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Inherited Coagulation Disorder Hereditary Deficiency X-Linked Recessive Disorder Haemophilia A Haemophilia B (Classic Disease) (Christmas Disease) Haemophilia

A Definition X-Linked Recessive Disorder Factor VIII activity Epidemiology Male Incidence 1/5000 Male populations May occur in Heterozygous Female (due to lyonization)(X-inactivation) Associated with serious Bleeding Laboratory Findings APTT Prolonged Factor VIII Level PT Normal Bleeding Time Normal vWF Level - Normal Mixing Test

Autosomal Disorder Von Willebrand disease

Management Factor VIII Concentrate IV Infusions Treatment


Bleeding Minor Severe Major Preoperative After Surgery Factor VIII Level 20-30 IU/dL 50 IU/dL

Prophylaxis
Severe Haemophilic patient (start prophylactic freeze-dried st Factor VIII 3 times/week after 1 spontaneous joint bleed during early childhood) Prevent recurrent bleeding into joints, joint damage Benefits Risk of Chronic Joints Damage Need for inpatient care

Factor VIII Gene Location Near tip of Long arm of X Chromosome (Xq2.6 region) Extremely large gene (with 26 exons) Components of Factor VIII Protein Triplicated region A1 A2 A3 Duplicated Homology C1C2 Heavy glycosylated B domain (removed when Factor VIII activated) Causes of Haemophilia A Factor VIII Deficiency (90%) +ve Family History Spontaneous Mutations (70%) (30%) Deletions Duplications Frameshift mutations Insertions Inversions (50%)

100 IU/dL > 50 IU/dL (maintain until healing occurred) Administration Twice Daily (Half-Life 12 hours) Other use Continuous infusion to cover surgery

Complications Viral Transmission (eg. HIV, Hepatitis B, Hepatitis C) Prevention Exclude Risk Blood donors, Test blood for HBsAg, HCV, HIV Antibodies, Inactivate viruses during plasma-derived concentrate preparations, Hepatitis A and B vaccination Antibodies to Infused Factor VIII (Inhibitors) Prevalence 5-10% Mainly in severe patients Develops rarely in moderate, mild haemophilia patients Disappear spontaneously or with continued treatment Management Dose Factor VIII Recombinant Activated Factor VII Activated Prothrombin Complex Concentrates Immunosuppression with Cyclophosphamide Intravenous Immunoglobulin Synthetic Vasopression (DDVAP) Patients with baseline Factor VIII level > 10 IU/dL (mild haemophilia) Advantage Avoid blood products transfusions complications Clinical Uses

Funtionally Abnormal Protein Synthesis (10%)

Flip-Tip Inversion During spermatogenesis, Single pair X chromosome pair with Y Chromosome X Chromosome is longer (compared to Y chromosome) Homologous Recombination between A genes (F8A, A2, A3) Disrupted Factor VIII Gene Failure of Complete, Normal Factor VIII Protein Transcription Dysfunctional Factor VIII Protein Laboratory Studies Activated Partial Thromboplastin Time (aPTT) Prothrombin Time (PT) Platelet count Bleeding Time Complete Blood Count (FBC) Specific Coagulation Factor Assay vWF Measurement Other Laboratory Test Liver Function Test Renal Function Test Colonoscopy, Endoscopy (GI Bleeding) Alpha-Fetoprotein Tumour Markers

Antidiuretic action lead to Hyponatremia Avoided in elderly Fluid restitution after use Haemophilia A Prevention Carrier Detection Family History Coagulation Factor Assays
( / Normal Factor VIII due to lyonization)

Antenatal Diagnosis Chorionic Villous Biopsy


(8-12 weeks gestation)

Molecular genetic testing for Direct Factor VIII gene mutations detection

Fetal Tissue for Molecular Analysis Fetal Blood (16-20 weeks gestation) obtained from umbilical vein through Ultrasound-guided needle aspiration Factor VIII level in Fetal Blood

Mu ous Membranes Bleedin Epistaxis Oropharyngeal Blee ing Acute Respiratory Obstruction y Cough y Exertional Dyspnea y Prolonge Expiratory Phase y Expiratory Whee ing Retropharyngeal Blee ing Gastrointestinal Blee ing Peptic Ulcer (blood in Stool, Upper GI Bleeding) Spontaneous Hematuria (blood in urine) Haemarthroses Severe pain in target joint Bogginess around joint y Inflamed synovium y Presence of Blood, Fluid Joint space, surrounding bursa fullness Joint mobility limitation
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Chroni Severe Arthritis Fusion, Loss of Cartilage Joint Space Deformities


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Joint deformity, crippling Bleeding into muscles

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Vas ular Synovium Synovial Joint Haemophili Pseudotumours Large encapsulated haematomas with progressive cystic swelling Results from repeated haemorrhage in Fascial, Muscle Planes Large muscle groups Long bones, Pelvis, Cranium Result from Subperiosteal Haemorrhage Bone Destruction New Bone Formation Common Sites Buttock Pelvis Thighs Compli ations Infection Central Nervous System (CNS) Haemorrhage Head Trauma in Children Spontaneous Intracerebral Haemorrhage Prolonged Bleeding after Dental Extraction Sublingual, Pharyngeal, Facial, Dissecting Neck Hematoma
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Clini l Featu es General Te e cy sy B s e No Petec iae Infants Profuse Post- ircumcision Haemorrhage Joint, Soft Tissue B ee s Excessive Bruising
  

Pathophysiology Easy Haemorrhage e Trauma/ Operation Recurrent Spontaneous Minor injury induced Painful Haemarthroses Synovial Hypertrophy Tendency for Recurrent Joint Bleeding Progressive, Permanent, Severe Joint Damage with Progressive Muscle wasting Destructive Chronic Synovitis with Destruction of Synovium, Cartilage, Bone Chronic severe Pain, Arthritis, Joint stiffness, Limited movement Intramuscular Haemorrhage Hematoma Hematoma dissecting Into Fascial Plane Nerve Compression Neuropathies, Ischaemic Necrosis Compartment Syndrome Symptoms (5Ps) Pain, Paralysis, Paraesthesia, Pallor, Pulselessness Signs Tight swelling Loss of Strength Loss of Sensation Repeated Haemorrhage develop under the Periosteum in Bone (subperiosteal haemorrhage) Symptoms Severe, Recurrent Pain Swelling Limited Movement Human Synovial cells Synthesize levels of Tissue Factor Pathway Inhibitor (TFPI) Degree of Factor Xa (FXa) Inhibition

Chronically fused Extended knee

Haemophilic Pseudotumours Repeated Haemorrhage in Bone, Soft Tissues Restricted by fascial planes of a muscle Pressure-induced Ischaemia Resorption of Neighbouring Bone

Erosion of Bony Cortex (Bone Destruction), New Bone Formation Nerves, Vascular Compromise (eg. Femoral Nerve Damage) Head Trauma Spontaneous in Children Intracerebral Haemorrhage Central Nervous System (CNS) Haemorrhage Symptoms Headaches Seizures Vomiting Focal Neurologic Defects Severity of Clinical Features (Depend on Factor VIII Level) (Normal Factor VIII Levels 50IU-150IU/dL) Factor VIII Level < 1 IU/dL 1-5 IU/dL Haemophilia Severe Moderate Clinical Features Fre uent Severe bleeding spontaneous following injury bleeding from Occasional early life spontaneous bleeds Haemarthrosis

> 5 IU/dL Mild Bleeding only after injury/ surgery

Haemophilia B Definition Factor IX Deficiency Factor IX Gene Located close to Factor VIII gene Factor IX Protein synthesis is Vitamin K-Dependent Factor IX Deficiency Incidence 0.2/5000 of Male populations Similar with Haemophilia A Clinical Features Management Methods of Prevention Laboratory Findings APTT Prolonged Factor IX Level PT Normal Bleeding Time Normal vWF Level - Normal Replacement Therapy High-purity Factor IX Concentrates Frequent Infusions (due to Half-Life 40-70 hours) Classic Disease vs Christmas Disease (Haemophilia A, Haemophilia B) Haemophilia A Haemophilia B Incidence 1/5000 Male populations 0.2/5000 Male populations Coagulation Factor VIII Level Factor IX Level Factor Assay Replacement Factor VIII Concentrate High-Purity Factor IX Therapy Intravenous Infusions Concentrates ( Frequent infusions) Synthetic Vasopression (DDVAP)

Haemophilia C Definition Factor XI Deficiency Absence of Bleeding into Joints, Muscles Male = Female Bleeding risk is not always influenced by severity of deficiency Difficult to manage than Haemophilia A, Haemophilia B (unpredictability) Prevalence Ashkenazi Iraqi Jews Autosomal but not completely recessive (Heterozygotes may have bleeding) Infants younger than 6 months Level of Factor XI Time required for Factor XI to reach normal levels observed in adults Factor XI Dimeric Serine Protease, Chains each weigh 80,000 Da Activated by Factor XIIa (Intrinsic Pathway of Blood Coagulation) Directly Activated by Thrombin (more important than activation by Factor XII) Factor XII Deficiency (even severe deficiency) Do not necessarily have tendency to bleed Absence of Factor XII is irrelevant to Factor XI Incidence of Ischemic Stroke Factor XI activate Factor IX then followed by Thrombin Generation Sustained Generation of Thrombin, lead to activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) (impairs conversion of Plasminogen to Plasmin) Serves both as Procoagulant Antifibrinolytic Inhibitors of Factor XIa Alpha-1 Antitrypsin (2/3 of Inhibition) C1 Esterase Inhibitor Antithrombin III Alpha-2 Antiplasmin Deficiency of Factor XI In Severe Deficiency, Bleeding related to Injury (eg. Trauma) involves Tissues Rich in Fibrinolytic Activators Oral mucosa Nose Urinary Tract Do not spontaneously bleed (compared with Haemophilia A, B) Severity of Factor XI Deficiency Partial Deficiency 20-60 U/dL Brown Sequard Syndrome Rare condition Caused by Penetrating wounds (stab wound to neck, back)(gunshot wounds) Tumour which obstruct blood flow to spine Hemisection of spinal cord results in Loss of Motor Control on 1 side Loss of Sensation (Temperature) on the opposite side Physical Examination Usually Normal, except when bleeding occurs Bruising may occur at unusual sites Signs Pallor Fatigue Tachycardia Excessive Bleeding Acquired Factor XI Deficiency (develop inhibitors to protein) Systemic Lupus Erythematosus Immunologic Diseases Noonan Syndrome Congenital Cardiac Abnormalities Short Stature Mental Retardation Coagulation defects

Noonan Syndrome Typical Webbed Neck Other Problems to be considered Abnormalities in Platelet function Other Clotting Factor Deficiencies Combined Deficiencies of Clotting Factor Uncommon Coagulopathies Investigation FBC aPTT - (Factor XI Deficiency)(Partial Deficiency can be missed) PT Normal TT Normal Measurement of Factor XI Levels Specific Assay for Factor XI Activity (necessary to confirm diagnosis) Factor VIII, vWF Measurement Assays of other clotting factors, platelet function (exclude a combined hereditary deficiency of Factor XI, other factors) Other Tests Genetic assay for mutation in Factor XI (determine mutation caused deficiency)

Severe Deficiency 15-20 U/dL or Lower Do not spontaneously bleed Risk of bleeding after surgery

Variations in Bleeding Tendencies Additional Clotting Factor Disorders von Willebrand Disease Associated Platelet Defects, Deficiency of Platelet Factor XI (Platelet Factor XI alternatively spliced product of Factor XI gene expressed specifically within megakaryocytes, platelets) Fibrinolysis at Surgical Sites (Fibrinolytic activity is particularly ) Oral cavity after Dental Extraction, Tonsillectomy Menorrhagia Bleeding related to Childbirth, Gynecologic surgery History Bleeding after surgery Prolonged Bleeding after injury Menorrhagia (women), Abnormal bleeding after childbirth Paradoxical Finding Severe Deficiency No Bleeding Tendency Mild Deficiency Bleed Excessively Unusual Presentation Massive Hemothorax Cerebral Hemorrhage Subarachnoid Hemorrhage Spinal Epidural Hematoma with Brown-Sequard syndrome Rare Hematuria Spontaneous Hemarthrosis

Von Willebrand Disease Definition Level or Abnormal Function of vWF Resulting from Point Mutation Major Deletion Epidemiology Most common inherited bleeding disorder 1 in general population (screening studies) Women Severe in people with Blood group type O Function of vWF Link between Subendothelial ECM, Platelet glycoprotein Carrier molecule for Factor VIII Stored in Endothelial cells, Platelet Investigations Bleeding Time (BT) APTT Normal/ vWF Level Factor VIII Level - (frequently) (if , perform Factor VIII vWF Bindnig Assay) Collagen-Binding Function Treatment Local Measures, Antifibrinolytic agent Tranexamic acid (for mild bleeding) Stimate/ Desmopressin Acetate (DDAVP) Nasal spray (mild von Willebrand disease) Induce release of vWF stored in Weibel-Palade bodies (in Endothelial cells) Plasma levels of vWF Carry no risk of Infectious disease (synthetic product) Factor VIII Concentrate Infusion (rich in von Willebrand Factor) For Excessive Bleeding Humate-P Alphanate (Antihemophilic factor) Bleeding in patients undergoing surgery, invasive procedure Contraindications Aspirin, Pain Killer Interfere Platelet function, cause bleeding

Haemophilia A, Haemophilia B, vWD Classification Type 1 Quantitative Partial Deficiency Haemophilia A Type 2 Functional Abnormality 2A Absence of High MW vWF multimers 2B Absence of Highest MW vWF multimers Binding to GP1b-IX-V Complex Mild Moderate Thrombocytopenia 2M Ultralarge vWF multimers 2N Mimics mild Haemophilia A Binding to Factor VIII Type 3 Complete Deficiency Inheritance Main Haemorrhage XL Muscle, Joints, Post-Trauma, Post-operative Haemophilia B XL Muscle, Joints, Post-Trauma, Post-operative Von Willebrand Disease Dominant (Incomplete) Mucous membranes, Skin cuts, Posttrauma, Postoperative N N /N May be N Impaired

Mode of Inheritance Autosomal Dominant Type I, Type II

Autosomal Recessive Type III, Type IIN

Platelet count Bleeding Time PT APTT VWF Factor VIII Factor IX Ristocetininduced platelet aggregation

N N N N N N

N N N N N N

Clinical Mucous Membrane Bleeding (eg. Epistaxis, Menorrhagia) Excessive Blood Loss Superficial cuts Abrasion Operative Post-traumatic haemorrhage Haemarthroses, Muscle Haematomas (Rare - Except in Type 3 Disease) Bleeding Intermittent Provoked by Aspirin use

Hereditary Disorders of Other Coagulation Factors


Fibrinogen Deficiency Afibrinogenamia Mode of Inheritance Symptoms AR Bleeding from Umbilical Stump Dysfibrinogenamia AD AR Bleeding from Umbilical Stump Bleeding Severe Prothrombin (Factor II) Deficiency AR Bleeding from Umbilical Stump Bleeding Severe Factor V Deficiency AR Factor VII Deficiency Combine Factor V, Factor VIII Deficiency AR AR Factor X Deficiency AR Umbilical Cord, CNS Bleeding Bleeding from Umbilical Stump Fertility Recurrent Miscarriages Cryoprecipitate SD-Treated plasma FXIII concentrate Prolonged Prolonged Factor XIII Deficiency

Treatment

Umbilical Cord, CNS Bleeding Bleeding from Umbilical Stump Haematuria (Frequent) Bleeding Severe Spontaneous Haematroses, Muscle Haematomas, Permanent damage to MSS (resulting Handicaps), Epistaxis (frequent), Excessive bl eeding after trauma (Surgery), Bleeding after circumcision, Haemorrages in GIT CNS Cryoprecipitate SD-Treated plasma SD-Treated plasma FVII Concentrate SD-Treated plasma SD-Treated plasma

Investigations

APTT PT

Prolonged Prolonged

Prolonged Prolonged

Prolonged Prolonged

Normal Prolonged

Prolonged Prolonged

SD Solvent/ Detergent

Physiotherapy Management of Haemophilia Aims of Physiotherapy Management Pain, Swelling Muscle Power, Control Range of Joint Movement Prevent Deformity Functional Capacity Exercise Tolerance Prevent Further Injury to susceptible joint Principles of Physiotherapy Management Strong muscles - Support, Protect joints Weak muscles Expose them to Trauma Splint in position of comfort (following acute bleeding) Strengthen unaffected joints when on bed rest Factor replacement (required prior to physiotherapy)(eg. Strenous exercise) Exercise can be done at Home Physiotherapy centre Protocol of Physiotherapy Management of Haemophilia Acute Sub Acute Chronic RICE for affected area RICE Factor Replacement Support for joint (splint) Support Electrotherapy Active exercise Isometric Exercise Exercises Unaffected Limb Affected Joint Mobilising Unaffected Joint of Strengthening Active Exercise affected limb Stretching Unaffected Limb Proprioceptive Unaffected Joint of Coordination affected limb Balancing Electrotherapy Postural corrective (relief pain) Gait Training Ultrasound Hydrotherapy SWD Training of functional TENS activities IT RICE Rest, Ice, Compression, Exercise TENS Transcutaneous Electrical Nerve Stimulation Recreational Activities Recommended Swimming Cycling Walking Darts Ping pong Bowling Snooker Golf Tennis Jogging Weight lifting Gymnastics

Discouraged Football Boxing Skating Volleyball Jumping Basketball Skiing