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Name two antithrombotic proteins
Tissue factor p/way inhibitor
Tissue factor p/way inhibitor
What does damage to vessel walls expose to the passing blood stream?
Procoagulant tissue factor & collagen
Name a less potent thrombophilic condition
Factor V Leiden
Prothrombin gene mutation
(less potent c/w antithrombin / Protein C / S def, but more common)
What is the p/p behind how FVL increases risk of VTE?
FVL disrupts the first three activated protein C (APC) cleavage sites -> slows degradation of activated factor V (factor Va) -> slows degradation factor VIIIa
How does antithrombin work in normal physiology? (and therefore, what's the p/p behind antithrombin def?)
Inhibits thrombin & factor Xa
Heparin accelerates antithrombin activity several thousand fold; antithrombin def can lead to heparin resistance
Usually VTE (as opposed to ATE); most unprovoked
Does antithrombin def usually manifest with provoked or unprovoked VTE?
Unprovoked. Mostly VTE (as opposed to ATE)
How does protein C work? (and therefore, what's the p/p behind protein c def?)
Inactivates factor Va & VIIIa
What % of trauma pts would get DVT / symptomatic PE without prophylaxis?
58% DVT / 4% symptomatic PE
Cancer increases risk of VTE by how much? How about metastatic disease?
4-20 x increased VTE risk for cancer / 2x increased VTE risk for metastatic disease
How do cancers increase risk of VTE?
Prothrombotic state: cancers express tissue factor on their surface
Name a cancer with higher than normal risk of VTE?
Highest: pancreas, brain
Intermediate: lung, lymphoma
Lower: breast, prostate
How long would you anticoag a cancer pt who gets VTE?
At least 3-6/12, OR as long as evidence of active cancer OR as long as cancer treatment persists (whichever one of the above is longer)
True or false? Antiphospholipid syndrome is an inherited coagulopathy
False. It's an acquired autoimmune disorder.
What are the clinical manifestations of antiphospholipid syndrome?
A/w VTE or ATE, miscarriage, thrombocytopenia, renal insufficiency, vasculitis, cardiac valve abnormalities
What is the p/p behind antiphospholipid syndrome?
Incompletely understood. Abs against phospholipids (eg cardiolipid) or phospholipid binding proteins (eg beta2, glycoprotein), which induce tissue factor expression, disrupts protein C & antithrombin function, activating plt / complement cascade
How is a pt managed who has VTE or ATE & positive for antiphospholipid antibodies?
Long-term Mx (high risk of recurrent VTE)
True or false? VTE is the most common cause of maternal death in Australia (although most pregnant women who develop VTE don't die)
False. 2nd most common.
When is VTE in pregnancy most likely to occur - antenatal or postpartum?
1/3 to ½ occur post-partum (w/in first 6 weeks). VTE occurring in antenatal period tends to be in first two trimesters
Should a pregnant woman with a PHx of unprovoked VTE or recurrent VTE get anticoag during pregnancy?
Group consensus level 1 evidence for extended antenatal & postpartum thromboprophylaxis. Clexane. NOT warfarin (teratogenic)
What are the three big umbrella causes of anaemia?
1) Low RC production (BM infiltrates eg. Aplastic anemia, MDS; Fe/B12/folate def; chemoTx, drugs; hormone def EPO, thyroxine)
2) Increased RC destruction (haemolysis when RC destroyed in <100 days, inherited conditions eg. Hereditary spherocytosis, Thal major, Sickle cell disease; acquired eg. PTP-HUS, autoimm anaemia, malaria)
3) Blood loss (most common cause)
Why does B12 & folate def anemia cause RC macrocytosis?
Lack of B12 / folate impairs DNA synthesis, & cells undergo fewer divisions, therefore are larger
Why does iron def anaemia cause RC microcytosis?
Because iron required to create haemoglobin chains; therefore lack of iron = lack of Hb chains = RC missing Hb component
Pt has rapid fall in Hb, high reticulocyte count, and fragmented RC on film, you think...?
You see schistocytes on blood film. What are they, and what does it indicate?
Schistocytes = fragmented / severed RCs. Indicates haemolysis.
What biochem would you see in haemolysis?
Low Hb, increased reticulocytes, increased LDH (from RC breakdown), decreased haptoglobin (building block for Hb).
Name two cancers commonly a/w autoimmune haemolytic anaemia? How does this occur?
Production of auto-Abs which attack RC membrane antigen. Common in: CLL, NHL, HL, Waldenstrom. Direct Coombs' test will be positive (as it's Ab-mediated).
Patient has sudden drop in Hb, fragmented RC on blood film, and a positive Direct Coombs test. What's going on?
Autoimmune haemolytic anaemia. Production of auto-Abs which attack RC membrane antigen. Common in: CLL, NHL, HL, Waldenstrom. Direct Coombs' test will be positive (as it's Ab-mediated). A negative direct Coombs would indicate microangiopathic haemolysis
Patient has sudden drop in Hb, fragmented RC on blood film, and a negative Direct Coombs test. What's going on?
Microangiopathic haemolysis. Can be due to either DIC or TTP-HUS. A positive Coombs would indicate autoimmune haemolytic anaemia.
What's the basic p/p behind DIC?
Formation of excess amounts of thrombin -> widespread & systemic intravascular fibrin deposition -> fibrin clots -> tissue ischemia & plt consumption -> excess bleeding
Name two underlying causes of DIC
Sepsis (more common with Gram neg bugs)
Trauma & tissue destruction
Cancer, esp solid tumours (7%), due to expression of cancer procoagulant
What's the difference in clinical picture b/w acute decompensated v chronic compensated DIC?
Acute, decompensated: intravasc coag - profound systemic bleeding diathesis, oozing from all wound sites / IV / deep tissue bleeds.
Chronic, compensated: excess procoagulants predispose to thrombosis. Liver & BM (if able to keep up with clotting factors & plt production) limits excessive bleeding
TTP-HUS is described of presenting with a clinical 'pentad' (ie. five features). Name 3.
Thrombocytopenia (usually <30)
Microangiopathic haemolytic anaemia
Neurological abN (mental state change)
Renal abN (proteinuria, haematuria)
Pt noted to have thrombocytopenia and sudden drop in Hb, fragmented RCs (schistocytes) on blood film, and negative direct Coombs test. No obvious cause for this. What's the provisional Dx? How is this treated?
Thrombocytopenia + microangiopathic haemolytic anaemia (not autoimmune haem anaemia b/c direct Coombs is negative, ie no Ab involved). DDx is TTP-HUS. CRITICAL Rx: plasma-exchange, improves mortality significantly
What's the Rx of TTP-HUS? When should this commence?
Plasma-exchange. To start immediately; significant improvement in mortality.
How is DIC treated?
Plts for those with <20, or those <50 and high bleeding risk (eg post-op)
If actively bleeding & higih INR & low fibrinogen = get cryoprecipitate or FFP
Name two causes of RC macrocytosis
Alcoholism. Even before alcohol-induced anaemia appears, 90% of alcoholics have macrocytosis. Unknown cause. Resolves win 2-4 months of ceasing ETOH.
Vit B12 / folate def
MDS (virtually all pts at presentation)
Hypothyroidism (mechanism unclear)
Drugs, eg. Azathioprine (inhibits DNA / RNA / protein synthesis, role for immunosuppression for organ Tx etc)
How do you work up macrocytic anaemia?
Vit B12, folate, TSH, LFTs
Protein electrophoresis (rare case of MM)
How is iron cycled in the body?
Free iron in blood highly toxic (that's why it's bound to transferring). Iron's major role is to bind O2 as part of Hb. Iron balance tightly regulated. Enters from food or iron supplements. Not excreted generally (just reused). Iron only lost through bleeding & epithelial cells.
What agent is the membrane-embedded iron exporter from cells to plasma transferring? Clue: 'transports the ferrin'
Ferroportin (transports the ferrin). Regulated by hormone 'hepcidin'; increased hepcidin levels DECREASES action of ferroportin; decreased hepcidin levels INCREASES action of ferroportin.
What's hepcidin? What does it do?
Hormone which regulates iron levels in body; either up- or down-regulates membrane protein ferroportin, which acts to help transport iron from gut into blood stream. Low levels iron in body DECREASES hepcidin, which allows for INCREASED action of ferroportin & thus more iron transported from gut into blood stream.
What's the r/ship b/w hepcidin & ferroportin.
Hepcidin is the hormone which regulates body iron levels. It acts negatively on ferroportin (membrane transport protein which helps get iron from gut into blood stream). Ie) low iron levels -> suppresses hepcidin increases ferroportin action (to increase iron levels)
Name 3 DDx for microangiopathic haemolysis (manifested as schistocytes, or fragmented cells, on blood film)
e. Malignant Hypertension
f. Malfunctioning Cardiac valves
g. Meds, (including chemoTx)
What anticoag do you use for someone at a high bleeding risk?
a. Mechanical thromboprophylaxis (intermittent pneumatic compression,
or graduated compression stockings). Start pharmacologic agents if high
bleeding risk decreases
What anticoag do you use for someone with impaired renal function?
Use renal-adjusted doses for enoxaparin (ie. 20mg/nocte), fondaparinux,etc.
Name five RFs for developing VTE
b. Acute exacerbations of chronic pulmonary disease
c. Stroke with paralysis
g. Age > 75
h. Presence of CA
i. PHx VTE
What's the usual time frame between starting heparin and the onset of heparin-
Usually within 10 days
What is the pathophysiology behind heparin-induced thrombocytopenia? Ie)
Antibodies against what?
Immune-mediated, abs against heparin-platelet factor 4 complex
What features make you suspect heparin-induced thrombocytopenia? Suspect in
pts who commenced heparin in previous 5-10 days / prolonged LMWH:
a. Otherwise unexplained thrombocytopenia
b. VTE / ATE a/w thrombocytopenia
c. Plt count that has fallen >50% from prior value
d. Necrotic skin lesions at heparin injection sites
e. Anaphylactoid rxn post IV heparin bolus
What are the 4 T's of heparin-induced thrombocytopenia diagnosis?
d. Exclusion of other causes of the above
How is heparin-induced thrombocytopenia diagnosed?
a. High pre-test probability (based on 4 T's - thrombocytopenia, timing,
thrombosis, exclusion of other causes) & positive ELISA test
How is heparin-induced thrombocytopenia managed?
Cease all heparin (including LMWH) immediately Start alternative anticoag (non-heparin) immediately (Grade 1B) unless
strong C/I (eg. Bleeding)
i. Argatroban, danaparoid, fondaparinux, bivalirudin (dose adjusted
for hepatic / renal failure)
c. To keep anticoag for >2/3 months in absence of thrombotic event
d. To keep anticoag for >3-6/12
e. Commence warfarin once pt stabilized on non-heparin anticoag & plt >150;
cont non-heparin anticoag until warfarin therapeutic
Name two non-heparin anticoagulants, besides warfarin
Argatroban, danaparoid, fondaparinux, bivalirudin (dose adjusted for
hepatic / renal failure)
Name two causes of thrombocytosis
Inflammation, Cancer, Infection (reactive thrombocytosis)
Underlying myeloproliferative disorder - Essential thrombocythemia or Polycythemia vera, or rarely the myelodysplastic process
True or false? Thrombocytosis a/w acute or chronic inflammation is a/w increased thrombotic risk.
False. Thrombocytosis associated with acute or chronic inflammation HAS NOT BEEN ASSOCIATED WITH INCREASEED THROMBOTIC RISK.
Combination of prolonged PT & APTT indicates deficiency of what factors?
Factor V, X, II or fibrinogen abnormalities
Where can you acquire clotting factor deficiencies from?
Acquired deficiencies more common than congenital
True or false? Platelet function can worsen when a pt (with CRI) is uremic.
True. Improves with HDx.
What is most common bleeding site in haemophilia?
Joints - 80% occurs in joints: ankles, elbows and knees most common
What does APPT (activated partial thromboplastin time) test?
Measure intrinsic and common pathway. Normal PTT times require the presence of the following coagulation factors: I, II, V, VIII, IX, X, XI, & XII.
What does PT - Prothrombin time - test?
Tests extrinsic coagulation and common pathway - tissue factor added to centrifuged plasma - I (fibrinogen), II (prothrombin), V, VII, and X
Which is more common haemophilia A or B? which factors are involved?
80% of people have haemophilia A - aka factor VIII deficiency. NB: Haemophilia B 'Christmas Disease' is Factor IX def.
Mucosal and cutaneous bleeding (eg epistaxis, gingival bleeding, bullous haemorrhage) is most characteristic of which haematologic disorder(s)?
Platelet dysfunction or VWD
What's the relationship b/w vWF & Factor VIII?
vWF is a carrier for factor VIII in the circulation, maintaining the normal level of factor VIII by increasing the half-life of factor VIII fivefold
What's the most common inherited bleeding disorder?
vWF deficiency. Affects. 1% of population, 1% of those (ie 0.01% of population) are symptomatic . Mostly AD inheritance; M=F. NB: Also acquired forms of VWD
What's von Willebrand factor's job?
Two jobs: 1) encourages platelet adhesion / aggregation, and 2) carriers factor VIII in circulation (increases half-life of FVIII by 5x)
What's the difference b/w Type 1, 2 & 3 von Willebrand's disease?
Type 1 - AD, most common VWF (75%), a quantitative deficiency of VWF.
Type 2 - AD, qualitative abN of VF.
Type 3- AR, very rare. Severely low / no detectable levels of VWF.
What part of the clotting screen is sensitive for effectiveness of dabigatran?
TCT (it's the only NOAC that is a direct THROMBIN inhibitor, ie thrombin clotting time)
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