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Coagulation

Coagulation is a complex process by which the blood forms clots to block and then heal a lesion/wound/cut and stop the bleeding. It is a crucial part of hemostasis - stopping blood loss from damaged blood vessels. In hemostasis a damaged blood vessel wall is plugged by a platelet and a fibrin-containing clot to stop the bleeding, so that the damage can be repaired.

Coagulation involves a cellular (platelet) and protein (coagulation factor) component.

P.T. : How is it used?

The prothrombin time (PT) test is ordered to help diagnose unexplained bleeding, often along with a partial thromboplastin time (PTT) test. The PT test evaluates the extrinsic and common pathways of the coagulation cascade, while the PTT test evaluates the intrinsic and common pathways. Using both examines the integrated function of all of the coagulation factors.

Occasionally, the tests may be used to screen people for any previously undetected bleeding problems prior to surgical procedures.

The PT and INR are used to monitor the effectiveness of the anticoagulant warfarin (COUMADIN®). This drug affects the function of the coagulation cascade and helps inhibit the formation of blood clots. It is prescribed on a long-term basis to people who have experienced recurrent inappropriate blood clotting. Common clinical indications for warfarin use are atrial fibrillation, the presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism (where the embolized clots first form in veins). Warfarin is also used in antiphospholipid syndrome, and occasionally in heart attacks. The goal with warfarin therapy is to maintain a balance between preventing clots and causing excessive bleeding. This balance requires careful monitoring, typically by PT/INR.

APTT : How is it used?

The PTT test is used to investigate unexplained bleeding or clotting. It may be ordered along with a PT (Prothrombin Time) test to evaluate hemostasis, the process that the body uses to form blood clots to help stop bleeding. The PTT evaluates the coagulation factors XII, XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high molecular weight kininogen (HK). A PT test evaluates the coagulation factors VII, X, V, II, and I (fibrinogen). By evaluating the results of the two tests together, a doctor can gain clues as to what bleeding or clotting disorder may be present.

A PTT is often used to monitor standard (unfractionated, UF) heparin anticoagulant therapy. Heparin is a drug that is given intravenously (IV) or by injection to prevent and to treat thromboemboli. When it is administered for therapeutic purposes, it must be closely monitored. If too much is given, the treated person may bleed excessively; with too little, the treated person may continue to clot.

If the PTT is prolonged and the cause is not anticoagulant therapy or heparin contamination, then a second PTT test is performed by mixing the patient's plasma with pooled normal plasma (a collection of plasma from a number of normal donors). If the PTT time returns to normal ("corrects"), it suggests a deficiency of one or more of the coagulation factors in the patient's plasma. If the time remains prolonged, then the problem may be due to the presence of an abnormal factor inhibitor (autoantibody). Further studies can then be performed to identify what factors may be deficient or determine if an inhibitor is present in the blood. Nonspecific inhibitors, such as lupus anticoagulant and anticardiolipin antibodies, are associated with clotting episodes and with recurrent miscarriages, especially those that occur in the second or third trimester. For this reason, PTT testing may be performed to help investigate recurrent miscarriages.

Based on carefully obtained patient histories, the PTT and PT tests are sometimes selectively performed as pre-surgical procedures to screen for potential bleeding tendencies.

Other testing that may be done along with a PTT includes:

  • Platelet counts – should always be monitored during heparin therapy to promptly detect any heparin-induced thrombocytopenia
  • Thrombin time testing – sometimes ordered to help rule out heparin contamination
  • Fibrinogen testing – may be done to rule out hypofibrinogenemia as a cause of PTT prolongation

Lupus Anticogulant : How is it used?

Lupus anticoagulant testing is used to help determine the cause of an unexplained thrombosis, recurrent miscarriages, or a prolonged PTT test. It is ordered to help determine whether a prolonged PTT is due to a specific inhibitor, such as an antibody against a specific coagulation factor or to a nonspecific inhibitor like the lupus anticoagulant. It may be ordered along with tests for cardiolipin antibody and anti-beta2-glycoprotein I to diagnose antiphospholipid syndrome. If someone has tested positive for the lupus anticoagulant, the series of tests may be done again in several weeks to see if the lupus anticoagulant is transient or persistent.

A sequence of several different tests is used to confirm the presence of a lupus anticoagulant. It is recommended that two tests be performed in order to detect lupus anticoagulant. The most sensitive tests are dilute Russell viper venom test (DRVVT) and a PTT or LA-sensitive PTT (PTT-LA), one that uses low levels of phospholipid reagents. Follow-up testing is performed to confirm or exclude the presence of lupus anticoagulant. These may include:

  • Mixing study: an equal volume of patient plasma is mixed with "normal" pooled plasma and a PTT or DRVVT is performed on this mixture.
  • Correction/neutralization: an excess of phospholipids is added to the patient sample and a PTT-LA or DRVVT is performed. (One such assay is called a hexagonal phase phospholipid assay).

A thrombin time test may also be done to rule out heparin contamination and a fibrinogen test may be done to rule out abnormal or deficient fibrinogen. These two conditions can cause prolongations in the test results and interfere with lupus anticoagulant detection.

Factor V Leiden : How is it used?

Factor V Leiden mutation and prothrombin 20210 mutation tests are ordered, along with other tests related to thrombophilia, to help diagnose the cause of venous thrombosis and/or thromboembolism (VTE). They are ordered to help determine the reason for an initial thrombotic episode, especially when it occurs in a person under 50 years old, is unprovoked, or is in an unusual place such as the liver (hepatic), the kidneys (renal), the brain (cerebral), the gut and pelvis (mesenteric), or in the eye veins.

Evaluation for factor V Leiden can begin with a test for activated protein C (APC) resistance, though it is not commonly performed. About 95% of the time, APC resistance is due to a factor V Leiden mutation. If resistance is present, then a test for the factor V Leiden gene mutation is performed on the affected person's DNA, both to confirm the diagnosis and to determine whether the person is heterozygous or homozygous for the mutation.

The PT 20210 mutation must be diagnosed with genetic testing, checking directly for the gene mutation in the person's DNA and determining whether the patient is heterozygous or homozygous. Although prothrombin levels are usually moderately elevated with this mutation and could be measured, they are not clinically useful in identifying the mutation.

Experts do not recommend screening the general population and are divided on testing family members of those with a factor V Leiden or PT 20210 mutation. If the mutation is present, then the person is at a higher risk for developing a blood clot, but there is variability in how the gene is actually expressed. With factor V Leiden, for example, only 10% of those with the factor V Leiden mutation will ever have a thrombotic episode.

There are other tests that may be used to help identify additional factors that may be contributing to thrombophilia. Some of these include:

  • Protein C and protein S
  • Antithrombin III
  • Methylene tetrahydrofolate reductase (MTHFR) gene
  • Homocysteine
  • Factor V gene R2 mutation

Protien C - Protien S : How is it used?

Tests for protein C and protein S are usually ordered as part of an investigation into a possible clotting (hypercoagulable) disorder and/or to help diagnose the cause of a deep venous thrombosis (DVT) or a venous thromboembolism (VTE), especially if it occurs in a relatively young person (less than 50 years old) or has formed in an unusual location, such as the veins leading to the liver or kidney or the blood vessels of the brain (cerebral). While immediate treatment of the VTE does not depend on the test result, the doctor will want to determine the cause and the likelihood of recurrent clotting once the affected person's condition has stabilized.

Tests for protein C and protein S may look at their function (activity) or quantity (antigen). Functional tests for protein C and protein S are usually ordered, along with other tests for hypercoagulability, to screen for sufficient, normal, factor activity. Based on those results, quantities of protein C antigen and free, or sometimes total, protein S antigen may be measured to look for decreased production due to an acquired or inherited condition and to classify the type of deficiency. If the shortage is due to a rare inherited genetic change, the quantity of protein C or protein S available and the degree of activity can be used to help determine whether a person is heterozygous or homozygous for the mutation.