D-Dimer test, Fragment D-dimer, Diagnosis of Disseminated Intravascular Coagulopathy (DIC)

D-Dimer test

Sample

1. Citrated plasma is needed.
2. It is stable for 8 hours at room temp. It can be kept at -20 °C for 6 months.

Indications

1. This test is done to diagnose DIC (disseminated intravascular coagulopathy).
2. It can diagnose other thromboembolic disorders (venous thrombosis).
3. It can diagnose Pulmonary embolism.
4. For the diagnosis of acute myocardial infarction.
   1. D-Dimer may be increased in atrial fibrillation, congestive heart failure, and cirrhosis.

Pathophysiology

Definition of D-dimer

1. D-Dimers are produced by the action of plasmin on cross-linked fibrin clots.
2. The presence of D-Dimer confirms that both thrombin generation and plasmin generation have occurred.
3. Factor XIII generates D-dimer, by covalently linking the D regions of the fibrin molecule.
4. D-dimer assesses both thrombin and plasmin activity.
5. Damaged blood vessels and exposure to collagen activates both intrinsic and extrinsic cascade of blood coagulation.
   

   D-dimer formation

Disseminated intravascular coagulopathy (DIC):

Definition of DIC

1. This is the most serious condition due to fibrinolysis in DIC.
2. This is a widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets which occurs due to many diseases with the release of procoagulants into circulation or this may cause widespread endothelial damage and platelets aggregation.
3. There is the deposition of microclots in the blood vessels and depleting the plasma fibrinogen, leading to the hemorrhagic syndrome.

Pathogenesis of DIC:

1. This is an acquired clinical syndrome that is due to increased protease activity in the blood.
2. It is the unregulated release of thrombin with the formation of fibrin and increased fibrinolysis.
3. This is mainly due to the activity of the coagulation cascade (procoagulants).
4. The possible factors that will increase the procoagulants activity are:
   1. Arterial hypotension, mostly accompanied by shock.
   2. Hypoxemia.
   3. Acidosis (acidemia).
   4. Stasis of the capillary blood flow.
5. The DIC is initiated by the release of tissue factor (TF) through direct endothelium damage, activation, or tissue damage.
   1. Tissue factor (TF) is also released directly into the blood:
      1. From the white blood cells (monocytes).
      2. Immune complexes.
      3. Malignant cells.
6. Tissue factor (TF) is present in the endothelial cells. It is released when there is damage to the endothelial cells.
7. Cell damaging agents are:
   1. Endotoxin.
   2. Cytokines (Interleukin-1, 6, and 8).
   3. Tumor necrosis factor-α.
   4. Platelet-activating factor.
8. Summary of DIC pathogenesis:
   1. Initiated by the endothelial cells damage and release of tissue factor (TF).
   2. Tissue factor (TF) stimulates the coagulation factors.
   3. Activation of plasmin and thrombin.
   4. Accelerated consumption of coagulation factors.
   5. Clotting and hemorrhage will take place.
   6. Snake venom can activate factor X to Xa.
9. Damaged endothelium and inhibited the anticoagulant activity, there is uninhibited thrombin activity and unrestricted formation of clots.
   

   DIC pathogenesis

Mechanism of DIC:

1. In DIC there is increased consumption of the coagulation factors which will lead to their depletion.
2. Also due to microclots, platelets are depleted.
3. Plasmin increases fibrinolysis and leads to fibrinogen degradation products (FDP) and D-dimer formation.
4. There is a trigger for the increased clot formation, then fibrinolysis leads to the formation of FDP and d-Dimer.
5. Plasmin acts on Fibrin polymer clots and gives rise to FDP and D-dimer.
6. FDPs and Plasmin act on the fibrin clot and give rise to D-dimer products.

Causes of DIC are:

1. Infections.
2. Malignancy.
3. Hypersensitivity reactions.
4. Vascular abnormalities.
5. Widespread tissue damage.
6. Other causes like liver failure, pancreatitis, snake venoms, heatstroke, and acute hypoxia.

S/S of DIC are:

1. The patient may have weakness and malaise.
2. The main feature is the bleeding, especially from the site of venipuncture or a recent injury.
   1. There may be bleeding in the gastrointestinal tract. oropharynx, into the lungs, and in the urogenital tract.
   2. During delivery, vaginal bleeding may be very severe.
   3. Acrocyanosis is irregular-shaped cyanotic patches.
3. Microthrombi may cause skin lesions.
   1. There may be gangrene of the finger or toes.
4. There may be occult bleeding to massive GIT bleeding.
   1. There is abdominal distension.
5. Patients may develop renal failure.
   1. There may be hematuria.
   2. There is oliguria.
6. Patients may have cerebral ischemia.
   1. There may be subarachnoid hemorrhage.
   2. There is slight confusion to convulsions and coma.
7. These patients have respiratory symptoms like:
   1. Cyanosis.
   2. Hypoxemia.
   3. Adult respiratory distress syndrome (ARDS).
   4. Tachypnea.
   5. Pulmonary infarction.
8. Some patients with mucin-producing adenocarcinoma may develop subacute or chronic DIC.

Complications of DIC:

1. Thrombotic problems such as deep vein thrombosis, sickle cell anemia, pulmonary embolism, and thrombosis of malignancy are associated with raised levels of D-dimer.
2. FDP and d-Dimer form as a complication of the disseminated intravascular coagulopathy (DIC).

Diagnosis of DIC:

1. Fibrinogen concentration is low.
2. Platelets are low.
3. Thrombin time is prolonged.
4. Fibrinogen degradation products (FDP) like D-imer are increased and found in the urine and serum.
5. PT and APTT are prolonged in the acute phase.
6. The D-Dimer test detects the cross-linked fibrin degradation products.
7. The D-dimer assay is more specific than the FDP assay.
8. D-dimer is a highly specific measurement of fibrin degradation products that occurs.
9. Combining the positive test of FDP and D-dimer is highly specific and sensitive for the diagnosis of DIC.
10. A positive D-dimer result is evidence for DIC or other causes of intravascular thrombosis.
11. D-dimer can be used as a screening test for deep vein thrombosis (DVT).
    1. The concentration of the fibrin breakdown products will increase when there is fresh venous thrombosis.
    2. A negative result is useful in the emergency department for excluding the DVT in the clinically suspected patients.
12. Advantage of D-dimer:
    1. There is no interference of the fibrinogen, so the test can be done on the plasma without any need to collect it in the special tube.
13. The disadvantage is that it has limited usefulness because of its use in fibrinolysis and it will not detect breakdown products from the fibrinogen.
    11. D-dimer elevated level has limited value in cancers, inflammation after the surgery, or trauma, this will limit its usefulness.

The main features of DIC are due to different factors:

The groups of DIC	Main lab criteria
Group 1 (Procoagulant activation)	Raised D-dimer Raised fibrinopeptide A Raised fibrinopeptide B Raised level of thrombin-antithrombin complex Raised prothrombin fragment
Group 2 (Fibrinolytic activation)	Raised level of D-dimer Raised level of fibrinogen degradation products (FDP) Raised plasmin-antiplasmin complex Raised level of plasmin
Group 3 (Inhibitor consumption)	Decreased protein C and S Decreased heparin cofactor II Decreased antithrombin III Decreased alpha-2 antiplasmin Raised level of plasmin-antiplasmin complex Raised thrombin-antithrombin complex
Group 4 (End-organ damage and failure)	Raised level of creatine raised level of LDH Decreased pH Decreased PaO2

Normal D-dimer

Source 1

• Negative
• <0.25 mg/L

Source 2

• Normal = negative ( no D-dimer fragments are seen).
• <250 ng/mL (<250 µg/L).

Source 4

• Normally plasma is negative for D-dimer.
• Qualitative: It is negative
• Quantitative : < 250 ng/mL or < 250  µg/L ( SI unit)
• Critical value >40 mg/L (40 µg/mL).

Source 6

• <0.4 mcg/mL

False-positive test:

1. This is seen in heparin therapy.
2. The Rheumatoid factor can give false high values of FDP.
3. This test is positive in patients after surgery or trauma.
4. The false-positive test is seen in estrogen therapy and pregnancy.

Increased Level is seen in:

1. Primary and secondary fibrinolysis.
   1. DIC
   2. Thrombolytic therapy.
   3. Deep vein thrombosis.
   4. Pulmonary embolism.
   5. Arterial thromboembolism.
   6. Vaso-occlusive crises of sickle cell anemia.
   7. pregnancy ( Especially the postpartum period).
   8. Malignancy.
   9. Surgery.

• Please see more details in the fibrinogen degradation products FDP.

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