Haem 8 - Abnormalities of haemostasis Flashcards
Platelet adhesion can occur via VWF or?
GP1A directly to endothelial cells
How does platelet aggregation occur?
ADP and TXA2 release–> platelet aggregation via GP2B/3A receptors
Primary haemostasis can go wrong at 3 points, which are
- Platelet
- VWF
- Vessel wall
Disorders of primary haemostasis may occur due to problems in platelets. How
Low numbers
- Bone marrow failure - e.g. leukaemia, B12 deficiency
- Accelerated clearance - e.g. immune thrombocytopenia, DIC
Impaired function
- Hereditary absence of glycoproteins or storage granules (e.g. Glanzmanns thrombasthenia - defective GP2B, Bernard Soulier syndrome -GP1B, Storage pool disease - problem with dense granules)
- Acquired due to drugs - aspirin, NSAIDs, clopidogrel
What is immune thrombocytopenia
Antiplatelet autoantibodies attach onto sensitised platelet –> cause it to be phagocytosed by a macrophage
What are the mechanisms and causes of thrombocytopenia
- Failure of platelet production by megakaryocytes
- Shortened half life of platelets
- Increased platelet pooling in an enlarged spleen (hypersplenism) and shortened half life
Disorders of primary haemostasis may be due to VWF. How
- Von Willebrand Disease - hereditary decrease of quantity and/or function OR acquired due to antibody
VWD is usually hereditary - Deficiency = type 1/3
Abnormal function = type 2
What are the roles of VWF
- Bridge between platelet and subendothelium (collagen)
2. Carrier protein for F8
Disorders of primary haemostasis may be due to vessel wall. How
- Inherited (rare) hereditary haemorrhagic telangiectasia / (Ehlers Danlos syndrome) and other connective tissue disorders
- Acquired - scurvy/steroid therapy/ageing/vasculitis
What is characteristic of thrombocytopenia (primary haemostasis)
Petechiae
What are the tests for disorders of primary haemostasis
- Platelet count, platelet morphology
- Bleeding time
- VWF assays
- Clinical observations
Primary platelet plug is sufficient for small vessel injury. In larger vessels it falls apart. Fibrin formation stabilises the platelet plug. So describe what the disorders of coagulation could be
Deficiency of coagulation factor production -
- Hereditary e.g. haemophilia A/B - F8/9
- Acquired - liver disease, dilution, anticoagulant drugs
Increased consumption -
- Disseminated intravascular coagulation (DIC)
- Immune - antibodies
Coagulation factor deficiencies can vary in severity. Describe
Haemophilia A/B = severe, but compatible with life. Spontaneous joint and muscle bleeding
Prothrombin deficiency (F2) = lethal
Factor 11 deficiency = bleed after trauma but not spontaneously
F12 deficiency = no excess bleeding at all
Describe what Disseminated intravascular coagulation is
It is generalised activation of coagulation - tissue factor.
Occurs in sepsis, major tissue damage, inflammation, etc
It consumes and depletes coagulation factors (so they can’t be used when actually needed)
Platelets consumed, and activation of fibrinolysis depletes fibrinogen
Fibrin deposition in vessels causes organ failure
Describe bleeding pattern in coagulation disorders
- Superficial cuts don’t bleed
- Bruising common, nosebleeds rare
- Spontaneous bleeding is deep, into muscles and joints
- Bleeding after trauma may be delayed and is prolonged
- Frequently restarts after stopping
What is the hallmark of haemophilia
Haemarthrosis - bleeding of joints
NEVER GIVE HAEMOPHILIA PATIENTS
Intramuscular injection
Differentiate bleeding due to coagulation defects vs platelet defects
Platelet defects = superficial bleeding into mucous/skin membranes. Bleeding immediate after injury
Coagulation defects = deep bleeding into tissues, muscles, joints. Delayed but severe bleeding, may be prolonged
What are the tests done to test for coagulation disorders
- Screening tests (“clotting screen”) - Prothrombin time (PT), activated partial thromboplastin time (APTT), Full blood count (platelets)
- Factor assays (for F8 etc)
- Tests for inhibitors
APTT would be low if f9/12/8 missing
Most bleeding disorders are not detected by routine clotting tests
T
Describe how there may be disorders of fibrinolysis
Fibrinolysis disorders = rare, but can cause abnormal bleeding
Hereditary -
1. Antiplasmin deficiency
Acquired -
- Drugs e.g. tPA
- DIC
Describe the genetics of haemophilia
X-linked recessive disorder
Describe the genetics of VWD
Autosomal dominant disorder
except type 3 (rare) - recessive
Describe the genetics of bleeding disorders (except haemophilia or VWD)
Autosomal recessive - much less common
Describe the treatment plan of abnormal haemostasis
If failure of production/function - replace missing factor/platelets (prophylactic / therapeutic), stop drugs
If immune destruction - immunosuppression (e.g. prednisone), splenectomy for ITP
If increased consumption - treat cause, replace as necessary
Describe some of the things we have to treat haemostatic disorders causing bleeding
- Factor replacement therapy - plasma (contains all coagulation factors), cryoprecipitate (rich in fibrinogen, F8, VWF, F13), factor concentrates (all factors minus f5, or prothrombin complex concentrates w/ f2, f7, f9, f10)
- Gene therapy - Haemophilia b/a
- Platelet replacement therapy
- Novel approaches - e.g. bispecific antibody, anti-TFPI antibody, antithrombin RNAi
What are some other haemostatic treatments that are used
- DDAVP (iv) - releases endogenous stores (used in mild disorders)
- Tranexamic acid - inhibits fibrinolysis, widely distributed - crosses placenta. Low conc in breast milk. Useful adjunctive therapy
- Fibrin glue/spray
Moderate haemophilia B will prolong which time?
APPT
Prolongation of the PT may result from
F7 deficiency
When are prothrombin complex concentrates used?
If no f2,7,910
What treatment may be used for VWD
Oral contraceptive, intermediate purity VWF concentrates, ddavp, tranexamic acid
