Def Acquired DIC Acquired Liver Disease Acquired Hypercoaguable State Fibrinolytic Disorders Thrombosis Disorders Factor X III Def Hemophilia A Von Willebrandss Disease

Hemophilia B (Christmas Disease) Hereditary Hemorrhagic Telangiectasia (Osler Weber Rendu) Antithrombin III Def. Proteins C & S Def.

Factoids:
Group A has incr gastic cancer risk while Group O has incr duodenal ulcer risk 6 major Rh Ags are DccEe which are inherited codominantly Most blood banks only test for D Ags to estabolish Rh Kell Ag is non Rh Ah present in 10% of pop. Anti-Kell develop for 2ndary exposure Leview Ab has no clinical significant, it is a naturally occuring IgM Ab Duffy Ags are missing in pts with p.vovax innate resistance i Ag is an IgM present in all newborns and then turns into I Ag in adults Anti i cold AI HA is assoc with EBV infections Anti I cold AI HA is assoc with Mycoplasma pneumonia infections Irraditation of blood to kill leukocytes & CMV in mymphocytes in IC pts Packed RBCs dont replace functional platelets or granulocytes Platelets sdo not have Rh Ags --- do have ABO, HLA, PLA1 Ags Cryoprecipitate contains factor VIII, fibrinogen, factor XIII, fibrinonextin Tisse thromboplastin is the only non circulating factor If you have normal BT, vWF must be normal Ca binding clotting facts onto platelet surface w/PF3 VIII:C & vWF form a complex which impedes VIII:C degeneration With Xa, V, PF# & Ca the Prothrombin Cplx forms Thrombin If thrombocytopenia (HS2) develops in heparin NEVER give again High molecular weight heparin is ok in prego given IV Warfarin causes a temporarily hypercoag state b/c of protein C loss Ristocetin cofactor assay is the best test for VIII:vWF def. 5 molar urea clot solubility test is for factor XIII def. Give protamine sulfate for Heparin OD Give FFP & IM Vit K for Warfarin OD TT thrombin time, PTT partial thromboplastin time, PT prothrombin time PT evaluates platelets & their fxns (evaluating vWF & vessel integrity) CML is the only leukemia associated with thrombocytosis Haptoglobin (sucicide protein)s synthesized in the liver & binds free Hb. Haptoglobin is low in intravascular hemolysis (b/c macrophages remove haptoglobin/Hb compl) Extrinsic system is considered the most important pt of the coag system b/c it generates small amounts of thrombin to initiate clotting Intrinsic system generates large amounts of thrombin & converges w/extrinsic pathwya at factor X to go to common pathway Low molecular weight heparin (enoxapairin) is given SC with better bioavailability. Be sure to test factor Xa levels during therapy. vWF is the only clotting factor made outside the liver (made in epithelial cells and alpha granules) Fresh frozen plasma contains all coag factors and should never be used as a volume expander Hypercoag states are increased by hypergammaglobulinemia (incr IgM presents as this in Waldenstroms macroglobulinemia) Normal Events with Vessel Injury Vessel injury activation of factor VII in the extrinsic coagulation system by tissue thromboplastin and activation of factor XII in the intrinsic system by exposed collagen platelets stick to VIII:VWF via their receptors (platelet adhesion) stimulus for platelet release of ADP from dense bodies causing platelet aggregation and synthesis of TXA2temporary platelet plug with fibrinogen draped over it (fibrinogen receptors on platelets) stops bleeding thrombin generated by coagulation pathway stimulation converts fibrinogen into fibrin and forms a stable platelet plug plasmin destroys the plug and reestablishes blood flow Warfarin therapy: Life-threatening complication Factors preventing small vessel clotting Heparin (enhances antithrombin III which neutralizes most serine protease coagulation factors -prothrombin, X, IX, XII, XI, thrombin) PGI2 (synthesized by endothelial cells, vasodilator, inhibits platelet aggregation) Protein C and S (inactivate factors V and VIII, enhance fibrinolysis) Tissue plasminogen activator (release of plasmin, which destroys coagulation factors and clots) Factors acting as procoagulants in small vessel injury Thromboxane A2 (synthesized by platelets, vasoconstrictor, enhances platelet aggregation; cyclooxygenase blocked by aspirin and NSAIDS) von Willebrand factor (VIII:VWF; synthesized by endothelial cells and megakaryocytes, platelet adhesion factor) Extrinsic and intrinsic coagulation systems

Hemorrhagic skin necrosis! Associated with patients who are heterozygotes for protein C deficiency Patients have 50% levels of protein C which quickly becomes 0% during the initial loading phase of warfarin therapy This produces widespread thrombosis of vessels in the skin with skin necrosis Functional and immunologic assays are available for both factors C and S Heparin is utilized in acute thrombosis and coumarin derivatives for long-term maintenance (low levels to prevent skin necrosis) Intrinstic Pathway: Extrinsic Pathway: 1) Platelets adhere to collagen by vWF & release ADP & TXA2. 1) Damaged endothelial cells release tussue factor thromboplastin 2) Activated platelets express phospholipid complex to trigger intrinsic pathway 2) TF triggers extrinsic factor 3) Pathway initiated when Hageman Factor (XII) is activated by HMWK, collagen, & kallikrein 3) TF activates Factor VII 4) XII XIa 4) Factor VII & TF activates Factors X & IX 5) XI IXa 6) IX aw/cofactor XIIIa converts Factor X into Xa Lack Isoagglutins: Old people <3month old monsters hypogammaglobulinemia Coag Inhibitors: Postpartum Chlorpromazine therapy Rx hemophila A pts w/factor VIII Prolong BT: Vascular disorders (scurvy, immune vasculitis, steroid therapy) Blood transmissible infections: HCV/HBC/HDV HIV & CMV syphilis Factor VIII: C/Ag/vWF Factor II: prothrombin (thrombin) Factor I: fibrinogen (fibrin) Factor XII: Hageman Factor Clinical Pre w/platelet probs: Epistaxis Petechia No HepB Risk: Factor VIII concentrates Synthetic volume expanders Igs & vaccines Prothrombin Complex: Xa V PF3 & Ca+ PT Most Sensitive for: Finding common pathway defs Factor VII def (extrinsic) Common Pathway: Factor X w/cofactor V converts prothrombin (II) into thrombin (IIa) Thrombin convers fibrinogen (I) into fibrin (1a) Vit K dependent Factors: Factors II, VII, IX, X Proteins C & S Warfarin: Inhibits factors II, IX, X, XII synth

Thrombocytopenia vWF aspirin/NSAIDs Qualative Platelet Disorders (incr BT) NSAIDs, aspirin Beta lactams, beta blockers, antihistamines, psychotropics Uremia Guanidinosuccinic acid & phenolic comps inhibit PF3 Multiple myeloma Myeloproliferative diseases

Ecchymoses (purpura) Easy bruising & bleeding Factor VIII: C made in liver Factor VIII: vWF is a plasma protein made by endothelial cells and alpha platelets granules ***C & vWF form a complex to
impede VIII:C degregation

Warfarin therapy pt followups ***Liver disease serverity ***Evaluating DIC Donor Blood Tests: RPV/VDRL HbsAg Anti HCV Serum ALT HIV Elisa HTLV-1Abs

Heparin Inhibits: XIIa, Xia, Ixa, VIIa, Xa Activates: Antithrombin III aPTT: Instrinsic Defs (XII, HMWK, XI, IX, VIII) Monitoring heparin therapy TT prolonged In: Fibrinogen Def Dysfibrinogenemias Heparin therapy

Bad Things Hemophilia A & B vWDF Def Antiphospholipid Synd Warfarin Heparin Fibrinolytic disorders DIC Factor XIII Def

BT

PT

aPTT

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