Inherited-Coagulation-Disorder by GerardLum

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Inherited Coagulation Dis order

Hereditary Deficiency                                                           Laboratory Findings
            X-Linke d Recessive Disorder                Autosomal Disorder      APTT – Prolonged
    Haemophilia A                Haemophilia B                                  Factor VIII Level ↓
                                                       Von Willebrand disease
   (Classic Disease)          (Christmas Disease)                               PT – Normal
                                                                                Bleeding Time – Normal
Haemophilia A                                                                   vWF Level - Normal

Definition                                                                      Mixing Test
X-Linked Reces sive 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




                                                                                Management
                                                                                Factor VIII Concentrate IV Infusions
                                                                                 Treatment                                   Prophylaxis
                                                                                    Bleeding          Factor VIII Level      Severe Haemophilic patient
                                                                                    Minor             20-30 IU/dL            (start prophylactic freeze-dried
                                                                                                                                                              st
                                                                                    Severe            ≥ 50 IU/dL             Factor VIII 3 times/week after 1
                                                                                    Major                                    spontaneous joint bleed during early
                                                                                    Preoperative       ≈ 100 IU/dL           childhood)
                                                                                    After Surgery      > 50 IU/dL
                                                                                                       (maintain until       Prevent recurrent bleeding into joints,
                                                                                                       healing occurred)     joint damage
                                                                                  Administration – Twice Daily
                                                                                                                             Benefits
                                                                                  (Half-Life – 12 hours)
                                                                                  Other use – Continuous infusion to cover   ↓ Risk of Chronic Joints Damage
Factor VIII Gene                                                                                                             ↓ Need for inpatient care
Location                                                                          surgery
Near tip of Long arm of X Chromos ome (X q2.6 region)                           Complications
Extremely large gene (with 26 exons)                                              Viral Transmission (eg. HIV, Hepatitis B, Hepatitis C)
Components of Factor VIII Protein                                                 Prevention
Triplicated region A 1A 2A 3                                                      Exclude ↑ Risk Blood d onors,
Duplicated Homology C1C2                                                          Test blood for HBsAg, HCV, HIV Antibodies,
Heavy glycosylated B domain (removed when Factor VIII activated)                  Inactivate viruses during plasma-derived concentrate preparations,
                                                                                  Hepatitis A and B vaccination
Causes of Haemophilia A                                                           Antibodies to Infused Factor VIII (Inhibitors)
             Factor VIII Deficiency                   Funtionally Abnormal        Prevalence – 5-10%
                    (90%)                            Protein Synthesis (10%)      Mainly in severe patients
 +ve Family History     Spontaneous M utations                                    Develops rarely in moderate, mild haemophilia patients
       (70%)                     (30%)                                            Disappear spontaneously or with continued treatment
                       Deletions                                                  Management
                       Duplications                                               ↑ Dose Factor VIII
                       Frameshift mutations                                       Recombinant Activated Factor VII
                       Insertions                                                 Activated Prothrombin Complex Conce ntrates
                       Inversions (50%)                                           Immunosuppression with Cyclophosphamide
                                                                                  Intravenous Immunoglobulin
Flip-Tip Inversion                                                              Synthetic Vasopression (DDVAP)
 During spermatogenesis, Single pair X chromosome pair with Y Chromosome        Patients with baseline Factor VIII level > 10 IU/dL (mild haemophilia)
                                        ↓                                       Advantage – Avoid blood products transfusions complications
                                                                                Clinical Uses
              X Chromosome is longer (compared to Y chromosome)
                                        ↓
           Homologous Re combination between A genes (F8A, A2, A3)
                                        ↓
                            Disrupted Factor VIII Gene
                                        ↓
           Failure of Complete, Normal Factor VIII Protein Transcription
                                        ↓
                         Dysfunctional Factor VIII Protein
                                                                                Antidiuretic action – lead to Hyponatremia
Laboratory Studies                               Other Laboratory Test          Avoided in elderly
Activated Partial Thromboplastin Time (aPTT)     Liver Function Test            Fluid restitution after use
Prothrombin Time (PT)                            Renal Function Test
Platelet count                                   Colonoscopy, Endoscopy         Haemophilia A Prevention
Bleeding Time                                    (GI Bleeding)                  Carrier Detection                            Antenatal Diagnosis
Complete Blood Count (FBC)                       Alpha-Fetoprotein              Family History                               Chorionic Villous Biopsy
Specific Coagulation Factor Assay                Tumour Markers                 Coagulation Factor Assays                    (8-12 weeks gestation)
vWF Measurement                                                                 (↓/ Normal Factor VIII due to lyonization)   Fetal Tissue for Molecular Analysis
                                                                                Molecular genetic testing for Direct         Fetal Blood (16-20 weeks gestation)
                                                                                Factor VIII gene mutations detection         obtained from umbilical vein through
                                                                                                                             Ultrasound-guided needle aspiration
                                                                                                                             ↓ Factor VIII level in Fetal Blood
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Clinical Features                                                     Pathophysiol ogy
General                                                                           Easy Haemorrhage
Tendency toward Easy Bruising, Haemorrhages after Trauma/ Operation                        ↓
No Petechiae                                                                    Recurrent Spontaneous
Infants                                                                          Minor injury induced                     Human Synovial cells
Profuse Post-Circumcision Haemorrhage                                           Painful Haemarthroses                    Synthesize ↑ levels of
Joint, Soft Tissue Bleeds                                                                  ↓                        Tissue Factor Pathway Inhibitor
Excessive Bruising                                                               Synovial Hypertrophy                           (TFPI)
                                                                                           ↓                                       ↓
                                                                                     Tendency for                        ↑ Degree of Factor Xa
                                                                               Recurrent Joint Bleeding                     (FXa) Inhibition
Mucous Membranes Bleeding                                                                  ↓                    ↙
Epistaxis                                                                 Progressive, Permanent, Severe
Oropharyngeal Bleeding                                                     Joint Damage with Progressive
      Acute Respiratory Obstruction                                                 Muscle wasting
      •     Cough                                                                          ↓
      •     Exertional Dyspnea                                              Destructive Chronic Synovitis
      •     Prolonged Expiratory Phase                                            with Destruction of
      •     Expiratory Wheezing                                               Synovium, Cartilage, Bone
Retropharyngeal Bleeding                                                                   ↓
Gastrointestinal Bleeding                                                   Chronic severe Pain, Arthritis,
Peptic Ulcer (blood in Stool, Upper GI                                   Joint stiffness, Limited movement
Bleeding)                                                                    Intramuscular Haemorrhage
Spontaneous Hematuria (blood in urine)                                                     ↓
Haemarthroses                                                                         Hematoma                  →      Symptoms
Severe pain in target joint                                                                ↓                           Severe, Recurrent Pain
Bogginess around joint                                                           Hematoma dissecting                   Swelling
•     Inflamed synovium                                                            Into Fascial Plane                  Limited Movement
•     Presence of Blood, Fluid                                                             ↓
Joint space, surrounding bursa fullness                                           Nerve Compression
Joint mobility limitation                                                                  ↓
                                                                                     Neuropathies,
                                                                                  Ischaemic Necrosis
                                                                                           ↓
                                                                               Compartment Syndrome             →      Symptoms (5Ps)
                                                                                                                       Pain, Paralysis, Paraesthesia,
                                                                                                                       Pallor, Pulselessness
                                                                                                                       Signs
                                                                                                                       Tight swelling
                                                                                                                       Loss of Strength
                                                                                                                       Loss of Sensation
                                                                      Haemophilic Pseudotumours
                                                                           Repeated Haemorrhage in                   Repeated Haemorrhage
                                                                               Bone, Soft Tissues                       develop under the
                                                                           Restricted by fascial planes                Periosteum in Bone
Chronic Severe Arthritis                        Chronically fused                  of a muscle                    (subperiosteal haemorrhage)
Fusion, Loss of Cartilage                       Extended knee                           ↓
Joint Space Deformities                                                   Pressure-induce d 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
                                                                                        ↘                                      ↙
Vascular Synovium                          Synovial Joint                                     Central Nervous System (CNS)
Haemophilic Pseudotumours                                                                              Haemorrhage
Large encapsulated haematomas                                                                               ↓
with progressive cystic swelling                                                                        Symptoms
Results from repeated haemorrhage in                                                                    Headaches
Fascial, Muscle Planes                                                                                   Seizures
Large muscle groups                                                                                      Vomiting
Long bones, Pelvis, Cranium                                                                      Focal Neurologic Defects
Result from
Subperiosteal Haemorrhage                                             Severity of Clinical Features (Depend on Factor VIII Level)
Bone Destruction                                                      (Normal Factor VIII Levels – 50IU-150IU/dL)
New Bone Formation                                                    Factor VIII Level         < 1 IU/dL           1-5 IU/dL             > 5 IU/dL
Common Sites                                                          Haemophilia                 Severe            Moderate                 Mild
Buttock                                                               Clinical Features     Frequent           Severe bleeding        Bleeding only
Pelvis                                                                                      spontaneous        following injury       after injury/
Thighs
                                                                                            bleeding from      Occasional             surgery
Complications                                                                               early life         spontaneous
Infection
                                                                                            Haemarthrosis      bleeds
Central Nervous System (CNS) Haemorrhage
                                                                                            Joint deformity,
Head Trauma in Children
                                                                                            crippling
Spontaneous Intracerebral Haemorrhage
                                                                                            Bleeding into
Prolonged Blee ding after Dental Extraction
                                                                                            muscles
Sublingual, Pharyngeal, Facial, Dissecting Neck Hematoma
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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 (d ue 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
                      Synthetic Vasopression      (↓ Frequent infusions )
                      (DDVAP)
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Haemophilia C

Definition                                                                        Brown Sequard Syndrome
Factor XI Deficiency                                                              Rare condition
Absence of Bleeding into Joints, Muscles                                          Caused by
Male = Female                                                                     Penetrating wounds (stab wound to neck, back)(gunshot wounds )
Bleeding risk is not always influenced by severity of deficiency                  Tumour which obstruct blood flow to spine
Difficult to manage than Haemophilia A, Haemophilia B (unpredictability)          Hemisection of spinal cord results in
↑ Prevalence                                                                      Loss of Motor Control on 1 side
Ashkenazi                                                                         Loss of Sensation (Temperature) on the opposite side
Iraqi Jews
Autosomal but not completely recessive                                            Physical Examination
(Heterozygotes may have bleeding)                                                 Usually Normal, except when bleeding occurs
Infants younger than 6 months                                                     Bruising may occur at unusual sites
↓ Level of Factor XI                                                              Signs
Time required for Factor XI to reach normal levels observed in adults             Pallor
                                                                                  Fatigue
Factor XI                                                                         Tachycardia
Dimeric Serine Protease, Chains each weigh 80,000 Da                              Excessive Bleeding
Activated by Factor XIIa (Intrinsic Pathway of Blood Coagulation)                 Acquired Factor XI Deficiency
Directly Activated by Thrombin (more important than activation by Factor XII)     (develop inhibitors to protein)
Factor XII Deficiency (even severe deficiency)                                    Systemic Lupus Erythematosus
Do not necessarily have tendency to bleed                                         Immunologic Diseases
Absence of Factor XII is irrelevant to Factor XI                                  Noonan Syndr ome
↓ Incidence of Ische mic Stroke                                                   Congenital Cardiac Abnormalities
Factor XI activate Factor IX then followed by Thrombin Generation                 Short Stature
Sustained Generation of Thrombin, lead to activation of                           Mental Retardation
Thrombin Activatable Fibrinolysis Inhibitor (TAFI)                                Coagulation defects
(impairs conversion of Plasmin ogen to Plasmin)
Serves both as
Procoagulant
Antifibrinolytic

Inhibitors of Factor XIa
Alpha-1 Antitrypsin (2/3 of Inhibition)
C1 Esterase Inhibitor
Antithrombin III                                                                                  Noonan Syndr ome
Alpha-2 Antiplasmin                                                                               Typical Webbed Neck

Deficiency of Factor XI                                                           Other Problems to be consi dered
In Severe Deficiency, Bleeding related to Injury (eg. Trauma) involves            Abnormalities in Platelet function
Tissues Rich in Fibrinolytic Activators                                           Other Clotting Factor Deficiencies
Oral mucosa                                                                       Combined Defi ciencies of Clotting Factor
Nose
                                                                                  Uncommon Coagulopathies
Urinary Tract
Do not spontaneously bleed (compared with Haemophilia A, B)
                                                                                  Investigation
                                                                                  FBC
Severity of Factor XI Deficiency
                                                                                  aPTT - ↑ (Factor XI Deficiency)(Partial Deficiency can be missed )
          Partial Deficiency                         Severe Deficiency
                                                                                  PT – Normal
20-60 U/dL                                15-20 U/dL or Lower
                                                                                  TT – Normal
                                          Do not spontaneously bleed
                                                                                  Measurement of Factor XI Levels
                                          Risk of bleeding after surgery
                                                                                  Specific Assay for Factor XI Activity (necessary to confirm diagnosis)
                                                                                  Factor VIII, vWF Measurement
Variations in Bleeding Tendencies
                                                                                  Assays of other clotting factors, platelet function
Additional Clotting Factor Disorders – von Willebrand Disease
                                                                                  (exclude a combined hereditary deficiency of Factor XI, other factors)
Associated Platelet Defects, Deficiency of Platelet Factor XI
                                                                                  Other Tests
(Platelet Factor XI – alternatively spliced product of Factor XI gene expressed
                                                                                  Genetic assay for mutation in Factor XI
specifically within megakaryocytes, platelets)
                                                                                  (determine mutation caused defi ciency)
↑ 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 Prese ntation
Massive Hemothorax
Cerebral Hemorrhage
Subarachnoid Hemorrhage
Spinal Epidural Hematoma with Brown-Sequard syndrome
Rare
Hematuria
Spontaneous Hemarthrosis
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Von Willebrand Disease

Definition                                                                  Investigations
↓ Level or Abnormal Function of vWF                                         Bleeding Time (BT) - ↑
Resulting from                                                              APTT – Normal/ ↑
Point Mutation                                                              vWF Level - ↓
Major Deletion                                                              Factor VIII Level - ↓ (frequently)
                                                                            (if ↓, perform Factor VIII vWF Bindnig Assay)
Epidemiology                                                                Collagen-Binding Function - ↓
Most common in herited bleeding disorder
≈ 1 in general population (screening studies)                               Treatment
Women ↑                                                                     Local Measures, Antifibrinolytic agent
↑ Severe in people with Blood group type O                                  Tranexamic acid (for mild bleeding)
                                                                            Stimate/ Desmopressin Acetate (DDAVP)
Function of vWF                                                             Nasal spray (mild von Willebrand disease)
Link between Subendothelial ECM, Platelet glycoprotein                      Induce release of vWF stored in Weibel-Palade bodies (in Endothelial cells)
Carrier molecule for Factor VIII                                            ↑ Plasma levels of vWF
Stored in Endothelial cells, Platelet                                       Carry no risk of Infectious disease (synthetic product)
                                                                            Factor VIII Concentrate Infusion (rich in von Wille brand 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
                                                                                                                                            Von Willebrand
Classification                                                                                    Haemophilia A        Haemophilia B
                                                                                                                                                 Disease
   Type 1                            Type 2                      Type 3
                                                                            Inheritance                 XL                   XL                Dominant
Quantitative     Functional Abnormality                        Complete
                                                                                                                                             (Incomplete)
Partial          2A      Absence of High MW vWF multimers      Deficiency
                                                                            Main                  Muscle, Joints,      Muscle, Joints,           Mucous
Deficiency       2B      Absence of Highest MW vWF multimers
                                                                            Haemorrhage            Post-Trauma,         Post-Trauma,        membranes, Skin
                         ↑ Binding to GP1b-IX-V Complex
                                                                                                  Post-operative       Post-operative          cuts, Post-
                         Mild → Moderate Thrombocytopenia                                                                                       trauma,
                 2M      Ultralarge vWF multimers                                                                                            Postoperative
                 2N      Mimics mild Haemophilia A                          Platelet count              N                    N                      N
                         ↓ Binding to Factor VIII                           Bleeding Time               N                    N                      ↑
                                                                            PT                          N                    N                      N
Mode of Inheritance                                                         APTT                        ↑                    ↑                    ↑/ N
Autosomal Dominant                       Autosomal Recessive                VWF                         N                    N                      ↓
Type I, Type II                          Type III, Type IIN                 Factor VIII                 ↓                    N                 May be ↓
                                                                            Factor IX                   N                    ↓                      N
                                                                            Ristocetin-                 N                    N                  Impaired
                                                                            induce d platelet
                                                                            aggregation




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
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Hereditary Disorders of Other Coagulation Factors

                                       Fibrinogen Deficiency                       Prothrombin (Factor II)                                                                           Combine Factor V, Factor
                                                                                                                        Factor V Deficiency             Factor VII Deficiency                                           Factor X Deficiency        Factor XIII Deficiency
                             Afibrinogenamia         Dysfibrinogenamia                   Deficiency                                                                                      VIII Deficiency
Mode of Inheritance       AR                       AD                         AR                                   AR                              AR                              AR                              AR                         AR
Symptoms                  Bleeding from                                       Bleeding from                        Bleeding from                                                                                    Umbilical Cord,           Umbilical Cord,
                          Umbilical Stump                                     Umbilical Stump                      Umbilical Stump                                                                                  CNS Bleeding              CNS Bleeding
                                                                              Bleeding ↑ Severe                    Bleeding ↑ Severe                                                                                Bleeding from             Bleeding from
                                                                                                                                                                                                                    Umbilical Stump           Umbilical Stump
                                                                                                                                                                                                                    Haematu ria (Frequent)    ↓ Fertility
                                                                                                                                                                                                                    Bleeding ↑ Severe         Recurrent Miscarriages
                          Spontaneous Haematroses, Muscle Haematomas, Permanent damage to MSS (resulting Handicaps), Epistaxis (frequent), Excessive bleeding after trauma (Surgery), Bleeding after ci rcumcision, Haemorrag es in GIT CNS
Treatment                 Cryoprecipitate                                SD-Treated plasma                  SD-Treated plasma                  FVII Concentrate                  SD-Treated plasma                  SD-Treated plasma         Cryoprecipitate
                                                                                                                                                                                                                                              SD-Treated plasma
                                                                                                                                                                                                                                              FXIII concentrate
Investigations   APTT     Prolonged                                           Prolonged                            Prolonged                       Normal                          Prolonged                                                  Prolonged
                 PT       Prolonged                                           Prolonged                            Prolonged                       Prolonged                       Prolonged                                                  Prolonged


SD – Solvent/ Detergent
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Physiotherapy Management of Haemophilia

Aims of Physiotherapy Management
↓ Pain, Swelling
↑ Muscle Power, Control
↑ Range of Joint Movement
Prevent Deformity
↑ unc onal Ca acity
↑ Exercise Tolerance
Prevent urther Injury to susce tible joint

Principles of Physiothera py Management
Strong muscles - Su ort, Protect joints
Weak muscles – Ex ose them to Trauma
S lint in osition of comfort (following acute bleeding)
Strengthen unaffected joints when on bed rest
 actor re lacement (required rior to hysiothera y)(eg. Strenous exercise)
Exercise can be done at
Home
Physiothera y centre

Protocol of Physiothera py Management of Haemophilia
          Acute                     Sub Acute               Chronic
RICE for affe cted area     RICE                    actor Re lacement
Su ort for joint (s lint) Su ort                   Electrothera y
Active exercise             Isometric Exercise     Exercises
Unaffected Li mb            Affected Joint         Mobilising
Unaffected Joint of         Active Exercise        Strengthening
affected limb               Unaffected Li mb       Stretching
                            Unaffected Joint of    Pro rioce tive
                            affected limb          Coordination
                            Electrotherapy         Balancing
                            (relief pain)          Postural corrective
                            Ultrasound             Gait Training
                            SWD                    Hydrothera y
                            TENS                   Training of functional
                            IT                     activities
RICE – Rest, Ice, Com ression, Exercise
TENS – Transcutaneous Electrical Nerve Stimulation

Recreational Activities
            Recommended                               Discouraged
Swimming                                  ootball
Cycling                                  Boxing
Walking                                  Skating
Darts                                    Volleyball
Ping ong                                 Jum ing
Bowling                                  Basketball
Snooker                                  Skiing
Golf
Tennis
Jogging
Weight lifting
Gymnastics

								
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