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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
↑ FuncNonal Capacity
↑ Exercise Tolerance
Prevent Further Injury to susceptible joint

Principles of Physiothera py 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 Physiothera py Management of Haemophilia

Acute Sub Acute Chronic
RICE for affe cted area RICE Factor Replacement
Support for joint (splint) Support Electrotherapy
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 Proprioceptive
affected limb Coordination
Electrotherapy Balancing
(relief pain) Postural corrective
Ultrasound Gait Training
SWD Hydrotherapy
TENS Training of functional
IT activities
RICE – Rest, Ice, Compression, Exercise
TENS – Transcutaneous Electrical Nerve Stimulation

Recreational Activities
Recommended Discouraged
Swimming Football
Cycling Boxing
Walking Skating
Darts Volleyball
Ping pong Jumping
Bowling Basketball
Snooker Skiing
Golf
Tennis
Jogging
Weight lifting
Gymnastics