hematologist or molecular genetics:
Why are the INR and PTT normal in factor V Leiden and prothrombin gene mutation?
Routine coagulation assays like PT (INR) and aPTT are in general more sensitive in the detection of hypocoagulability rather than hypercoagulability. This is because their reagents contain very high concentrations of clotting activators and the end-point of these tests (clot formation) does not accurately depicts the whole coagulation process. The case of FV Leiden, however, is particular, because aPTT is used to detect it, provided it is performed in the absence and presence of standard amounts of exogenous activated protein C (APC) and an APC-sensitiviy ratio is then calculated.
Hope this can help.
Thank you Fabrizio Semeraro very much .
i found another answer but indeed more details about this to confirm the normal of this test.(
In factor V Leiden, patients have a point mutation in the factor V gene that produces a mutated factor V (it’s called factor V Leiden because this mutation was first described in Leiden, Netherlands). It turns out that this mutated factor V participates just fine in the coagulation cascade. The problem is that it can’t be turned off by protein C! The mutation in factor V Leiden just happens to be in one of the sites where protein C cleaves (and therefore inactivates) factor V; so in factor V Leiden, cleavage at that site doesn’t happen, and factor V “lasts” longer. So the mutated factor V just keeps working, even when the body is sending signals to stop making fibrin.
Back to the lab tests. The INR and PTT are normal in factor V Leiden because the patient with factor V Leiden makes fibrin at the same rate as a person with normal factor V. It’s just that later on, when the body tries to turn factor V off, the factor V Leiden patient will keep on making fibrin. Neither the INR nor the PTT measure this; in fact, no routine coag test measures it (they all just measure the time it takes to make fibrin).
PT and APTT are blunted assays. Plasma is unphysiologically hyper-activated to yield about 1-10 IU/ml thrombin. Ultra-specific chromogenic thrombin generation assays are the future in coagulation testing.
Factor V Leiden produces resistance to APC, the best measure to approximate to FVL is the levels of PC and APC, not the INR, PT or PTT, if you want a exactly measure of FVL you should do a q-PCR . This is the major problem in the treatment of patients with FVL, they have a risk of hypercoagulation but they don't have an specific measure that evidence the risk (all of the measure and indirect and no necessarily specific of FVL)
aPTT performed in the absence and presence of APC is the screening test to detect APC resistance. Once APC resistance has been confirmed, a genetic test will determine if such resistance is due to the Leiden mutation of FV. To my knowledge, levels of PC or APC do not relate to FVL, neither they can be used to hint at the presence of FVL.
If you want to increase sensitivity and specificity of APC testing in an aPTT-based assay (in presence and absence of APC), a predilution of the sample in FV deficient plasma may be used. This eliminates the influence of FVIII, Protein S, Heparin and most of the Lupus anticoagulant related disturbances (and so on).
The prothrombinmutation leads to an unaltered prothrombin molecule as the mutation is not translated into the protein sequence. PT usually reflects the average of FVII, FX, FII (and depending on the reagent FV) +/- 5% (in Germany we like to express PT and factor concentrations in [% of norm] and here you see one reason why). The concentration of prothrombin is somewhat increased compared to non-carriers. There might be (actually is) an effect on PT but it is smaller than the natural variation in a normal population. The latter also applies for the aPTT assay.
- Badges
- Science method