**2. Neurological complication of anticoagulation therapy**

The most common intracranial complication during regular treatment by anticoagulant drugs is intracerebral hemorrhage (ICH) [22–25]. Basically, the cause of ICH is classified into two groups as primary cause due to spontaneous rupture of small vessels or amyloid angiopathy as a majority of the patients about 78%-88% and secondary cause associated with tumor, impaired coagulopathy as a minority group. Even though small in number but significant risk factors with ICH such as hemophilia or acute leukemia with thrombocytopenia or patient during treatment by anticoagulant drugs, massive intracranial hemorrhage is often cause of death.

#### **2.1 Cause of intracranial hemorrhage (ICH)**

#### ACQUIRED:

Iatrogenic coagulopathy


Neoplastic coagulopathy


Rare cause of ICH


CONGENITAL:

• Hemophilia

#### **2.2 Physiology of hemostasis**

Two important mechanisms against bleeding are blood coagulation and plateletmediated hemostasis. The coagulation cascade is triggered as soon as blood contacts the injured endothelial lining. The combination of both coagulation cascade and active formation of the platelet plug is effective autoregulation mechanisms in occlusion of a vascular lesion. Coagulation cascade mechanism have its own two main pathways: 1) intrinsic pathway by physical-chemical activation which its role is not well understanding and 2) extrinsic pathway activated by tissue factor released from the damaged cell.

Extrinsic Pathway: When blood vessel wall injuries exposed plasma to tissue factor, then, Factor VII is a plasma protein bind to tissue factor and activated to factor VIIa, this complex will activate factor IX, X to factor IXa, Xa. Factor Xa and its cofactor Va form a phospholipid-bound complex called the prothrombinase complex, which is highly activated on the surface of platelets and cleaves prothrombin (factor II) to thrombin (factor IIa). Thrombin cleaves fibrinogen (factor I) to fibrin (factor Ia), which is covalently cross-linked by factor XIIIa into fibrin strands. Factor VIII binds to vWF (an adhesive protein important for the generation of the initial platelet plug). Thrombin feedback is important to the entire system. Thrombin, one generated is powerful procoagulant further conversion factor V, VIII to factor Va, VIIIa and covert more prothrombin to thrombin. Thrombin will further accelerate the entire cascade in the formation of a large amount of fibrin.

Regulatory mechanism of the coagulation cascade, such as tissue factor pathway inhibitor, antithrombin III, activated protein C and protein S, thrombomodulin, and fibrinolytic system, is to limit the amount of fibrin clot avoiding tissue ischemia and to prevent widespread thrombosis.

#### **2.3 Pathophysiology of bleeding disorders**

Coagulopathies leading to intracranial hemorrhage mostly from acquired caused. Iatrogenic coagulopathy from aspirin, anticoagulants, and thrombolytic agent treatment.

#### *Neuroimaging in Common Neurological Diseases Treated by Anticoagulants DOI: http://dx.doi.org/10.5772/intechopen.105128*

**Antiplatelet drugs:** Aspirin is the most common antiplatelet drug that is used daily in clinical practice such as acute MI and arterial occlusive cardiovascular disease. Its mechanism is to inactivation enzyme cyclooxygenase result in decreased platelet aggregant thromboxane A2. Incidence of intracranial hemorrhage due to aspirin In the 1991 Swedish Aspirin Low-Dose Trial investigators of patients with a history of TIA or minor stroke reported that the prevalence of intracranial hemorrhage was 1.5%. Finally, in 1997, the International Stroke Trial Collaborative Group concluded that administration of 300 mg aspirin daily compared with placebo following acute stroke pre-vented 1.2 ischemic strokes per 100 treated patients but caused in excess of 0.41 ICHs. Aspirin therapy for primary or secondary stroke prevention and primary MI prevention may slightly increase the low baseline risk of ICH but the increased risk is usually outweighed by the benefits of aspirin. Other antiplatelet agents: clopidogrel (Plavix), abciximab (Reopro), etc. act as glycoprotein IIb/IIIa inhibitors. The incidence of ICH in the clopidogrel group was 0.33%, whereas it was 0.47% in the aspirin group. The newer antiplatelet agents seem to be associated with an ICH risk profile similar to that of aspirin.

**Anticoagulant drugs:** Warfarin, heparin, and enoxaparin are the most common anticoagulants in routine clinical practice.


Anticoagulant therapy related ICH is about 10%-20% and ICH is the most dreaded and least treatable complication. The mortality rate is about 46%-68%. The distribution of intracranial hemorrhage related to anticoagulant therapy is in the brain parenchyma, intracerebral hemorrhage (ICH) about 70% followed by subdural hemorrhage (SDH). There is no specific predilection in the brain. Risk factors such as hypertension, increasing age, and previous cerebral infarction. The mechanism of spontaneous ICH developing during anticoagulants is not clearly understood. Postulate that patients with underlying hypertension with hemorrhage derived from small vessel vasculopathy, usually have normal hemostatic mechanisms but fail when anticoagulant.

**Thrombolytic agent:** Fibrinolytic agents have been used in clinical practice, such as acute MI and acute stroke. The examples of drugs in this group are the exogenous substances streptokinase, urokinase, and endogenous tPA. The mechanism in action is to activate the body's fibrinolytic system by converting plasminogen to plasmin. Plasmin binds to fresh fibrin clots, dissolving them and generating fibrinogen degradation products. Intracranial hemorrhage cause by the thrombolytic agent is in lobar hemorrhage 70%–90% and multiple locations in almost one-third of patients. ICH related to rtPA tended to have fluid levels in the hematomas (suggesting continuing or repeated hemorrhages), multiple parenchymal hemorrhages, and blood in multiple compartments (intraventricular, subarachnoid, subdural, and parenchymal). Patients with post-rtPA ICH also tended to suffer a catastrophic clinical course, with dying or ending up in a persistent vegetative state within hours of hemorrhage onset. Thus, in the case of acute ischemic stroke, there is a summary of absolute and relative contraindication to IV rtPA [6].

Absolute and relative contraindications to IV rt-PA for acute ischemic stroke.
