Bleeding Disorders

Bleeding Disorders



Rachid Baz, Tarek Mekhail



EVALUATION


The accurate diagnosis and treatment of patients with bleeding require some basic understanding of the pathophysiology of hemostasis. The process is divided into primary and secondary components. Primary hemostasis is the formation of a platelet plug at the site of injury and occurs within seconds of injury. Secondary hemostasis involves the coagulation system and results in fibrin formation. It requires several minutes to complete. The fibrin strands strengthen the hemostatic platelet plug. This process is particularly important in bleeding originating from large vessels and in preventing recurrent bleeding hours or days after the initial injury (Fig. 1).


image

Figure 1 Overview of hemostasis.


Vessel wall injury leads to expression of tissue factor (TF) on endothelial cells. TF complexes with factor VIIa to activate factors X and Xa in the presence of factor V, which leads to the activation of thrombin (IIa). Thrombin activates factors VIII, XI, and V fibrinogen to fibrin, as well as activating platelets to degranulate. This extrinsic pathway is turned off by tissue factor pathway inhibitor (TFPI), produced from endothelial cells. The intrinsic pathway-activated factor XIa activates factor IX, which in the presence of factor VIIIa activates factor X, resulting in the thrombin burst. Fibrin complexing with thrombin and factor XIII generates factor XIIIa, which cross-links fibrin strands. The fibrinolytic pathway plasminogen is converted to plasmin by tissue plasminogen activator (t-PA). Plasminogen activator inhibitor-1 (PAI-1) is produced by endothelial factor VIII. Antithrombin III (ATIII), a circulating plasma protease inhibitor, inhibits factors II, X, IX, and XI (its inhibition is further accentuated by binding to heparin). ADP, adenosine diphosphate; GpIa-IIa, glycoprotein Ia/IIa (binds collagen; deficiency causes mild bleeding diathesis); GpIb, glycoprotein Ib (binds vWF; deficiency causes Glanzmann’s thrombasthenia); GpVI, glycoprotein VI (binds collagen; deficiency causes a severe bleeding diathesis); 5HT, serotonin; NO, nitric oxide; PAR1 and 4, protease-activated receptors 1 and 4 (thrombin receptors); PDGF, platelet-derived growth factor; PGI2, prostaglandin I2; TxA2, thromboxane A2; vWF, von Willebrand factor; red arrows, inhibition; black arrows, stimulation.


Bleeding disorders can thus be categorized into three groups: disorders of platelet function or number, disorders of clotting factors, and a combination of these. Platelet disorders are discussed elsewhere in this section (“Disorders of Platelet Function and Number”). A focused history, physical examination, and screening laboratory tests are of paramount importance in directing the evaluation in a time-saving and cost-effective manner.



HISTORY AND PHYSICAL EXAMINATION


The evaluation of the bleeding patient should be focused primarily on whether and how the patient is bleeding.


Determine if the patient is bleeding. Surrogate markers of bleeding (e.g., a declining hemoglobin level) are often subject to misinterpretation. Hence, deciding whether the patient is bleeding should not be based solely on a declining hemoglobin level or sudden hypotension. Hemolysis or hemodilution represent other causes of a decrease in the hemoglobin level.


If bleeding is suspected, identify the site and severity, duration of bleeding, and clinical setting. Mucocutaneous bleeding suggests a platelet disorder. It manifests as petechiae, ecchymoses, epistaxis, and genitourinary and gastrointestinal bleeding. Bleeding into potential spaces (joints, fascial planes, and retroperitoneum) suggests a coagulation factor deficiency. In hospitalized patients, bleeding from multiple sites can be seen with disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP).


A complete history should include a past medical history; a history of human immunodeficiency virus (HIV) infection, liver or kidney disease, or malabsorption is often associated with bleeding. A medication history should be obtained, with particular attention to anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, antibiotics, ethanol, and dietary vitamins K and C. The response to past hemostatic challenges, such as trauma, tooth extraction, pregnancy, surgery, sports, and menstruation, should be determined. A family history of bleeding disorders may be helpful for assessing pathologic bleeding.


Acute massive mucocutaneous bleeding in a patient previously without symptoms should suggest immune thrombocytopenic purpura (ITP). Massive bruising and oozing from multiple sites in otherwise asymptomatic patients might suggest accidental warfarin ingestion or acquired factor VIII inhibitors (particularly in older patients). Postoperative bleeding at a surgical site is usually related to a local surgical problem. Spontaneous or excessive posttraumatic (immediate or delayed) bleeding can indicate a localized pathologic process or a disorder of the hemostatic process.


The physical examination should focus on identifying signs of bleeding (e.g., petechiae, mucosal bleeding, soft tissue bleeding, ecchymoses) as well as signs of systemic disease.



DIAGNOSTIC LABORATORY TESTING


Initial laboratory investigations should include a complete blood count (CBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), and peripheral smear. A preoperative screen for a patient with a negative history and examination should include a CBC, PT, and aPTT only. The following is a brief description of tests available for the evaluation of hemorrhagic disorders.


In the platelet count, always verify thrombocytopenia by reviewing a peripheral smear. For example, platelet clumping with ethylenediaminetetraacetic acid (EDTA) does not represent true thrombocytopenia, and an accurate platelet count can be obtained by using citrated, or heparinized tubes.


The aPTT represents the time for clot formation after adding calcium, phospholipids, and kaolin to citrated blood. It is prolonged by heparin, direct thrombin inhibitors, a deficiency of or inhibitor for factors in the intrinsic and common pathways (e.g., factors II, V, VIII, IX, X, XI, and XII) as well as lupus anticoagulant, vitamin K deficiency, or severe liver disease.


The PT represents the time for clot formation after the addition of thromboplastin (tissue factor) and calcium to citrated blood. It is prolonged with deficiencies of factors II, V, VII, and X or fibrinogen; liver disease; vitamin K deficiency; and warfarin use. The international sensitivity index is a measure of thromboplastin sensitivity. Table 1 illustrates causes of a prolonged PT, aPTT, or both.


Table 1 Causes of Prolonged Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT)































Prolonged PT Prolonged aPTT Prolonged PT and aPTT
Inherited
Factor VII deficiency vWF, factor VIII, IX, XI, or XII deficiency Prothrombin, fibrinogen, factor V, X or combined factor deficiency
Acquired
Vitamin K deficiency Heparin use Liver disease
Liver disease Inhibitor of vWF, factors VIII, IX, XI or XII DIC
Warfarin use Antiphospholipid antibodies Supratherapeutic heparin or warfarin
Factor VII inhibitor   Combined heparin or warfarin useInhibitor of prothrombin, fibrinogen, factor V or XDirect thrombin inhibitor

The thrombin time (TT) is the time to clot formation after the addition of thrombin to citrated blood. The TT is prolonged by heparin, direct thrombin inhibitors, fibrin degradation products (FDPs), paraproteins, and fibrinogen deficiency (qualitative and quantitative). Protamine is added to neutralize the heparin so the TT can be interpreted without heparin interference. This assay has been used to establish the presence of adequate fibrinogen but is not being used as widely now.


Reptilase time measures the time to clot formation after the addition of reptilase, a thrombin-like snake enzyme, to citrated blood. Unlike the TT, it is not affected by heparin. It can be useful to determine whether heparin is the cause of the prolonged TT.


The 1 : 1 mixing study is done when the PT or aPTT is prolonged. The patient’s plasma is mixed with normal plasma, and the test is repeated. If the mixing of normal plasma corrects the abnormal result (PT or aPTT), a factor deficiency is suggested; otherwise, an inhibitor is suspected. Similarly, an incubated mixing study is done 1 hour (and occasionally 2 hours) after mixing of the patient’s plasma with normal plasma. It is used to differentiate a lupus anticoagulant from clotting factor inhibitors; the latter usually results in immediate-acting inhibitors, whereas the former results in delayed inhibitors).


The urea clot solubility test relies on the ability of urea to dissolve unstable clots, which are formed in the absence of factor XIII. Normal clots are not dissolved by urea or monochloroacetic acid, unlike clots in patients with factor XIII deficiency.


Fibrin degradation products are fragments resulting from the action of plasmin on fibrin or fibrinogen and reflect high fibrinolysis states (such as DIC) when their levels are elevated.


D dimers are FDPs that can be measured specifically by enzyme-linked immunosorbent assay (ELISA). Their level is usually higher in DIC and in thrombotic conditions, such as deep venous thrombosis and pulmonary embolisms. Their elevation in the absence of symptoms does not imply the presence of these disorders.


Platelet function screening is performed on the PFA-100, which is a platelet function analyzer that is slowly supplanting the bleeding time in the clinical arena. It tests the ability of platelets to aggregate into two cartridges (collagen–adenosine diphosphate [ADP] and collagen-epinephrine). It has a reported sensitivity of approximately 95% and specificity of approximately 89% in detecting platelet dysfunction, and a 98% positive predictive value in detecting aspirin-induced platelet defects.


Platelet aggregation studies remain the gold standard in detecting platelet function defects. In these tests, platelet aggregation is tested in response to various agents: ADP, epinephrine, collagen, arachidonic acid, and ristocetin. Platelets of patients with Glanzmann thrombasthenia (dysfunctional or deficient glycoprotein IIb/IIIa complex in platelets) only aggregate with ristocetin, whereas platelets of patients with Bernard-Soulier syndrome (absent or decreased glycoprotein Ib complex on platelets) have no aggregation with ristocetin, reduced aggregation with collagen, and normal aggregation with ADP, arachidonic acid, and epinephrine.


von Willebrand factor (vWF) screening includes tests of platelet function. It has a low negative predictive value and can require repeat testing. It includes the vWF antigen (vWF:Ag)-immunoassay for circulating vWF, and vWF activity (vWF:RCo), which measures the functional ability of a patient’s vWF to agglutinate platelets in the presence of ristocetin. Factor VIII:C activity is a functional assay for factor VIII that is measured by mixing normal plasma with factor VIII-deficient plasma. Levels of vWF:Ag and vWF:RCo may be elevated during pregnancy, oral contraceptive use, and liver disease. They are decreased by hypothyroidism and type O blood.

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Jul 18, 2017 | Posted by in GENERAL SURGERY | Comments Off on Bleeding Disorders

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