Bleeding due to platelet disorder

Bleeding disorder Year 5 Group 4

Overview of Hemostasis Hemostasisis a process of forming clots in the walls of damaged blood vessels and preventing blood loss while maintaining blood in a fluid state within the vascular system.Maintain a balance between coagulation and anticoagulation

Role of HaemostasisStopping bleeding from site of blood vessel injury

Prevent extensive clot

Breakdown such clot once damage is repaired.

Systems involved in Hemostasis Vascular systemInjured vessel initiates vasoconstrictionPlatelet SystemInjured vessel exposes collagen that initiates platelet aggregation and help form plugCoagulation Systemprotein factors of intrinsic and extrinsic pathways produce a permanent fibrin plug

5 major componentsBlood vessels PlateletsCoagulation FactorsCoagulation inhibitor (anticoagulant)5. Fibrinolytic system

Blood vesselsEndothelial cells are arranged closely with each other without gaps in between- Prevents contact of blood with subendothelial layerVasoconstriction

7Function of endothelial cell

Tissue factor (TF) is a transmembrane glycoprotein that functions as the primary cellular initiator of blood coagulationEndothelial cells convert arachidonic acid into prostacyclin with the help of COX --1 or COX--2 and prostacyclin synthase.82. Platelet

To form primary (10) hemostatic plug Procoagulant activityplatelet membrane phospholipidcontact factors Biconcave discDiameter 2-4m, volume 5-8flContain -granule and dense-granulePlasma membrane- contain a number of specific glycoprotein(GP) receptors.

9HEMOSTASISPrimary vs. Secondary vs. TertiaryPrimary HemostasisBlood vessel contraction Platelet Plug FormationDependent on normal platelet number & functionInitial Manifestation of Clot FormationSecondary HemostasisActivation of Clotting Cascade & Deposition & Stabilization of FibrinTertiary HemostasisDissolution of Fibrin ClotDependent on Plasminogen ActivationPrimary HemostasisWhen a blood vessel is damaged, 1. Vasoconstriction occur to reduces blood flow to injured area. It is trigger by direct injury to vascular smooth muscle and release of endothelin by endothelial cellrelease of vasoconstrictors liberated from platelets that adhere to the walls of the damaged vessels eg: serotonin, ADP , Thromboxane A22. Platelet plug formationplatelet adhere to exposed subendothelium to form temporary plug.

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Platelet Adhesion Platelet ADHERES to exposed collagen.vWF acts as glue to help platelets to stick to vessel wall.lipid mediator platelet-activating factor (PAF) synthesized by endothelial cells promotes the activation of platelets and their adhesion to the endothelial cells

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The role of von Willebrand factor (vWF) in platelet adhesion. High flow rates induce conformational changes in vWF allowing interaction of its A3 domain with matrix collagen. This induces a conformational change in the A1 domain, thereby allowing interaction with glycoprotein (GP) platelet receptor Ib-IX-V. This interaction stimulates calcium release, subsequent platelet activation, and subsequent conformational change of the fibrinogen receptor (GPIIb/IIIa), which can interact with fibrinogen and vWF to favor the interaction between platelets (platelet aggregation process). ADP indicates adenosine diphosphate; RGD, Arg-Gly-Asp amino acid sequences14Shape changeBecoming more spherical Form pseudopodsReorganization of internal constituents- forcing granules towards the plasma membraneFacilitating secretion of their contents

Release ReactionSecretion of its granule contentsADPSerotoninFibrinogenPDGFActivate arachidonic acid pathway which lead to formation and release of Thromboxane A2

Recruitment and AggregationRelease ADP and TX2 cause additional platelets to aggregate at the site of vascular injury.Results in formation of large platelet plug (10 hemostatic plug)

Secondary hemostasis

Activation of Clotting Cascade & Deposition & Stabilization of Fibrin3. Coagulation FactorIntrinsic pathwaysExtrinsic pathwaysCommon pathways

Xa: Prothrombin activator

(IIa)(II)Vitamin K dependent clotting factors20

Fibrin polymer which is formed re enforce the platelet plug.

Thus the platelet plug formed becomes more stable.

The fibrin polymer further stabilized and the clot become retracted and solidified.

4. Coagulant inhibitorsEffect of thrombin is limited to the site of injuryTissue factor pathway inhibitor (tFPI) -inactivates complex FXa, FVIIa and TFProtein C and Protein S -inactivate coagulation cofactors, FVIII and V.Antithrombin -inactivates thrombin and other serine protease.XIIXIIaXIXIaIXIXaXXaIIIIaFibrinogenFibrinXIIIXIIIaVIIVIIaTFCa 2+Ca 2+Ca 2+Ca 2+VIIIVIntrinsic pathwayExtrinsic pathwayContact TFPIProtein CProtein CAntithrombinProtein C: inactivating proteinsFactor VaandFactor VIIIa (which are very pro-coagulant)24Tertiary hemostasis Fibrinolysis - Dissolve the fibrin.PlasminogenPlasminFibrinFibrin degradation product (FDP)tPA

Summary of reaction involved in hemostasis

1 hemostasis2 hemostasisPLATELET DISORDERPlatelet are produced in the bone marrow by fragmentation of the cytoplasm of megakaryocyte.Main function of platelets is the formation of mechanical plugs during the normal haemostatic response to vascular injuryThe normal platelet count is 150-400x10^9/LAverage life span of 7-10 daysPlatelet disorders typically characterized by bleeding by purpura and bleeding from mucous membrane

IntroductionDefined as reduced in the platelet count< 150 x 10^9/L abnormal bleeding, that characterized by spontaneous bleeding and mucosal hemorrhageTHROMBOCYTOPENIAUsually part of generalized bone marrow failure, ex:-cytotoxic drugs, radiotherapy, aplastic anemia, leukaemia, myelodydplastic syndrome, myelofibrosis, marrow infiltration by carcinoma or lymphoma, megaloblastic anaemiaCan also be due to selective megakaryocyte depression cause by drug or chemical toxicity and viral infection

Decrease Platelet ProductionCaused by splenomegalyUsually, only 1/3 of total platelet are within the spleen When the spleen enlarges, it can retain or sequester up to 80-90% of body platelets and decreased platelets in the peripheral circulation.plt lifespan is normal SequestrationMost common cause of thrombocytopaeniaImmune destruction and non-immune destructionIncreased destructionImmune-MediatedDrug induced ThrombocytopeniaHeparin-Induced ThrombocytopeniaIdiopathic Thrombocytopenic Purpura(ITP)Post-Transfusion (within 5 to 14 days)VasculitisAutoimmune Hemolytic AnemiaChronic Lymphocytic Leukemia(CLL)Antiphospholipid SyndromeSystemic Lupus Erythematosus(SLE) in 10% of casesSarcoidosisLymphomaHuman Immunodeficiency Virus(HIV)Cytomegalovirus(CMV)HerpesVirusinfectio

351) autoimmune idiopathic (ITP)-a diagnosis of exclusion, acute or chronicassociated with autoimmune disease or malignancy eg;SLE, CLL, lymphoma2) drugs-quinidine and heparin, bind to a plasma protein and elicit the production of an IgG antiplatelet antibody. The antibody-coated platelet is then removed by the reticuloendothelial (RE) system. Tx by stop all suspected drugs and transfuse platelet concentrates.3) infections- immune complexes are absorbed onto the platelet surface, which are then removed by the RE system eg: HIV Immune destruction4)alloimmune eg; post transfusion purpurathrombocytopaenia occuring 7-10 days after bld transfusion due to antibody against human plt antigen-1a (HPA-1a)on transfused plt. Antibody also destroys self plt. Bleeding may be severe.Tx: Plasmapheresis, steroid and IVIG.

Immune destructionMost common autoimmune-mediated thrombocytopeniaMay divided intoAcute ITPChronic ITP (starts after the disease has been present for > 6 months).Antiplatelet autoAb(usually IgG) that bind to platelet membrane.The antibody-coated platelets are removed following binding to Fc receptors on macrophage causing their premature destruction by the reticuloendothelial system(spleen)normal lifespan of platelet is 7-10 days but in ITP is reduced to a few hours

Immune Thrombocytopenic purpura

antibody-coated platelets are removed following binding to Fc receptors on macrophage

Most common in children, the peak age is 2-4 yearsgirls and boys are equally affected self-limiting disorder that resolves spontaneouslyusually within 2 monthsEpisode follows vaccination or viral infections in the preceding 2-4 weeks.75% of patients remit spontaneously with 70% achieving platelet count of more than 50x10^9/L by the 4th week of illnessIn 5-10% of cases, the disease becomes chronic( > 6months)

Acute ITPClinical features: Acute onset, with a spectrum of bleeding severity ranging from superficial (petechiae, purpura) to lifethreatening. Hepatosplenomegaly or lymphadenopathy is absent.Diagnosis: clinical diagnosis, (history and PE)full blood count (isolated thrombocytopenia), and examination of the peripheral blood smear (reduce plt num and presence of giant platelet). Bone marrow examination is only indicated in patients not responding to therapy (Normal/ increased megakaryocyte)Additional investigations are done as clinically indicatedAcute ITPAdditional Ix:ANF and antiDNA antibodies in those progressing into chronic ITPimmunoglobulin levels in those with recurrent infections HIV screening for those at risk e.g. parents with HIV infection, intravenous drug users. Coagulation profile is needed for those with suspected non-accidental injury, inherited bleeding disorders or meningococcal infection.Acute ITPTx: Tx as outpatient(observation and monitoring) in platelet count > 20 x10^9/L without bleeding tendencies. Advice for precaution with physical activities, avoidance of contact sports and seeking immediate medical attention if bleeding occurs.Hospitalisation: acute severe life-threatening(ICH) or mucosal bleeds regardless of platelet count or if platelet count is < 20 x109/L without bleeding but with poor access to health care.Tx options include : IVIG 0.8 g/kg as a single dose, ororal prednisolone 2 mg/kg/day for not more than 14 days, ororal prednisolone 4 mg/kg/day for 4 days

Acute ITPHighest incidence in women aged 15-50 years old.most common cause of thrombocytopenia without anemia/ neutropenia.Plt sensitization with auto abs-IgG: remove by the macrophages of the RES esp spleen prematurely.insidious onset, with no prodromal illness.Total megakaryocytes and plt turnover are increased.Symptoms and signs are highly variable, ranging from the common asymptomatic patient with mild bruising or mucosal bleeding to frank haemorrhage from any site, the most serious of which is intracranial but rare.

chronic ITPThe degree of bleeding is largely dependent on the platelet count and patients with platelet counts below 10x10^9/l (and usually below 5x10^9/l)are at greatest risk of bleeding, including intracranial haemorrhage( rare).Spleen not enlarged unless there is associated dz causing splenomegalyTend to relapse and remit spontaneouslyMay be seen in a/w SLE, HIV, CLL, hodgkins disease or autoimmune haemolytic anaemiachronic ITPDIAGNOSISClinical diagnosis Investigations1) Full blood countLow platelet countNormal Hb and WBC 2) Peripheral smearReduced platelets numgiant platelets (signs of thrombopoietin-induced megakaryocyte stimulation) 3)Bone marrow examinationnormal or increased megakaryoctes number

4) Coagulation testsProlong bleeding time, normal PT and aPTT 5) ANF and anti-DNA antibodies: to exclude other autoimmune diseases which may be associated with thrombocytopenia, e.g. systemic lupus erythematosus or antiphospholipid syndrome. 6)HIV antibody testing should also be done in patients with risk factors for HIV infection

giant platelets reflect the increased megakaryocytic mass in the marrowgiant platelets, reflects of increased thrombopoietin-induced stimulation of the bone marrowBM shows an increase in the number of megakaryocytes and signs of thrombopoietin-induced megakaryocyte stimulation (increase in number and ploidy, decrease in cytoplasm), resulting in large platelets in the periphery

Indication for Bone Marrow Examination:Over 60 years of agePrior to splenectomyAtypical featuraesPoor response to first lineRelapse ITP following complete remission

47TREATMENTPatients with platelet counts exceeding 30 x 10^9/L require no treatment.Treat when symptomatic or when platelet count indicated in : - patients with symptoms and platelet count < 30 x 10^9/L despite 3 months of steroid therapy - require unacceptably high dose steroids to maintain platelet count > 30 x 10^9/L

Immunosuppressive drugsFor those do not respond sufficiently to steroid and splenectomyEx: azathioprine, cyclophosphamide Indications for platelet transfusion in ITPPlatelet transfusion in ITP is only given in the following situations:1. life-threatening haemorrhage e.g. intracerebral haemorrhage (ICH)2. severe thrombocytopenia < 10 x 109/L and patient has to undergo an emergency surgeryHigh dose IV steroids and IVIG must also be given together to raise the platelet counts and to stop the haemorrhage. Platelet survival is increased if the platelets are transfused immediately after IVIG infusionRecommendations : Platelet Transfusion Dosage 6-8 U of platelet concentrate, or 1 U/10 kg body weight1 U of platelets to increase count of a 70-kg adult by 5-10 x 109/L and an 18-kg child by 20 x 109/L

FeatureAcuteChronicAge / SexChildren (2-4 y.o)Girls and boys equally affectedAdult Female (15-50 y.o)OnsetAcuteInsidiousPredisposing Factors2-4 weeks after exposure to viral infection/ immunization-Duration6monthsSpontaneous remissionCommon(self limiting with spontaneous recovery occurring in several weeks to several months)Uncommon viral infection- chickn pox53

AspirinAspirin is the most common. Associated with GI haemorrhage.Purpura may not be obvious and produce prolonged bleeding timeinhibition of cyclo-oxygenase with impaired thromboxane A2 synthesis.hence, this will impair the release reaction and aggregation.defect after single dose lasts 7-10 days.Tx: withold aspirin ( if pre-op, stop 1 week prior to it)

Antiplatelet drugsDipyridamolephosphodiesterase inhibitor, lead to increase cAMP level and inhibit platelet aggregation.used as an adjunct to oral anticoagulantsClopidogrel - inhibit ADP binding to platelet receptor, impair platelet aggregation. IV agent (abciximab)aglycoprotein IIb/IIIareceptor antagonistused in pt undergoing PCI with unstable angina and ACSrisk of transient thrombocytopenia and need platelet transfusion

Dipyridamole adjunct to anticoagulant

57Inhibits plt function by uremic toxins, Abnormal bleeding is common.Bleeding time is prolonged. Blood vessels in patients with uraemia produce greater quantities of platelet-inhibitory prostaglandin and synthesize less thromboxane A2Tx: platelet transfusiondialysis

uremiaa/w multiple myeloma may cause interference with platelet adherence, release and aggregation

HyperglobulinaemiaCOAGULATION DISORDERSHaemophilia A and B Anticoagulant (Warfarin and Heparin) Acquired Factor VIII Inhibitor

Causes of Coagulation Deficiency and Coagulation DysfunctionA) INHERITED Common GroupDisorder PathophysiologyMode of InheritanceMolecular geneticsApproximate incidenceHaemophilia A Factor VIII deficient or defectiveXLDeletions ,inversions,missense,nonsense,insertions,splicing100Von Willebrands diseaseVon Willebrand factor deficient or defectiveAD or ARDeletions,missense,nonsenseAD : 100 or moreAR : 1Haemophilia BFactor IX deficient XLDeletions ,missense,nonsense , splicing20Haemophilia CFactor XIAD or RMissense,nonsense splicing5 % in Ashkenazi Jews,others rareXL ,X linked recessive ; AD, autosomal dominant ; AR , autosomal recessiveDisorderMode Of InheritanceMolecular GeneticsApproximate incidence per 106 populationFactor X deficiencyARDeletions, Missense1Factor V deficiencyAR1Factor VII deficiencyARMissense, Nonsense, deletion, splicingFactor II (prothrombin) deficiencyARMissense1Factor XIII deficiencyARMissense, deletion1AfibrinogenaemiaARDysfibrinogenaemiaADMissense1Factor V plus VIII deficiencyARMissense, Nonsense, Deletion, Insertion1Hyperplasminaemia 2-antiplasmin deficiencyARMissense, InsertionVery RareRare GroupB) ACQUIREDVit K def- Hemorhagic Disease Newborn -Biliary obstruction -drugs- warfarin and heparin (anticoagulant)Liver disease, Renal disease, MalabsorptionDIC disseminated intravascular coagulationInhibitors of coagulation: FVIII inhibitor/antibody to factor VIII eg in autoimmune disease (SLE)Massive transfusion syndrome- massive blood loss due to low factor VIII and factor V due to dilutional effect.

Haemophilia A & B

Haemophilia AFactor VIII (antihaemophilic factor) deficiencyThe most common hereditary clotting factor deficiencies.Sex linked inheritance (recessive).33% spontaneous mutation and therefore no family historyClinical features: based on severity of the disease.

Haemophilia A

Hemophilia A: correlation of factor activity and disease severity.Coagulation factor activity (%) Clinical features

Compartment SyndromePainful haemathrosesProlonged bleeding after dental extractionsGIT bleeding/hematuriaOperative and traumatic bleeding: may be life threatening in both severely and mildly affected pts.Intra cranial bleeding- high mortality.Right Knee Haemathrosis

Right knee haemarthrosis with muscle wasting at the medial sight of thigh

Stages of Haemarthrosis

Chronic Haemophilic Athropathy

Diagnosed Chronic Haemophilic Athropathy by Plain Radiograph

Grade 1 Grade 2 Grade 3 Grade 4- popliteal soft tissue fullness indicative of synovial thickening and osteopenia of the tibial epiphysis.-normal cartilage interval, early joint surface erosions, widened epiphyses, and juxta-articular osteopenia.- medial compartment has surface irregularity, subchondral cysts, reactive sclerosis, and partially narrowed cartilage interval- complete loss of cartilage interval, extensive surface erosions, a large synovial cyst, tibiofemoral subluxation, and lateral subluxation of the patella.Muscles hematomas

Laboratory: Prolonged APTT& corrected APTT by mixing testImmunological: Factor VIII assayDNA study: For diagnosis and carrier detection.InvestigationsManagementMultidisciplinary teamFactor VIII replacement therapyCryopercipitate from blood donorsPorcine factor VIII concentratesRecombinant factor VIII ( therapeutic or prophylactic)DDAVP ( 1- desamino-8-D-arginine-vasopressin) mild hemophilia; Cause increase release of factor VIII from endogenous storesSupportive care (Resting and prevention from further trauma) joint bleedingProphylactic treatment: home therapy

Factor concentratesComplicationsDevelopment of Factor VIII antibody/inhibitor

Especially in Hemophilia A (5-10%)Poor response to treatmentContinue to bleed despite on the replacementIx: Factor VIII inhibitor assayMx: APCC activated prothrombin complex concentrates FEIBA- Factor eight inhibitor bypassing agents Principle of haemostatic tests- APTT and Mixing test

APTTMixing test: Use to detect factor deficiency or factor inhibitorProlonged APTT = 67 secs ( 30- 39 secs)Mix normal plasma and patient plasma (1: 1)Do clotting test (repeat APTT)Check APTT result again: i) clotting time: 36 secs (corrected factor deficiency)ii) Clotting time 60 secs( not corrected-still prolonged factor inhibitor)

Mixing TestNormal plasmaPatient plasmaAnaemiaChronic haemophilic arthritispseudotumorhematurianeurologyCNSSpinal cordPeripheral nerves

HIV/AIDSThe hemophilic patients get HIV/AIDS from the blood of the HIV/AIDS donor due to the transmission of HIV virus from the donors blood to the recipients blood.HepatitisSame goes to the hepatitis virus by spreading from the donors blood to the recipients blood.Muscular Damage (eg: muscle atrophy)

Clinical features are the same with Hem AFactor IX deficiencyThe two disorders can be distinguished only by factor assay.Lab Ix: - Prolonged APTT-Low in the factor IX levels- Bleeding time and Prothrombin time are normalRx: Factor IX concentrates (biological long half-life-> infusions do not have to given as frequently) -Recombinant FIX

Haemophila B (Christmas disease)Von Willebrands diseaseMost common inherited bleeding disorderDeficiency of vWF (factor)vWF has 2 roles:- promotes platelet adhesion to damage endothelium- Carrier protein for FVIII protecting from premature destruction( in vWD factor VIII level may be reduced) Types: Type I- partial reduction in vWFType 2-abnormal vWFType 3- total lack of vWF

AD- varying expressionSeverity of bleeding is variable.

Clinical Features

Bleeding from mucous membrane and skinExcessive bleeding from cuts and abrasionsOperative and post traumatic bleedingHaemathroses and muscle haematomas are very rare presentation except in type 3

Lab Investigations:

bleeding time is prolongedFac VIII levels are lowProlonged APTTvWF/antigen is low (type 1)Platelet count=normal; thrombocytopenia (type2B)Y? abnormally high affinity for plateletsTreatment:

antifibrinolytic agents(tranxenamic acid for mild bleeding)DDAVP- for type I (C/I in type 2B)Immediate-purity factor concentrates contain vWF(Contain both VWF and factor VIII)-> very low VWF levelscryoprecipitates- not recommended nowadays

Anticoagulant-induced coagulation disorderWarfarinHeparin

WarfarinVitamin K antagonistDecreased biological activity of the vitamin K dependent factors II, VII, IX and X.After warfarin is given, factor VII levels fall considerably within 24H but prothrombin has a longer plasma half-life and only falls to 50% of normal at 3daysThe patient is fully anticoagulated only after this period

Typical starting regime for warfarin would be 10mg on day 15mg on day 25mg on third dayAfter this, dosage adjusted according to PTUsual maintenance dose 3-9mg/dayCrosses placenta and is teratogenicContinue warfarin for 3-6months for DVT, PE.

Target levels for INR Pulmonary embolism and DVT Aim INR of 2-3; 3.5 if recurrent

Atrial fibrillation For stroke prevention: Target INR; 2-3

Prosthetic metallic heart valves For stroke prevention: Target INR; 3-4Day INRDosage15 or 1025 or 103 (16 hrs)4.0854.54.03.53.02.521.510.5NA44.08Stay-1.0Omit next days dose then 2.0Drug Interactions

97% bound to albuminFree fraction enter liver parenchymal cells and is activeIn liver cells, degraded in microsomes to inactive water-soluble metabolite which is conjugated and excreted in the bile and partially reabsorbed to be also excreted in urineDrug that affect the albumin binding or excretion of warfarin or those that decrease the absorption of vitamin K will interfere with the control of therapyManagement of warfarin overdose

INR>4.5 without bleeding, stopped for 1 or 2 days, then dose adjusted according to INR.The long half-life of warfarin (40H) delays the full impact of dose changes for 4-5days.If INR is very high (>8) without bleeding, oral dose of 0.5-2.5mg vitamin K may be given. Mild bleeding only need INR assessment, drug withdrawal and dosage adjustment.

Serious bleeding may need cessation of therapy, vitamin K therapy or the infusion of fresh frozen plasma or prothrombin concentrates.Vitamin K is the specific antidoteOral or IV dose of 2.5mg is usually effectiveHigher doses result in resistance to further warfarin therapy for the 2-3 weeks.

Management of surgery

For minor surgery (eg dental extraction) anticoagulant can be maintained and mouth rinses with tranexamine acid given.For major surgery, warfarin is stopped to get an INR 2.0 on 2 successive days

Coagulation profile to be taken before IV bolus and subsequently 6 hourlyResults of coagulation profile to be reviewed and acted upon within 2 hours of taking the APTTLoading DOSE: 75u/kgInitial maintenance dose: 13u/kg

APTTRate of ChangeRepeat APTT120Withhold 60min (-200u)6HaPTTIV Heparin dose modification90sWithhold infusion for 1 hour and reduce by 200u/hrLoading DOSE: 5000uInitial maintenance dose: 1000u/hrLMWHGiven by subcutaneous injectionLonger half-life, given once a dayMore predictable dose-response which avoids the need for routine monitoringLess risk of thrombocytopenia or osteoporosisTypical treatment regimes: 200 anti-Xa units/kg OD or 100 anti Xa units/kg BDLMWH is preferred for DVT & PE.

ComplicationRisk of complication reduced by 50% by the use of LMWH

a)Bleeding during heparin therapy-Protamine able to inactivate heparin immediately-Severe bleeding 1mg/100u-heparin

b) Heparin-induced thrombocytopenia

c) Osteoporosis-occurs with long-term (>2months) heparin therapy-the drug complexes minerals from the bone

Heparin-induced thrombocytopenia

Mild platelet lowering in first 24H as a result of platelet clumping, no clinical consequence HIT type 1 HIT type II, may occur in 5% of patients with standard heparin. Binding of heparin to platelets heparin-platelet factor 4 (PF4) complexGeneration of IgG to PF4 complex platelet activation.Presentation: Fall of >50% of platelet count, 5 days or more after starting heparin treatment and thrombosis.Heparin must be discontinued.Thrombin inhibitors such as hirudin or lepirudin or argatroban and heparinoid danaparoid as alternatives.

Acquired Factor VIII InhibitorAcquired hemophilia A; has no known genetic inheritance patternRare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality The incidence of acquired hemophilia A increases with age, being a very uncommon condition in children. The age distribution of autoantibodies is typically biphasic with a small peak between 20 and 30 years, due to postpartum inhibitors and a major peak in patients aged 68 to 80 years.The incidence in men and women is similar except in the age range 20 to 40 years, when the effect of pregnancy results in a preponderance in women.

Type 1 inhibitors develop in patients with congenital hemophilia A and are generally alloantibodies that show complete neutralization of FVIII activity.Acquired inhibitors to FVIII show type 2 kinetics, with a rapid neutralization phase, followed by an equilibrium in which residual FVIII activity can be detected in vitro. Although the type 2 inhibitors usually do not totally inactivate factor VIII in vitro, the measurable factor activity offers little or no protection against hemorrhage in vivo.

Conditions associated with acquired hemophilia ADiagnosisBased on: (1) the initial detection of an isolated prolongation of activated partial thromboplastin time (APTT), which cannot be corrected by incubating for 2 hours at 37C equal volumes of patient plasma and normal plasma (mixing study); and (2) subsequent identification of a reduced FVIII level with evidence of FVIII inhibitor activity (titrated using the Bethesda assay or its Nijmegen modification)In congenital hemophilia A patients treated with factorVIII, alloantibodies to FVIII develop in 20-40% of patients.By contrast, acquired inhibitors/autoantibodiesagainst FVIII in nonhemophiliacs occur in only about onecase per million per year.4 In acquired hemophilia, autoantibodiesare characteristically non-complement fixing, nonprecipitatingimmunoglobulins from the IgG family thatbind FVIII in a time- and temperature-dependent manner.5118Clinical FeaturesHemarthroses are the hallmark of congenital hemophilia, but they seldom occur in acquired hemophilia. Classically presents with purpura or soft tissue bleeding. Severe muscle bleeding, hematuria, epistaxis, gastrointestinal bleeding and even intracerebral bleeds are seen more frequently.Inhibitor development in congenital hemophilia no longer appears to increase mortality, whereas patients with acquired hemophilia continue to exhibit an increased mortality Manifest more dramatically by excessive bleeding following trauma or surgery

TreatmentTreatment of acute bleeding episodes and thelong-term eradication of the autoantibody

A) Treatment of Acute HaemorrhagesBypassing Treatment First-line treatmentBoth the recombinant activated factor VII (rFVIIa) and the activated prothrombin complex concentrate (aPCC) factor 8 inhibitor bypassing activity (FEIBA)= EFFECTIVETreatment of Raise Circulating FVIII To achieve hemostatic levels in situationsEg: Porcine FVIII concentrates, Human FVIII concentrates, Desmopressin

B) Long-term Eradication of the Autoantibody (Inhibitor)

Immunosuppressive agents (steroids, cytotoxic drugs such as cyclophosphamide, azathioprine and vincristine, cyclosporine, and rituximab [Immunosuppressive agents])High-dose intravenous immunoglobulin (IVIG), immunoadsorptionImmune tolerance

Thank You for your attentionBleeding rose

and Heart

BLEEDING DUE TO BOTH PLATELET AND CLOTTING FACTOR DISORDER. A) Disseminated intravascular coagulation (DIC)B) Liver diseaseC) Massive blood transfusionD) von Willebrand disease (vWD)

In what condition they co-exist?DICDisseminated Intravascular Coagulation Systemic activation of the blood coagulation system result in the generation and deposition of fibrin Micro-vascular thrombi in various organs development of multi-organ failure

ongoing activation of the coagulation systemConsumption of coagulation protein and plateletsinduce severe bleeding complicationDICACUTE CHRONIC clinically is life threatening, need to recognize/diagnose fast and manage as haematologic emergency need to treat the primary disorder and give blood transfusion support

develops when sudden exposure of blood to procoagulants (eg, tissue factor [TF], or tissue thromboplastin) generates intravascular coagulation.

Compensatory hemostatic mechanisms are quickly overwhelmed, and, as a consequence, a severe consumptive coagulopathy leading to hemorrhage develops. Abnormalities of blood coagulation parameters are readily identified, and organ failure frequently results.

Acute DICnot criticalpossible conversion to acute DIC as a result of haemostatic decompensation need to treat the cause/ primary disorder but usually blood transfusion is not indicated

reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of TF. Compensatory mechanisms in the liver and bone marrow are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC.

more frequently observed in solid tumors and in large aortic aneurysms.

Chronic DICAetiology of DICAcuteInfection/sepsisObstetric complicationsTrauma-severeTransfusion of ABO incompatible blood

ChronicMalignancyRetained dead fetussevere localised intravascular coagulationHematologic disordersAutoimmune diseases

Triggered by

the entry of procoagulant material into the circulationWidespread endothelial damage and collagen exposure

Involves 2 steps

PATHOPHYSIOLOGYabnormal activation of coagulation by triggering mechanismResult in thrombin generationFirst step

Activation of thrombin leads to:Conversion of fibrinogen to fibrinActivation of platelets Activation of factors: FV and FVIIIActivation of endothelial cellsActivation of fibrinolysis

Disseminated micro/macrothrombosis

Consumption of coagulation factors, and plateletsActivation of fibrinolysisGeneration of plasminLocally dissolves the microthrombusproduction of Fibrin/fibrinogen degradation products (FDPs).Second step

Bleeding

combine with circulating fibrin monomers soluble fibrin monomer (sFM). Inhibit thrombin actioninterferes with fibrin monomer polymerization impair hemostasisBind to platelet membranesPlatelet function defect biodegrades factor V,VIII,IX,XI and others

FDP(Fibrin Degradation Product)

Trigger factorVessel wall damagePlatelet activationActivation of coagulation cascadeFibrin-platelet thrombosisLow platelet countCoagulation factor deficiencyFibrinolysis activationInterfere fibrin monomer polymerizationGeneralized bleeding tendencyEnd organ damageDistored and fragmented RBC Intravascular hemolysisHypotension,ShockBind to platelet membrane Inhibit thrombinFDPs generatedbiodegrades factor V,VIII,IX,XI and othersClinical Features(acute) Thrombosis

Haemorrhage

Cytokine and Kinin generationRenal failureComaLiver failureRespiratory failure (Chest pain and dyspnea, hemoptysis, and cough)Skin necrosis/gangreneVenous thromboembolism : i) Pain, redness, warmth, and swelling in the lower legii) Headaches, speech changes, paralysis ,dizziness, and trouble speaking and understanding 1) Thrombosis

Persistent bleeding/oozing at the venipuncture/surgical sitesSpontaneous bruisingPetechiaeGIT bleedingResp tract bleedingICB2) Hemorrhage

Meningococcemia ( purpura fulminans ) bleeding from GI tract, gingival bleeding, epistaxis, pulmonary haemorrhage, hematuria

Circulatory signs :-Signs of spontaneous and life-threatening hemorrhage-Signs of subacute bleeding-Signs of diffuse or localized thrombosis-Bleeding into serous cavities

Central nervous system signs :-Nonspecific alteredconsciousness or stupor-Transient focal or neurologic deficits

Cardiovascular signs :-Hypotension-Tachycardia-Circulatory collapse

Respiratory signs :-Pleural friction rub-Signs of acute respiratory distress syndrome (ARDS)

GI signs :-Hematemesis-Hematochezia

Genitourinary signs :-Signs of azotemia and renal failure-Acidosis-Hematuria-Oliguria-Metrorrhagia-Uterine hemorrhage

Dermatologic signs :-Petechiae-Jaundice (liver dysfunction or hemolysis)-Purpura-Hemorrhagic bullae-Acral cyanosis-Skin necrosis of lower limbs (purpura fulminans)-Localized infarction and gangrene-Wound bleeding and deep subcutaneous hematomas-Thrombosis

150TachycardiaShockHypotensionOedema3) Cytokine and kinin generation

CompensatedFew or no clinical signsNon-obvious multiple small microthrombosisNo or few bleedingRisk of decompensationClinical finding of Chronic DIC superficial and extensive ecchymosis of extremities without petechiae which may be intermittent or can persist. recurrent episodes of epistaxis or internal mucosal bleeding. impairment of renal function, confusion, repeated episodes of cerebral thrombosisCont.

Laboratory tests:

No single test for confirmationPanel of tests needed in coagulation studyScreening testsMore Specific tests

DiagnosisPTaPTTPlatelet countThrombin timeFibrinogen levelAcute phase proteinCoagulation factor assayScreening testsTo suggest the presence of abnormally high concentration ThrombinFDPsFibrin monomerD-DimerMore specific assay

Acute ChronicPT/PTTProlongedNormalPlateletsDecreasedNormalFibrinogenDecreasedNormalFibrin monomer PositivePositive

FDP Positive

Positive ( concentration)D-Dimer Positive

PositiveTT Prolonged

Often normalFactor assay Usually decreased FV & FVIIIAntithrombinUsually lowUsually normalMorphological findings in DICSchistocytes are red cell fragnents seen in 50% of patient with DICAbsence of red blood cell fragments does not rule out diagnosis of DIC-mild reticulocytosis-mild leucocytosis-(L) shift

Supportive measures and removal of triggering mechanism are the key to successful management.

Outcome depends primarily on the ability to deal with the trigger and not on direct attempts to correct the coagulation deficit. ManagementIndicated only in patients with active bleeding and in those requiring an invasive procedures or otherwise at risk for bleeding complication

Should not instituted on the basis of laboratory results alone!Replacement therapy Platelet count > 50microliter Fibrinogen concentration > 1g / L Prothrombin values less than double the normal range. GoalsPacked red cellsPlt concentrate FFPCryoprecipitateAT concentratesFactor concentratesBlood products Fresh Frozen Plasma ( FFP ) 0.7- 1.0 U/ml of factors II,V,VII,VIII,X,XI, XII, XIII and 2.5mg/ml fibrinogen Dosage : 15ml/kg

Cryoprecipitate Fibrinogen 150mg/bag , factor VIII 80-120 units/bag , factor XIII & vWB Dosage : 1 bag/ 5kg bw Random donor platelets ( RDP) : 5.5x10^10 platelets Dosage : 1 unit/10kg

Single donor platelets: 3x10^ 11 platelets

Fresh blood : Indicated in severe trauma to replace acute massive blood loss. Heparin and other anticoagulant therapy to inhibit thrombin. Indicated in patients with clinically overt thromboembolism, chronic DIC and extensive fibrin deposition. Dosage : weight < 30kg 10U/kg/hr weight > 30kg 4U/kg/hr Anticoagulation therapyLiver diseaseCan present with diffuse bleeding from minor trauma-Multiple coagulation defects due to-decreased factor synthesis-thrombocytopenia related to hypersplenism associated with portal hypertensionBiliary obstruction results in impaired vitamin K absorption decreased factor II,VII, IX, X

Severe hepatocellular disease reduced factor V and fibrinogen and increased plasminogen activator

Dysfibrinogenaemia is found in many patient

Thrombocytopenia due to decreased thrombopoietin production

Hypersplenism a/w portal HPT.

FBP: low plateletLFTAPTT and PT-prolongedLow in fibrinogen

Tests:

FFPPlatelet concentrate Cryoprecipitate

Therapy:

Approach to bleeding disorderAPPROACH TO BLEEDING DISORDERHISTORY AgeEarly or late onsetGenderMale is predominant in haemophiliaSite of bleeding-multiple sites-mucosal bleeding (epistaxis, gum bleeding, menorrhagia)-skin bruises-hemarthrosisDuration and precipitating causes-spontaneous bleeding-excessive bleeding after trauma/surgeryMedical history-liver disease -renal disease-malignancies -poor nutrition (vit k and c deficiency)Drug history-aspirin -anticoagulant-alcohol -anticancer-traditional medicineFamily historyGenetic causes (haemophilia,vWf disease)Obstetric/menstual history-menorrhagia-post partum haemorrhageClinical differences between diseases of platelets/vessel walls or coagulation factorsFinding Platelet/vessel wallCoagulation Mucosal bleedingPetechiaeDeep hematomasBleeding from skin cutsSex of patientCommonCommon RarePersistent

EqualRareRareCharacteristicMinimal

>80% malePhysical findingPallorSkin: petechiae (1cm or larger) Gum hypertrophy and mucous membrane bleedingFundal haemorrhageJoint swellingLymphadenopathy, hepatosplenomegaly

Petechiae

Purpura

Ecchymoses

Haemarthrosis

Clinical effects cause by different levels of platelet countPlatelet count(x10^9/L)Clinical defect>500500-100100-50

50-20