**2.5 Investigations of hypercoagulability**

Hypercoagulability has been recognised as an abnormal complex condition of the haemostasis and as such, the diagnosis of hypercoagulability syndromes involves a combination of associated risk factors, screening tests and confirmation tests [21]. Assessment guidelines vary between medical associations. Some associations suggested that young patients with unprovoked or recurrent VTE, patients with a strong family history of abnormal blood clotting, patients with a recurrent blood clot, women with a history of recurrent miscarriage, stroke at a young age, thromboses in unusual sites, such as hepatic, renal, cerebral, mesenteric, neonatal purpura fulminans, warfarin-induced skin necrosis, and foetal loss should be screened for haemophilia. Also, patients with a history of suspected APS, unexplained prothrombin time (PT), thrombin time (TT), may require APS investigation, screening for APLAs and the diluted Russell venom viper test (dRVVT) [21].

The baseline investigations for hypercoagulability states, including routine coagulation studies, such as aPPT, which measures the blood clot time, usually to monitor heparin treatment, prothrombin time (PT) test is used to calculate INR, to monitor warfarin (Coumadin) treatment, FN levels, d-dimer and complete blood counts (CBC) should be carried out. The most advanced and essential screenings for thrombophilia include functional assays for ATIII, protein C and S deficiencies, PCR for prothrombin G2021A mutation and FVL mutation, testing for APLAs and homocysteine levels [19].

Screening for undetected cancer and unexplained VTE in older patients, including patients history and physical examination, ESR, hepatic and renal function tests, urinalysis, and chest X-ray (XR), tumour markers, CT of the chest, abdomen and pelvis mammography in women above 40 years [20], prostate ultrasound in men of more than 50 years, lower endoscopy, Papanicolaou smear and faecal occult blood test are recommended. In patients with hypercoagulability syndromes, there is an increased risk of venous thrombosis than ischemic stroke. Existing evidence has indicated that venous thrombosis could progress to arterial strokes by paradoxical embolism, therefore young adults with stroke should be screened for venous thrombosis, as the incidence of stroke is gradually increasing in young adults. The report has indicated an association between the homocystinuria and APLA syndrome with arterial strokes, and stroke has been investigated as the common arterial condition progressing to APLA syndrome. Hence, screening for APLA syndrome should be performed on stroke patients younger than 45 years [19].

#### *2.5.1 Other tests to investigate acquired hypercoagulable states*

Anticardiolipin antibodies (ACA) or beta-2 glycoproteins, LA, which are part of the APLA syndrome, to evaluate patients with recurrent miscarriage and venous or arterial thrombosis. Heparin antibodies (in patients who have decreased platelet counts after exposure to heparin) [19].

#### **2.6 Management of hypercoagulability**

*Anticoagulant medications include* synthetic drugs, including warfarin (Coumadin), which is taken orally, heparin, which is given either intravenously (IV), or subcutaneously. LMWH is injected also subcutaneously, fondaparinux (Arixtra) is also injected subcutaneously and are the most commonly prescribed drug available worldwide [19, 26].

The ATIII can be substituted for inherited or acquired defects, such as enhanced consumption in DIC and sepsis. Fresh frozen plasma (FFP) for the maintenance of natural balance between procoagulant and anticoagulant factors [30]. Also, various types of anticoagulants and antiplatelets are established to treat recurrent VTE [31], such as vitamin K antagonist (VKA), aspirin (as evaluated in the WARFASA and ASPIRE trials), rivaroxaban (EINSTEIN trial), dabigatran (RE-MEDY and RE-SONATE trials), and apixaban (AMPLIFY trial. The CLOT trial also evaluated LMWH against warfarin in cancer patients and was approved by food and drugs administration [32], rosuvastatin was approved for the prevention of occurrence of VTE [19].
