Bleeding that is spontaneous, excessive, or delayed in onset following tissue injury results from one or more of the following:
•A localized pathologic process
•Disorders involving vascular integrity
•Disorders of platelet number and/or function
•Disorders of the various coagulation factors
•Increased fibrinolysis
●A careful assessment of the presenting complaint and the patient's bleeding history can provide important clues as to where a defect might reside in the hemostatic process and whether the defect is inherited or acquired (table 1). (See 'Patient history' above and "Preoperative assessment of hemostasis", section on 'The classic approach' and "Approach to the adult with unexplained thrombocytopenia", section on 'Overview of our approach'.)
●The physical examination is helpful in determining the type of bleeding present, as well as for detecting other conditions that might be present. (See 'Clinical manifestations' above and "Preoperative assessment of hemostasis", section on 'The physical examination' and "Approach to the adult with unexplained thrombocytopenia", section on 'Physical examination'.)
●In many patients the likely diagnosis will be apparent from the history and physical examination alone; the diagnosis can then be confirmed with the appropriate specific tests.
●When the diagnosis is not immediately apparent, three initial tests should be performed: platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) (table 2). (See 'Laboratory testing' above and"Clinical use of coagulation tests".)
●The pattern of results provides a presumptive diagnosis which can then be confirmed with specific testing (table 3 and table 4). (See 'Diagnostic approach' above.)
Clinical manifestations of bleeding disorders
| Bleeding symptoms | Bleeding disorder | |
| Platelet defects (qualitative or quantitative) | Clotting factor deficiencies (eg, factor VIII or factor IX deficiencies) | |
| Overview of bleeding events |
Mucocutaneous bleeding
(oral cavity, nasal, gastrointestinal, and genitourinary sites) | Deep tissue bleeding (including joints and muscles) |
| Excessive bleeding after minor cuts | Yes | Not usually |
| Petechiae | Common | Uncommon |
| Ecchymoses | Generally small and superficial; may be significant, depending upon the defect or degree of thrombocytopenia | May develop large subcutaneous and soft tissue hematomas |
| Hemarthroses, muscle hematomas | Uncommon | Common in severe deficiency states or in association with injury in those with mild to moderate deficiency states |
| Bleeding with invasive procedures, including surgery | Often immediate, with degree of bleeding dependent upon the severity of the defect, ranging from none (eg, mild degrees of thrombocytopenia or mild platelet function defect) to mild to severe (eg, Glanzmann thrombasthenia) | May be associated either with procedural bleeding or delayed bleeding, depending upon the type and severity of the defect |
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Petechiae in Immune Thrombocytopenia (ITP)
Petechiae in a man with immune thrombocytopenia (ITP).
(A) Dense, cutaneous petechiae on the foot and ankle. There are no petechiae on the sole of his foot, a site at which the vessels are protected by the strong subcutaneous tissue.
(B) Occasional petechiae on the patient's face and large, bullous hemorrhages on the buccal mucosa, which are related to the lack of vessel protection by the submucosal tissue. Similar petechiae and hemorrhagic bullae can be seen in patients with thrombocytopenia of any cause.
(A) Dense, cutaneous petechiae on the foot and ankle. There are no petechiae on the sole of his foot, a site at which the vessels are protected by the strong subcutaneous tissue.
(B) Occasional petechiae on the patient's face and large, bullous hemorrhages on the buccal mucosa, which are related to the lack of vessel protection by the submucosal tissue. Similar petechiae and hemorrhagic bullae can be seen in patients with thrombocytopenia of any cause.
Reproduced with permission from: Stein JH, Internal Medicine, 5th ed, Mosby, St. Louis, 1998.
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Pseudothrombocytopenia due to platelet clumping in EDTA
This peripheral blood smear shows platelet clumping (arrows) in an EDTA-anticoagulated blood sample. This patient had an EDTA-dependent platelet agglutinin which caused in vitro platelet clumping, resulting in an artifactually low platelet count (ie, "pseudothrombocytopenia"). No platelet clumping was seen, and the platelet count was normal, in a blood sample from this patient anticoagulated with sodium citrate.
Reproduced with permission from Beutler, E, Lichtman, MA, Coller, BS, et al, Hematology, 5th ed, McGraw-Hill, New York, 1995.
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Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several platelets (arrows) and a normal lymphocyte (arrowhead) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (dashed arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
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Intrinsic, extrinsic, and common coagulation pathways
Schematic representation of the intrinsic (in red), extrinsic (in blue), and common (in green) coagulation pathways. Contact factors include prekallikrein and high molecular weight kininogen (HMWK). In the clinical laboratory, the intrinsic (and common) pathway is assessed by the activated partial thromboplastin time (aPTT) and the extrinsic (and common) pathway by the prothrombin time (PT). The thrombin time (TT) assesses the final step in the common pathway, the conversion of fibrinogen to fibrin, following the addition of exogenous thrombin. Fibrin is crosslinked through the action of factor XIII, making the final fibrin clot insoluble in 5 Molar urea or monochloroacetic acid. This latter function is not tested by the PT, aPTT, or TT.
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Indications for obtaining PT testing alone, aPTT testing alone, or PT and aPTT testing combined
| Clinical circumstance(s) | PT testing alone | aPTT testing alone | PT and aPTT testing combined |
| Monitoring anticoagulation | |||
| Warfarin only (without heparin) | √ | – | – |
| Therapeutic unfractionated heparin (without warfarin) | – | √ | – |
| Transitions between heparin and warfarin therapy | – | – | √ |
| Patient assessment | |||
| Assessment of patients with signs or symptoms of hemorrhage or thrombosis | – | – | √ |
| Assessment of patients with history of condition known to be associated with risk of bleeding or thrombosis due to extrinsic coagulation pathway abnormalities, either genetic or acquired | √ | – | – |
| Assessment of patients with history of condition known to be associated with risk of bleeding or thrombosis due to intrinsic coagulation pathway abnormalities, either genetic or acquired | – | √ | – |
| Assessment of risk of hemorrhage or thrombosis in patients who are going to have a medical intervention known to be associated with increased risk of bleeding or thrombosis | – | – | √ |
PT: prothrombin time; aPTT: activated partial thromboplastin time.
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Causes of a prolonged prothrombin time (PT) and/or a prolonged activated partial thromboplastin time (aPTT)
| Test result | Causes of test result pattern | |
| PT | aPTT | |
| Prolonged | Normal | Inherited |
| Factor VII deficiency | ||
| Acquired | ||
| Mild vitamin K deficiency | ||
| Liver disease | ||
| Warfarin administration* | ||
| Acquired inhibitor of factor VII | ||
| Lupus anticoagulant (more commonly causes isolated prolonged aPTT; may be associated with thrombosis rather than bleeding) | ||
| Normal | Prolonged | Inherited |
| Deficiency of factors VIII, IX, or XI | ||
| Deficiency of factor XII, prekallikrein, or HMW kininogen (not associated with a bleeding diathesis) | ||
| von Willebrand disease (variable) | ||
| Acquired | ||
| Heparin administration* | ||
| Inhibitor of factors VIII, IX, XI, or XII | ||
| Acquired von Willebrand disease | ||
| Lupus anticoagulant (may be associated with thrombosis rather than bleeding) | ||
| Prolonged | Prolonged | Inherited |
| Deficiency of prothrombin, fibrinogen, or factors V or X | ||
| Combined factor deficiencies | ||
| Acquired | ||
| Liver disease | ||
| Disseminated intravascular coagulation | ||
| Supratherapeutic doses of anticoagulants | ||
| Severe vitamin K deficiency | ||
| Combined heparin and warfarin administration | ||
| Direct thrombin inhibitor administration (eg, argatroban, dabigatran)* | ||
| Direct factor Xa inhibitor administration (eg, rivaroxaban, apixaban, edoxaban) | ||
| Fondaparinux administration (slight prolongation) | ||
| Inhibitor of prothrombin, fibrinogen, or factors V or X | ||
| Primary amyloidosis-associated factor X deficiency | ||
| Anticoagulant rodenticide poisoning | ||
Refer to UpToDate topics on use of coagulation tests and on evaluation of patients with bleeding or specific inherited and acquired conditions for additional details.
PT: prothrombin time; aPTT: activated partial thromboplastin time; HMW: high molecular weight.
* The most common effects of the anticoagulants are shown. In principle, many anticoagulants affect common pathway factors and can prolong both the PT and the aPTT if present at high enough levels. As examples:
* The most common effects of the anticoagulants are shown. In principle, many anticoagulants affect common pathway factors and can prolong both the PT and the aPTT if present at high enough levels. As examples:
- Warfarin typically prolongs the PT alone, but at high levels warfarin can prolong both tests.
- Heparin typically prolongs the aPTT alone (because PT reagents contain heparin-binding agents that block heparin effect), but at high levels heparin can prolong both tests.
- Direct thrombin inhibitors typically prolong both tests, but at low levels dabigatran may not prolong the PT.
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Expected results of tests for hemostatic function in representative bleeding disorders
| Disorder | Plt | PT | aPTT | TT | Fib |
| Vasculopathies, connective tissue diseases, or collagen disorders affecting skin | Normal | Normal | Normal | Normal | Normal or increased* |
| Thrombocytopenia | Low | Normal | Normal | Normal | Normal |
| Qualitative platelet abnormalities | Normal or low¶ | Normal | Normal | Normal | Normal |
| Hemophilia A (factor VIII deficiency) | Normal | Normal | Long | Normal | Normal |
| von Willebrand disease | NormalΔ | Normal | Long◊ | Normal | Normal |
| Disseminated intravascular coagulation | Low | Long | Long | Long | Low |
Plt: platelet count; PT: prothrombin time; aPTT: activated partial thromboplastin time; TT: thrombin time; Fib: fibrinogen.
* Fibrinogen may be elevated as an acute phase reactant in disorders of inflammation.
¶ The platelet count in myeloproliferative disorders is usually high (eg, essential thrombocythemia) and platelets may also be qualitatively abnormal, predisposing to hemorrhagic and thrombotic diatheses.
Δ The platelet count may be low in some patients with type 2B von Willebrand disease.
◊ The aPTT may be normal in those with Factor VIII activity >40 percent.
* Fibrinogen may be elevated as an acute phase reactant in disorders of inflammation.
¶ The platelet count in myeloproliferative disorders is usually high (eg, essential thrombocythemia) and platelets may also be qualitatively abnormal, predisposing to hemorrhagic and thrombotic diatheses.
Δ The platelet count may be low in some patients with type 2B von Willebrand disease.
◊ The aPTT may be normal in those with Factor VIII activity >40 percent.
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Coagulation factor levels required for hemostasis and plasma half-life
| Factor | Plasma half-life | Hemostatic level* |
| Fibrinogen | 2 to 4 days | 50 to 100 mg/dL |
| Prothrombin (factor II) | 3 to 4 days | 20 to 30 percent |
| Factor V | 36 hours | 15 to 20 percent |
| Factor VII | 4 to 6 hours | 15 to 20 percent |
| Factor X | 40 to 60 hours | 15 to 20 percent |
| Factor XI | 40 to 70 hours | 15 to 20 percent |
| Factor XIII | 11 to 14 days | 2 to 5 percent |
| Factor V + factor VIII combined deficiency | 36 hours for factor V and 10 to 14 hours for factor VIII | 15 to 20¶ percent |
| Multiple vitamin K-dependent factor deficiencies (factors II, VII, IX, X) | Refer to individual factor half-lives above | 15 to 20¶ percent |
Refer to UpToDate topics on factor XI deficiency, rare inherited coagulation disorders, and fibrinogen disorders for details.
* Level of factor activity generally required for hemostasis, expressed as a percent of normal except for fibrinogen, which is expressed in mg/dL.
¶ Higher levels of factor VIII needed post-surgery.
¶ Higher levels of factor VIII needed post-surgery.
Adapted from: Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104:1243. Copyright © 2004 American Society of Hematology.
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