Traditional view

Intrinsic System Extrinsic System

Collagen / Kallikrein

Prekallikrein HMWK

XII

XIIa

VII

XI

XIa X
Phospholipid + VIII

Tissue Factor

IX

Ca2+

IXa

Ca2+

VIIa + Tissue Factor

Xa
V + Phospholipid + Ca
2+

Fibrinogen

Final
Prothrombin Thrombin

Common Pathway
XIII XIIIa
Ca2+

Fibrin

Cross Linked Fibrin

The starter motor..

PT
Switched off by Tissue Factor

Pathway
Inhibitor

Provides initial Thrombin burst

Factors measured in Prothrombin Time

The engine..

APTT

Thrombin from initial burst back activates intrinsic system

TT

Fibrin then cross linked by XIII

Haemophilia
A = reduced VIII; B = reduced IX Both sex-linked recessive Queen Victoria Intronic rearrangements, point mutations, gene deletions Haemophilia A 1 in 10,000 male infants Prolonged APTT (normal PT and TT) Mild Rx: Tranexamic acid, DDAVP (not HB) Severe Rx: factor replacement recombinant or pooled donor Home prophylaxis Past problem with HIV, now HCV ??? CJD

Von Willebrand factor

A lack of High-molecular weight multimers of VWF can reduce the platelet-collagen interaction and lead to a bleeding diathesis.

Some patients with VWD have low (type I) or very low (type III) levels of a normal VWF molecule. Other patients have normal levels of a VWF molecule which lacks one (or many) of the three functions above or cannot form multimers properly (type II).

Von Willebrand factor

VWF is a large complex molecule. It has three main functions: 1)It sticks to platelets (via GpIb) 2)It sticks to collagen 1) + 2) means it lets platelets stick to collagen 3)It binds VIII and protects it from degrading and therefore increases its half-life VWF is made by endothelial cells and megakaryocytes (not the liver like the other factors). When released into the circulation it is in the form of Ultra-large molecular weight multimers (like a large bundle of straw). Ultra-large multimers of VWF are processed in the circulation into smaller High-molecular weight multimers, these are important for platelet interactions. Smaller multimers are also found in the circulation as a result of continued processing.

Von Willebrands Disease

Functions of VWF:

1. Sticks to platelets (GPIb) 2. Sticks to collagen in subendothelium (Important in small blood vessel lesions; high shear stress) 3. Binds to and protects VIII (labile)
Therefore in VWD see long APTT (low VIII) and bleeding where VWF platelet interaction important

Von Willebrands Disease

Type 1: mild- moderate quantitative deficiency Type 2: qualitative changes (functional) Type 3: severe deficiency Type 2N : reduced VIII binding in isolation Type 2A : absent HMW multimers Type 2B : increased affinity for platelet GPIb Type 2M : HMW multimers present

Von Willebrands Disease

Treatment options DDAVP, antifibrinolytics NB DDAVP causes fluid retention. NOT for type 2B Intermediate purity VIII concentrate VWF concentrate (NB takes hours for VIII to follow so may need to give both) (NB type I may auto-correct in pregnancy)

Massive blood loss

Defined as loss of > one circulating volume in 24 hours Coagulopathy is multifactorial: Loss of factors only once 80% of volume replaced Dilution of factors during fluid resuscitation Inhibitory effect of some colloids on clotting factors DIC secondary to trauma Acidosis Hypothermia (enzymes) (blood warmer)

Massive blood loss

Regular checks of FBC and PT,APTT,TT and Fibrinogen Aim for platelets > 50x109/l or >100x109/l if polytrauma or CNS injury Aim for fibrinogen >1g/l Aim for PT and APTT <1.5x control times FFP 12-15ml/kg Cryoprecipitate 1-1.5 packs /10kg if fibrinogen fails to correct with FFP ? rVIIa
Stainsby D, MacLennan S, Hamilton PJ. Management of massive blood loss: a template guideline. Br J Anaesth. 2000 Sep;85(3):487-91.

Disseminated intravascular Coagulation

..an acquired syndrome characterised by the intravascular activation of coagulation with loss of localisation arising from different causes. DIC can originate from and cause severe damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction. ISTH definition

Causes of DIC
Conditions associated with overt DIC

sepsis/severe infection (any organism) trauma (e.g. polytrauma, neurotrauma, fat embolism) organ destruction (e.g. severe pancreatitis) malignancy massive blood loss with inadequate fluid replacement therapy
vascular abnormalities (e.g. Kassbach-Merrit syndrome) severe hepatic failure severe toxic or immunological reactions (e.g. recreational drugs, transfusion reactions, transplant rejection)

Pathogenesis of DIC

Basically.
Excess thrombin generation Reduced natural anticoagulant activity Decreased fibinolysis

Excess thrombin generation

Increased tissue factor (monocytes and endothelial cells due to pro-inflammatory cytokines. Tissue thromboplasin (the stuff in the PT reagent from damaged tissue or malignant tissue) Direct activation of clotting factors by snake venoms

Reduced natural anticoagulant activity

Low antithrombin (increased TAT clearance and decreased liver biosynthesis) Lower protein C activity (reduced thrombomodulin, low protein S (bound to c4b binding protein), reduced synthesis)

Decreased fibinolysis
Increased PAI I
Levels correlate with outcome in meningococcal sepsis

Clinical features

Mucosal oozing, bleeding from surgical wounds or indwelling canulae Multi organ failure secondary to microthrobi (and hypovolaemia)

Diagnosis
Diagnostic algorithm for the diagnosis of overt DIC Does the patient have an underlying disorder known to be associated with overt DIC? (If yes, proceed; if no, do not use this algorithm) Order global coagulation tests (platelet count, PT, fibrinogen, soluble fibrin monomers (SFM) or fibrin degradation products (FDP). Score coagulation test results: Platelet count (>100=0; <100=1, <50=2) Elevated FDP or SFM (no increase=0; moderate increase=2; strong increase=3) Prolonged PT (by <3 seconds=0; >3 but <6 seconds=1; >6 seconds=2) Fibrinogen level (>1g/l=0; <1g/l=1) Score >=5 compatible with overt DIC Score <5 suggestive (not affirmative) of non-overt DIC; repeat tests in 1-2 days

Management of DIC
TREAT THE CAUSE Fluid resus as needed, antibiotics if sepsis If bleeding or need surgery give FFP, Platelets, Cryoprecipitate (Aim Platelets>50x109/l, PT and APTT < 1.5x normal)

If thrombotic manifestations eg. Dermal ischaemia consider low dose heparin infusion.

Questions