Congenital bleeding disorders

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Information about Congenital bleeding disorders
Technology

Published on June 22, 2014

Author: mia_g_lesaca

Source: slideshare.net

Description

gives an overview of congenital bleeding disorders especially the more common ones - hemophilia and von willebrand disease

Congenital Bleeding Disorders Ma. Ysabel Lesaca-Medina, MD Pediatric Hematology-Oncology

Prince Leopold Born 1853

Princess beatrice, 9th child Princess louise Prince leopold, 8th child

Married to Princess Helene: 1882

Princess Alice Hemophilia carrier

London news: Death of the duke of albany March 27, 1884 Villa Nevada Morphine side effects

Prince charles Princess alice

Outline  What is and how does hemostasis occur?  How does one evaluate a patient presenting with bleeding?  What are the features of the Congenital Bleeding Disorders?  Hemophilia A, Hemophilia B  Von Willebrand Disease  Platelet function disorders  Rare Coagulation Factor Deficiencies

What is Hemostasis ?  Maintenance of fluid blood flow  Prevention of bleeding

Hemostasis – 3 stages 1. Vascular – vasoconstriction 1. Platelet (PRIMARY HEMOSTASIS) – Platelet plug formation 1. Coagulation (SECONDARYHEMOSTASIS) – Fibrin thrombus formation – Clotting factors

Intact vessel

Platelet Phase

platelet phase

Resting  activated platelets

Coagulation phase

Fibrin Clot

PTT

APTT

PT

TT

Factor XIII cross links fibrin

Clinical Evaluation of Bleeding patient

Clinical History

Detailed History  Symptoms:  Epistaxis gum bleeding, easy bruising, menorrhagia, hematuria, GI bleeding (platelet problem)  hemarthrosis, intramuscular bleed (coagulation problem)  Delayed onset bleeding (factor XIII problem)

Detailed History Response to hemostatic challenge: circumcision, surgery, phlebotomy, immunization, suture placement/removal Underlying medical conditions :  liver disease, renal failure, vitamin K deficiency Medications:  antiplatelet drugs, anticoagulants, antimetabolites, antibiotics

Detailed History  Family history:  similar symptoms  response to hemostatic challenge,  consanguinity  Menorrhagia  > 3 soaked pads /day  Flooding  Hb < 10g/L

Physical Examination

Physical Examination Petechiae < 2mm Purpura 2mm – 1 cm Hematoma Ecchymoses > 1 cm

Physical Examination HEMARTHROSIS

Physical Examination INTRAMUSCULAR BLEED, PSOAS

Laboratory evaluation

Laboratory Evaluation  Initial lab tests  CBC with platelet  PT (extrinsic)- VII, X, V, II, I  PTT (intrinsic)- XII, XI, IX, VIII, X, V,II, I  Further work up:  Thrombin time  PFA, platelet aggregation  Mixing Studies, clotting factor assays, VW antigen tests, urea clot lysis assay

DDX, based on initial screen ↑ PT Normal plt, Normal PTT ↑ PTT Normal plt, Normal PT ↑ PT,PTT Normal plt •Early Liver Disease •Early Vit K Def •F VII Def •F VIII def (hemophilia or VWD) •F IX, XI, XII def •Inhibitors •Late Liver Disease •Late Vit K deficiency •Massive Transfusion

↑ PTT, TT Normal PT, Normal plt All normal Platelet dec Heparin - activates AT III  AT III inactivates thrombin - PTT more sensitive to heparin VWD Platelet fxn d/o Mild factor def (VIII, IX, XI, XIII ) Collagen Disorder Vitamin C def CAMT, TAR,BSS WAS, GPS ITP Infection CAMT = Congenital Amegakaryocytic Thrombocytopenia BSS = Bernard Soulier Syndrome TAR = Thrombocytopenia with Absent Radius GPS = Gray Platelet Syndrome WAS = Wiskott Aldrich Syndrome

Out Patient Clinic Time

6 year/ M  Needs dental extraction; sent for hematologic clearance  History of easy bruisability  Mother and aunts report easy bruisability and strong menses  2 cousins died during delivery of unknown cause

 Labs  CBC Normal  PT Normal  PTT 39.3 (23 – 33 secs)

DDX, Normal plt, Normal PT prolonged PTT,  Dec Factor VIII due to  Hemophilia A  VWD  Dec Factor IX, XI, XII  Lupus anticoagulant or other coagulation factor inhibitors

 Factor VIII : 0.29 u/ml (0.5 – 1.5 u/ml)  VWF : 1.2 u/ml (0.5 – 1.5 u/ml)

Hemophilia A, mild Diagnosis

HEMOPHILIA  Essentials  Factor VIII (or IX ) deficiency  X-linked (2/3) or spontaneous mutation (1/3)  Sxs: Bruising, soft tissue bleeding, hemarthrosis  Labs: Prolonged PTT + dec factor VIII (or IX) levels

HEMOPHILIA  Most common severe congenital bleeding disorder  Prevalence  Hemophilia A (Factor VIII)  1 / 10,000 males  Hemophilia B (Factor IX)  1 / 50,000 males

HEMOPHILIA – severity classification  Factor VIII – reported in units / ml ( 1 unit/ml = 100% factor activity) - Normal range: 0.5 – 1.5 IU/ml (50 – 150%) Classification - Severe (60% of cases) : < 1% factor VIII (spontaneous bleeding) - Moderate : 1 to < 5% - Mild : 5 – 50 % ( only with trauma and surgery)

HEMOPHILIA- Lab findings  PTT (normal plt; normal PT)  Dx is confirmed by Factor Assay  F VIII ( with normal VWF ) = Hemophilia A  Dec F IX = Hemophilia B

HEMOPHILIA- S/Sx  Severe Hemophiliacs  Usually initial presentation in 1st 2 years of life ( severe bruising and joint bleeds)  40 – 50% present in the 1st month of life  1- 4% present in the neonatal period (birth trauma)

HEMOPHILIA  Mild or Moderate  Boys  Trauma related bruising or bleeding  Excessive bleeding following surgery or dental extraction  Girls ( carriers ) ~ Often with Factor VIII < normal  Mild bruising or bleeding  Heavy menstrual periods

HEMOPHILIA-Cxs  Hemarthroses  If recurrent  joint destruction  Intracranial hemorrhage  Leading cause of death among hemophilliacs  Intramuscular hematomas  Compartment syndrome  muscle and nerve death ( anterior forearm, anterior tibial compartment)

HEMOPHILIA-Cxs • Infection • HIV, Hep B, Hep C • Not at risk, With current donor screening and viral inactivation of factor concentrates, • But still at risk for: • Hepatitis A • Creutzfeld-Jakob Disease • Parvovirus B-19 • Recommend Hep A and Hep B vaccines for all pxs

HEMOPHILIA-Cxs • Acquired antibody to Factor VIII • Antibody that inactivates F VIII function • Develops in • 30% of pxs with severe hemophilia • < 5% of Hemophilia B

Antibody to factor VIII • Quantified by Bethesda units • 1 Bethesda unit – inactivates 50% of F VIII function • TREATMENT: • < 5 B.U. • Increase dose of F VIII • > 5 BU • Bypass agents: prothrombin complex conc ; FVII • ITI (immune tolerance induction)

HEMOPHILIA- Tx General aim of Mx: correct factor VIII to w/in normal limits  prevent or stop bleeding Mild May respond to desmopressin (ADH) - Releases endothelial stores of VWF Most still need exogenous F VIII after

HEMOPHILIA-Tx • Factor VIII dose • Non-life/limb threatening bleed • 20 to 30 u/kg  40 – 60% F VIII activity • Large hemarthrosis and life/limb threatening bleed • 50 u/KG  100% F VIII activity • Cryoprecipitate • 100 u F VIII / unit • e.g. 10 kg child –> 20 u/kg = • 200 u F VIII -> 2 u cryoppt) • (FFP (contains factor IX) – used for Hemophilia B)

HEMOPHILIA-Tx  Prophylaxis  Preventive F VIII infusions  2 to 3x, weekly  To achieve F VIII level >1%  Expensive  Initiate after 1st joint bleed  Do not start before 6 months of age – increases risk of inhibitor devlpt

HEMOPHILIA TREATMENT in the pipe line GENE THERAPY

 NEXT PATIENT please…

13 / female Cc: menometrorhagia  Easy bruising and occasional epistaxis since childhood  Gum bleeding on toothbrushing  No previous BT  Iron supplement in the past

 Family History  Maternal grandmother and mother with epistaxis and heavy menses  3 brothers and 2 sisters normal

 Hb 114  Platelet 300 (150 – 450)  PT : normal; 12.9 sec INR 1.1  PTT : normal; 32.5 (23.5 – 33.5)

↑ PTT, TT Normal PT, platelet All normal Platelet dec Heparin VWD Platelet fxn d/o Mild factor def (VIII, IX, XI, XIII ) Collagen Disorder Vitamin C def CAMT, TAR,BSS WAS, GPS ITP 2 Infection

 VIII  0.48 u /ml (0.5 – 1.5 u/ml)  VWF Ag  0.20 u /ml (0.5 – 1.5 u/ml)

VonWillebrand Disease, type 1 DIAGNOSIS

Von Willebrand Disease  Most common inherited bleeding disorder (Prevalence: 1% - by lab def’n; only 10% symptomatic)  Quantitative or Qualitative deficiency of vWF  Easy bruising / epistaxis from childhood / menorrhagia Dr. Erik Von Willebrand, 1926

Diagnosis  Criteria  VWF Ag < 30%  Or VWF Ag 30-50% , in patient with clinical symptoms supportive of VWF

The Von Willebrand Factor  Protein in plasma  Function 1. Tethers platelets to damaged endothelium 2. Binds and protects Factor VIII Endothelial cells w/stored VWF

vWD

vWD- Classification  Type 1  Classic ; 80% of patients  Partial quantitative deficiency  Type 2  Dysfunctional VWF- qualitative  Type 3  Nearly COMPLETE deficiency

vWD-Inheritance  Mostly AD ; can be AR  Theoretically, equal males and females  But more females dxd (menorrhagia)  Can be acquired  rare  Hypothyroidism, Wilms tumor, Cardiac disease, Renal disease or SLE / Valproic acid  Most often caused by Ab to VWF

vWD- S/Sx  Increased bruising and excessive epistaxis  Prolonged bleeding with trauma or surgery  Menorrhagia  Significant menorrhagia from menarche  prompt investigation for congenital bleeding d/o

vWD-Labs  Initial screen: - PT normal - PTT sometimes prolonged > in type 3 (factor VIII dec) - Platelet sometimes dec > in types 2 and 3  Most of the time: PT, PTT, platelet --- NORMAL  Blood type ‘O’ – normally lower vWF

VWD  Bleeding time - prolonged  Platelet function analyzer – prolonged closure time  vWF assay - Definitive test

vWD -Treatment  VWD types 1 and 2  Desmopressin  Releases vWF from endothelial stores  IV or intranasal ( high concentration spray )  Variable response  measure VIII and vWF 60 minutes after  May cause fluid shifts (hyponatremia seizures )  Tachyphylaxis occurs (stored VWF limited)  Further therapy with VWF concentrate or cryoprecipitate

VWD -treatment  Intermediate purity F VIII concentrates  Cryoprecipitate

AdjunctiveTreatment  Antifibrinolytic agents (Tranexamic acid / E-aminocaproic acid )  Prevents plasminogen  plasmin  For mucosal bleeding  Topical thrombin and fibrin glue  Estrogen containing contraceptive tx  For menorrhagia

Rare Coagulation Disorders

Rare coagulation disorders  Other congenital coagulation factor deficiencies  Afibrinogenemia /hypofibrinogenemia  Deficiencies of factor V, VII, X, XI, XIII  Combined, occur in 1-500,000 to 1:2,000,000  Autosomal recessive  Most common : Factor VII def  Causes most bleeding sxs: Factor X and Factor XIII def

Rare coagulation disorders  S/Sx  Umbilical stump bleeding  Delayed cord separation  Intracranial or intestinal hemorrhage  Muscle hematomas  Easy bruising  Prolonged bleeding ff heelprick

Inherited platelet Disorders

Inherited platelet disorders  Decreased number and abn function  Bernard Soulier Syndrome (BSS)  Wiskott Aldrich Syndrome (WAS)  Gray Platelet Syndrome (GPS)  Normal number but abn function  Glanzman Thrombasthenia (GT)  Storage Pool Disorder (SPD)

Dec # and abn platelet fxn Defect S/Sx Labs BSS No GPIb/IX plt receptor -> defective binding to VWF ARecessive Bruising/ bleeding from infancy Moderate thrombocytopenia Large platelets GPS Alpha granule deficiency Severe bruising bleeding from early age Mild thrombocytopenia Large gray/Agranular platelets

GLANZMANN THROMBASTHENIA Defect S/Sx Labs Normal number Normal morph Platelet GP IIb/IIIA (fibrinogen receptor) – FAILS TO AGGREGATE ARecessive Severe spont’ mucosal bleeding Presents in infancy BT Flow cytometry Plt aggregation

SUMMARY

Summary  Hemostasis  3 stages  Vasoconstriction  Platelet phase  Coagulation phase  Congenital bleeding disorders  Hemophilia A, B  VWD  Rarer coagulation disorders  Inherited platelet disorders

Summary  Suspect a congenital bleeding disorder  Symptoms presenting in early infancy/childhood  Similar symptoms in family members  Consanguinity  Most common disorders  Hemophilia  VWD

Summary  Do coagulation screen  Deranged PTT only  Think…  Hemophilia – hemarthrosis/intramuscular bleed  VWD – bruising / petechiae, epistaxis  Platelet, PT, PTT all normal  Think…  VWD  Platelet function disorder  Mild coagulation disorders

Hemophilia A or B (factor VIII /IX def) VWD (VWF def or abn) Inheritance X linked De novo (1/3) AD (few AR) S/Sx Easy bruisability Hemarthrosis Soft tissue bleed Menorrhagia Easy bruisability Epistaxis Menorrhagia Labs Prolonged PTT Normal plt, PT, PTT < Prolonged PTT (few) > Confirmatory test Factor VIII /IX assay VWF assay Treatment Desmopressin (for mild Hemophilia A) Recomb Factor VIII /IX Cryoprecipitate /FFP Desmopressin Intermediate purity FVIII Cryoprecipitate

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