Anti-coagulants and blood products Flashcards
How does Heparin and LMWH work?
Unfractionated Heparin - By binding to antithrombin III and causing the active site to undergo a conformational change, heparin increases its availability to its normal ligands, including factor Xa and thrombin. The result is an increase in the activity of antithrombin, which manifests in the form of the anticoagulant effect. S/E bleeding, the possibility of HITS. Also osteopenia, mineralocorticoid deficiency alopecia and LFT derangement
LMWH i.e fractionated/shortened - binding to antithrombin III and causing the active site to undergo a conformational change, low molecular weight heparin increases its affinity for factor Xa (but not thrombin). The result is an increase in the activity of antithrombin on Factor Xa, which manifests in the form of the anticoagulant effect. No significant side effects apart from the possibility of HITS (which is much smaller than with UFH)
What is the difference in mechanism between UFH and LMWH?
In summary, unfractionated heparin affects thrombin, whereas low molecular weight heparin only affects Xa. This also explains why measuring APTT is not going to tell you whether the low molecular weight heparin dose is therapeutic.
The unfractionated heparin also affects the activity of Factor 9, but not the activity of Factor 7. Thus, the intrinsic and common pathways are affected, which increases the APTT. The extrinsic pathway is unaffected, and the PT does not rise very much. Because thrombin is unaffected by low molecular weight heparin, the APTT remains essentially unchanged.
Unlike heparin and the heparin-like drugs which make their effect felt by binding to antithrombin, most of the available alternatives (hirudin, lepirudin, bivalirudin, argatroban) are direct thrombin inhibitors.
What are the different types of HITS?
It is an immune-mediated thrombocytopenia
More frequently associated with unfractionated heparin
More frequent in the elderly; unheard of in children
Typically occurs 5-10 days after start of heparin
Comes in 2 flavours: type 1 and type 2.
HITS Type 1:
Mild transient thrombocytopenia, platelet count above 100
Totally reversed by heparin cessation
Occurs in up to 10% of patents
NOT associated with an increased risk of thrombosis
Probably not even immune in origin
HITS Type 2:
Nasty severe thrombocytopenia, platelet count might drop to nil
Occurs in something like 1% of patients
Associated with thrombosis in 30% of cases
Due to the formation of antibodies to the complex made up of platelet factor 4 (PF4) and heparin; this complex forms on the surface of platelets.
When the HIT antibody binds to this complex, it causes platelet activation and aggregation, and so there is a tendency towards clotting (because all the platelets are activates) as well as a simultaneous tendency towards bleeding (as there is a destruction of antibody-coated platelets in the reticuloendothelial system)
What does Prothrombin Time measure?
Laboratory test for the extrinsic and common pathways . Basically, you add “tissue factor” to a sample of plasma, and measure the time it takes for the sample to clot.
Abnormal in:
- factor deficiency (Vit K sensitive factors II, VII, X)
- warfarin therapy
- direct thrombin inhibitor therapy
- direct Xa inhibitor therapy
What does Activated Partial Thromboplastin Time measure?
Laboratory test for the intrinsic and common pathways.
Abnormal in:
- factor deficiency (XII, XI, X, IX, II)
- heparin therapy
- direct thrombin inhibitor therapy
- direct Xa inhibitor therapy
- antiphospholipid syndrome
What is ROTEM and TEG?
TEG is ThromboElastoGraphy, and ROTEM is ROtational ThromboElastoMetry, both acronyms being registered trademarks. Both are tools of assessing whole blood clotting. Whole blood (a minute amount of it, no more than 1ml) at body temperature (37º) is added to a heated cuvette (a little cup). A pin is suspended into the cup, and then some sort of rotation takes place. In fact the main difference between TEG and ROTEM is the bit which rotates (TEG rotates the cup, and ROTEM rotates the pin). Irrespective of which bit is rotating, some impediment to the rotation develops as the blood clots. The degree of this impediment is recorded as “amplitude”, and displayed on the time vs. amplitude graph.
What would a prolonged clotting time (CT) or Reaction Time (R) suggest?
The TEG uses “R” and ROTEM uses “CT” to describe the time it takes for the amplitude to start climbing.
Causes of prolonged CT and R-value
-Anything that causes a raised PT and APTT:
-Deficiency of clotting factors
-Heparin (very sensitive - prolonged by 0.15 units per ml of blood, or a systemic heparin dose of less than 750 units for a 70kg adult)
-Warfarin
-Direct thrombin inhibitors
The reaction to a prolonged CT could consist of the administration of replacement factors (eg. FFP or factor concentrates) or antagonists to anticoagulants (eg. protamine).
What would a prolonged K value and CFT suggest?
ROTEM uses CFT and TEG uses the K value to describe the time from clot initiation (when the amplitude gets to 2mm) to 20mm. The CFT and K also relate to the activity of the clotting factors, but also incorporates a measure of the effectiveness of fibrin polymerisation, platelet activity and Factor XIII activity. In states of extreme coagulopathy, the clot may never actually form and the CFT will not be reported.
Causes of prolonged CFT
-Thrombocytopenia
-Platelet dysfunction
-Low fibrinogen
-Severe deficiency of other factors
Causes of Shortened CFT
-Hypercoaguable states
-The reaction to a prolonged CFT might sensibly consist of platelet transfusion, or cryoprecipitate.
What does the alpha-angle measure?
For the α-angle, TEG uses the slope of a line connecting the point at which the R interval ends and the point at which the K interval ends. ROTEM, in contrast, uses the slope of the line at the 2mm amplitude mark. In either case, the slope is determined by the rate of reaction between platelets, fibrin and the clotting cascade factors. It is therefore probably a nonspecific variable. However, the manufacturer of the device insists that fibrinogen activity plays the greatest role in determining the α-angle.
Causes of a decreased α-angle
- Low fibrinogen
- Poor fibrinogen polymerisation
- Thrombocytopenia, or platelet dysfunction
The reaction to a decreased α-angle might sensibly consist of cryoprecipitate transfusion, or of fibrinogen concentrate (where available).
What is Maximum clot firmness (MCF) and maximum amplitude (MA)?
Both the TEG and ROTEM terms refer to the point at which the clot is at its thickest, causing the greatest amount of impediment to the cup-pin movement. This variable is primarily a measure of platelet count, platelet function and fibrinogen concentration. The MA on the TEG has to be performed on a clean native sample with no activator, or from the combined Tissue Factor/kaolin activated TEG. There is a strong linear correlation between the log platelet count and MA.
The reaction to a decreased MCF is usually to either give platelets or DDAVP. However, clot instability may be also be the consequence of excessive fibrinolysis, which would manifest in the A60 or the LI30 indices.
What is in Cryoprecipitate, how is it prepared?
One unit - 300mg fibrinogen
70IU factor VIII
vWF
Cryo is thawed to 1-6C
Stored at -24
Ten units - one pack
What is Time to lysis (LOT and CLT)?
Ideally, this would be “time to complete lysis”, or 98% lysis, but we don’t have all day, and so some surrogate measure must exist. The TEG defines the term CLT as 2mm from MA, i.e. the time it takes for the clot to soften enough for the amplitude to decrease by 2mm from its maximum. The ROTEM term LOT (Lysis Onset Time) refers to the time it takes for the amplitude to drop by a 15% difference from the MCF, which is a slightly different parameter. Other machines have slightly different nomenclature again. In essence, an abnormally short time to lysis would suggest some sort of fibrinolysis is taking place.
The reaction to a decreased CLF is usually to give tranexamic acid or (in the old days) aprotinin.
Blood storage and shelf life
CPDA
35 days
C - Citrate - binds calcium (anti coag)
P - Phospate - ATP substrate
D - Dextrose - energy for glycolysis
A - Adenine - increase ATP
USA - SAGM, saline, adenine, glucose, mannitol (42 days)
What is FFP and how is it prepared?
Clotting factors and albumin
What remains after centrifuging then frozen to maintain V, VIII
Stored at -30C - 1 year
Use within 24 hours thaw
What is in Beriplex and Octaplex
Solvent detergent treated FFP - concentrates the factors
From 1500 donors
