Page 2161 - Hematology_ Basic Principles and Practice ( PDFDrive )

1914 Part XII Hemostasis and Thrombosis

these problems are more frequent and more severe in individuals platelet function (e.g., use of fish oil supplements, ingestion of
with bleeding disorders. 1–5,7,9,14–18 Menorrhagia requiring treatment herbal supplements with aspirin-like properties), as can acute alcohol
is common among women, and it can sometimes be life-threatening intoxication. 3,15
in those with severe bleeding disorders. 10,12,14,16,17 With moderate or Among adults with von Willebrand disease, factor VIII deficiency,
severe disorders, there is less uncertainty about the disease prevalence and factor XIII deficiency, about 10% of the cases result from an
than there is for milder disorders (e.g., type 1 von Willebrand disease) acquired, autoantibody-induced deficiency state. Autoimmune
where there is ongoing debate about the diagnostic criteria that define causes of other bleeding disorders include immune thrombocyto-
9
a pathologic abnormality. There is less information on the prevalence penia, immune-mediated platelet dysfunction (more commonly
of disorders that require complex tests for diagnosis and have many arising from antibodies against glycoprotein IbIXV or α IIbβ 3),
1,3
potential causes (e.g., platelet function disorders). Undefined disor- and acquired factor V deficiency. Bone marrow disorders are
ders (definite bleeding problems despite normal or nondiagnostic associated with an increased risk for autoimmune or nonimmune
test findings) have emerged as a common cause of mucocutaneous bleeding problems, including thrombocytopenia, secondary platelet
bleeding. 18,19 function defects of diverse etiology (e.g., acquired forms of dense
The process of referral for bleeding makes it likely that the person granule deficiency, Glanzmann thrombasthenia, or Bernard-Soulier
15
has had some bleeding symptoms that may or may not reflect an syndrome), or acquired von Willebrand disease. They can also
1,3
underlying congenital or acquired bleeding problem. Because of result from the evolution of an inherited bleeding disorder (e.g.,
this referral bias, the prevalence of bleeding disorders in tertiary the development of acute myelogenous leukemia or myelodysplas-
referral clinics is much higher than in the general population. The tic syndrome in a person with a RUNX1 or ANKRD mutation).
prevalence of inherited bleeding disorders in the general popula- Acquired bleeding problems can also occur with renal impairment,
1,3
tion is quite low (from 0.00023% to over 1% for von Willebrand liver disease, hypothyroidism, or Cushing syndrome. Some
disease, with much lower estimates based on studies of bleeding patients present with acquired skin bleeding that, on examination,
disorder–clinic cases compared with those derived from population is restricted to exposed parts of the body and reflects sun damage to
screening studies that used higher cutoffs to define quantitative the skin.
deficiencies; 0.005% to 0.01% for hemophilia; and much lower
for other coagulation factor deficiencies). Consequently, unselected
screening is not recommended. 1,3,9,20 Founder effects in populations PATHOBIOLOGY
can alter the prevalence of both common and rare inherited bleeding
disorders. There are many different components of the hemostatic, fibrinolytic
A person with a first-degree relative with an autosomal dominant and vascular response to injury that are important for prevention and
bleeding problem (e.g., Case 2), or a sibling with a recessively inher- control of bleeding (see Chapters 122, 123, 125–127, 130, 131, 135,
ited disorder, has a higher pretest probability of an inherited bleeding 137 and 138). Normal hemostasis requires platelet adhesion to col-
7,9
disorder. When assessing the relative of someone with a positive lagen and platelet activation and aggregation at sites of tissue injury,
family history of a bleeding problem, it is important to realize that processes that require von Willebrand factor and other adhesive
the person may have the same condition, with or without additional proteins; the initiation of coagulation by tissue factor; followed by
7
defects, or a different bleeding problem. Furthermore, it is common amplification and propagation of coagulation to generate thrombin
for affected family members to show some variability in the severity and convert fibrinogen to fibrin. It also requires stabilization of fibrin
7,9
of their bleeding symptoms (e.g., Case 2). Index cases typically have through the cross-linking actions of activated factor XIII. The activa-
1,4
more severe bleeding symptoms. Accordingly, laboratory investiga- tion of fibrinolysis (which is important for wound healing) is part of
tions are often used to assess family members at high risk, even in the normal response to tissue injury and repair. Fibrinolysis is retarded
the absence of a remarkable personal bleeding history. by platelets (which release large quantities of stored plasminogen
Common bleeding disorders that are inherited as autosomal activator inhibitor 1 [PAI-1]) and accelerated by deficiencies or
dominant traits include von Willebrand disease, many common defects in PAI-1 or α 2 -antiplasmin, gain-of-function defects in plas-
platelet function disorders (including many secretion defects, MYH9- minogen activators, and pathologic states that increase fibrinolysis.
related disorders, gain-of-function disorders such as platelet-type von The interdependence of hemostatic mechanisms explains why a
Willebrand disease and Quebec platelet disorder), and dysfibrinogen- failure of platelet adhesive mechanisms (e.g., from defects in platelet
emia. 1,3,9,15 Because the diagnostic criteria for mild von Willebrand number or function or von Willebrand disease) may cause persistent,
9
disease have changed, a positive personal or family history often delayed, and/or recurrent bleeding from a wound site, particularly if
requires reevaluation over time. initial hemostasis was inadequately managed or controlled. That
X-linked bleeding disorders include hemophilia A, hemophilia B, activation of fibrinolysis occurring during hemostasis explains why
and X-linked congenital platelet disorders (e.g., Wiskott-Aldrich fibrinolytic inhibitors are often effective for treating diverse bleeding
syndrome or thrombocytopenia caused by GATA1 mutations). 1,3,15 problems (e.g., menorrhagia and bleeding from oral/nasal surgical or
X-linked disorders typically affect males but can affect women with dental procedures) in patients with conditions ranging from von
skewed X-chromosome inactivation or Turner syndrome. Recessively Willebrand disease and platelet disorders to factor deficiencies and
inherited bleeding disorders are the rarest, and their prevalence is fibrinolytic defects. Some individuals with severe nosebleeds or
highest in populations in which consanguinity is culturally accepted. 21 gastrointestinal bleeds from platelet function disorders (e.g., Glanz-
Acquired bleeding problems are common, and the most frequent mann thrombasthenia) that are refractory to platelet transfusions
1,3
cause is a drug-induced defect. Drugs that alter hemostasis may (because of development of antibodies) may respond to treatment
cause bleeding on their own or they may unmask or worsen symp- with recombinant factor VIIa.
toms from a mild or moderate underlying bleeding disorder. 1,3,9,22 Hemostasis is also influenced by other factors, such as anemia.
Drug-induced problems to consider include the following: (1) use The red cell number in blood influences platelet margination, which
of prescription or nonprescription nonsteroidal antiinflammatory facilitates platelet adhesion to the injured vessel wall. Accordingly,
drugs (NSAIDs) that transiently inhibit platelet cyclooxygenase-1 anemia can worsen bleeding and increase bleeding risk. Some disor-
(patients may not recall taking these drugs if they received them after ders of hemostasis reflect defects in the vessel wall. For example,
a surgical procedure 2,3,22 ); (2) aspirin or P2Y 12 or α IIb β 3 inhibitors hereditary hemorrhagic telangiectasia (HHT), which is often (but not
used for acute or chronic prevention or treatment of cardiovascular always) associated with telangiectasia on the nose, lips and oral
25
disorders; (3) anticoagulants prescribed for the prevention or treat- cavity, can cause troublesome bleeding from vascular malforma-
ment of venous thromboembolic disease, atrial fibrillation, or acute tions. HHT can cause epistaxis (present in about 95% of persons
management of atherosclerotic disease; (4) antidepressant medica- with this disorder), gastrointestinal bleeding, and less commonly,
tions (e.g., serotonin reuptake inhibitors), which may cause bruising; intracranial or pulmonary hemorrhage, typically without excessive
and (5) glucocorticoid therapy. 1,19,23,24 Some dietary practices affect bleeding with surgical procedures or menorrhagia. 1,3,25