BLEEDING DISORDERS
Dr.Abdulhak A. Alnuemi FICMS,CABMInjury : * vess.wall cont * plat adhesion&aggregation * fibrin clot
Bleeding tendency? Or local Anatomical defect or disease?
Duration of bleeding--minutes ? Medical history : Liver disease ?, Malabsorption, Renal disease, nasal bleed– hypertension or ENT..?,DU ,Piles , malignancies, antibiotic therapy , poor nutrition (Vit. K or C)Fever? + hemorrhagic rashBleeding tendency likely in
Bleeding from 2 sites simultaneously spontaneous Bleeding is prolonged..hours following tooth extraction, minor surgery, childbirth, menorrahgia BL. that needs transfusion Family hx of bleeding from multiple sites(absence does no exclude--)Types of bleeding lesions
Petechiae --pinpoint bleeds into dermis due to cap.leak-----platelet disordersPurpura—collection of blood of few mm in the skin---palpable?Ecchymosis--subcutaneous collection due to leak from arteriols&veniols--few cms—(bruises)Hematomas--deeper &palpable collection--platelet or coagulation disordersHemarthrosis--coagulation disorder---nearly always factor VIII or IX defPrimary vs secodary hemostatic defect
Skin &mucous mem.-----usually pr Immediately after trauma----pr Readily controlled by pressure &local measures----pr petechiae&ecchymosis Vs hematomas&hemarthrosis Family history Aut.Dom.in platelet dysfunction . Aut. or X-linked Rec. in case of coagulation disordersPlatelates
The platelet(150-450 th/mm) contains lysosomes, granules, and trilaminar plasma membrane, microtubules. Granules are key in primary hemostasis and contain ADP, Thromboxane, platelet factor 4, adhesive and aggregation glycoproteins, coagulation factors, and fibrinolytic inhibitors
The Coagulation Cascade
Common PathwayLaboratory Evaluation of the Coagulation Pathways
Partial thromboplastin time (PTT)Prothrombin time (PT)
Intrinsic pathway
Extrinsic pathway
Common pathway
Thrombin time
Thrombin
Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium
Thromboplastin Tissue factor Phospholipid Calcium
Fibrin clot
Fibrinolysis
Tissue Plasminogen activator (tPA) Released from endothelial cells Converts plasminogen to plasmin which degrades fibrinogen and fibrin into FDP & D-Dimers
A word on clotting factors
Vitamin K Dependent FactorsIntrinsic Pathway : IX, XCommon Pathway: IIExtrinsic Pathway: VIIWarfarin act by depleting vit K depending factors All clotting Factors are produced in liver except vWFF VIII produced by the vascular endothelium , liver & possibly other sites spleen &kidneys Sites of heparin activity :IIa, IXa, Xa…inhibition is the major site, XIa , Platelet factorTesting the hemostatic system
Platelet count Thrombocytopenia and bleeding: Less than 50,000 Spontaneous bleeding possible: Less than 20,000 Count does not have anything to do with functionality of plateletTesting the hemostatic system
Bleeding time Tests vascular integrity and platelet function Incision on volar aspect of the forearm 1mm deep and 1 cm long BP cuff inflated to 40 mmHg Normal < 8 minutes Affected by ASA (permanent) and NSAIDs thrombocytopenia,thrombasthenia.. Prolong BTTesting the hemostatic system
Bleeding time Prolonged with platelet counts below 100,000 When BT prolonged with platelet count over 100,000; this suggests platelet dysfunctionTesting the hemostatic system
Prothrombin Time Test of extrinsic and common pathways International Normalized Ratio (INR) used to compensate for differences in thromboplastin reagents Used for Warfarin Elevated in patients with liver disease and abnormalities in vitamin K dependant factorsTesting the hemostatic system
Partial Thromboplastin Time (PTT) Tests intrinsic and common pathway Average normal 25-29 sec PTT to be affected ..only when Factor levels less than 40%. Affected by heparin Can be effected by Warfarin at supra-therapeutic levels due to effects on the common pathwayTests of coagulation defect (summery)
PT---(II,V,VII,X&Fibrinogen) APTT---(XII,XI,IX,VIII,V,II&Fibrinogen) TT---(abn of Fibrinogen, Thrombin inhibition by Heparin or FDPs) Specific factor assay Mixing study Tests of increased Fibrinolysis: high FibrinogenDP& FDP High level of Plasmingen activator
Hemostatic defect due to vess. Wall abn.
HHT Ehler-Danlos, Pseudoxanthom elasticum Acq : Senile purpura Infection: measles ,Meningococcemia Long Steroid treatment ScurvyPlatelet diseases
Adhesion defect: VWD Bernard-solour:Ib/ IX receptor absence or dysfunction Aggregation defect: Glansmanns thrombasthenia: GPIIb/ IIIa Platelet release defect: decrease COX enz. Activity---Cong? Or Acq.as in Aspirin ,NSAID useThrombocytopenia
Three mechanisms of Thrombocytopenia Decreased production Usually chemotherapy, myelophthisic disease, or BM effects of alcohol or thiazides Splenic Sequesteration Rare Results from malignancy, portal hypertension, or increased Splenic destruction , st. association with autoimmune hemolytic anemia Increased Destruction, as in ITP& other immune thrombocytopeniasImmune Thrombocytopenia
Multiple causes including drugs, lymphoma, leukemia, collagen disease (SLE) Drugs Include Digitoxin, sulfonamindes, phenytoin, heparin, ASA, cocaine, Quinine, quinidine, glycoprotein IIb-IIIa antagonists * After stopping drugs platelet counts usually improve over 3 to 7 days Prednisone (1mg/kg) with rapid taper can shorten courseITP
Diagnosis of exclusion,mucocut.bleedingAssociated with IgG anti-GP IIb-IIIaPlatelet count usually falls to less that 20,000Acute FormMost common in children 2 to 6 yearsViral Prodrome(URTI) common, 3 weeks priorSelf Limited and > 90% remission ratePrednisolone 2mg/kg/d for sever purpura or epistaxis & count less 10,000Persistent bl ,IC &Retinal bleeding…Platelet transfusion & IVIG(1gm/kg)
ITP
Chronic Form Adult disease primarily Women more often than men Insidious onset with no prodrome 6 months or more of Symptoms ,include: easy bruising, prolonged menses, mucosal bleeding Bleeding complications are unpredictable,Mortality is 1% Spontaneous remission is rare
ITP
Chronic Form:ManagementHospitalization common because of a complex differential diagnosis Pred.1mg/kg/d is the usual treatment.IV Immune Globulin (1g/kg) beneficial for short term Only Life threatening bleeding is treated with platelet transfusion ….bec.platelets cleared from circulation within hours.Relapses usually treated with increasing dose of prednisolone if 2 relapses…splenectomy(curative in70%)Remainder(30%):low dose maitenance 5mg/d prednisolone,if still no response Vincristine or Cyclophosphamide or Rituximab or repeated transfusion of IVIG.
Bleeding &Tests are normal: DD
simple purpura senile purpura Factor XIII deficiency (result in less stable fibrin clot) mild factor deficiency amyloidosis vascular disorders: Hereditary hemorrhagic telangiectasia scurvy Ehlers-Danlos syndrome? Henoch-Schonlein purpura alpha-2-antiplasmin deficiencyvon Willebrand’s Disease (vWD) autosomal dominant ,vWF gene lie in ch.no.12 (quantitative or qualitative def. of vWF) patients range from asymptomatic to spontaneous bleeding similar to a severe hemophiliac characterized by mucocutaneous bleeding
von Willebrand’s Disease-Types Type I Partial def. but normal molecules of vWF Type II(qualitative) 2A:loss of HMW multimers 2B:high affinity to platelets (thrombocytopenia) 2M:defective GP1b binding site 2N:decrease affinity to FVIII Type III Severe def.
vWD- Tests
BT prolongedaPTT, usually prolongedFactor VIII activity ,diminished Von Willebrand’s Factor decreaseDefective platelet aggregation with Ristocetin (normal with adrenalin,ADP,Thrombin&Collagen)von Willebrand’s Factor multimersvWD Treatment
DDAVP (desmopressin) 0.3 micrograms/kg IV in 50cc NS over 30 minutes intranasally 2 puffs for adults, 1 puff for children Intermediate purity F VIII :Factor VIII product containing VWF Cryoprecipitate ONLY IF VWF/VIII PRODUCT NOT AVAILABLE! 1 bag/10 kg q 12 to 24 hours depending upon severity of bleeding Amino caproic acid ,Tranexamic acidHemophilia
X-linked RecClinical manifestations (hemophilia A & B indistinguishable) *FVIII :vascular endoth. &liver *FVIII Ѕ t is12hr,*FVIII carried by vWF, *Carrier of Hem.A have reduced FVIII activity&mild bl disorder may occur. *Antenatal diag.possible(chorionic villous sampling 11wk of gestation).*clinical manifestation usually after 6 mo of lifeHemarthrosis (most common)Soft tissue hematomas (e.g., muscle)Muscle atrophyShortened tendonsOther sites of bleedingUrinary tractCNS, neck (may be life-threatening-closed space..) ,Psoas m.bleeding…Fem.n.compressionProlonged bleeding after surgery or dental extractionsHemophilia A and B
Hemophilia A Hemophilia B factor deficiency Factor VIII Factor IX Inheritance X-linked X-linked recessive recessive Incidence 1/10,000 males 1/50,000 males Severity Related to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 5-20(50) % - Mild - bleeding with surgery or trauma *In sever Hemophilia patient may sustain 1-2 bleeds/week *Normal FVIII level is 50-150% Complications shortening tendon, muscle wasting, j.destructionTreatment of hemophilia A
Intermediate purity plasma product contain von Willebrand factor High purity (monoclonal) plasma products No functional von Willebrand factor Recombinant factor VIII Virus free/No apparent risk No functional von Willebrand factor Prophylactic Home Treatment To keep FVIII level above 1%(recommended in USA) FVIII kept in domestic refrigerators ( in 4%C)Dosing guidelines for hemophilia A
Complications of therapyFormation of inhibitors (antibodies) 10-15% of severe hemophilia A patients(treatment by using porcine FVIII or using FVIIa or FEIBA ie Prothrombin complex.) 1-2% of severe hemophilia B patients * Mixing study (aPTT uncorrected by mixing normal plasma with Hemophiliac plasma which contain antibodies against FVIII, while aPTT prolongation will be corrected if no inhibitors ) Viral infections Hepatitis A,B,C. HIV, parvovirus * Vaccination against HAV&HBV needed.