Week 6 - Haemostasis Flashcards
What are the indications for the evaluation of bleeding disorders?
- Asymptomatic patients undergoing a surgical procedure if personal or family history of bleeding is a concern.
- Patients with a history of increased bleeding, easy bruising, delayed wound healing.
- Patients with a previous bleeding disorder diagnosis.
• Detailed history is important. Family history, drugs etc.
• Lab tests: FBC, platelet count (platelets commonest cause of bleeding clinically), PTT, PT, fibrinogen/TT (thrombin time).
• Other factor assays, platelet function studies, bone marrow exam - only on special indications.
• Suspected VWD (combined platelet function and FVIII deficiency):
- VWF:Ag
- VWF:Rcofactor assay (plt function study)
- Factor VIII (levels)
Identify the clinical features of bleeding disorders.
• Superficial bleeding usually due to blood vessel/platelet disorder.
- Petechiae
- Purpura
- Echymosis
• Deep bleeding usually due to coagulation disorders (more common with congenital disorders).
- Haematoma
- Joint bleeds
• When severe - there is no differentiation i.e. a platelet disorder can give rise to a deep haematoma and severe coagulation disorders can give rise to superficial bleeding.
Outline the diagnosis of bleeding disorders.
- History
• Age, duration, spontaneous or induced, severity.
• H/o fever, drugs (aspirin, warfarin), other disease.
• Personal and family history of bleeding tendency. - Physical Examination - to differentiate between superficial bleed (platelet) or deep (coagulation).
• Site of bleeding - superficial or deep (plt/coag)
• Joints in haemophilia, oral cavity in platelet deficiency etc. - Laboratory Investigations
• FBC/platelet count, PT/INR, aPTT and TT, bleeding time.
• Urine and stool (occult) test for blood.
• Factor Assay, platelet function tests, bone marrow - rare - specialised investigations.
• Anticoagulants.
How are blood samples stored?
- Blood sample in sky blue cap: sodium citrate.
- Sample usually sent in sky blue cap which is sodium citrate → binds calcium and halts all coagulation processes. Therefore, preserves all the coagulation factors.
Describe the basic tests for bleeding disorders.
• Bleeding time
- Normal: < 10 minutes.
- Prolonged in blood vessel/platelet disorders.
- Not routine.
• Platelet count
- Important - platelets are the commonest cause of bleeding clinically.
• Prothrombin time (PT)
- Tests extrinsic and common pathway (factor VII + I, II, V, X).
- Prolonged in acquired disorders, liver disease, warfarin therapy, vitamin K deficiency.
- INR (international normalised ratio) - correction of different thromboplastin reagent (animal product). Normal 0.9-1.3.
• Partial thromboplastin time (PTT or aPTT)
- Tests intrinsic and common pathway (factor VIII, IX, XII + I, II, V, X).
- Prolonged in congenital bleeding disorders e.g. VWD, haemophilia.
- When PT and PTT both increased → suspect problem in the common pathway.
• Thrombin time (TT)
- Tests fibrinogen levels (common pathway).
- Useful in DIC.
- Not routine.
- Used when both PT and PTT are abnormal (mainly used for fibrinogen levels).
• FDP/D-dimer
- Fibrin degradation products.
- Increased in DIC.
- Specialised investigation.
Describe the test principle for PT and PTT.
- For both PT and PTT, take patient’s plasma which is preserved in sodium citrate (blocks all the calcium) - all coagulation factors are in their original non-activated state.
- PT - add tissue thromboplastin to start PT test → incubate and add calcium, immediately extrinsic pathway is activated. The time for clot formation is measured (the time from adding calcium to the formation of a clot).
- PTT - use cephalin and kaolin which activates the surface factors. Then add calcium and start the clock. Time taken to clot → PTT.
How do you differentiate a clotting factor deficiency from a clotting factor inhibitor?
• Prolonged PT/aPTT → mix patient’s plasma with normal plasma (1:1) and incubate.
• If PT/aPTT corrects → clotting factor deficiency (the normal plasma has provided the deficient factor).
• If PT/aPTT inhibited → inhibitor (inhibits the normal plasma too and therefore remains prolonged). Conduct further testing to determine type of inhibitor.
- Drug: heparin, direct thrombin inhibitor.
- Specific factor inhibitor e.g. FVIII or FV.
- Non-specific inhibitor: lupus anticoagulants.
What is a thromboelastogram (TEG)?
- Quick test before and during major surgery e.g. open heart surgery.
- Measures clot formation, strength and its lysis.
- Global assessment of haemostatic function.
- Line diagram of clot formation - shape indicates type of disorder e.g. fibrinolysis (excess fibrinogen - clot breaks down faster).
Identify the lab findings of common haemostasis disorders:
- ITP
- VWD
- Haemophilia
- DIC
- Aspirin
- Warfarin or heparin
Platelet count, BT, PT, PTT:
• ITP - decreased, increased, normal, normal.
• VWD - normal, increased, normal, increased.
• Haemophilia - normal, normal, normal, increased.
• DIC - decreased, increased, increased, increased.
• Aspirin - normal, increased, normal, normal.
• Warfarin or heparin - normal, normal, increased, increased.
What is the commonest cause of bleeding?
Thrombocytopenia (decreased platelets). • Immune - autoantibodies to platelets. • Drugs. • Infections - especially viral. • Marrow disease.
Describe the production of platelets.
- Megakaryocytes under the influence of thrombopoietin hormone → mature and divide endomitotically and the cytoplasm fragments separate out as platelets.
- The platelets are loaded with coagulation factors that help in haemostasis.
- Lifespan is 10 days - either used up in haemostasis or destroyed in spleen.
- Bleeding usually superficial and small blood vessels (capillary damage). Clinically produce petechiae, purpura, ecchymosis.
Outline platelets.
• Normal wear and tear of endothelium (microscopic damages) healed by platelet adhesion and aggregation, no need for coagulation.
• Platelets contain many factors (of haemostasis) - ADP, calcium, VWF, PF4 (platelet factor 4), fibrinogen.
- Disorders of platelet granules: platelets are present but non-functional or surface glycoproteins.
- Platelet disorders usually lead to small capillary bleeds.
• Platelet counts (x10^9/L)
- Normal: 150-450
- Excess bleeding: <50
- Spontaneous bleeding: <20
• Thromobocytopenia: - Autoimmune, drugs, infections - Bone marrow suppression - MBA - Increased consumption - DIC, TTP & HUS. • Platelet function disorders (less common): - VWD - Bernard Soulier syndrome - Glanzman thrombasthenia.
What is Immune Thrombocytopenic Purpura (ITP)? What are the 2 types of ITP?
- Autoimmune disorder - IgG antibody against platelets.
- Platelets destroyed in spleen → thrombocytopenia.
- Petechiae, purpura, ecchymosis, easy bruising.
2 types - acute and chronic:
• Acute ITP - common in children, post infection, self limited.
• Chronic ITP - females, 20-40 years, chronic and severe.
Outline the laboratory diagnosis for ITP.
- FBC - thrombocytopenia, giant immature platelets on blood film.
- PT, PTT - normal (coagulation normal - only platelets decrease).
- Bone marrow - increased immature megakaryocytes (in response to loss of platelets).
Describe the aetiology and pathogenesis of viral haemorrhagic fevers?
Aetiology: • Dengue • Chikungunya • Measles • Malaria • Yellow fever • Ebola
Pathogenesis:
• Endothelial damage by virus and anti-viral antibodies - vasculitis → platelet activation → thrombocytopenia → bleeding.
Outline the laboratory diagnosis of viral haemorrhagic fevers.
- Thrombocytopenia.
- PT and PTT usually normal.
• Rarely DIC e.g. Dengue shock syndrome. Activation of coagulation and platelet aggregation.
- Very severe viral infections can also give rise to activation of coagulation.
- Platelets also stimulate coagulation and in that case → would produce DIC with abnormal PT and PTT as well as thrombocytopenia.
Outline haemophilia A and B.
• X-linked recessive. Factor 8 (A) or 9 (B).
• Rare congenital bleeding tendency due to coagulation factor 8 or 9 (both X-linked recessive).
• Haemophilia A - factor 8 deficiency.
• Haemophilia B - factor 9 deficiency.
• Females carriers, males affected.
- Females have 2 X chromosomes - usually have factor levels around 55% and don’t produce any bleeding tendency.
- Males have a single X chromosome - 1% factors → severe bleeding.
Identify the clinical features of haemophilia.
• Mild >5%, severe <1% (>30% factor - no bleeding) - only when coagulation factors <30%, patient may produce mild bleeding. Severe bleeding when coagulation factors <1%.
• Increased wound bleeding and deep haematoma.
- Commonest presentation is excess bleeding following wounds.
- Coagulation important for deep haemorrhages therefore develop deep haematoma and not petechiae or purpura.
• Joint bleeds* (skin/mucosal bleeding - in severe).
- Muscular bleeding, internal haemorrhages all common in coagulation disorders.
- Deeper bleeds in muscles or joints. Young kids develop haematoma in joints - get destroyed as they grow up.
Describe the diagnosis and treatment of haemophilia.
Diagnosis:
• PTT - prolonged (suggests it is affecting intrinsic pathway).
• FVIII assay - deficient.
Treatment:
• DDAVP/FVIII concentrate - DDAVP stimulates endothelium to release the stored factors or FVIII or FIX concentrate can be used.
Outline vitamin K deficiency.
- Acquired.
- Vitamin K - present in green veg and intestinal bacteria.
- Necessary for carboxylation of factors 2, 7, 9, 10 in liver.
- Causes - diet, drugs and liver disease.
- Warfarin blocks vitamin K action* - some drugs such as warfarin specifically block vitamin K action - prevent thrombophilia.
- Lab - increased PT, aPTT normal/increased (late).
- Although it affects all factors, factor 7 has the shortest half-life. Consequently, warfarin therapy first affects factor 7 and later affects other factors. Therefore, use PT value to detect early warfarin excess. aPTT will usually be normal until late stage.
Outline Von Willebrand disease (VWD) and the function of VWF.
• Congenital bleeding disorder. VWF useful for platelet adhesion to the damaged epithelium.
• VWF by endothelial cells - platelet and coagulation - double function.
- VWF produced by both platelets and endothelial cells.
- Helps in adhesion of platelets (not aggregation - aggregation is via fibrinogen).
• Platelet adhesion to collagen and carry/protect FVIII.
- Usually VWF is in the subendothelial region and in plasma. In the plasma, carries FVIII and prevents its early degeneration. Therefore, deficiency of VWF also leads to deficiency of FVIII.
• VWD is a combination of both a lack of platelet adhesion and FVIII deficiency → causes superficial and deep bleeds (both platelet and coagulation abnormal).
• VWD is an autosomal dominant disorder - many subtypes. Mild to severe bleeding clinically.
• Both males and females are affected (not X-linked).
- Congenital bleeding tendency in female → most likely VWD. Only in males → likely haemophilia.
Describe the diagnosis and treatment of VWD.
Diagnosis:
• Normal platelet count but increased bleeding time (platelets cannot function without VWF).
• Normal PT but aPTT is increased (due to decreased FVIII levels - VWF carries and protects FVIII).
Treatment:
• Fresh frozen plasma/cryoprecipitate - contain VWF.
Outline the aetiology of disseminated intravascular coagulation (DIC).
• Systemic activation of coagulation → consumption of all factors and platelets → severe bleeding.
Aetiology - infection, trauma, cancer (common causes).
• Infection - widespread endothelial damage.
• Trauma - tissue factor release into circulation.
• Common causes - release of tissue factor into circulation or widespread endothelial damage leading to activation.
Explain the pathogenesis of DIC.
- Activation of coagulation → microthrombi - infarction.
- Consumption of haemostatic factors - bleeding.
- Activation of fibrinolysis - excess fibrin breakdown products.
• Some stimulus leading to activation of coagulation forming microthrombi and breakdown of the thrombi by fibrinolysis ultimately using up all the coagulation factors and platelets → results in severe bleeding (thrombi → bleeding → loss of factors).
