1. Prothrombin time (PT)
a. International normalized ratio standardizes the PT, so that the results are the same regardless of the re- agents used.
Most common cause of prolonged bleeding time:
aspirin
PT is prolonged only when the level of a clotting factor is 30-40% of normal.
Chapter 14 Coagulation Disorders 167
TABLE 14-2 Causes of Prolonged Bleeding Time
Cause Nature of Defect Comments
Aspirin or NSAIDs Platelet aggregation defect Normal platelet count Inhibition of platelet cyclooxygenase,
which ultimately inhibits synthesis of thromboxane A2
Bernard-Soulier syndrome Platelet adhesion defect Thrombocytopenia, giant platelets Autosomal recessive disease with Lifelong bleeding problem
absent Gplb platelet receptors for vWF
Glanzmann's disease Platelet aggregation defect Lifelong bleeding problem Autosomal recessive disease with
absent GpIlb-Illa fibrinogen receptors;
absent thrombosthenin
Renal failure Platelet aggregation defect Reversed with dialysis and desmo- Inhibition of platelet phospholipid by pressin acetate
toxic products
Scurvy Vascular defect May cause hemarthroses
Caused by vitamin C deficiency; defec- tive collagen resulting from poor cross-linking
Thrombocytopenia Decreased platelet number Prolonged bleeding time when platelet count < 90,000 cells/4
Von Willebrand's disease Platelet adhesion defect Other factor VIII coagulation defects Autosomal dominant disorder with
absent or defective vWF
NSAID, nonsteroidal ant-inflammatory drug; vWF, von Willebrand's factor
b. Uses
(1) Evaluates the extrinsic system in clot forma- tion: factors VII, X, V, prothrombin, and fibrin- ogen (see Figure 14-1)
(2) Monitors patients taking warfarin derivatives (3) Evaluates liver function
2. Partial thromboplastin time (PIT)
a. Evaluates the intrinsic system in clot formation:
factors XII, XI, IX, VIII, X, V, prothrombin, and fi- brinogen (see Figure 14-1)
b. Monitors patients taking heparin
Anticoagulation with heparin or warfarin causes both the PT and PTT to become prolonged, because both drugs inhibit factors in the final common pathway. Studies show that the PT monitors warfarin more accurately, whereas the PTT monitors heparin more accurately.
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
168 Pathology
Figure 14-3 Petechiae in idio- pathic thrombocytopenic purpura showing pinpoint hemorrhages, a sign of platelet dysfunction, in the skin over the thorax and shoulders. When touched, pete- chiae do not blanch with pressure
C. Studies used to evaluate fibrinolysis 1. Tests
a. FDP assay: detects all products of plasmin cleavage of fibrinogen or insoluble fibrin clots
b. D-dimer assay: detects only cross-linked insoluble fibrin monomers in a fibrin clot
2. Uses
a. Screening for disseminated intravascular coagulation (DIC) and pulmonary emboli
b. Evaluating response to fibrinolytic therapy for de- grading venous and arterial clots
III. Platelet Disorders
A. Clinical findings associated with platelet dysfunction 1. Epistaxis (nosebleeds): most common symptom of plate-
let dysfunction
2. Petechiae and multiple small ecchymoses (purpura) a. Petechiae: pinpoint areas of hemorrhage
(Figure 14-3)
b. Ecchymoses (purpura): larger areas of hemorrhage (diameter, 2 cm)
Palpable (raised) purpura is a sign of a small- vessel vasculitis, not a platelet disorder. Senile purpura is a normal finding in elderly patients and results from impaired collagen production and capillary fragility. Nonpalpable purpura de- velops in areas of trauma (e.g., back of hands, shins) (Figure 14-4).
3. Bleeding from superficial cuts or abrasions: no tempo- rary platelet plug is present to stop bleeding.
4. Easy bruisability, bleeding from mucosal membranes;
central nervous system, gastrointestinal, and genitouri- nary bleeding occur in cases of very severe thrombo- cytopenia.
B. Quantitative platelet disorders
1. Thrombocytopenia: decreased number of platelets a. Pathogenesis
Chronic autoim- mune thrombocyto- penic purpura is most common in women with SLE.
Chapter 14 Coagulation Disorders 169
Figure 14-4 Senile purpura showing the large, irregular areas of hemorrhage on the back of both hands This benign condi- tion primarily occurs in body areas that are frequently trauma- tized
(1) Decreased production (e.g., aplastic anemia, leukemia)
(2) Immunologic destruction (e.g., autoimmune rombocyto pem a I
(3) Increased consumption (e.g., thrombotic thromhocytopenic purpura, DIC)
(4) Sequestration in the spleen (e.g., hypersplen- ism in portal hypertension)
b. Types (Table 14-3)
2. Thrombocytosis: increased platelet count
a. Reactive thrombocytosis (e.g., chronic iron defi- ciency, infections, splenectomy, malignancy) b. Primary thrombocytosis (e.g., essential throm-
bocythemia, polycythemia Vera)
C. Qualitative platelet disorders: acquired (e.g., aspirin use) or hereditary (e.g., Glanzmann's disease) (see Table 14-2) IV. Coagulation Disorders
A. Pathogenesis
1. Decreased production (e.g., hemophilia A, cirrhosis) 2. Pathologic inhibition (e.g., acquired circulating anti-
bodies, or inhibitors, of coagulation factors)
3. Excessive consumption of coagulation factors in fibrin clots (e.g., DIC)
B. Clinical findings
1. Delayed bleeding (e.g., tooth extraction, appendectomy) a. A temporary platelet plug is the only mechanical
block preventing bleeding; this plug is easily dis- lodged, causing delayed bleeding.
h. Lack of thrombin prevents formation of a stable platelet plug.
2. Menorrhagia
3. Gastrointestinal and genitourinary bleeding 4. Hemarthroses and retroperitoneal bleeding: only in
severe factor deficiencies (factor levels < 5%)
Most common cause of thrombocy- topenia in children:
idiopathic throm- bocytopenic purpura
IgG antibodies directed against GpIlb:Illa receptors (type II hypersensitivity reaction)
Macrophages phagocytose platelets IgG antibodies directed against Gpllb:llla
receptors (type II hypersensitivity reaction)
Type I variant: nonimmune; develops early; transient
Type II variant: macrophage removal of platelets surfaced by IgG antibody directed against heparin attached to PF 4 (type II hypersensitivity) Similar to ITP
Deficiency in vWF-cleaving metallopro- tease in endothelial cells
Increase in circulating multimers of vWF increases platelet adhesion to areas of endothelial injury at arteriole-capillary junctions
Platelets are consumed because of production of platelet thrombi in areas of injury (not DIC)
Endothelial damage at arteriole-capillary junction caused by Shiga-like toxin of 0157:H7 serotype of Escherichia coli;
organisms proliferate in undercooked beef
Causes thrombocytopenia in children;
abrupt onset after upper respiratory tract infection
Responds well to corticosteroids Most common in women with SLE;
insidious onset Splenomegaly
Occurs 5-14 days after heparin treat- ment
Must discontinue heparin
Most common hematologic abnormality in HIV (not AIDS-defining condition) Occurs in women; usually acquired Clinical pentad: fever, thrombocyto-
penia, renal failure, microangiopathic hemolytic anemia with schistocytes (damage by platelet thrombi), CNS deficits
Occurs in children
Clinical findings similar to TM; CNS findings are less frequent
PF4, platelet factor 4; SLE, systemic lupus
Factor VIII:C activity of < 1`)/0 leads to severe hemophilia
170 Pathology
TABLE 14-3 Types of Thrombocytopenia
Type Pathogenesis Comments
Idiopathic thrombocyto- penic purpura (ITP)
Chronic autoimmune thrombocytopenic purpura
Heparin-induced throm- bocytopenia
HIV thrombocytopenia Thrombotic thrombocy-
topenic purpura (TTP)
Hemolytic uremic syndrome
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
• •
••
• •
• •
• •
• •
• •
CNS, central nervous system; DIC, disseminated intravascular coagulation;
erythematosus; vWF, von Willebrand's factor.