Prevention of blood loss while maintaining maximal perfusion requires the interaction of the blood vessels, platelets, coagulation factors, and fibrinolytic agents. Normal Hemostasis and Hemostasis Testing Prevention of blood loss while maintaining maximal perfusion requires the interaction of the blood vessels, platelets, coagulation factors, and fibrinolytic agents. Normal anticoagulation in small blood vessels Small blood vessels include capillaries, venules, arterioles. 1. Heparinli!e molecules a. "nhance antithrombin ### $%&###' activity b. Neutrali(e serine protease coagulation factors )actors *##, *#, #*, and *+ prothrombin $factor ##'+ and thrombin ,. Prostaglandin $P-' #, $prostacyclin' a. Synthesi(ed by intact endothelial cells b. P-H, is converted by prostacyclin synthase to P-#,. c. .asodilator and inhibits platelet aggregation d. %spirin does not inhibit synthesis of P-#, by endothelial cells. /. Protein 0 and S a. .itamin 1dependent factors b. #nactivate factors . and .### c. "nhance fibrinolysis 2. &issue plasminogen activator $tP%' a. Synthesi(ed by endothelial cells b. %ctivates plasminogen to release plasmin c. Plasmin degrades coagulation factors and lyses fibrin clots $thrombi'. Procoagulants released in small vessel in3ury page ,45 page ,46 )actor .###70 is synthesi(ed in the liver. 8hen .###70 is activated by thrombin, it dissociates from the .###7v8) complex and performs its procoagulant function in the intrinsic coagulation cascade system. 1. &hromboxane %, $&*%,' a. Synthesi(ed by platelets i. P-H, is converted into &*%, by thromboxane synthase. ii. %spirin irreversibly inhibits platelet cyclooxygenase. Prevents formation of P-H,, the precursor for &*%, iii. 9ther nonsteroidal antiinflammatory drugs reversibly inhibit platelet cyclooxygenase. b. )unctions of &*%, in hemostasis .asoconstrictor, enhances platelet aggregation 22 .on 8illebrand factor $v8)' a. Synthesi(ed by endothelial cells and mega!aryocytes i. Synthesi(ed in 8eibelPalade bodies in endothelial cells ii. Platelets carry v8) in their :granules. b. )unctions of v8) i. Platelet adhesion molecule ;inds platelets to exposed collagen Platelets have glycoprotein $-p'#b receptors for v8). ii. 0omplexes with factor .###70 in the circulation .###7v8) complexes prevent degradation of factor .###70 $procoagulant factor'. <ecrease in v8) secondarily decreases .###70 activity. ,. &issue thromboplastin $factor ###' c. Noncirculating ubiquitous substance =eleased from in3ured tissue b. %ctivates factor .## in the extrinsic coagulation system 22 "xtrinsic and intrinsic coagulation systems $see below' Platelet structure and function page ,46 page ,4> 1. <erivation a. 0ytoplasmic fragmentation of mega!aryocytes b. %pproximately 1??? to /??? platelets are produced per mega!aryocyte. ,. @ocations a. Peripheral blood $live for >1? days' b. %pproximately one third of the total platelet pool is stored in the spleen. /. Platelet receptors a. -lycoprotein receptors for v8) are designated -p#b. b. -lycoprotein receptors for fibrinogen are designated -p##b7###a. i. &iclopidine and clopidogrel #nhibit %<Pinduced expression of platelet -p##b7###a receptors Prevent fibrinogen binding and platelet aggregation ii. %bciximab Aonoclonal antibody that is directed against the -p##b7###a receptor 2. Platelet factor / $P)/' a. @ocated on the platelet membrane b. Phospholipid substrate required for the clotting sequence 4. Platelet structure a. 0ontractile element i. 0alled thrombosthenin ii. Helps in clot retraction b. <ense bodies contain7 i. %denosine diphosphate $%<P', an aggregating agent ii. 0alcium, a binding agent for vitamin 1dependent factors c. :-ranules contain7 i. v8), fibrinogen ii. Platelet factor 2 $P)2' Heparin neutrali(ing factor B. Platelet function a. )ill gaps between endothelial cells in small vessels i. Prevents lea!age of =;0s into the interstitium ii. Platelet dysfunction causes lea!age of =;0s, producing petechia. b. )ormation of the hemostatic plug in small vessel in3ury c. Plateletderived growth factor stimulates smooth muscle hyperplasia. #mportant in the pathogenesis of atherosclerosis 0oagulation system page ,B? 8arfarin is an anticoagulant that inhibits epoxide reductase, which prevents any further Ccarboxylation of the vitamin 1dependent coagulation factors. However, full anticoagulation does not immediately occur, because previously C carboxylated factors are still present. Prothrombin has the longest halflife+ therefore, full anticoagulation requires at least / to 2 days before all functional prothrombin has disappeared. &his explains why patients are initially placed on both heparin and warfarin, because heparin immediately anticoagulates the patient by enhancing %&### activity. page ,B? page ,B1 8hen blood is drawn into a clot tube $no anticoagulant is added', a fibrin clot is formed. 8hen the tube is spun down in a centrifuge, the supranate is called serum, which, unli!e plasma, is missing fibrinogen, prothrombin $##', factor ., and factor .###. 1. 0oagulation cascade a. "xtrinsic system $factor .##' b. #ntrinsic system $factors *##, *#, #*, .###' ,. "xtrinsic system a. )actor .## is activated $factor .##a' by tissue thromboplastin. b. )actor .##a activates factor * in the final common pathway. /. #ntrinsic system a. )actor *## $Hageman factor' is activated by7 i. "xposed subendothelial collagen ii. Highmolecularweight !ininogen $HA81' b. )unctions of factor *##a i. %ctivates factor *# ii. %ctivates plasminogen $produces plasmin' iii. %ctivates the !ininogen system $produces !alli!rein and brady!inin' c. )actor *#a activates factor #* to form factor #*a i. )ourcomponent complex is formed $#*a, .###, platelet factor /, calcium' ii. 0omplex activates factor * in the final common pathway. iii. 0alcium binds factor #*a, a vitamin 1dependent coagulation factor. 2. )inal common pathway a. #ncludes factors *, ., prothrombin $##', and fibrinogen $#' b. Prothrombin complex i. )ourcomponent system consisting of factor *a, factor ., platelet factor /, and calcium ii. 0alcium binds factor *a, a vitamin 1dependent coagulation factor. iii. 0omplex cleaves prothrombin into thrombin $en(yme'. c. )unctions of thrombin i. %cts on fibrinogen to produce fibrin monomers plus fibrinopeptides % and ; ii. %ctivates fibrin stabili(ing factor *### )actor *###a converts soluble fibrin monomers to insoluble fibrin. "nhances proteinprotein crosslin!ing to strengthen the fibrin clot iii. %ctivates .###70 in the intrinsic system 4. .itamin 1dependent factors a. )actors ##, .##, #*, *, protein 0, and protein S b. Synthesi(ed in the liver as nonfunctional precursor proteins c. )unction of vitamin 1 i. .itamin 1 is activated in the liver by epoxide reductase. Aa3ority of vitamin 1 is synthesi(ed by colonic bacteria. ii. %ctivated vitamin 1 Ccarboxylates each factor. 0arboxylated factors can bind to calcium and P)/ in the cascade sequence. B. 0ertain coagulation factors are consumed in the formation of a fibrin clot. o 0onsumed factors are fibrinogen $#', factor ., factor .###, and prothrombin $##' )ibrinolytic system 1. %ctivation a. tP% activates plasminogen to release the en(yme plasmin. %lteplase and reteplase are recombinant forms of tP% used in thrombolytic therapy. b. 9ther activators of plasminogen 22 )actor *##a 222 Strepto!inase $derived from streptococci' 2222 %nistreplase $complex of strepto!inase and plasminogen' 2v2 Dro!inase $derived from human urine' b. %minocaproic acid 0ompetitively bloc!s plasminogen activation, thereby inhibiting fibrinolysis 22 )unctions of plasmin a. 0leaves insoluble fibrin monomers and fibrinogen into fibrin$ogen' degradation products $)<Ps' )ragments of crosslin!ed insoluble fibrin monomers are called <dimers. b. <egrades factors . and .### c. :,%ntiplasmin $synthesi(ed in the liver' inactivates plasmin. Small vessel hemostasis response to in3ury page ,B, 1. Sequence involves vascular, platelet, coagulation, and fibrinolytic phases. ,. .ascular phase a. &ransient vasoconstriction occurs directly after in3ury. b. )actor .## $extrinsic system' is activated by tissue thromboplastin. c. "xposed collagen activates factor *## $intrinsic system'. /. Platelet phase a. Platelet adhesion Platelet -p#b receptors adhere to exposed v8) in damaged endothelial cells. b. Platelet release reaction =elease of adenosine diphosphate $%<P' causes platelet aggregation in the lumens of in3ured vessels. c. Platelet synthesis and release of &*%, 22 .essels constrict $reduce blood flow'. 222 Platelet aggregation is further enhanced. b. &emporary platelet plug stops bleeding. 22 %ggregated platelets have fibrinogen attached to their -p##b###a receptors. 222 #t is an unstable plug that can easily be dislodged. ,. 0oagulation phase a. &hrombin is produced by locali(ed activation of the coagulation cascade. 9ccurs in the vascular phase b. )ibrinogen attached to -p##bE###a receptors is converted to insoluble fibrin monomers. c. Stable platelet plug is formed. 22 )ibrinolytic phase a. Plasmin cleaves the insoluble fibrin monomers holding the platelet plug together. b. ;lood flow is reestablished. Platelet tests Table 14-1. Causes of Prolonged Bleeding Time Cause Nature of Defect Comments %spirin or NS%#<s Platelet aggregation defect #nhibition of platelet 09*, which ultimately inhibits synthesis of &*%, Normal platelet count ;ernardSoulier syndrome Platelet adhesion defect %utosomal recessive disease %bsent -p#b platelet receptors for v8) &hrombocytopenia, giant platelets @ifelong bleeding problem -lan(mannFs disease Platelet aggregation defect %utosomal recessive disease %bsent -p##b###a fibrinogen receptors @ifelong bleeding problem %bsent thrombosthenin =enal failure Platelet aggregation defect #nhibition of platelet phospholipid by toxic products =eversed with dialysis and desmopressin acetate Scurvy .ascular defect 0aused by vitamin 0 deficiency <efective collagen resulting from poor cross lin!ing Aay cause ecchymoses and hemarthroses &hrombocytopenia <ecreased platelet number #ncreased bleeding time when platelet count G>?,??? cellsEH@ .on 8illebrand disease Platelet adhesion defect %utosomal dominant disorder %bsent or defective v8) <ecreased .###70 0ombined platelet and coagulation factor disorder 09*, cyclooxygenase+ NS%#<, nonsteroidal antiinflammatory drug+ &*%,, thromboxane %,+ v8), von 8illebrand factor. page ,B, page ,B/ 1. Platelet count a. Normal count is 14?,??? to 2??,??? cellsEH@. b. % normal count does not guarantee normal platelet function. ,. ;leeding time a. "valuates platelet function up to the formation of the temporary platelet plug Normal reference interval is , to 5 minutes. b. <isorders causing a prolonged bleeding time are listed in /. Platelet aggregation test a. "valuates platelet aggregation in response to aggregating reagents b. %ggregating agents include %<P, epinephrine, collagen, and ristocetin. 2. &ests for v8) a. =istocetin cofactor assay 22 "valuates v8) function 222 %bnormal assay 0lassic von 8illebrand disease $deficiency of v8)' ;ernardSoulier disease $absent -p#b receptor' b. v8) antigen assay 22 Aeasures the quantity of v8) regardless of function 222 <ecreased in classic von 8illebrand disease 0oagulation tests page ,B2 8hether the patient is anticoagulated with heparin or warfarin, both the P& and P&& are prolonged, because both inhibit factors in the final common pathway. "xperience has shown that the P& performs better in monitoring warfarin, while the P&& performs better in monitoring heparin. 1. Prothrombin time $P&' a. "valuates the extrinsic system down to formation of the fibrin clot )actors evaluated include .##, *, ., ##, and # b. Normal reference interval for P& is 11 to 14 seconds. 9nly prolonged when a factor level is /?I to 2?I of normal c. #nternational normali(ed ratio $#N=' 22 Standardi(es the P& for use in warfarin therapy 222 =esults are the same regardless of the reagents used to perform the test. b. Dses of P& 22 )ollow patients who are ta!ing warfarin for anticoagulation 222 "valuate liver synthetic function #ncreased P& indicates severe liver dysfunction. 2222 <etect factor .## deficiency ,. Partial thromboplastin time $P&&' a. "valuates the intrinsic system down to formation of a fibrin clot )actors evaluated include *##, *#, #*, .###, *, ., ##, and #. b. Normal reference interval for P&& is ,4 to 2? seconds. 9nly prolonged when a factor level is /?I to 2?I of normal c. Dses of P&& 22 )ollow heparin therapy Heparin enhances %&### activity. P&& is not required to follow lowmolecularweight heparin therapy. 222 <etect factor deficiencies in the intrinsic system )ibrinolytic system tests page ,B2 page ,B4 1. )ibrin$ogen' degradation products $)<Ps' o <etects fragments associated with plasmin degradation of fibrinogen or insoluble fibrin in fibrin clots ,. <<imer assay a. 9nly detects crosslin!ed insoluble fibrin monomers in a fibrin clot b. <oes not detect fibrinogen degradation products $not crosslin!ed' c. Aost specific test for evidence of degradation of a fibrin clot $thrombus'+ examples7 i. &hrombolytic therapy for coronary artery thrombosis &hrombus is composed of platelets held together by fibrin ii. Screening test for pulmonary thromboembolism &hrombus is composed of =;0s, platelets, white blood cells $8;0s' held together by fibrin iii. Screening test for disseminated intravascular coagulation $<#0' &hrombus is composed of =;0s, platelets, and 8;0s held together by fibrin $see Section ###'. Platelet Disorders 0lassification of platelet disorders 1. Juantitative platelet disorders a. &hrombocytopenia b. &hrombocytosis ,. Jualitative $functional' platelet disorders 0lassification of platelet disorders 1. Juantitative platelet disorders a. &hrombocytopenia b. &hrombocytosis ,. Jualitative $functional' platelet disorders Pathogenesis Table 14-2. Disorders Producing Thrombocytoenia Disorder Pathogenesis Comments %cute idiopathic thrombocytopenic purpura $#&P' #g- antibodies directed against -p##b7###a receptors $type ## hypersensitivity reaction' Aacrophages phagocytose platelets Aost common childhood cause of thrombocytopenia %brupt onset after an upper respiratory tract infection %bsence of lymphadenopathy and splenomegaly =esponds to corticosteroids 0hronic idiopathic thrombocytopenic purpura #g- antibodies directed against -p##b7###a receptors $type ## hypersensitivity reaction' Aost common cause of thrombocytopenia in adults Newborn infants may have transient thrombocytopenia due to transplacental passage of #g- antibodies Secondary causes7 S@", H#. Heparininduced thrombocytopenia &ype ## variant7 macrophage removal of platelets surfaced by #g- antibody directed against heparin attached to P)2 $type ## hypersensitivity' 9ccurs 412 days after heparin treatment Aust discontinue heparin =elease of P)2 after platelet destruction may cause vessel thrombosis H#. thrombocytopenia Similar to #&P Aost common hematologic abnormality in H#. $not %#<Sdefining condition' &hrombotic thrombocytopenic purpura $&&P' %cquired or genetic deficiency in v8) cleaving metalloprotease in endothelial cells "xcess of v8) increases platelet adhesion to areas of endothelial in3ury at arteriolecapillary 3unctions Platelets consumed in the formation of thrombi causes thrombocytopenia "nhanced by factors that damage endothelial cells $e.g., ticlopidine, hypertension' 9ccurs in adult females 0linical pentad7 fever, thrombocytopenia, renal failure, microangiopathic hemolytic anemia with schistocytes $damage by platelet thrombi', 0NS deficits &reated with plasmapheresis Aortality rate is 1?,?I Hemolytic uremic syndrome $HDS' "ndothelial damage at arteriolecapillary 3unction caused by Shigali!e toxin of ?1457H5 serotype of Escherichia coli 9rganisms proliferate in undercoo!ed Primarily occurs in children 0linical findings similar to &&P 0NS findings are less frequent Aortality rate /4I beef 0NS, central nervous system+ <#0, disseminated intravascular coagulation+ P)2, platelet factor 2+ S@", systemic lupus erythematosus+ v8), von 8illebrand factor. 1. &hrombocytopenia o <ecreased number of platelets a. <ecreased production "xamplesaplastic anemia, leu!emia b. #ncreased destruction 22 #mmune "xamplesidiopathic thrombocytopenic purpura, drugs 222 Nonimmune "xamplesthrombotic thrombocytopenic purpura, <#0 b. Sequestration in the spleen Hypersplenism in portal hypertension ,. &hrombocytosis o #ncreased platelet count o Primary thrombocytosis "xamplesessential thrombocythemia, polycythemia vera o Secondary $reactive' thrombocytosis "xampleschronic iron deficiency, infections, splenectomy, malignancy ,. Jualitative platelet disorders o %cquired $e.g., aspirin' or hereditary $e.g., -lan(mannFs disease' 0linical findings associated with platelet dysfunction "cchymoses $purpura' can be caused by a variety of disorders unrelated to platelet dysfunction. Palpable purpura $purpura that can be felt' is a sign of a small vessel vasculitis . ;ecause vasculitis is a type of acute inflammation, the lesions are palpable due to increased vessel permeability and not a platelet disorder. Senile purpura is a normal finding in elderly patients and is due to vessel instability . "cchymoses develop in areas of trauma $e.g., bac! of the hands, shins'. 1. "pistaxis $nosebleeds' is the most common symptom. ,. Petechia and multiple small ecchymoses $purpura' a. Petechia are pinpoint areas of hemorrhage in subcutaneous tissue . =;0s lea! through gaps in the endothelium of venules and capillaries. b. "cchymoses are the si(e of a quarter. /. ;leeding from superficial scratches o No temporary platelet plug is present to stop bleeding from in3ury to small vessels. 2. 9ther findings a. Aenorrhagia, hematuria b. ;leeding from tooth extraction sites c. -astrointestinal and intracranial bleeding Coagulation Disorders 0lassification of coagulation disorders 1. %cquired o Single or multiple coagulation factor deficiencies ,. Hereditary o Dsually a single coagulation factor deficiency 0lassification of coagulation disorders 1. %cquired o Single or multiple coagulation factor deficiencies ,. Hereditary o Dsually a single coagulation factor deficiency Pathogenesis page ,B5 page ,B6 1. <ecreased production o "xampleshemophilia %, cirrhosis ,. Pathologic inhibition o "xampleacquired circulating antibodies $inhibitors' against coagulation factors /. "xcessive consumption o "xampledisseminated intravascular coagulation 0linical findings in coagulation disorders 1. @ate rebleeding after surgery or wisdom tooth extraction a. &emporary platelet plug is the only mechanical bloc! preventing bleeding. b. @ac! of thrombin prevents formation of a stable platelet plug held together by fibrin. ,. )indings in severe factor deficiencies a. Hemarthroses b. =etroperitoneal and deep muscular bleeding /. )indings similar to platelet disorders a. "cchymoses, epistaxis b. Aenorrhagia, hematuria c. ;leeding from tooth extraction sites d. -astrointestinal and intracranial bleeding Hemophilia % page ,B6 page ,B> Hemophilia ; $0hristmas disease' is an *lin!ed recessive disorder involving a deficiency of factor #*. #t is clinically indistinguishable from hemophilia %. 1. "pidemiology a. *lin!ed recessive i. )emales are asymptomatic carriers. ii. )emales transmit the abnormal * chromosome to 4?I of their sons. b. %bsent family history of hemophilia Aost li!ely due to a new mutation $/?I of cases' b. )emale carriers with symptomatic disease i. <ue to inactivation of more maternal than paternal * chromosomes ii. )emales become Khomo(ygousK for the abnormal * chromosome ,. Pathogenesis o <ecreased synthesis of factor .###70 in the intrinsic system 2. 0linical findings in hemophilia % a. Signs and symptoms correlate with the level of factor .###70 activity i. %ctivity below 1I correlates with severe disease $e.g., spontaneous hemarthroses'. b. ;leeding problems may occur in newborns $1?14I of cases'. i. "xcessive bleeding may occur after circumcision or umbilical cord separation. c. @aboratory findings in hemophilia % i. #ncreased P&& and a normal P& ii. <ecreased factor .###70 activity iii. <ecreased factor .###7antigen $.###7%g' )actor .### protein iv. <etection of female carriers <N% techniques are most sensitive. 2. &reatment of hemophilia % a. Aild cases respond to desmopressin acetate i. #ncreases .###70 activity b. Severe cases require infusion of recombinant factor .### i. No ris! for H#. 0lassic von 8illebrand disease $v8<' 1. "pidemiology a. %utosomal dominant disorder b. Aost common hereditary coagulation disorder ,. Pathogenesis o <ecreased v8) and factor .###70 activity 2. 0linical findings in v8< a. Aenorrhagia, epistaxis, easy bruisability b. %ssociation with angiodysplasia of the right colon /. @aboratory findings in v8< c. #ncreased P&& and a normal P& d. #ncreased bleeding time <ue a platelet adhesion defect e. %bnormal ristocetin cofactor assay f. <ecreased v8) antigen g. <ecreased .###7%g and .###70 activity 2. &reatment of v8< h. <esmopressin acetate $increases v8) and .###70 activity' i. 9ral contraceptive $estrogen has a similar action as desmopressin' 0irculating anticoagulants $inhibitors' 1. Pathogenesis a. 0oagulation factor is destroyed by antibodies. b. Aost common type is antibodies against factor .###70 $e.g., postpartum'. ,. 0linical findings o Similar to those with coagulation factor deficiencies due to decreased production 2. @aboratory findings a. Prolonged P& andEor P&&, depending on the factor deficiency <oes not differentiate immune destruction versus decreased production b. Aixing studies Normal plasma is mixed with patient plasma in a test tube. 22 No correction of P& andEor P&& indicates immune destruction. 222 0orrection of P& andEor P&& indicates decreased production. .itamin 1 deficiency page ,5? page ,51 1. )unction of vitamin 1 o C0arboxylates vitamin 1dependent factors ##, .##, #*, * and proteins 0 and S ,. 0auses of vitamin 1 deficiency a. <ecreased synthesis of vitamin 1 by colonic bacteria i. Newborns lac! bacterial coloni(ation of the bowel. .itamin 1 levels normally decrease between days , and 4. <anger of severe bleeding $e.g., intracerebral hemorrhage' Newborns require an intramuscular in3ection of vitamin 1 at birth. ;reast mil! contains very little vitamin 1. ii. Prolonged treatment with antibiotics %ntibiotics sterili(e the bowel causing decreased production of vitamin 1. Aost common cause of vitamin 1 deficiency in a hospitali(ed patient b. <ecreased small bowel reabsorption of vitamin 1 i. Aalabsorption of fat causes malabsorption of fatsoluble vitamins. ii. "xampleceliac disease c. <ecreased activation of vitamin 1 by epoxide reductase in the liver i. 8arfarin inhibits epoxide reductase. .itamin 1dependent factors are nonfunctional. =at poison contains warfarin. 0hildren may have exposure to warfarin from elders living in the household. ii. 0irrhosis <ecreased activation of vitamin 1 and synthesis of vitamin 1 dependent coagulation factors Prolonged P& is not corrected with intramuscular in3ection of vitamin 1. ,. 0linical findings of vitamin 1 deficiency a. -astrointestinal bleeding b. ;leeding into subcutaneous tissue c. ;leeding at the time of circumcision d. #ntracranial hemorrhage /. &reatment of vitamin 1 deficiency a. #f bleeding is not severe, treatment is an intramuscular in3ection of vitamin 1. 0orrects bleeding in a few hours 22 #f bleeding is severe, treatment is with fresh fro(en plasma. i. #mmediate correction ii. .itamin 1dependent factors are Ccarboxylated. Hemostasis disorders in liver disease 1. Pathogenesis a. <ecreased synthesis of coagulation factors i. Aultiple coagulation factor deficiencies ii. <ecreased Ccarboxylation of vitamin 1dependent factors b. <ecreased synthesis of anticoagulants "xamples%&###, proteins 0 and S b. <ecreased synthesis of fibrinolytic agents $e.g., plasminogen' c. <ecreased clearance of )<Ps and <dimers #nterfere with platelet aggregation and polymeri(ation of fibrin d. <ecreased clearance of tP% and decreased synthesis of :,antiplasmin Aay produce primary fibrinolysis $see section #.' 22 @aboratory findings in liver disease a. #ncreased P& and P&& b. #ncreased )<Ps and <dimers c. #ncreased bleeding time <isseminated intravascular coagulation $<#0' page ,51 page ,5, 1. 0auses of <#0 a. Sepsis 0ommon pathogens include E. coli $most common' and Neisseria meningitidis b. <isseminated malignancy 22 %cute promyelocytic leu!emia 222 Pancreatic cancer with release of procoagulants in mucin b. 9ther causes 0rush in3uries, rattlesna!e envenomation, amniotic fluid embolism 22 Pathogenesis a. %ctivation of the coagulation cascade <ue to release of tissue thromboplastin andEor endothelial cell in3ury b. )ibrin thrombi develop in the microcirculation. 22 &hrombi obstruct blood flow. 222 &hrombi consume coagulation factors $#, ##, ., .###' and trap platelets. b. %ctivation of the fibrinolytic system Secondary fibrinolysis due to activation of plasminogen by factor *## 22 0linical findings in <#0 a. &hrombohemorrhagic disorder 22 #schemia from occlusive fibrin thrombi 222 ;leeding from anticoagulation )actors #, ##, ., and .### are consumed in the fibrin thrombi c. Shoc! due to blood loss d. <iffuse oo(ing of blood from all brea!s in the s!in and mucous membranes e. Petechiae and ecchymoses ,. @aboratory findings in <#0 a. 0oagulation abnormalities 22 #ncreased P& and P&& 222 <ecreased fibrinogen b. Platelet abnormalities 22 &hrombocytopenia 222 #ncreased bleeding time c. )ibrinolysis abnormalities Presence of )<Ps and <dimers b. Normocytic anemia with schistocytes and reticulocytosis =;0s are damaged by fibrin thrombi $microangiopathic hemolytic anemia'. 22 &reatment a. &reating the underlying disease is most important. b. &ransfuse blood components 22 )resh fro(en plasma for multiple coagulation factor deficiencies 222 Pac!ed =;0s for anemia 2222 Platelet concentrates for thrombocytopenia !ibrinolytic Disorders Primary fibrinolysis page ,5, page ,5/ 1. 0auses a. 9pen heart surgery 0ardiopulmonary bypass causes a decrease in :,antiplasmin and increase in tP%. b. =adical prostatectomy 0auses increased release of uro!inase c. <iffuse liver disease 0auses a decrease in the synthesis of :,antiplasmin ,. Pathogenesis a. )<Ps interfere with platelet aggregation. b. Plasmin degrades coagulation factors causing multiple factor deficiencies. /. 0linical findings o Severe bleeding 2. @aboratory findings a. #ncreased P& and P&& <ue to multiple factor deficiencies b. #ncreased bleeding time <ue to interference with platelet aggregation c. Positive test for )<Ps d. Negative <dimer assay No fibrin thrombi are present. e. Normal platelet count Primary fibrinolysis page ,5, page ,5/ 1. 0auses a. 9pen heart surgery 0ardiopulmonary bypass causes a decrease in :,antiplasmin and increase in tP%. b. =adical prostatectomy 0auses increased release of uro!inase c. <iffuse liver disease 0auses a decrease in the synthesis of :,antiplasmin ,. Pathogenesis a. )<Ps interfere with platelet aggregation. b. Plasmin degrades coagulation factors causing multiple factor deficiencies. /. 0linical findings o Severe bleeding 2. @aboratory findings a. #ncreased P& and P&& <ue to multiple factor deficiencies b. #ncreased bleeding time <ue to interference with platelet aggregation c. Positive test for )<Ps d. Negative <dimer assay No fibrin thrombi are present. e. Normal platelet count Secondary fibrinolysis 1. 0ompensatory reaction in the presence of intravascular coagulation 2. #ncrease in both )<Ps and <dimers "ummary of #aboratory Test $esults in Hemostasis Disorders Table 14-%. #aboratory !indings in Common Hemostasis Disorders Disorder or Condition Platelet Count Bleeding Time PT PTT &hrombocytopenia #&P, &&P, HDS Normal Normal .on 8illebrand disease Normal Normal Hemophilia % Normal Normal Normal <#0 Primary fibrinolysis Normal %spirin or NS%#< use Normal Normal Normal 8arfarin or heparin use Normal Normal <#0, disseminated intravascular coagulation+ HDS+ hemolytic uremic syndrome+ #&P, idiopathic thrombocytopenic purpura+ NS%#<, nonsteroidal antiinflammatory drug+ P&, prothrombin time+ P&&, partial thromboplastin time+ &&P, thrombotic thrombocytopenic purpura. Thrombosis "yndromes %cquired thrombosis syndromes page ,5/ page ,52 1. %ntiphospholipid syndrome $%P@S' a. "pidemiology %ssociations include S@" and H#. b. Pathogenesis 22 Presence of antiphospholipid antibodies $%P%s' <irected against phospholipids bound to plasma proteins 222 %P%s include anticardiolipin antibody and lupus anticoagulant. %nticardiolipin antibody reacts with the cardiolipin reagent in the rapid plasma reagin test for syphilis. b. 0linical findings in %P@S 22 Produce arterial and venous thrombosis syndromes 222 =epeated abortions due to thrombosis of placental bed vessels 2222 Stro!es, thromboembolism ,. 9ther acquired causes of thrombosis a. Postoperative state with stasis of blood flow b. Aalignancy 22 #ncrease in coagulation factors 222 &hrombocytosis 2222 =elease of procoagulants from tumors, particularly pancreatic cancers c. )olate or vitamin ;1, deficiency <ue to increased plasma homocysteine levels b. 9ral contraceptives "strogen increases the synthesis of coagulation factors and decreases %&### c. Hyperviscosity 22 Polycythemia syndromes 222 8aldenstrLmFs macroglobulinemia %cquired thrombosis syndromes page ,5/ page ,52 1. %ntiphospholipid syndrome $%P@S' a. "pidemiology %ssociations include S@" and H#. b. Pathogenesis 22 Presence of antiphospholipid antibodies $%P%s' <irected against phospholipids bound to plasma proteins 222 %P%s include anticardiolipin antibody and lupus anticoagulant. %nticardiolipin antibody reacts with the cardiolipin reagent in the rapid plasma reagin test for syphilis. b. 0linical findings in %P@S 22 Produce arterial and venous thrombosis syndromes 222 =epeated abortions due to thrombosis of placental bed vessels 2222 Stro!es, thromboembolism ,. 9ther acquired causes of thrombosis a. Postoperative state with stasis of blood flow b. Aalignancy 22 #ncrease in coagulation factors 222 &hrombocytosis 2222 =elease of procoagulants from tumors, particularly pancreatic cancers c. )olate or vitamin ;1, deficiency <ue to increased plasma homocysteine levels b. 9ral contraceptives "strogen increases the synthesis of coagulation factors and decreases %&### c. Hyperviscosity 22 Polycythemia syndromes 222 8aldenstrLmFs macroglobulinemia Hereditary thrombosis syndromes &here is a potential for hetero(ygote carriers of protein 0 deficiency to develop hemorrhagic s!in necrosis when placed on warfarin. Hetero(ygote carriers have 4?I protein 0 activity. Protein 0 has a short halflife $B hours'. 8hen patients are placed on warfarin, protein 0 activity falls to (ero activity in B hours, causing a hypercoagulable state due to increased activity of factors . and .###. &his causes cutaneous vessel thrombosis and concomitant s!in necrosis. 1. "pidemiology a. %utosomal dominant syndromes b. <eep venous thrombosis and pulmonary emboli occur at an early age. c. .enous thromboses often occur in unusual places. "xampleshepatic vein, dural sinus ,. )actor .@eiden a. Aost common hereditary thrombosis syndrome. b. Autant form of factor . cannot be degraded by protein 0 and protein S. /. %ntithrombin ### $%&###' deficiency a. )unctions of %&### 22 %ctivity is enhanced by heparin. 222 Neutrali(es serine proteases $e.g., factors *##, *#, #*, *, ##, thrombin' b. No prolongation of P&& after in3ecting a standard dose of heparin c. &reatment 22 #nfuse a greater dose of heparin than normal P&& eventually increases due to enhancement of whatever %&### is present. 222 Send the patient home on warfarin. ,. Proteins 0 and S deficiency a. Pathogenesis 0annot inactivate factors . and .### b. &reatment 22 ;egin with heparin and a very low dose of warfarin to reduce the ris! for developing hemorrhagic s!in necrosis. 222 Send the patient home on warfarin.