Bleeding Disorders HOPE Maram Al-anbar

Bleeding Disorders HOPE Maram Al-anbar 9-9 - 2014

^^ Attention Please ^^ We ( correction team of pediatric package^hope/2010^ ) had decided to make one lecture of bleeding disorders in place of the two lectures we had in our package Including the content of the previous lectures Plus other sources to make it one organized lec. Hoping for you to get the most benefit,, study easily,, and not getting distracted or bothering yourself looking at other sources the sources of this lecture are : Previous 2 lectures + Nelson + Pediatric in Page + some youtube videos... Soo.. Let s begin our lecture,, Shall We ^^ ** NORMAL HOMEOSTASIS ** it s a dynamic process that occur in area of VASCULAR INJURY composed of :: *platelets *vascular wall *procoagulant proteins * anticoagulant proteins Now.. What is the sequence of events that occur in this process?!! Once there is injury to the vascular endothelium what happens?? :: 1* Vasoconstriction.. 2* Primary Homeostatic mechanism (platelet plug formation).. 3* Secondary Homeostatic mechanism (fibrin clot,, thrombus).. 4* Anti thrombotic and Fibrinolytic events.. It starts with injury to vascular endothelium exposure of subendothelial collagen confrontational changes in vwf (von-willebrand factor) platelets bind to vwf via their receptor GPIb in a process called ADHESION then these platelets get activated and produce substances ex. ADP that recruit other platelets from circulation to come then platelets bind with each other in layers using their receptors GPIIb-IIIa using fibrinogen as a ligand between the receptors in a process called AGGREGATION 1

forming in the end Primary Homeostatic Plug ( Platelet Plug ) that will temporally stop the bleeding,, Soo... **Adhesion is : Platelet - Subendothelial Interaction (GP-Ib _vwf) **Aggregation is : Platelet - Platelet Interaction ( GPIIb/IIIa _ fibrinogen_gpiib/iiia ) ** Then comes the Secondary Homeostatic mechanism that totally aims at the process of conversion of FIBRINOGEN into FIBRIN ( remember the fibrinogen that served as a ligand between platelets in the plug now we want to convert it into fibrin and organize it in a strong & stable network (clot) that permanently stop the bleeding ),, and this is done by what s called COAGULATION CASCADE and this cascade has two pathways :: 2

** EXTRINSIC ** ** INTRINSIC ** Shorter pathway.. Longer pathway.. Starts with factor 7.. Starts with factor 12.. Stimulated with tissue factor as a result of trauma to the vessel.. Stimulated with inflammatory mediator as a result of inflammation.. The pathway is 7 10* 12 11 9(in presence of activated F8 + Ca + PF) 10* *At F10 starts the common pathway 10(in presence of activated F5 + Ca + PF) 2 1 details below WARFARIN can block this pathway (inhibiting the production of vit.k dependent factors -10,9,7,2- by inhibiting the activation of vit.k.. Measured by PT/ INR tests.. HEPARIN can block this pathway (stimulating antithrombine III that inhibits thrombin(f2) & factors -11,10,9-.. Measured by aptt test.. Cascade means in a step wise manner where the active form of the factor acts as an Enzyme,, where as the inactive form acts as a Substrate Ex. FXIIa act as an enzyme,, FXI act as a substrate... أفضل تعريف لذاتك أنك لست أفضل من أحد ولست كأي أحد ولست أقل من أحد... 3

Now how this cascade occur?!! Let s take the Intrinsic pathway :: 1 st we have inflammatory mediator that activates FXII from inactive into active form FXIIa XII XIIa (then this will activates XI) XI XIa(then this activates IX) IX IXa (then this with VIIIa +Ca +PF activates X ) X Xa (then this with Va +Ca +PF activates prothrimbin II into thrombin IIa ) II IIa(here thombin convert fibrinogen I into FIBRIN I * the final product that we need ) I Ia NOW fibrin Ia is stabilized with FXIII for clot formation ^^ 4

Now let s talk about thrombin and the imp. Functions that performs :: 1* conversion of fibrinogen into FIBRIN.. 2* activation of FXIII( fibrin stabilizing factor ) that will bind fibrin and stabilize it into a CLOT.. 3* act as platelet AGONIST ( attracts more and more platelets ).. 4* activates plasminogen into PLASMIN ( which is fibrinolytic enzyme ) 5* activates factors V, VIII, XI.. ** Imp Note all coagulation factors are made in the liver except FVIII made in vascular endothelium and bound with vwf ** another Note : Deficiency of FVIII, FIX lead to sever bleeding disorder Deficiency of FXI lead to mild bleeding disorder Deficiency of FXII is asymptomatic AND the last stage after the thrombus(clot) has been formed and the bleeding has been stopped now we want to : ** prevent further thrombotic events by anti thrombotic enzymes ex. Anti-thrombin III,, protein C,, protein S... ** Dissolve the thrombus and resume the blood flow by fibrinolytic enzymes ex. Plasmin.. 5

Soo we ve just finished the normal process of homeostasis ^^hoping that it was clear enough so that we start with the imp. part of the lec. :: BLEEDING DISORDERS :: They can be classified into : 1- Platelet disorders.. 2- Coagulation disorders.. 3- Blood vessel disorders : ** Congenital ex. Ehler-danlos Syndrome,, Osler-Weber-Rendu Syndrome.. **Acquired ex. Senile Purpura,, HSP (henoch schoenlein purpura ).. 6

Clinical presentation :: ** superficial bleeding ** in 1-skin in form of *petechia(pinpoint rash <3mm),, *purpura(adjoining petechia 3-10mm),, *ecchymosis( >1cm).. 2-mucous membranes as in epistaxis,, menorrhagia.. ** Immediate bleeding ** immediately after injury.. Lab tests we order :: 1- Platelet count (CBC) : NL (150-400)x1000/microL.. 2- Bleeding time (time needed for bleeding to stop) NL 3-10 minutes.. Platelets disorders Can be classified into :: Qualitative disorders where the platelet count is normal but abnormal function :: ** Inherited : 1- Bernard soulier syndrome (BS).. 2- Glanzmann thrombasthenia (GT).. 3- von-willebrand disease (vwd).. ** acquired : 1- Uremia (renal failure ).. 2- Aspirin.. 3- Alcohol.. Quantitative disorders where the platelet count is low ( thrombocytopenia ) :: ** Decreased marrow production : 1- Aplastic Anemia.. 2- BM infiltration ex. Leukemia.. ** Excess Destruction : 1- ITP ( idiopathic thrombocytopenic purpura ) 2- TTP ( thrombotic thrombocytopenic purpura ) 3- HUS ( hemolytic uremic syndrome ) 4- DIC ( disseminated Intravascular Coagulopathy ) 5- HIT ( heparin induced thrombocytopenia ) ** Sequestration :Hypersplenism.. 7

Now let s talk about some of the Quantitative disorders :: >> I stands for : **Idiopathic ( unknown reason ) **Immune ( involvement of auto antibodies) **Isolated ( cuz only Thrombocytopenia is present No Anemia,, No Leukopenia ) >> T stands for Thrombocytopenic ( cuz it s quantitative disorder with low platelet count ) >> P stands for Purpura ( cuz the usual presentation is purpuric rash ) Etiology >> it s thought to be auto immune with auto antibodies ( IgG, IgM ) that bind with platelet membrane,, signaling them for destruction by macrophages in Spleen.. >> it affects young children more likely.. >> can be divided into *Acute ( last < 6 months,, affect young children ) and *Chronic (last > 6 months,, affect young adults mainly females ).. Clinical presentation ITP >> superficial bleeding ex. Petechia,, epistaxis,, easy bruising.. >> these symptoms usually follow acute viral illness (1-4 weeks after).. >> imp << it s unusual to have splenomegaly Diagnosis >> Diagnosis of exclusion.. >> 1* clinical presentation 2* CBC ( plt count is low,, NL RBC,, NL WBC ),, Bleeding time high 3* Bone Marrow biopsy (we ll notice Increases in Megakaryocyte) it s actually not necessary but can be used to rule out Other Dx ex. Leukemia,, aplastic anemia 8

Therapy >> therapy doesn t affect long term outcome of ITP but rather increase plt count in acute conditions.. >> not necessary if plt count >30,000 >> if <30,000 it depends on severity of symptoms :: 1* IVIG ( it has the same effect of steroids but with rapid action >> WE start with it, if it doesn t work start steroids ) 2* Corticosteroids ( before using it U should do BM biopsy to exclude malignancy ex. Leukemia cuz steroids are contraindicated in leukemic patients ) 3* anti-rhd Ig ( for Rh +ve ) these 3 ways can decrease rate of clearance of sensitized platelets rather than decreases antibodies production... 4* Platelets transfusion ( not preferred cuz ITP is autoimmune so Abs can attack the transfused platelets ) used only in sever plt reduction... 5* Splenectomy used in *chronic type,, and *acute type only with life threatening bleeding ( it should be the last modality if previous ways didn t work ) >> 80% resolve in 6 months.. >> 1% can develop Intra Cranial Hemorrhage ICH.. >> Now moving into other Disorders << ** But before that you need to know about what s called MAHA ( Micro Angiopathic Hemolytic Anemia ) and How it Occurs :: It starts with vascular endothelial damage Thrombus formation In this thrombus this will trigger Platelets are consumed Thrombocytopenia Fibrin strands cause mechanical destruction of RBCs passing in that vessel Hemolytic Anemia 9

Now this MAHA happens in many conditions like what we re concerned with now >> HUS,, TTP,, DIC <<.. HUS ** H stands for Hemolytic ( hemolytic anemia which is characterized by schistocytes <fragmented RBCs> in Blood film ).. ** U stands for Uremic ( uremia due to acute renal failure that occurs bcz of renal vessels being affected ).. ** S stands for Syndrome.. Etiology >> 90% are caused by E.coli O157:H7 that produces verotoxin which attacks the endothelial lining of renal vessel leading to MAHA.. >> Childhood disease.. Clinical presentation >> Kidney is the main organ involved << >> Bloody Diarrhea.. >> Blood in Urine ( Hematuria ).. >> Signs of ARF ( Acute Renal Failure ).. Tests >> CBC :: platelets,, Hb.. >> Blood film :: schistocytes.. >> their may be Hematuria,, Proteinuria.. Therapy >> often resolves spontaneously.. >> Dialysis might be needed for ARF.. >> Plasma exchange in sever persistent disease.. 10

TTP ** Thrombotic Thrombocytopenic Purpura ** Etiology >> Genetic or Acquired deficiency of ADAMTS13 which is protease that normally cleaves multimers of vwf soo.. These multimers causing platelet aggregation, with fibrin strands they cause MAHA.. >> adulthood disease Clinical Presentation >> multiple organs are involved << >> Fever.. >> CNS signs ( seizure,, altered level of consciousness,..) >> signs of renal failure.. >> superficial bleeding.. Tests >> same as HUS Therapy >> TTP is more severe than HUS with higher mortality.. >> it s Hematological Emergency << >> urgent Plasma Exchange may be life saving.. >> steroids,, IVIG,, Splenectomy in non-responders.. 11

>> this disease is actually both Platelet & Coagulation disorder << >> it s mostly seen in ICU patients,, usually with shock << Etiology DIC >> their are different causes :: * malignancy.. * sepsis ex. Meningococcemia.. * trauma.. * obstetric events.. **These causes lead to widespread activation of coagulation from the release of procoagulants into circulation leading to :: ** clotting factors consumption & platelets consumption Bleeding anywhere.. ** Fibrin strands in vessels destruct passing RBCs Hemolysis.. ** Fibrinolysis is also activated.. Clinical Presentation >> bleeding and clotting manifestations.. Tests >> platelets >> bleeding time >> PT, PTT >> fibrin degradation products(d-dimer),,>> fibrinogen Therapy **Treatment of DIC is challenging,, what we do is : 1- Treat the underlying cause 2- Replace *Platelets by transfusion *clotting factors by FFP(fresh frozen plasma ) *Fibrinogen by cryoprecipitate 3- using Heparin for thrombosis is controversial 12

Now moving into Inherited Qualitative Disorders :: Bernard-soulier (BS) >> autosomal recessive AR >> NL platelet count,, AbNL ADHESION **adhesion occur when platelet bind via it s receptor GP-Ib with vwf ** >> here we have deficiency of GP-Ib... Glanzmann Thrombasthenia (GT) >> NL Platelet count,, NL Adhesion,, AbNL AGGREGATION ** aggregation occur when platelets bind with each other via their receptor GPIIb-IIIa having fibrinogen in between as ligand ** >> here we have deficiency of GPIIb-IIIa... von-willebrand Disease (vwd) >> Deficiency of vwf >> this disease is both Platelet & Coagulation disorder << ** Platelet disorder cuz vwf is part of platelet adhesion process.. ** Coagulation Disorder cuz FVIII is bound with vwf in circulation.. >> it has 3 types :: <> Type 1 <> - Quantitative ( partial reduction ) of vwf - the most common one affecting around 80% - Autosomal Dominant AD - usually asymptomatic <> Type 2 <> - Qualitative defect in vwf ( can t bind FVIII ) - Hemophilia equivalent cuz their will be FVIII deficiency <> Type 3 <> - Quantitative ( absolute reduction ) of vwf - Autosomal Recessive AR - v.low FVIII 13

And NOW moving into the LAST PART of the lecture Clinical Presentation ** Deep Bleeding ** >> Hematoma ( bleeding in tissue outside BV ) >> Hemarthrosis ( bleeding in joints ) ** Delayed Bleeding ** due to the compensatory role of Platelets ( primary Homeostasis ) Lab tests we order :: ** PT ( prothrombine time ) : indicates problem in Extrinsic pathway when prolonged ( NL value 10-12 sec ).. ** aptt ( activated partial thromboplastin time ) : indicates problem in Intrinsic pathway when prolonged ( NL value 25-40 ).. ** Thrombin time : for the common pathway,, it tests conversion of fibrinogen into fibrin.. COAGULATION DISORDERS 1- Hemophilia A,, B 2- DIC 3- vwd 4- Liver Disease 5- Vitamin K Deficiency 6- Drugs ex. Heparin,, warfarin 14

Hemophilia >> vwd is the MOST common inherited bleeding disorder << Where as >> Hemophilia (A+B) is the most common SEVER inherited disorder << Etiology >> Hereditary Deficiency of pro-coagulant proteins :: * F VIII in Hemophilia A * F IX in Hemophilia B >> both are X-Linked disorders >> Males are mainly affected 1 : 5000 in A,, 1 : 25,000 in B >> Female is usually asymptomatic carrier, unless, her father is affected and mother is carrier, turner syndrome (XO), or lionization of chromosome X.. >> Hemophilia A accounts for 80-85 % of cases >>Severity of disease correlates with Degree of Deficiency :: 1* SEVER :: * <1% of normal factor level * spontaneous bleeding * bleeding with minor trauma * manifest in Infancy 2* MODERATE :: * 1-5 % of normal factor level * bleeding requires moderate trauma 3* MILD :: * 6-40 % of normal factor level * bleeding requires significant trauma * might go undiagnosed many years 15

Clinical Presentation >> Deep bleeding :: Hematoma,, Hemarthrosis.. >> Delayed bleeding >> CNS bleeding may occur so should do CT scan.. >> Intra-abdominal bleeding can occur and suspected when patient complains of abdominal pain after minor trauma.. Tests >> aptt will be High >> specific factor assay ( to determine whether F VIII or F IX ) Therapy >> Replacement Therapy << ** in life threatening bleeding :: - level of 80-100 % of factor is needed ** in mild to moderate bleeding :: - level of 40% of factor VIII is needed - level of 30-40 % of factor IX is needed *** for << F VIII >> we need 0.5U/Kg to increase the level by 1% Soo... Dose of F VIII = ( Desired level (%) * weight (kg) * 0.5 ) *** for << F IX >> we need 1.5U/Kg to increase the level by 1% Soo... Dose of F IX = ( Desired level (%) * weight (kg) * 1.5 ) 16

Vitamin K deficiency :: ** Vit.K is synthesized by Intestinal bacteria.. ** it s imp for clotting factors (10,9,7,2).. ** deficiency due to :: 1- newborn not receiving vit.k 2- malabsorption as in cystic fibrosis 3- medications antagonize vit.k like warfarin Liver Disease :: ** we said earlier that all clotting factors except 8 are synthesized in the liver so both Intrinsic & Extrinsic pathway are affected.. ** PT / INR,, aptt will be high.. ** intrinsic pathway will be mostly affected so PT will be High & INR (PT measured / PT standard ) will be High as well.. **aptt can be slightly high due to F 9 being affected.. FXIII deficiency :: ** bleeding,, but,, ** NL PT,, aptt 17

Bleeding after circumcision.. Umbilical bleeding after being detached,, or delayed Bleeding during delivery,, CNS bleeding ( cephalhematoma ).. Family history ex. Hemophilia.. Imp points in HISTORY TAKING when patient comes with bleeding Hematoma after IM injection like when vaccinated.. onset of bleeding : Immediate vs delayed.. Site of bleeding : *superficial :: Epistaxis,, gum bleeding,, bleeding after tooth extraction,, petechia,, purpura.. *deep :: hematoma,, hemarthrosis.. Drug history ex. Aspirin,, warfarin,, heparin.. what about OSCE??! Example :: case of ITP :: U should be able to answer them ^^ >>> 4 YO boy presented by his mother with multiple bruises on lower limbs and elbow >>> Q1 what are the questions you would like to ask?? As in the previous page + ( imp Q ) any recent viral infection?? Q2 what are the signs you would like to examine?? 18

Q3 what are your DDx?? And most likely Dx?? Q4 what tests you would like to order?? Q5 if platelets count was 5000,, what s your next step?? Q6 how does IVIG work?? Q7 if IVIG didn t work,, what should you do?? Q8 what test should be done before using steroid?? Why?? Q9 if all didn t work,, what is your final way?? 19