1. BLEEDING & CLOTTING DISORDERS
Dr. M. A Sofi
MD; FRCP (London); FRCPEdin; FRCCSEdin

2. BLEEDING DISORDERS:
Hemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting, which is used to stop bleeding when a blood vessel is broken.
Hemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, present in about 1 in 5,000– 10,000 male births.
Hemophilia B (factor IX deficiency) occurs in around 1 in about 20,000–34,000 male births.
Hemophilia C – Inherited deficiency of factor XI; also called Rosenthal syndrome; an autosomal recessive disorder
Like most recessive sex-linked, X chromosome disorders, hemophilia is more likely to occur in males than females.
Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation.

3. Coagulation factor VIII, procoagulant component
X-linked recessive inheritance

4. Queen Victoria passed hemophilia on to some of her descendants.
Ryan White an American hemophiliac who became infected with HIV/AIDS through contaminated blood products.

5. HEMOPHELIA Disorder caused by deficiency of clotting factor VIII.
Inherited but acquired forms do exist, largely in older patients, due to autoantibodies directed against factor VIII or hematological malignancy.
Severity of disease depends upon levels of remaining factor activity, with normal range expressed as %
Severity of factor VIII deficiency
Severity
Factor VIII activity level
Age of presentation
Percentage of sufferers
Severe disease
<1%
Infancy
43-70%
Moderate disease
1-5%
Before 2 years
15-26%
Mild disease
>5%
Older than 2 years
15-31%

6. ETIOLOGY
Haemophilia A results from heterogeneous mutations in the factor VIII gene that map to Xq28.
Carrier detection and prenatal diagnosis can be carried out by testing against the range of known mutations or indirectly by linkage analysis.
There is marked phenotypical variability leading to a spectrum of severity.
Inheritance is usually X- linked recessive, affecting males born to carrier mothers
There is usually a clear family history but sporadic cases do occur due to novel mutations or effects of mosaicism.
Females born to affected fathers can (rarely) have the disease due to homozygosity for the gene, where there is marriage to close relatives.

7. PRESENTATION
Neonatal bleeding in around a third to a half of cases. This may follow circumcision or other operative procedures.
ICH occurs in approximately 5% of all untreated
History of spontaneous bleeding into joints, especially the knees, ankles and elbows, without a history of significant trauma.
Spontaneous haemarthroses are virtually pathognomonic
Intramuscular hemorrhage may also occur.
Gastrointestinal and mucosal hemorrhage do occur but are more often associated with haemophilia B/von Willebrand's disease.
Hematuria may be a feature, which can vary from self- limiting minor episodes to gross hematuria

8. PRESENTATION Signs and symptoms
Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage.
Signs of hemorrhage include:
General: Weakness, orthostasis, tachycardia, tachypnea
Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
Gastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal pain
Genitourinary: Hematuria, renal colic, and post circumcision bleeding

9. PRESENTATION Untreated cases of severe disease
Arthropathy and joint deformity - may require replacement of affected joints. 
Soft tissue hemorrhages - common; may cause complications, including compartment syndrome and neurological damage.
Extensive retroperitoneal bleeds - with hemodynamic compromise.
Hematoma formation - spontaneously or following trauma and may require fasciotomy.
Moderate disease
Often presents with bleeding following venepuncture.
Mild disease
Only bleed after major trauma or surgery, with moderate disease after minor trauma or surgery.

10. Laboratory findings:
Laboratory studies for suspected hemophilia include:
Complete blood cell count
Coagulation studies
FVIII assay
Expected laboratory values are:
Hemoglobin/hematocrit: Normal or low
Platelet count: Normal
Bleeding time and prothrombin time: Normal
Activated partial thromboplastin time (aPTT):
Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophilia
Screening tests include: PT
aPTT (Normal aPTT does not exclude the possibility of mild hemophilia)
Platelet count

11. Imaging studies:
Imaging choices are guided by clinical suspicion and the anatomic location of involvement:
CT brain without contrast to assess for spontaneous or traumatic ICH
MRI scans of the head and spinal column for further assessment of spontaneous or traumatic hemorrhage
MRI is also useful in the evaluation of the cartilage, synovium, and joint space
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions

12. HEMOPHELIA Differential diagnosis
Haemophilia B (factor IX deficiency).
Von Willebrand's disease.
Vitamin K deficiency/antagonism with anticoagulants.
Hemophilia C (factor XI deficiency).
Disorders of fibrinogen or fibrinolytic production.
Platelet disorders.
Blood vessel disorders.
Acquired hemophilia
Glanzmann Thrombasthenia
Ehlers-Danlos syndrome

13. MANAGEMENT
Doses should be tailored to the individual - e.g., just before physical education lessons.
Prophylaxis should be encouraged to continue until physical maturity is achieved.
If after stopping prophylaxis further spontaneous hemorrhage occurs then prophylaxis should be reinstated.
Some patients will need to have long-term prophylaxis - e.g., ICH with no other cause.
Prophylaxis
Children with severe hemophilia should receive prophylactic infusions (once- weekly or, ideally x 3/week of factor VIII to prevent hemarthroses and other bleeding episodes.
This should begin before the occurrence of a second joint bleed or significant soft tissue bleed (associated with possible reduced risk of development of haemarthrosis in later life).

14. MANAGEMENT
Fresh frozen plasma and cryoprecipitate should only be used in an emergency.
The aim is to correct factor VIII activity to 100% for severe and to 30-50% for minor hemorrhage.
Enhanced factor VIII levels are maintained for 7-10 days for severe bleeds and for 1-3 days for minor bleeds.
Desmopressin and aminocaproic acid may be used to boost factor VIII activity and reduce factor VIII administration requirements.
Acute bleeding episodes 
Patients who are able should administer their normal factor VIII, until they attend hospital.
Fresh frozen plasma containing factor VIII, monoclonal-antibody purified factor VIII and recombinant factor VIII are the available sources of factor VIII used to treat acute hemorrhage, with recombinant factor VIII preferred.

15. MANAGEMENT
Infants usually receive prophylaxis from the age of 2 years. However, if bleeding risk is high, prophylaxis at an earlier age should be considered.
There is strong evidence that prophylactic treatment can preserve joint function in children with hemophilia compared to on-demand treatment.
Scheduled surgical procedures
Aim for % factor activity for 2-7 days after surgery.
In brain or prostate surgery, nearer 100% is required.
Desmopressin may help increase factor levels.
Prophylaxis is usually given for those with severe disease, as intermittent recombinant factor VIII injections or continuous infusion

16. MANAGEMENT
Mode of delivery should be informed by both obstetric and haemostatic factors.
The diagnosis of hemophilia should be established using uncontaminated cord blood as soon as possible following delivery.
Recombinant factor VIII should be given as soon as the diagnosis is confirmed.
Pregnancy
Pregnant women with hemophilia carrier should be undertaken by an experienced obstetrician in conjunction with a haemophilia expert.
Fetal sexing undertaken by maternal blood sampling at around 10 week or by U/S scan between weeks.
Third-trimester amniocentesis may be considered where confirmation of an affected male fetus will influence management at delivery.

17. MANAGEMENT Complications Monitoring
Degenerative joint disease due recurrent hemarthrosis.
Antibody inhibitor formation affects about 25–30%.
Risk of life-threatening hemorrhage.
Risk plasma-derived factor VIII, infection with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV).
Immune toleration induction (ITI) is recommended for patients with severe hemophilia A
Monitoring
Prophylaxis phase clinical and laboratory markers used for monitoring.
Adherence should regularly be determined and noted.
Factor VIII levels routinely measured.
Inhibitor levels checked at regular intervals.
Radiological surveillance of joints is not needed unless there is a specific indication.

18. MANAGEMENT Prevention Prognosis
Genetic screening for carrier mothers and affected families.
Patient education helps to prevent morbidity and mortality associated with acute bleeds.
Medical emergency identification bracelets or similar can help to identify sufferers rapidly in case of hemorrhage/trauma, etc
Prognosis
Much improved with modern recombinant factor VIII and approaches near-normal life expectancy.
Those infected with HIV or other blood-borne viruses carry a worse prognosis.
Avoid competitive sports which will increase the risk of hemarthroses and head injuries.
Encourage to take part in other sports - e.g., racquet sports, athletics or swimming

19. Von Willebrand's Disease
This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. 
Pathophysiology
Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF).
vWF is a multimeric glycoprotein encoded for by gene map locus 12p13. 
It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions:
It assists in platelet plug formation by attracting circulating platelets to the site of damage.
It binds to coagulation factor VIII preventing its clearance from the plasma.

20. Von Willebrand's Disease
Epidemiology
Prevalence is as high as 1-2% in the general population on unselected screening.
Worldwide incidence is around 125 per million with between 0.5 and 5 per million being severely affected.
Most patients have mild disease.
It is more common in females.
It is more severe with blood type O.

21. Von Willebrand's Disease
Presentation
This varies according to the extent of the deficiency:
Bleeding tendency from mucosa - e.g., epistaxis, menorrhagia (consider in women with no other obvious cause).
Spontaneous bleeding - e.g., internal or joint bleeding (only in the most severe of cases).
Delayed bleeding - May occur up to several weeks after surgery
Heavy bleeding - Common after tooth extraction or other oral surgery, such as tonsillectomy and adenoidectomy
Menorrhagia - Common presenting complaint in women
Exacerbation of bleeding symptoms - After ingestion of aspirin
Amelioration of bleeding symptoms with use of oral contraceptives

22. Von Willebrand's Disease
Etiology
Hereditary - three types
vWD Type I, vWD Type II, and vWD Type III
Within the three inherited types of vWD there are various subtypes.
Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in:
Lymphoproliferative
Myeloproliferative disorders
Solid tumors
Immunological disorders
Cardiovascular disorders e.g., aortic stenosis, 
Wilms'tumor, 
Hypothyroidism.

23. Von Willebrand's Disease
Types of hereditary von Willebrand's disease (vWD)
Type 1
60-80%
Quantitative defect (19-45% of enzyme level present)
Heterozygous for defective gene
Inherited as AD
Normal lifespan
Occasionally easy bruising and/or menorrhagia
Bleeding after dental work, major surgery
Type 2
20-30%
Qualitative defect - multimers abnormal or subgroups absent
Usually AD inheritance (rarely AR)
Bleeding tendency varies
Four  subtypes: 2A, 2B, 2M, 2N
Type 3
Rare - the most severe form; 1-5% of cases
Quantitative - levels very low or undetectable
Homozygous for defective gene
AR inheritance
No vWF antigen
Low factor V
Severe mucosal bleeding
May have haemarthrosis (as in haemophilia
Platelet type
Rare - fewer than 70 cases described
Functional mutations of vWF receptor on platelet
Autosomal dominant

24. Von Willebrand's Disease: Subtypes of 2
Type 2A
Abnormal synthesis or proteolysis of vWF multimers.
Leads to small multimers in circulation; factor VIII still binds as normal.
Type 2B
Spontaneous binding of platelets with rapid clearance of platelets and large vWF multimers.
Mild thrombocytopenia.
Factor VIII binding normal or low normal.
Desmopressin will not help, as it leads to unwanted platelet aggregation.
Type 2M
Low or absent binding to receptor on platelets.
Factor VIII binds as normal.
Type 2N
Autosomal recessive rather than X-linked.
Shows incomplete response to haemophilia A treatment.
Factor VIII levels reduced to around 5%, as vWF has a reduced affinity for factor VIII.

25. Von Willebrand's Disease: Investigations
The severity of vWD varies and many patients will never be diagnosed, as their disorder may never come to light
Bloods including FBC, fibrinogen level, platelet count, clotting screen, factor IX levels. The platelet count and morphology are normal.
Plasma levels of vWF - deficiency can be quantitative or qualitative.
Quantitative deficiency - detected by vWF antigen assay.
Qualitative deficiency - detected by a glycoprotein binding assay, ristocetin cofactor activity, ristocetin- induced platelet agglutination.

26. Von Willebrand's Disease: Investigations
Factor VIII measurement:
Factor VIII binds to vWF which in turn prevents the rapid breakdown of factor VIII; thus, a deficiency of vWF can also lead to deficiency of factor VIII.
In type 2 vWF - factor VIII levels are normal; studies of platelet aggregation with sub-endothelium are necessary.
Estrogens, vasopressin and growth hormone all elevate levels.

27. Von Willebrand's Disease: Differential diagnosis
Conditions to consider in the differential diagnosis of von Willebrand disease include the following:
Hemophilia A
Hemophilia B
Bernard-Soulier syndrome
Platelet function defects
Antiplatelet drug ingestion
Fibrinolytic defects
Platelet-type (or pseudo) vWD
Acquired vWD
Factor X
Factor XI Deficiency
Hemophilia A

28. Von Willebrand's Disease: Management
Provide advice regarding drugs that must be avoided such as non-steroidal anti- inflammatory drugs and antiplatelet drugs.
Minor bleeding problems,, may not require any treatment.
The two main treatment options are:
Desmopressin (DDAVP)
Transfusion therapy.
Platelet transfusions may be helpful with disease refractory to other therapies.
DDAVP can be used to treat bleeding complications or to prepare patients for surgery.

29. Von Willebrand's Disease: Management
Prophylaxis in major surgery or for treatment of serious bleeding episodes, vWF-containing factor VIII concentrates are the treatment of choice. 
DDAVP is first-line in type I vWD.
In all other types, factor VIII-vWF concentrates are first line therapy
In type 2B, DDAVP may cause a paradoxical drop in the platelet count and should not be used without prior testing to see how the patient responds.
DDAVP is ineffective in type 3 as there are no vWF levels to boost.
Patients who have alloantibodies to vWF will require recombinant factor VII.