Week 6 - HAEMOSTASIS Flashcards
Diagnosing Hemostatic Disorders, Bleeding Disorders, DIC, Hypercoagulability, Transfusion
What is placed in samples of blood and why?
- blood sample in sky blue cap
- SODIUM CITRATE –> halts coagulation process and preserves coagulation factors (by blocking calcium)
What is normal bleeding time?
<10 mins
What does prothrombin time (PT) measure and when is it prolonged?
- tests extrinsic and common pathway
- prolonged in acquired disorders:
- vit. K deficiency
- liver disorders
- warfarin Tx.
What is INR?
International Normalised Ratio
- standardised PT value
- correction for different thromboplastin reagents used (animal product)
What does an INR of 1 mean?
-pts. plasma has the same extrinsic pathway as that of a normal plasma corrected for various commercial reagents
** high INR = longer it takes for blood to clot
What is suspected if both PT + PTT are increased?
pathology is in the COMMON pathway
What does partial thromboplastin time (PTT) measure and when is it prolonged?
- intrinsic + common pathways
- prolonged in congenital bleeding disorders
- hemophilias (A + B)
- von Willebrand disease
When is thrombin time performed and what does it test?
- when both PT + PTT are abnormal
- tests fibrinogen levels (COMMON pathway)
- *useful in DIC
When is FDP/D-Dimer increased?
DIC (clot breakdown occurring)
What are the test priniples for PT + PTT?
PT:
-animal tissue thromboplastin (with sodium citrate) –> FVIIa –> CLOT
PTT:
-kaolin + cephalin –> FXIIa –> FVIIIa/FIXa –> CLOT
What is suspected if a pts. plasma with increased PT/PTT is mixed with normal plasma and the PT/PTT corrects?
clotting factor deficiency
What is suspected if pts. plasma with increased mixed with normal plasma and the PT/PTT does not correct?
- PT/PTT inhibited
- therefore –> coagulation inhibitors
i.e. heparin; specific factor inhibitor (FVIII or FV); non-specific inhibitor (lupus anticoagulants)
What is a thromboelastogram (TEG)?
- quick test before and during major surgery
- measures clot formation, strength + lysis
- global assessment of hemostatic function
What are the lab. findings (Plt count, BT, PT, PTT) for common hemostatic disorders:
- ITP?
- vWD?
- Hemophilia?
- DIC?
- Aspirin?
- Warfarin/Heparin?
ITP:
- plt count –> low
- BT –> high
- PT –> normal
- PTT –> normal
vWD:
- plt count –> normal
- BT –> high
- PT –> normal
- PTT –> high
Hemophilia:
- plt count –> normal
- BT –> normal
- PT –> normal
- PTT –> high
DIC:
- plt count –> low
- BT –> high
- PT –> high
- PTT –> high
Aspirin:
- plt count –> normal
- BT –> high
- PT –> normal
- PTT –> normal
Warfarin/Heparin:
- plt count –> normal
- BT –> normal
- PT –> high
- PTT –> high
Where is vWF located and what does this mean for its function?
Subendothelial region
-aidss plt. adhesion to endothelial defects
Plasma
-carries FVIII and prevents early degeneration
Clinically, what is the commonest bleeding disorder?
Thrombocytopenia
-commonest cause of bleeding
Outline plt production
thrombopoietin stimulates endomitotic synchronous nuclear replication of megakaryocytes –> cytoplasmic granulation –> cytoplasmic fragments separate out as platelets (loaded w coag. factors)
What is the lifespan of plts and what results afterwards?
8 - 9 days
-either involved in hemostasis
OR
-destroyed in spleen
Describe typical bleeding characteristics in thrombocytopenia
-superficial bleeding (capillary damage)
Clinically:
- petechiae
- purpura
- ecchymosis
What hemostatic factors are contained in platelets?
- ADP
- calcium
- vWF
- PF4
- fibrinogen
What are the causes of thrombocytopenia?
- autoimmune, drugs, infections - viral
- BM suppression
- megaloblastic anemia
- aplastic anemia
- increased consumption (DIC, TTP + HUS)
- Plt function disorders: - less common
- vWD, Bernard Soulier syndrome, Glauzman thrombasthenia
- plts are present but NOT functional
What is normal plt. count and what counts result in excess + spontaneous bleeding?
normal: 150 - 250 x 10^9/L
excess bleeding: <50 x 10^9/L (i.e. after trauma/surgery)
spontaneous bleeding: <20 x 10^9/L (severe and life-threatening)
What is ITP and what are the clinical features?
- immune thrombocytopenic purpura
- autoimmune disorder –> IgG Ab against plts –> plts destroyed in spleen –> thrombocytopenia
CF’s:
- petichiae
- purpura
- ecchymosis
- easy bruising
What are the 2 types of ITP?
- acute
- children, post-infection, self-limited - chronic
- F (20-40yrs)
- chronic + severe
What are the lab. findings in ITP?
CBC:
- thrombocytopenia
- giant immature plts
PT/PTT:
-normal (coagulation is normal)
BM:
-immature megakaryocytes increased –> compensatory in response to loss of plts.
What are the common causes of viral haemorrhagic fevers and what is the pathogenesis?
Causes:
-dengue, chikungunya, measles, malaria, yellow fever, Ebola, etc
Patho:
-endothelial damage by virus +/or anti-viral Abs –> vasculitis –> plt. activation –> thrombocytopenia –> bleeding
*PT/PTT usually normal
What coag. factor deficiency is present in hemophilia A + B?
A –> FVIII
B –> FIX
What type of genetic abnormality is hemophilia + what does this mean?
x-linked recessive
- increased in females (carriers)
- increased in males (affected)
True or False?
-hemophilia A/B results in petichiae/purpura/ecchymosis
False
- as coag. factors (NOT plts) are affected, bleeding is deep NOT superficial
- increased wound bleeding and deep hematoma
- joint bleeds (skin/mucosal bleeding in severe)
What is the therapy for hemophilia?
DDAVP
-releases factors from endothelium
FVIII/FIX concentrate
Where is vit. K found and what is it necessary for?
- green leafy veggies + intestinal bacteria
- necessary for carboxylation of factors 2, 7, 9, 10 in the liver
What are the causes of vit. K deficiency?
- diet
- drugs
- liver disease
- warfarin inhibits vit. K action (to prevent thrombophilia)
Why is PT increased and PTT normal until late in vit. K deficiency/warfarin Tx.?
-factor VII (extrinsic pathway - PT) has the shortest half-life –> warfarin affects this factor first
What is vWD?
- von willebrand disease
- low vWF –> deficiency of both platelet adhesion to damaged endothelium AND deficiency in FVIII
- both plt. and coag. = abnormal –> superficial and deep bleeds
What is vWF produced by?
both plts. and endothelial cells
True or False?
-vWD is an x-linked recessive disorder
False
- autosomal dominant
- both males + females affected
Why is there increased BT despite normal plt. count in vWD?
- low vWF in vWD
- plts cannot function without vWF (cannot bind to collagen in endothelial defects) –> increased BT
Why is normal PT but PTT increased in vWD?
- vWF carries + protects FVIII
- no vWF in vWD = FVIII deficiency –> increased PTT
What is therapy for vWD?
fresh frozen plasma (FFP)/cryoprecipitate which contain vWF
What is DIC?
Disseminated Intravascular Coagulation
-systemic activation of coagulation –> consumption of coag. factors + plts –> severe bleeding
What is the cause/etiology of DIC?
-infection/trauma/cancer
-release of tissue factor into circulation –> trauma
OR
-widespread endothelial damage –> infection
What is the pathogenesis of DIC?
activation of coagulation –> microthrombi –> infarction –> consumption of hemostatic factors –> bleeding –> activation of fibrinolysis –> excess fibrin breakdown
What are the clinical features of DIC?
- thrombosis
- severe bleeding
- shock
- renal failure
What are lab Dx. for DIC?
- decreased coag. factors (deep) + plts (superficial) –> ALL tests abnormal
- FDP + D-Dimer increased
- life-threatening
What are the 2 clinical syndromes of thrombotic microangiopathy? and how do they differ to DIC?
- thrombotic thrombocytopenic purpura (TTP) - adults
- hemolytic uremic syndrome (HUS) - children
- unlike DIC, coagulation factors remain normal or mild decrease
- ONLY activation of plts.
What is thrombotic microangipathy?
- widespread thrombosis in microcirculation leading to organ infarctions + microangipathic hemolytic anemia (fragmented RBCs)
- TTP + HUS
What are the predominant consequences of TTP + HUS?
TTP –> neurologic defects/strokes
HUS –> kidney failure
What enzyme is deficient in TTP? What is its normal function and how can one be deficient in it?
ADAMTS13
- protease which normally breaks down vWF multimers to stop plt activation
- essentially, TTP is opposite to vWD as there is increased vWF –> increased plt. activation + loss –> extensive systemic thrombosis
Acquired:
-Ab to ADAMTS13 –> deficiency
Congenital:
-mutation –> ADAMTS13 deficiency
How is TTP treated?
-plasma exchange with fresh frozen plasma or cryoprecipitate to remove Ab or replace ADAMTS13 (previously 90% fatal)
True or False?
ADAMTS13 levels are decreased in childhood HUS
False
- normal levels
- E. coli/shigella infection + shiga toxin causing extensive endothelial damage –> plt activation
What is adult HUS?
TTP with predominant renal failure
What are the natural anticoagulants?
Protein C + S –> inhibit FVIIIa + FVa
Heparin –> inhibits thrombin (FIIa)
What is the most common anticoagulant drug + what does it inhibit?
warfarin
- inhibits vit. K reductase
- decreased vit. K dependent coag factors (2, 7, 9, 10)
What are the hereditary causes of hypercoagulability?
Factor V Leiden mutation
- Factor V is resistant to protein C inhibition
- uncontrolled factor V activation
Protein C/S deficiency
-decreased inhibition of FVa + FVIIIa
What are acquired causes of hypercoagulability?
- trauma, inflamm., cancer
- heart disease, atherosclerosis, HTN, DM, etc
- stasis of blood
- drugs, Abs –> antiphospholipid antibody syndrome (AAS)
- *Virchow’s Triad (Blood - BV - Blood Flow)
What are clinical features of hypercoagulability?
THROMBOSIS
- vein –> DVT (potential PE)
- artery –> thrombosis; stroke
- placenta (pregnancy) –> abortion
What is AAS + what Abs are involved?
antiphospholipid antibody syndrome
- Abs to plt. phospholipids:
1. anticardiolipin
2. lupus anticoagulant
N.B. following infection in children/pts with autoimmune dis./drugs
What % of SLE pts develop AAS?
30%
How does AAS differ clinically from in the laboratory?
- clinically, autoantibodies activate coagulation in body
- in lab. autoantibodies bind to phospholipid part of reagent –> prolong PTT
What is the lab Dx. of AAS?
- normal PT but prolonged PTT –> looks like deficiency but is hypercoagulability
- PTT remains prolonged even after adding 50% normal plasma –> unlike factor deficiency
What is contained in fresh frozen plasma + cryoprecipitate and what are the indications for transfusion?
FFP –> all coag. facotrs –> bleeding
cryoprecipitate –> factor 1, 8, 9, vWF –> specific deficiency
*factor 1 = fibrinogen
What is the shelf-life of platelet concentrate?
5 days
Why are RBCs easier to match in transfusions compared to WBCs/plts?
WBCs/plts
- have HLA Ag
- difficult to match
- more reactions/rejections
RBCs
- no HLA Ag
- only major blood groups
What are the clinically significant blood group systems + why?
ABO + Rh
-naturally occurring strong IgM antibodies
What is the commonest + rarest blood group?
commonest = O+ rarest = AB-
What is Landsteiner Law?
when a person has a blood group Ag, corresponding Ab is ABSENT from plasma
What is the substance known as on red cell membranes that is modified by A, B, O genes?
H substance
-A, B, O genes control synthesis of enzymes that modify red cell membrane glycolipid (H substance)
What are the 3 genes involved in Rh system?
- C/c
- D/d
- E/e
Rh+ = D –> strong/clinically significant
Rh- = d
-little letter denotes negative
What is bombay blood group?
- absence of H substance in ABO blood system
- anti-H antibodies present
- clinically seen as O group
Compare IgG vs. IgM
IgG:
- small, monomer
- optimum reaction @37degrees
- able to cross placenta
- coat cells –> no agglutination
- main type produced following preg./transfusion (alloantibodies)
IgM:
- large, pentamer
- optimum reaction @-20degrees
- does NOT cross placenta
- agglutinates
- often “naturally occuring” Abs - ABO blood group
What is a major + minor cross match?
major = donor RBC with pt. plasma minor = donor plasma with pt. RBC
–> to prevent hemolytic transfusion reaction
What is the purpose of Ab screening?
- many other Ags on donor RBC
- additional Ab screening done to detect alloantibodies in pt. plasma with known reagent RBC (post transfusion/pregnancy)
What are the 3 main transfusion reactions and what are each caused by?
- allergic –> plasma proteins
- febrile –> Abs to donor leucocytes
- hemolytic –> immune/mismatch
What are the Sx. of hemolytic transfusion reaction?
- hemoglobinuria
- chest pain
- apprehension
- lower back pain
- fever/chills
- decr. BP/incr. RR
- acute kidney failure*
Why is bacterial contamination of blood products more common with plts?
They are kept at increased temp. (22degrees)
What is “lookback program”?
-identify + notify recipients of blood products from previously negative/screened donor who is now positive for infectious agent
