BLEEDING & CLOTTING

DISORDERSDr. M. A Sofi

MD; FRCP (London); FRCPEdin; FRCCSEdin

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.

BLEEDING DISORDERS:

X-linked recessive inheritance

Coagulation factor VIII, procoagulant component

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.

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 50-200%

HEMOPHELIA

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%

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.

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.

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

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

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

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

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.

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.

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

Laboratory findings:Laboratory studies for suspected hemophilia include: Complete blood cell

count Coagulation studies FVIII assayExpected laboratory values are: Hemoglobin/hematocrit:

Normal or low Platelet count: Normal Bleeding time and

prothrombin time: Normal

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

Imaging studies:

Disorders of fibrinogen or fibrinolytic production.

Platelet disorders. Blood vessel

disorders. Acquired hemophilia Glanzmann

Thrombasthenia Ehlers-Danlos

syndrome

HEMOPHELIA

Differential diagnosis Haemophilia B (factor

IX deficiency). Von Willebrand's

disease. Vitamin K

deficiency/antagonism with anticoagulants.

Hemophilia C (factor XI deficiency).

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.

MANAGEMENT

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).

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.

MANAGEMENT

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.

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.

MANAGEMENT

Scheduled surgical procedures

Aim for 50-100% 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

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.

MANAGEMENT

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 18-20 weeks.

Third-trimester amniocentesis may be considered where confirmation of an affected male fetus will influence management at delivery.

Complications 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

MANAGEMENT

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.

Prevention 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

MANAGEMENT

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

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.

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.

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

Von Willebrand's Disease

EtiologyI. Hereditary - three types vWD Type I, vWD Type II, and vWD Type III Within the three inherited types of vWD there are

various subtypes. II. 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.

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 variesFour  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

Von Willebrand's Disease

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.

Von Willebrand's Disease: Subtypes of 2

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.

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.

Von Willebrand's Disease: Investigations

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

Von Willebrand's Disease: Differential diagnosis

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.

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.

Von Willebrand's Disease: Management