Bleeding Disorders Flashcards
What are bleeding disorders?
Symptoms vary from easy bruising to spontaneous or life-threatening haemorrhage
Occur when components of haemostasis are deficient to an extent that you get excess bleeding
Abnormal bleeding:
- Vascular disorders (not enough constriction)
- Vascular and platelet disorders tend to be associated with
bleeding from mucous membranes and skin, e.g. nose bleeds
- Vascular and platelet disorders tend to be associated with
- Thrombocytopenia (100/400 x10^9 per L is a normal platelet
count,<150 is thrombocytopenia, but needs to be lower than
that to be symptomatic) - Defective platelet function (haemolytic cascade - not
reinforcing plug) - Defective coagulation
- Coagulation disorders bleeding is often into the joints or soft tissue
What are common symptoms of bleeding disorders?
- Epistaxis
- Gingival bleeds
- Bruising
- Purpura
- Petechiae
- Menorrhagia
- Joint bleeds
- Muscle bleeds
- Chronic anaemia
What are examples of acquired and inherited bleeding disorders?
Acquired:
Vitamin K deficiency
Liver disease
- most coag factors are made in the liver
Disseminated intravascular coagulation
Massive blood loss
Auto-antibodies
- Haemophilia develops autoantibodies to factor 8.
In theory you can get an inhibitor to any coag factors as they
are proteins!
Inherited: Haemophilia Von Willebrand Disease Bernard-Soulier syndrome Glanzmann's thrombasthenia
What is vitamin K deficiency?
Vitamin K serves as an essential cofactor for a carboxylase that catalyses carboxylation of glutamic acid residues on vitamin K-dependent proteins
Key vitamin K-dependent proteins include:
• Coagulation proteins: factors II (prothrombin), VII, IX and X
• Anticoagulation proteins: proteins C, S and Z
Need to post-translationally modified to be active
Leads to a prolonged APTT AND PT
- Affecting all parts of all three pathways
Deficiency can be caused by:
1. malabsorption of fat-soluble vitamins
2. oral anticoagulation therapy (e.g. warfarin),
3. liver disease
4. dietary deficiency associated with antibiotic treatment that
destroys gut bacteria that can synthesize vitamin K.
5. newborn infants have low levels of vitamin K and are at risk of
intracranial bleeds – breast fed infants will receive vitamin K
injections
How does liver disease cause bleeding disorders?
The clotting factors that are produced by the liver are I, II, V, VII, IX and X and some FVIII
The order in which the levels of these are reduced in liver disease is:
- VII - the earliest to be reduced
- II, X - next to be reduced
- I, V - these persist despite severe liver disease
Patients with liver disease therefore have prolonged prothrombin times and a tendency to bleed
What is Disseminated intravascular coagulation (DIC)?
Inappropriate activation of blood coagulation:
— Generation and deposition of fibrin
— Leads to microvascular thrombi in various organs
— Consumption and subsequent exhaustion of coagulation proteins
and platelets
- Clinical features usually dominated by bleeding
- Caused by a wide variety of conditions such as trauma, shock, infection and pregnancy complications
(a) Confluent purpura of arm
(b) Peripheral gangrene of feet
Tends to be when you have had shock, almost always with sepsis.
Total disregulation of haemostasis coagulation
Lots of fibrin microdesposited over vessels = lots of microthrombi that use up all the platelets
Because it is all used up you get lots of bleeding
clinical features are a bleeding phenotype due to innapropriate clotting.
Medical emergency: SYMPTOM NOT DISEASE IN ITSELF
Pathogenesis:
- Activation of hemostasis by triggering processes leads to clotting
and bleeding simultaneously
- Intravascular fibrin formation results in occlusion of vessels
- During clotting, several coagulation factors and platelets are
consumed, leading to bleeding.
What is haemophilia?
Haemophilia, which means love “philia” of blood
Prolonged and excessive bleeding
X chromosome-linked bleeding disorders
Deficiency of FVIII is haemophilia A
- Inherited bleeding disorder resulting from low functional levels
of blood coagulation factor VIII
- Caused by mutations in the coagulation factor VIII gene
- Most common of the severe inherited bleeding disorders (1 case
per 5,000 male births)
- Bleeding episodes may be more frequent in childhood and
adolescence than in adulthood.
- Approximately 10% of carrier females are at risk for bleeding
Deficiency of FIX is haemophilia B (Christmas disease)
How is haemophilia diagnosed?
If haemophilia is already known to be in the family, the disorder is usually diagnosed before the occurrence of significant bleeding
Usually in the neonatal period or earlier by prenatal diagnostic methods
In sporadic cases (30%–40% of cases), the severe patients are diagnosed before the age of one year because of mucosal or soft tissue haemorrhages, usually after trauma
The diagnosis of haemophilia A is established in individuals with low factor VIII clotting activity in the presence of a normal von Willebrand factor (VWF) level
- Because one of the function of VWF is to stabilise factor 8 and
prevent it from degradation. In haemophilia you have low factor
8, but VWF is fine.
Molecular genetic testing of F8, the gene encoding factor VIII, identifies
pathogenic variants in as many as 98% of individuals with haemophilia A
What are the symptoms of haemophilia?
General - Weakness and orthostasis
Musculoskeletal (joints)
—Tingling, cracking, warmth, pain,
Central nervous system (CNS)
Headache, stiff neck, vomiting, lethargy, irritability, spinal cord syndromes
Gastrointestinal (GI)
—Haematemesis, abdominal pain
Genitourinary
—Haematuria, post-circumcision bleeding
Excessive bleeding with routine dental procedures
What are the genetics of haemophilia?
Haemophilia A and B are X-linked recessive
Genes are close together on the long arm of the X chromosome.
Factor VIII gene is relatively large.
Deletions account for 5% of cases frameshift, missense and inversions are also seen.
‘Flip’ inversion- 50% of severe cases
What is Von Willebrand’s disease?
Most common hereditary coagulation abnormality -1 in 10 000
A quantitative or qualitative defect in von Willebrand factor VWD affects
individuals of all ethnic backgrounds, and the clinical symptoms can present at any age
VWF in primary haemostasis
- Serves as a bridge between GPIb/IX receptors on activated
platelets and subendothelial collagen exposed when the vessel
is injured
VWF in secondary haemostasis
- Complexes and stabilises FVIII in plasma
Different types of VWD:
1: not producing enough
3: not producing any
2: producing it but it isn’t working properly
On an autosomal chromosome - so males and females are equally affected
VWD is divided into three major categories:
- Type I – Partial quantitative vWF deficiency
- mild to moderate quantitative deficiency of VWF - Type II – Qualitative vWF deficiency
- qualitative deficits in VWF - Type III - Total vWF deficiency
- severe quantitative deficiency of VWF
Type 1, 2A, 2B, and 2M is an autosomal dominant trait
Type 3 and 2N is inherited as autosomal recessive
What are symptoms of VWD?
Nosebleeds (epistaxis) and haematomas
Easy bruising - common but nonspecific
Prolonged bleeding - after minor trauma to skin or mucous membranes
Oral cavity bleeding
Excessive menstrual bleeding (menorrhagia)
— amelioration of bleeding symptoms with use of oral contraceptives
Gastrointestinal and Joint bleeding rarely occurs.
Delayed bleeding - may occur up to several weeks after surgery
Exacerbation of bleeding symptoms - After ingestion of aspirin
How is VWD treated?
The two main treatment options for patients with von Willebrand disease (vWD) :
- desmopressin (DDAVP)
- von Willebrand factor/factor VIII (vWF/FVIII) concentrates
DDAVP causes the release of VWF from endothelial stores
Antifibrinolytic drugs (tranexamic acid) can be used to treat mild mucocutaneous bleeding
Topical agents (eg, fibrin sealants) for dental surgery and for surface wound bleeding
Platelet transfusions may be helpful in some patients with vWD
(eg, type 3)
- Cryoprecipitate and fresh frozen plasma contain functional vWF
but should be avoided if at all possible because of the potential
transmission of viral disease
