8. Abnormalities of haemostasis Flashcards
What are common causes of minor bleeding?
- Family history
- Easy bruising
- Gum bleeding
- Frequent nosebleeds
- Bleeding after tooth extraction
- Post-operative bleeding
What are the common causes of minor bleeding, in women?
- Menorrhagia
* Post-partum bleeding
When would bleeding be considered abnormal?
- Epistaxis (nosebleed) not stopped by 10 minutes of compression
- Cutaneous haemorrhage or bruising without apparent trauma
- Prolonged (>15min) bleeding from trivial wounds recurring spontaneously in 7 days after wound
- Spontaneous GI bleeding => anaemia
- Menorrhagia requiring treatment or => anaemia, (not due to structural lesions)
- Heavy, prolonged bleeding after surgery/dental extractions
What usually causes abnormal haemostasis?
• Lack of specific factor (quantitative defect)
- failure of production: congenital and acquired
- increased consumption/clearance
• Defective function of a specific factor (qualitative defect)
- genetic defect
- acquired defect e.g. drugs
What can lead to disorders of primary haemostasis?
Problems with platelets
• Low numbers - bone marrow failure, accelerated clearance, pooling and destruction in enlarged spleen
• Impaired function - acquired due to drugs e.g. NSAIDs, hereditary absence of glycoproteins
Name a common cause of thrombocytopenia
Auto-Immune Thrombocytopenic Purpura (auto-ITP)
How are platelets ‘sensitised’?
• By platelet autoantibodies coating them
• whole complex cleared by the reticulo-endothelial system
Name 3 diseases/causes of hereditary platelet defects
- Glanzmann’s thrombasthenia - lack of GpIIb/IIIa, autosomal recessive
- Bernard Soulier syndrome - lack of Gp1b, autosomal recessive
- Storage pool disease - broad term, issues with granular storage and release
- Glycoproteins are important in reversible adhesion to surfaces, and irreversible adhesion to each other
- Disorder => problems with primary haemostasis
What causes Von Willebrand disease?
- Hereditary decrease of quantity and function
- Acquired due to antibody (acquired vW syndrome)
- Can’t initiate primary haemostasis
What are the 2 functions of vWF in haemostasis?
- Binding to collagen and capturing platelets
* Stabilising factor VIII
What can causes problems with the vessel wall (leading to disorders of primary haemostasis)?
- Inherited - hereditary haemorrhagic telangiectasia, Ehlers-Danlos syndrome and other connective tissue disorders
- Acquired defects - scurvy, steroids, ageing, vasculitis
What are petechiae?
- Small blood spots in thrombocytopenia
- Appear spontaneously
- Pathognomonic sign of low platelet count
How can you test for disorders of primary haemostasis?
- Platelet count, morphology
- Bleeding time
- Assays of vWF
- Clinical observation
What is the role of the coagulation cascade in secondary haemostasis?
- Generate a burst of thrombin
- This converts fibrinogen into fibrin
- Necessary in larger vessels
What can you use to illustrate thrombin generation?
Thrombogram
Summarise the causes of secondary haemostasis disorders
- Deficiency of coagulation factors - hereditary failure of production, acquired
- Increased consumption (acquired) - DIC, immune autoantibodies
Why does haemophilia cause problems with bleeding?
- Have collagen vWF and platelets, so primary platelet plug is formed
- Factor 8 or 9 affected
- Not enough thrombin produced - plug will fall apart
- Delayed bleeding
How does liver disease affect secondary haemostasis?
- Most coagulation factors synthesised in the liver
* However, anticoagulants are also made in the liver, so this tends to balance out
What are the acquired causes of defects in secondary haemostasis?
- Liver disease
- Drugs (warfarin)
- Dilution (red cell transfusions - without plasma)
- Consumption (DIC)
How serious are different coagulation factor deficiencies?
- Factor 8 + 9 (haemophilia) - severe but compatible with life
- Factor 2 (prothrombin deficiency) - lethal
- Factor 11 - bleed after trauma, not spontaneous
- Factor 12 - no excess bleeding at all
What causes disseminated intravascular coagulation (DIC)?
- aka consumptive coagulopathy
- Generalised activation of coagulation - tissue factor is triggered - uncontrolled
- Consumes and depletes coagulation factors and platelets
- Activation of fibrinolysis depletes fibrinogen - increases fibrin degradation products (FDPs)
- Deposition of fibrin in vessels causes organ failure
- Associated with sepsis, obstetric causes, major tissue damage and inflammation
What are the consequences of DIC?
- Widespread bleeding from IV lines, bruising + internal
* Organ failure
Outline the patterns of bleeding in problems with secondary haemostasis?
- Often delayed
- Prolonged, stop-start
- Deeper: joints and muscles
- Bruising
- Delayed, prolonged bleeding after trauma/surgery
- Bleeding after IM injections
- Nosebleeds are rare
- Superficial cuts don’t bleed due to platelets - primary is ok
What is the hallmark of haemophilia?
Haemarthrosis - bleeding into the joints
• pressure builds up
• joint becomes swollen and painful
How can you test for disorders of secondary haemostasis (coagulation disorders)
- Screening tests - PT, APTT, full blood count
- Factor assays
- Test for inhibitors
What is the APTT and PT in haemophilia?
- APTT - prolonged, not making factor 8 or 9
* PT - normal - extrinsic pathway not affected
Which bleeding disorders are not detected by routine clotting tests?
- Mild factor deficiencies
- vW disease
- Factor 13 deficiency
- Platelet disorders
- Excessive fibrinolysis
- Vessel wall disorders
- Metabolic disorders
What are the hereditary and acquired disorders of fibrinolysis?
- Hereditary - antiplasmin deficiency
* Acquired - drugs (e.g. tPA), DIC
Outline the genetics of haemophilia and vW disease?
Haemophilia
• X-linked recessive
• Disease tends to be carried by females, and affects males
• Varying degrees of lyonization
vW disease
• Autosomal
• Type 1 + 2 - autosomal dominant
• Type 3 (and the rest) - autosomal recessive (rare)
How do you treat abnormal haemostasis, with references to general causes
- Failure of production - replace missing factor/platelets, stop drugs causing it
- Immune destruction - immunosuppression, splenectomy for ITP
- Increased consumption - treat the cause of the DIC, replace what is missing
What can factor replacement therapy involve?
• Plasma - contains all coagulation factors
• Cryoprecipitate - rich in fibrinogen, factor 8 + 13, vWF
• Factors concentrates
- all factors except factor 5
- prothrombin complex concentrates (PCCs): factors 2, 7, 9, 10
• Recombinant forms of factor 8 and 9 available
How could haemophilia be treated (in the future)?
Gene therapy
What novel approaches are there in development for haemostatic disorders?
- Bispecific antibodies
- Anti-TFPI antibodies
- Antithrombin RNAi
How can desmopressin (DDAVP) act as a haemostatic treatment?
- Vasopressin derivative
- Causes 2-5 fold rise in vWF and factor 8
- Causes released from endogenous stores - only useful in mild disorders
- Can be given as a nasal spray (300μg) or IV (0.3μg/kg)
How can tranexamic acid act as a haemostatic treatment?
• Inhibits fibrinolysis (binding of tPA to fibrin)
• Widely distributed, crosses placenta, low conc. in breast milk
• Adjunctive therapy
- IV: 0.5g tds (three times a day)
- oral: 1.5g tds
- mouthwash: 1g (10ml 5%) qds (four times a day)
