Hematopoietic System: Case 3 Flashcards
Certain elements of the history are particularly useful in determining whether bleeding is caused by:
- an underlying hemostatic disorder
- by a local anatomic defect
One clue is a history of bleeding following common hemostatic stresses such as:
dental extraction, childbirth, or minor surgery
What merits special attention?
Bleeding that is sufficiently severe to require blood transfusion
What suggests a systemic disorder?
A family history of bleeding and bleeding from multiple sites that cannot be linked to trauma or surgery
Since bleeding can be mild, lack of a family history of bleeding does not exclude an inherited hemostatic disorder.
This is usually localized to superficial sites such as the skin and mucous membranes, comes on immediately after trauma or surgery, and is readily controlled by local measures.
Bleeding from a platelet disorder
Differences in the Clinical Manifestations of Disorders of Primary and Secondary Hemostasis
Primary
Platelet Defects
Onset of bleeding after trauma: Immediate
Sites of bleeding: Superficial— skin, mucous membranes, nose, GI and genitourinary tracts
Physical findings: Petechiae, ecchymoses
Family history: Autosomal dominant
Response to therapy: Immediate; local measures effective
Secondary
Plasma Protein Defects
Onset of bleeding after trauma: Delayed — hours or days
Sites of bleeding: Deep — joints, muscle, retroperitoneum
Physical findings: Hematomas, hemarthroses
Family history: Autosomal or X-linked recessive
Response to therapy: Requires sustained systemic therapy
In contrast, bleeding from plasma coagulation defects occurs when?
hours or days after injury and is unaffected by local therapy. Such bleeding most often occurs in deep subcutaneous tissues, muscles, joints, or body cavities.
● A thorough history may establish presence of a hemostatic disorder and guide initial laboratory testing.
The most common site to observe bleeding is in the:
skin and mucous membranes
Collections of blood in the skin are called ___________ and may be subdivided on the basis of the site of bleeding in the skin.
Purpura
Small pinpoint hemorrhages into the dermis due to the leakage of red cells through capillaries are called ________ and are characteristic of platelet disorders in particular, severe thrombocytopenia.
Petechiae
Larger subcutaneous collections of blood due to leakage of blood from small arterioles and venules are called:
ecchymoses (common bruises) or, if somewhat deeper and palpable, hematomas
They are also common in patients with platelet defects and result from minor trauma.
What may cause bleeding without any hemostatic defect?
Dilated capillaries, or telangiectasia
In addition, the loss of connective tissue support for capillaries and small veins that accompanies aging increases the fragility of superficial vessels, such as those on the dorsum of the hand, leading to:
extravasation of blood into subcutaneous tissue — senile purpura
What is sometimes a serious problem in women with severe thrombocytopenia or platelet dysfunction?
Menorrhagia
Some patients with primary hemostatic defects, especially von Willebrand’s disease, may have:
- recurrent gastrointestinal hemorrhage
- often associated with angiodysplasia
- a common vascular malformation in the gastrointestinal tract
Bleeding into body cavities, the retroperitoneum, or joints is a common manifestation of:
plasma coagulation defects
What may cause synovial thickening, chronic inflammation, and fluid collections and may erode articular cartilage and lead to chronic joint deformity and limited mobility?
Repeated joint bleeding
Joint deformities are particularly common in patients with deficiencies of factors what?
VIll and IX, the two sex-linked coagulation disorders referred to as the hemophilias.
For unclear reasons, _____________ are much less common in patients with other plasma coagulation defects.
hemarthroses
What can cause secondary necrosis of tissues or nerve compression?
Blood collections in various body cavities or soft tissues
Retroperitoneal hematomas can cause femoral nerve compression, and large collections of poorly coagulated blood in soft tissues occasionally mimic malignant growths:
the pseudotumor syndrome
Two of the most life-threatening sites of bleeding are in the ___________, where bleeding can compromise the airway, and in the central nervous system.
oropharynx
What is one of the leading causes of death in patients with severe coagulation disorders?
Intracerebral hemorrhage
Because of their need for plasma and factor concentrates derived from multiple donors, many patients with hemophilia were infected with:
HIV before effective testing of donors was in place
What can induce thrombocytopenia and exacerbate bleeding in hemophilia patients?
HIV infection
The most important screening tests of the primary hemostatic system are:
(1) a bleeding time (a sensitive measure of platelet function), and
(2) a platelet count
What is a sensitive measure of platelet function?
Bleeding time
What correlates well with the propensity to bleed?
platelet count
What is the normal platelet count?
150,000 to 450,000 /uL of blood
As long as the count is >100,000/uL, patients are usually:
Asymptomatic, and
Bleeding time remains normal
Platelet counts of 50,000 to 100,000/uL cause what?
Mild prolongation of the bleeding time;
bleeding occurs only from severe trauma or other stress.
Patients with platelet counts <50,000/uL have:
- easy bruising
- manifested by skin purpura after minor trauma
- bleeding after mucous membrane surgery.
Patients with a platelet count <20,000/uL have:
- appreciable incidence of spontaneous bleeding,
- usually have petechiae, and
- may have intracranial or other spontaneous internal bleeding
What are the causes of thrombocytopenia?
Decreased marrow production of megakaryocytes
Marrow infiltration with tumor, fibrosis
Marrow failure __ aplastic, hypoplastic anemias, drug effects
Splenic sequestration of circulating platelets
Splenic enlargement d/t tumor infiltration
Splenic congestion d/t portal hypertension
Increased destruction of circulating platelets
Nonimmune destruction
> vacular prostheses, cardiac valves
> DIC
> sepsis
> vasculitis
Immune destruction
> autoantibodies to plt antigens
> drug-associated antibodies
> circulating immune complexes (SLE, viral agents, bacterial sepsis)
Patients with qualitative platelet abnormalities have a:
normal platelet count
prolonged bleeding time
What is ascertained by making a small, superficial skin incision and timing the duration of blood flow from the wounded area?
Bleeding time
What are the primary hemostatic (platelet) disorders?
Defects of platelet adhesion
von Willebrand’s disease
BSS (absence or dysfxn of GpIb/IX)
Defects of platelet aggregation
Glanzmann’s thrombasthenia (absence or dysfxn of GpIIb/IIIa)
Defects of platelet release
Decreased cyclooxygenase activity
> drug-induced — aspirin, nonsteroidal anti-inflammatory agents
> congenital
Granule storage pool defects
> congenital
> acquired
Uremia
Platelet coating (e.g., penicillin or paraproteins)
Defect of platelet coagulant activity
Scott’s syndrome
With careful standardization, what is a reliable and sensitive test of platelet function?
Bleeding time
A ______________________________ controls the length and depth of the incision (usually 1 mm deep by 9 mm long),
and a sphygmomanometer inflated to _______________ distends the capillary bed of the forearm uniformly.
A template or an automated scalpel controls the length and depth of the incision (usually 1 mm deep by 9 mm long),
and a sphygmomanometer inflated to 40 mmHg distends the capillary bed of the forearm uniformly.
The bleeding time test must be performed by an experienced technician, as small differences in technique have a big effect on outcome.
Any patient with a bleeding time _____________ has an increased risk of bleeding, but the risk does not become great until the bleeding time is _____________.
Any patient with a bleeding time >10 min has an increased risk of bleeding, but the risk does not become great until the bleeding time is >15 or 20 min.
the relationship between the platelet count and the bleeding time is
roughly linear
When a defect in ______________ is uncovered, specialized testing is needed to determine the cause of the platelet dysfunction.
Primary hemostasis (check again card 37)
Lab work-up of bleeding disorders facts:
● A precise diagnosis is important in determining the proper treatment.
● Occasional patients with a strong history of bleeding, particularly those with mild von Willebrand’s disease, may have a normal bleeding time when initially tested, owing to cyclical variations in the level of the vWF.
● Repeated testing may be necessary to establish an accurate diagnosis.
What is not an effective screening test for preoperative patients?
Bleeding time
Plasma coagulation function is readily assessed with the:
the PTT,
prothrombin time (PT),
thrombin time (TT), and
quantitative fibrinogen determination
Relationship between secondary hemostasis disorders and coagulation test abnormalities
Prolonged partial thromboplastin time (PTT)
No clinical bleeding — factors XII, HMWK, PK
Mild or rare bleeding — factor XI
Frequent, severe bleeding — factors VIII and IX
Prolonged prothrombin time (PT)
Factor VII deficiency
Vitamin K deficiency— late
Warfarin anticoagulant ingestion
Prolonged PTT and PT
Factor II, V, or X deficiency
Vitamin K deficiency — late
Warfarin anticoagulant ingestion
Prolonged thrombin time (TT)
Mild or rare bleeding — afibrinogenemia
Heparin-like inhibitors or heparin administration
Prolonged PT and/or PTT not corrected with normal plasma
Specific or nonspecific inhibitor syndromes
Clot solubility in 5M urea
Factor XIII deficiency
Inhibitors or defective cross-linking
Rapid clot lysis
a2 plasmin inhibitor
The PTT screens the:
Intrinsic limb of the coagulation system and tests for the adequacy of factors XII, HMWK, PK, XI, IX, and VIII.
The PT screens the:
Extrinsic or tissue factor-dependent pathway.
Both tests also evaluate the common coagulation pathway involving all the reactions that occur after the activation of what factor?
Factor X
Prolongation of the PT and PTT that does not resolve after the addition of normal plasma suggests a:
Coagulation inhibitor
A specific test for the conversion of fibrinogen to fibrin is needed when both the PTT and PT are prolonged — either a _______________ can be employed.
A specific test for the conversion of fibrinogen to fibrin is needed when both the PTT and PT are prolonged — either a TT or a clottable fibrinogen level can be employed.
When abnormalities are noted in any of the screening tests, more specific coagulation factor assays can be ordered to determine the nature of the defect.
Several rare coagulation abnormalities may be missed as they do not affect these screening tests:
Factor XIlI deficiency,
a2 plasmin inhibitor deficiency,
PAI-1 deficiency (PAl-1 is the major inhibitor of plasminogen activators), and
Scott’s syndrome, a platelet coagulant defect.
What is the major inhibitor of plasminogen activators?
PAI-1
What is a platelet coagulant defect?
Scott’s syndrome
A test for factor XIll-dependent fibrin cross-linking, like clot solubility in 5 M urea, should be ordered when
When the PT and PTT are both normal
but the history of bleeding is strong.
The fibrinolytic system can be assessed by measuring the:
rate of clot lysis with the euglobulin lysis or whole blood clot lysis tests and by measuring the levels of a2 plasmin inhibitor and PAI-1.
Scott’s syndrome can be detected by
measuring the serum PT, which assesses the amount of residual prothrombin.
What are the disorders of primary hemostasis?
QUANTITATIVE PLATELET DISORDERS (Thrombocytopenia & Thrombocytosis)
IDIOPATHIC THROMBOCYTOPENIC PURPURA
VON WILLEBRAND’S DISEASE
BERNARD SOULIER SYNDROME
GLANZMANN’S THROMBASTHENIA
AFIBRINOGENEMIA AND DYSFIBRINOGENEMIA
UREMIA
GRAY PLATELET SYNDROME AND DENSE BODY DEFICIENCY
EFFECT OF ASPIRIN ON PLATELET FUNCTION
QUANTITATIVE PLATELET DISORDERS
● Thrombocytopenia
● Thrombocytosis
The many causes of thrombocytopenia can be classified into the four major categories listed:
- Decreased production of platelet
- Decreased platelet survival
- Sequestration
- Dilution
CAUSES OF THROMBOCYTOPENIA
Decreased production of platelet
Selective impairment of platelet production
> drug-induced: alcohol, thiazides, cytotoxic drugs
> infections: measles, HIV
Nutritional deficiencies
B12 folate deficiency (megaloblastic leukemia)
BM failure
Aplastic anemia
BM replacement
Leukemia, disseminated cancer, granulomatous dse
Ineffective hematopoiesis
Myelodysplastic syndromes
Decreased platelet survival
~ Immunologic destruction ~
Primary autoimmune
> chronic ITP
> acute ITP
Secondary autoimmune
SLE, B-cell lymphoid neoplasms
Alloimmune: posttransfusion and neonatal
Drug-associated: quinidine, heparin, sulfa compounds
Infections: HIV, infectious mononucleosis (transient, mild), dengue fever
~ Nonimmunologic destruction ~
DIC
Thrombotic microangiopathies
Giant hemangiomas
Sequestration
Hypersplenism
Dilution
Transfusion
Thrombocytopenia due to excessive platelet destruction is best exemplified in _________, which is a common disease entity in pediatric practice implying an acquired form of thrombocytopenia.
idiopathic thrombocytopenic purpura (ITP)
Etiology of ITP
● Its etiology, previously referred to as idiopathic or “unknown” could very well be an autoimmune phenomenon although available data do not as yet warrant its change of name.
● The nomenclature as it stands today still indicates the absence of a known cause such as systemic lupus erythematosus, the other collagen diseases and drugs such as sulfonamides, quinine, and quinidine.
● The disease is further distinguished as to whether it is:
○ Acute ITP, characterized by a sudden onset, rapid spontaneous recovery within 6 weeks to 6 months with no recurrence; or
○ Chronic ITP, in contrast, characterized by an insidious onset and as the term implies a very low incidence of spontaneous recovery.
○ This latter disease is more often found among adults and rarely occurs in childhood.
● ITP occurs more often between the ages of two and six years.
● No sex prevalence is demonstrated.
● The history of antecedent infections notably measles and chickenpox a month or so previously may be elicited.
● One to four weeks following exposure to a common viral infection, a small number of children develop an autoantibody directed against the platelet surface.
The disease is further distinguished as to whether it is:
○ Acute ITP, characterized by a sudden onset, rapid spontaneous recovery within 6 weeks to 6 months with no recurrence; or
○ Chronic ITP, in contrast, characterized by an insidious onset and as the term implies a very low incidence of spontaneous recovery.
What disease is more often found among adults and rarely occurs in childhood?
Chronic ITP
ITP occurs more often between the ages of:
two and six years
The history of antecedent infections notably:
measles and chickenpox a month or so previously may be elicited
One to four weeks following exposure to a common viral infection
A small number of children develop an autoantibody directed against the platelet surface.
Clinical Manifestations of ITP
● The child presents with alarming skin manifestations of petechiae, ecchymoses and on occasions epistaxis and bleeding gums.
● Significant is the observation that the child is active, comfortable and afebrile.
● Minimal splenomegaly is observed in 10% of cases; there are no bone pains nor tenderness.
● Concomitant anemia should be interpreted either as a consequence of hemorrhage, an associated marrow hypoplasia involving the red cell or a hemolytic disease.
● Most adults present with a more indolent form of thrombocytopenia that may persist for many years and is referred to as chronic ITP.
● Women aged 20 to 40 are afflicted most commonly and outnumber men by a ratio of 3:1.
● They may present with an abrupt fall in platelet count and bleeding similar to patients with acute ITP.
● More often they have a prior history of easy bruising and menometrorrhagia.
Diagnosis of ITP
● This includes the demonstration of a low platelet count usually below 50,000/cumm and a bone marrow examination which appears normal except for numerous megakaryocytes often referred to as the “lymphoid type”, characterized by the absence of platelet fragments around its cytoplasm.
● Unlike the experience in other countries where the leukocyte count is normal with mild to moderate lymphocytic predominance and slight eosinophilia, it is not unusual in the Philippines to obtain leukocyte counts of 15,000-20,000/cumm with marked eosinophilia of 25-40% much like those found in cases of toxocara infections.
● Other tests such as bleeding time, clot retraction time and tourniquet test may show normal or equivocal results.
Prognosis of ITP
● Most acute ITP will recover spontaneously.
● If excessive bleeding will occur, this usually happens within the first 7-10 days of the ailment.
● In chronic ITP despite the persistently low platelet count, overt and life-threatening hemorrhages seldom occur.
Treatment of ITP
● A selective approach to therapy is indicated, that is, the child and not the platelet should be treated.
● In children with minimal bleeding, no therapy other than purely defensive management is needed such as restriction of physical activity and complete avoidance of all contact sports and playground activities; for older children, avoidance of antiplatelet aggregating agents such as aspirin, antihistamines, phenothiazines and glyceryl guaiacolate.
● Live viral vaccines should not be given and intramuscular injections and femoral venipunctures should not be done during the period of thrombocytopenia.
● In acute ITP, it is doubtful if corticosteroids influence the recovery time or improve the prognosis.
● The justification for the continuing use of steroids is their known immunosuppressive effect and direct capillary vessel action.
● A suggested regimen with the use of prednisone is as follows: 2 mg/kg/day is given for 2 to 4 weeks depending on the platelet response. If platelets normalize within this time, the drug is tapered off within 1 week.
● The routine use of platelet transfusions in acute IT is not indicated as the transfused platelets are rapidly destroyed in the recipient’s circulation. Platelet transfusions have a limited role in the arrest of a hemorrhagic episode that is life-threatening.
● In chronic ITP where the thrombocytopenia persists with mild exacerbations and remissions splenectomy is usually advised after a year. It is usual to attempt several courses of ACTH or prednisone before subjecting the patient to surgery. Some seriously consider splenectomy for a child whose platelet count does not attain a level of approximately 50,000 to 60,000 cells per cumm with significant bleeding six months after diagnosis.
● The decision to perform elective splenectomy in children with chronic ITP should be postponed until the child is at least four years of age, if possible, because of the increased risk of overwhelming sepsis. The risk of sepsis after splenectomy is over-emphasized. However, acute febrile illnesses in splenectomized children should be handled with vigilance.
● A child who initially responds to splenectomy but later has a recurrence of thrombocytopenia should be evaluated for an accessory spleen. Careful examination of a peripheral blood smear for the presence of Howell-Jolly bodies should be the first step. If these are not demonstrated, a spleen scan may suggest the presence of an accessory spleen.
● Immunosuppressive agents like cyclophosphamide and azathioprine are reserved for cases whose thrombocytopenic state persists with platelet counts of less than 20,000 to 30,000 cell per cumm, despite splenectomy.
● Intravenous immune globulin (IVIG) has been sparingly used in acute and chronic IT because of its prohibitive cost. The suggested dosage is 400 mg/kg body weight daily for 5 days. It may become necessary to give monthly maintenance courses of 400 mg/kg body weight single dose to maintain the platelet rise. This modality of management can be resorted to especially in patients at high risk of intracranial hemorrhage.
CAUSES AND CLINICAL SIGNIFICANCE OF THROMBOCYTOSIS
● Platelet counts exceeding 500,000/cumm may be a manifestation of tuberculosis, sarcoidosis, rheumatoid arthritis, chronic hepatitis, chronic osteomyelitis, the myeloproliferative syndromes and immediate postsplenectomy phase.
● The danger here is the tendency to thromboembolic reactions, myocardial infarctions and paradoxically, bleeding manifestations on the basis of consumption coagulopathy. Treatment is usually directed towards destruction of marrow platelets and megakaryocytes. Drugs like busulfan have been tried.
What is the most common inherited bleeding disorder, occurring in 1 in 100 to 500 individuals?
vWD
VON WILLEBRAND’S DISEASE
● vWD is the most common inherited bleeding disorder, occurring in 1 in 100 to 500 individuals.
● The von Willebrand factor (vWF) is a heterogeneous multimeric plasma glycoprotein with two major functions: (1) It facilitates platelet adhesion under conditions of high shear stress by linking platelet membrane receptors to vascular subendothelium; and (2) it serves as the plasma carrier for factor VIlI, the antihemophilic factor, a critical blood coagulation protein.
● Discrete domains in each WWF level is 10 mg/L. The vWF activity is distributed among a series of plasma multimers with estimated molecular weights ranging from 400,000 to >20 million.
● A single large vWF precursor subunit is synthesized in endothelial cells and megakaryocytes, where it is cleaved and assembled into the disulfide-linked multimers present in plasma vWF concentration or a selective loss in the high-molecular weight multimers decreases platelet adhesion and causes clinical bleeding.
● Although WWD is heterogeneous, certain clinical features are common to all the syndromes. With one exception (type lll disease), all forms are inherited as autosomal dominant traits, and affected patients are heterozygous with one normal and one abnormal vWF allele.
● In mild cases, bleeding occurs only after surgery or trauma. More severely affected patients have spontaneous epistaxis or oral mucosal, gastrointestinal, or genitourinary bleeding. The laboratory findings are variable.
● The most diagnostic pattern is the combination of (1) a prolonged bleeding time in the presence of a normal platelet count, (2) a reduction in plasma vWF concentration. (3) a parallel reduction in biologic activity as measured with the ristocetin cofactor assay, and (4) reduced factor VIII activity.
● The variability in laboratory tests is related to both the heterogeneous nature of the defects in WWD and the fact that plasma levels are influenced by ABO blood group type, central nervous system disorders, systemic inflammation, and pregnancy.
● Since vWD is an autosomal-dominant disorder, some vWF is produced by the remaining normal allele. The patients with mild defects may have laboratory values that fluctuate over time and may occasionally be within the normal range.
● More than 20 variants of von Willebrand disease have been described, which can be grouped into two major categories: type 1 and type 3 vWD are associated with a reduced quantity of circulating vWF.
● Type 1, an autosomal dominant disorder, accounts for approximately 70% of all cases and is relatively mild. Reduced penetrance and variable expressivity characterize this type, and hence clinical manifestations are varied.
● Type 3 (an autosomal recessive disorder) is associated with extremely low levels of functional vWF, and the clinical manifestations are correspondingly severe. Because a severe deficiency of vWF has a marked effect on the stability of factor VIII, some of the bleeding characteristics resemble those seen in hemophilia.
● Type 2 vWD is characterized by qualitative defects in VF: there are several subtypes, of which type 2A is the most common. It is inherited as an autosomal dominant disorder. Because of missense mutations, the vWF formed is abnormal, leading to defective multimer assembly. Large and intermediate multimers, representing the most active forms of vWF, are missing from plasma.
● Type 2 vWD accounts for 25% of all cases and is associated with mild to moderate bleeding.
● Patients with vWD have prolonged bleeding time despite a normal platelet count.
● The plasma level of active VWF. measured as the ristocetin cofactor activity, is reduced. Because WWF stabilizes factor VIll by binding to it, a deficiency of vWF gives rise to a secondary decrease in factor VIll levels. This may be reflected by a prolongation of the PTT in vWD types 1 and 3.
● To summarize, patients with vWD have a compound defect involving platelet function and the coagulation pathway.
● Even within families in which a single defective allele is segregating, there is often wide variability in the clinical expression of vWD.
● This appears to be due to additional genetic factors that influence circulating levels of vWF, which vary greatly in normal populations.
● However, except in the most severely affected type 3 patients, adverse complications of factor VIll deficiency, such as bleeding into the joints, is uncommon.
What are the two major functions of vWF?
(1) It facilitates platelet adhesion under conditions of high shear stress by linking platelet membrane receptors to vascular subendothelium; and
(2) it serves as the plasma carrier for factor VIlI, the antihemophilic factor, a critical blood coagulation protein.
Discrete domains in each vWF level is _______. The vWF activity is distributed among a series of plasma multimers with estimated molecular weights ranging from ____________________.
Discrete domains in each vWF level is 10 mg/L. The vWF activity is distributed among a series of plasma multimers with estimated molecular weights ranging from 400,000 to >20 million.
What is synthesized in endothelial cells and megakaryocytes, where it is cleaved and assembled into the disulfide-linked multimers present in plasma vWF concentration or a selective loss in the high-molecular weight multimers decreases platelet adhesion and causes clinical bleeding?
A single large vWF precursor subunit
In mild cases, bleeding occurs only after
after surgery or trauma
More severely affected patients have spontaneous what?
epistaxis or oral mucosal, gastrointestinal, or genitourinary bleeding.
The laboratory findings are variable.
The most diagnostic pattern of vWD is the combination of:
(1) a prolonged bleeding time in the presence of a normal platelet count,
(2) a reduction in plasma vWF concentration.
(3) a parallel reduction in biologic activity as measured with the ristocetin cofactor assay, and
(4) reduced factor VIII activity.
The variability in laboratory tests is related to both the heterogeneous nature of the defects in vWD and the fact that plasma levels are influenced by:
ABO blood group type
central nervous system disorders
systemic inflammation
pregnancy
● Since vWD is an autosomal-dominant disorder, some vWF is produced by the remaining normal allele. The patients with mild defects may have laboratory values that fluctuate over time and may occasionally be within the normal range.
● More than 20 variants of von Willebrand disease have been described, which can be grouped into two major categories: type 1 and type 3 vWD are associated with a:
reduced quantity of circulating vWF
What accounts for approximately 70% of all cases and is relatively mild. Reduced penetrance and variable expressivity characterize this type, and hence clinical manifestations are varied?
Type 1, an autosomal dominant disorder
What is associated with extremely low levels of functional vWF, and the clinical manifestations are correspondingly severe. Because a severe deficiency of F has a marked effect on the stability of factor VIII, some of the bleeding characteristics resemble those seen in herophilia?
Type 3 (an autosomal recessive disorder)
What is characterized by qualitative defects in VF: there are several subtypes, of which type 2A is the most common?
It is inherited as an autosomal dominant disorder. Because of missense mutations, the vWF formed is abnormal, leading to defective multimer assembly. Large and intermediate multimers, representing the most active forms of vWF, are missing from plasma.
Type 2 vWD
● Type 2 vWD accounts for 25% of all cases and is associated with mild to moderate bleeding.
Patients with vWD have what?
prolonged bleeding time despite a normal platelet count
The plasma level of active VWF measured as the ristocetin cofactor activity, is reduced or increased?
Reduced
Because vWF stabilizes factor VIll by binding to it, a deficiency of vWF gives rise to a secondary decrease in factor VIll levels. This may be reflected by a prolongation of the PTT in vWD types 1 and 3.
● To summarize, patients with vWD have a compound defect involving platelet function and the coagulation pathway.
● Even within families in which a single defective allele is segregating, there is often wide variability in the clinical expression of vWD.
● This appears to be due to additional genetic factors that influence circulating levels of vWF, which vary greatly in normal populations.
● However, except in the most severely affected type 3 patients, adverse complications of factor VIll deficiency, such as bleeding into the joints, is uncommon.
Bleeding resulting from defective adhesion of platelets to the subendothelial matrix is best illustrated by the autosomal recessive disorder ____________________, which is caused by an inherited deficiency of the platelet membrane glycoprotein complex Ib-IX.
Bernard-Soulier syndrome
● This glycoprotein Ib-IX is a receptor for vWF and is essential for normal platelet adhesion subendothelial matrix.
● Bleeding due to defective platelet aggregation is exemplified by __________________, which is also transmitted as an autosomal recessive trait.
● Thrombasthenic platelets fail to aggregate in platobes response to adenosine diphosphate (ADP), collagen, epinephrine, or thrombin owing to deficiency or dysfunction of glycoprotein lIb-Illa, a protein complex that participates in the formation of “bridges” between platelets by binding fibrinogen and vWF.
Glanzmann’s thrombasthenia
AFIBRINOGENEMIA AND DYSFIBRINOGENEMIA
● Although fibrinogen is needed for platelet aggregation and fibrin formation, severe fibrinogen deficiency does not usually cause serious bleeding except after surgery.
● Patients with afibrinogenemia, who have no detectable fibrinogen in the plasma or platelets, may have infrequent, mild bleeding episodes.
● Patients with dysfibrinogenemia have a slightly prolonged PT and PTT, a prolonged thrombin time, and a disparity in levels of fibrinogen measured with functional and immunologic assays.
● Despite these abnormalities, most patients have no symptoms or only moderate bleeding.
What is the second condition exemplifying an acquired defect in platelet function?
Uremia
Although the pathogenesis of bleeding in uremia is complex and not fully understood, several abnormalities of platelet function are found.
What is caused by the absence of platelet alpha granules resulting in platelets that appear gray on the Wright stain of peripheral blood?
Gray platelet syndrome
● This rare syndrome has absent aggregation and release with most agonists other than thrombin and ristocetin.
● Dense body deficiency is characterized by the absence of the granules that contain ADP, ATP, calcium and serotonin.
EFFECT OF ASPIRIN ON PLATELET FUNCTION
Ingestion of aspirin and other nonsteroidal anti-inflammatory drugs significantly prolongs the bleeding time.
What is a potent, irreversible inhibitor of the enzyme cyclooxygenase, which is required for the synthesis of thromboxane A2 and prostaglandins?
Aspirin
● These mediators play important roles in platelet aggregation and subsequent release reactions.
● The antiplatelet effect of aspirin forms the basis for its use in the prophylaxis of thrombosis.
DISORDERS OF SECONDARY HEMOSTASIS
- Hemophilias
- Vitamin K deficiency
- Liver disease
- Acquired Prothrombin Complex Deficiency (APCD)
- Disseminated intravascular coagulation (DIC)
HEMOPHILIAS
● This is a broad term referring to an inherited deficiency or defective synthesis of a factor or factors necessary in the first stage of coagulation.
● By far the most common of these deficiencies involve factor VIII (AHF) and IX (PTC), often referréd to as hemophilia A and B, respectively.
● Hemophilia C lacks factor XI (PTA). It is estimated that 80% of the heritable coagulation disorders is hemophilia A or classic hemophilia while approximately 15% is hemophilia B or Christmas disease. Hemophilia, although often referred to as a disease afflicting royalty, has been found in Filipinos in significant numbers.
● Estimate as to the prevalence of hemophilia cases among Filipinos is between 2,000-3,000 for the present population of 65 million.
By far the most common of these deficiencies involve factor VIII (AHF) and IX (PTC), often referred to as:
hemophilia A and B, respectively
Hemophilia C lacks what factor?
factor XI (PTA)
It is estimated that 80% of the heritable coagulation disorders is hemophilia A or classic hemophilia while approximately 15% is hemophilia B or Christmas disease. Hemophilia, although often referred to as a disease afflicting royalty, has been found in Filipinos in significant numbers.
● This is a severe coagulation disorder transmitted as an x-linked recessive trait. Thus females with both the x-linked hemophilia trait and normal X chromosome serve as carriers, while the males manifest the disease.
● In one-fourth of the cases, a negative family history is not unlikely either because of unrecognized disease or de novo mutation in female carriers of hemophilia males.
● The severity of the disorder depends on the degree of deficiency of AHF.
● Most affected males usually have from 1 to 3% AHF activity. Those who are deficient but possess 10% or more of normal AHF may, with caution, live without manifesting serious bleeding episodes.
Classic Hemophilia
What is also inherited as an x-linked recessive trait and as a general rule is milder than classic hemophilia?
Hemophilia B
What is transmitted as an incompletely recessive trait, the major PTA deficiency resulting from a homozygous state and the minor form from the heterozygous state?
Hemophilia C
● In this deficiency spontaneous hemorrhage is rare, overt bleeding episodes usually coming as a result of trauma.
Clinical Manifestations of Hemophilias:
● Bleeding may become manifest in neonates either spontaneously from the umbilical cord or following injury in the form of circumcision, lacerations or venipunctures.
● Serious hemorrhage more often becomes manifest later in infancy as a result of trauma.
● Hemarthrosis, the hallmark of the disorder, especially involving the big joints (knees, ankles, elbows and shoulders) may result in permanent crippling if not promptly attended to.
● The tendency to hemorrhage seems to occur at cyclic intervals of 3 to 8 weeks.
Confirmatory Tests for Hemophilias:
● Hemophilia cases will manifest abnormal coagulation time, a short prothrombin consumption time and abnormal partial thromboplastin time.
● The thromboplastin generation test (TGT) is now passed with the availability of direct factor assays for hemophilia A and B.
Management of Hemophilias:
● In a child with hemophilia, management can be considered in two aspects, the recognition and treatment of acute hemorrhagic episodes and chronic care with attention directed toward preventive measures against bleeding and long-term musculoskeletal complications of the disease as well as genetic counseling.
● In addition to the important care provided by the primary physician, it is ideal that hemophiliac patients be followed periodically in a multidisciplinary hemophilia center.
● Home treatment programs have been developed in centers abroad to institute early and prompt therapy for hemophiliacs.
● For the control of bleeding blood products are used for infusion therapy.
● In classic hemophilia, the use of fresh frozen plasma, cryoprecipitate of fresh plasma or AHF concentrates (available commercially) is the treatment of choice.
● Adequate hemostasis must aim at elevating AHF level to more than 10% of normal values. The half-life of the infused AHF is 8-12 hours, hence the need of an infusion at least every 8 hours until an adequately stable clot has been formed.
● A therapy schedule using fresh plasma is as follows:
○ (A) In emergency and major surgery: 10-20 mL/kg; repeat every 4 hours for 2 days at 5
mL/kg; every 6-8 hours thereafter from day 3 to day 5.
○ (B) Bleeding from hazardous sites (e.g. brain); initial dose of 10 mL/kg; to be repeated in 12 hours if pain persists; maintenance dose of 5 mL/kg every 4-6 hours. Following control of bleeding early active motion of involved joints is preferred rather than prolonged passive immobilization.
● In hemophilia B and C, stored plasma although adequate to correct the deficiency in vitro has been proven ineffective especially in the treatment of traumatic bleeding. Fresh plasma is preferred.
● The half-life of PTC is 24 hours, that of PTA is 40-80 hours.
What are the complications of hemophilias?
● Most hemophilia patients have had multiple episodes of hepatitis, and a majority have elevated hepatocellular enzyme levels and abnormalities on liver biopsy.
● Donated blood is now being screened for various types of hepatitis, so the risk of this disease is diminishing.
● Along with homosexuals and intravenous drug abusers, long-time hemophiliacs are at high risk for AIDS becaues they frequently received blood products before the era of testing them for HIV.
● Despite frequent bleeding, severe iron-deficiency anemia is uncommon because most of the bleeding is internal and iron is effectively recycled.
● Following multiple transfusions, 10-20% of patients with severe hemophilia develop inhibitors to factor VIII. Inhibitors are usually IgG antibodies that rapidly neutralize factor VIll activity.
Genetic counseling and carrier detection
● It is possible to trace the defective allele in some families by examining the inheritance of restriction fragment length polymorphism (RFLP) linked to the factor VIll gene.
● In addition, in families in which a specific mutation has been defined in the factor VIll gene, it can be readily detected by gene amplification and allele-specific oligonucleotide hybridizaton.
PATHOGENESIS
Vitamin K deficiency
● With vitamin K deficiency, plasma levels of all the prothrombin complex proteins decrease.
● Those with the shortest half-lives, factor VIl and protein C, decrease first. Because of the rapid fall in factor VIl, patients with mild vitamin K deficiency may have a prolonged PT and a normal PTT.
● Later, as the levels of the other factors fall, the PTT will also become prolonged. Parenteral administration of 10 mg vitamin K rapidly restores vitamin K levels in the liver and permits normal production of prothrombin complex proteins within 8 to 10 hours.
● Severe hemorrhage can be treated with FFP, which immediately corrects the hemostatic defect. If the cause of vitamin K deficiency cannot be eliminated, patients may need monthly injections.
PATHOGENESIS
Liver disease
● Patients with hepatocellular disease cannot store vitamin k optimally and may have some degree of vitamin K deficiency.
● Cholestasis, a frequent feature of liver disease, impairs vitamin K absorption and further decreases liver vitamin K stores.
● Abnormalities in the carboxylation of prothrombin complex proteins independent of vitamin K and the production of abnormal proteins have also been described. Patients may also have decreased production of other coagulation proteins, including fibrinogen and factor V.
● The liver also produces inhibitors of coagulation such as antithrombin Ill and proteins C and S and is the clearance site for the activated coagulation factors and fibrinolytic enzymes. Thus patients with liver disease are also “hypercoagulable” and predisposed to developing DIC or systemic fibrinolysis.
● Coagulation defects in advanced liver failure are often distinguished from those of DIC.
PATHOGENESIS
Acquired Prothrombin Complex Deficiency (APCD)
● An acquired bleeding disorder in infants between the ages of 1 and 12 months attributed to severe prothrombin complex deficiency of unknown etiology has been first reported in Bangkok, Thailand.
● Such syndrome seems to occur principally in the geographic location of Southeast Asia, the Philippines included.
● Important features of the condition include its prevalence among breast-fed infants (80%), intracranial hemorrhage (70%), skin and muscle ecchymoses (30%), gastrointestinal bleeding (20%), mild hepatomegaly (75%). Assays point to deficiency of the vitamin K-dependent clotting factors.
Disseminated intravascular coagulation (DIC)
● DIC is an acute, subacute, or chronic thrombohemorrhagic disorder characterized by the excessive activation of coagulation, which leads to the formation of thrombi in the microvasculature of the body.
● It occurs as a secondary complication of many different disorders. Sometimes the coagulopathy is localized to a specific organ or tissue.
● As a consequence of the thrombotic diathesis there is consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolysis.
● DIC can present with signs and symptoms relating to the tissue hypoxia and infarction caused by the myriad microthrombi; with hemorrhage caused by the depletion of factors required for hemostasis and the activation of fibrinolytic mechanisms; or both.
Etiology and Pathogenesis of DIC:
● At the outset, it must be emphasized that DIC is not a primary disease. It is a coagulopathy that occurs in the course of a variety of clinical conditions.
● In discussing the general mechanisms underlying DIC, it is useful to briefly review the normal process of blood coagulation and clot removal (see Chapter 4 for more details).
● Clotting can be initiated by either of two pathways: (1) the extrinsic pathway, which is triggered by the release of tissue factor (“tissue thromboplastin”); and (2) the intrinsic pathway, which involves the activation of factor XIl by surface contact with collagen or other negatively charged substances.
● Both pathways, through a series of intermediate steps, result in the generation of thrombin, which in turn converts fibrinogen to fibrin.
● At the site of injury, thrombin further augments local fibrin deposition by directly activating the intrinsic pathway and factors that inhibit fibrinolysis.
● Once clotting is initiated, it is critically important that it be limited to the site of injury.
● Remarkably, as thrombin is swept away in the bloodstream and encounters normal vessels, it is converted to an anticoagulant through binding to thrombomodulin, a protein found on the surface of endothelial cells.
● The thrombin-thrombomodulin complex activates protein C, which is an important inhibitor of two procoagulants, factor V and factor VIII. CHECK AGAIN
● Other activated coagulation factors are removed from the circulation by the liver, and as you will recall, the blood also contains several potent fibrinolytic factors, such as plasmin.
● These and additional checks and balances normally ensure that just enough clotting occurs at the right place and time.
● From this brief review it should be clear that DIC could result from pathologic activation of the extrinsic and/or intrinsic pathways of coagulation or the impairment of c1 inhibitor mechanisms.
● Since the latter rarely constitute primary mechanisms of DIC, we will focus on the abnormal initiation of clotting.
● Two major mechanisms trigger DIC: (1) release of tissue factor or thromboplastic substances into the circulation, and (2) widespread injury to the endothelial cells. Thromboplastic substances can be derived from a variety of sources, such as the placenta in obstetric complications and the cytoplasmic granules of acute pro myelocytic leukemia cells. Mucus released from certain adenocarcinomas can directly activate factor X, independent of factor VII.
● Endothelial injury can initiate DIC in several ways. Injuries that cause endothelial cell necrosis expose the subendothelial matrix, leading to the activation of platelets and both arms of the coagulation pathway.
● However, even subtle endothelial injuries can unleash procoagulant activity.
● One mediator of such effects is TNF (tumor necrosis factor), which is implicated in DIC occurring with sepsis.
● TNF induces endothelial cells to express tissue factor on their cell surfaces and to decrease the expression of thrombomodulin, shifting the checks and balances that govern hemostasis towards coagulation.
● In addition, TNF upregulates the expression of adhesion molecules on endothelial cells, thereby promoting the adhesion of leukocytes, which can damage endothelial cells by releasing reactive oxygen species and preformed proteases.
● Widespread endothelial injury may also be produced by deposition of antigen-antibody complexes (e.g., systemic lupus erythematosus), temperature extremes (e.g., heat stroke, burns), or microorganisms (e.g., meningococci, rickettsiae).
● Even subtle endothelial injury can unleash pro-coagulant activity by enhancing membrane expression of tissue factor.
● DIC is most likely to be associated with obstetric complications, malignant neoplasms, sepsis, and major trauma. The triggers in these conditions are often multiple and interrelated. For example, in bacterial infections endotoxins can injure. endothelial cells and inhibit the expression of thrombomodulin directly or through production of TNF; stimulate the release of thromboplastins from inflammatory cells; and activate factor XII.
● Antigen-antibody complexes formed in response to the infection can activate the classical complement pathway, giving rise to complement fragments that secondarily activate both platelets and granulocytes. In massive trauma, extensive surgery, and severe burns, the major trigger is the release of tissue thromboplastins.
● In obstetric conditions, thromboplastins derived from the placenta, dead retained fetus, or amniotic fluid may enter the circulation.
● Hypoxia, acidosis, and shock, which often coexist in very ill patients, can also cause widespread endothelial injury, and supervening infections can complicate the problems further.
● Among cancers, acute pro myelocytic leukemia and adenocarcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC. The possible consequences of DIC are twofold (Fig. 14-27).
● Firstly, there is widespread deposition of fibrin within the microcirculation.
● This leads to ischemia of the more severely affected or more vulnerable organs and a microangiopathic hemolytic anemia, which results from the fragmentation of red cells as they squeeze through the narrowed microvasculature. Secondly, the consumption of platelets and clotting factors and the activation of plasminogen leads to a hemorrhagic diathesis. Plasmin not only cleaves fibrin, but it also digests factors V and VIII, thereby reducing their concentration further. In addition, fibrin degradation products resulting from fibrinolysis inhibit platelet aggregation, fibrin polymerization, and thrombin.
● All of these derangements contribute to the hemostatic failure seen in DIC.
Morphology of DIC
● Thrombi are most often found in the brain, heart, lungs, kidneys, adrenals, spleen, and liver, in decreasing order of frequency, but any tissue can be affected.
● Affected kidneys may have small thrombi in the glomeruli that evoke only reactive swelling of endothelial cells or, in severe cases, microinfarcts or even bilateral renal cortical necrosis.
● Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated with pulmonary. edema and fibrin exudation, creating “hyaline membranes” reminiscent of acute respiratory distress syndrome (Chapter 15).
● In the central nervous system, fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage, which can sometimes lead to variable neurologic signs and symptoms. The manifestations in the endocrine glands are of considerable interest.
● In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the probable basis for the massive adrenal hemorrhages seen in Waterhouse-Friderichsen syndrome (Chapter 24). Similarly, Sheehan postpartum pituitary necrosis (Chapter 24) is a form of DIC complicating labor and delivery.
● In toxemia of pregnancy (Chapter 22) the placenta exhibits widespread microthrombi, providing a plausible explanation for the premature atrophy of the cytotrophoblast and syncytiotrophoblast that is encountered in this condition.
● An unusual form of DIC occurs in association with giant hemangiomas, in which thrombi form within the neoplasm because of statis and recurrent trauma to fragile blood vessels.
Clinical Features of DIC
● The onset can be fulminant, as in endotoxic shock or amniotic fluid embolism, or insidious and chronic, as in cases of carcinomatosis or retention of a dead fetus.
● Overall, about 50% of the affected are obstetric patients having complications of pregnancy.
● In this setting the disorder tends to be reversible with delivery of the fetus. About 33% of the affected patients have carcinomatosis. The remaining cases are associated with the various entities previously listed.
● It is almost impossible to detail all the potential clinical presentations, but a few common patterns are worthy of description.
● These include microangiopathic hemolytic anemia; dyspnea, cyanosis, and respiratory failure; convulsions and coma; oliguria and acute renal failure; and sudden or progressive circulatory failure and shock.
● In general, acute DIC, associated with obstetric complications or major trauma, for example, is dominated by a bleeding diathesis, whereas chronic DIC, such as occurs in cancer patients, tends to present with thrombotic complications.
● The diagnosis is based on clinical observation and laboratory studies, including measurement of fibrinogen levels, platelets, the PT and PTT, and fibrin degMdation products.
Prognosis and treatment of DIC
● The prognosis is highly variable and largely depends on the underlying disorder.
● The only definitive treatment is to remove or treat the inciting cause.
● The management requires meticulous maneuvering between the Scylla of thrombosis and the Charybdis of bleeding diathesis.
● Administration of anticoagulants or procoagulants has been advocated in specific settings, but not without controversy.
DISORDERS ARISING FROM VESSEL WALL ABNORMALITIES
- THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
- PATHOGENESIS OF BLEEDING IN AND SALIENT FEATURES
> Hemolytic-Uremic Syndrome
> Henoch-Schonlein Purpura - Acquired vessel wall abnormalities
What is a fulminant, often lethal disorder that may be initiated by endothelial injury and subsequent release of VWF and other procoagulant materials from the endothelial cell?
TTP
Causes of TTP include:
- pregnancy
- metastatic cancer
- chemotherapy
- HIV infection
- certain drugs such as the antiplatelet agent ticlopidine
Characteristic findings of TTP include:
○ microvascular deposition of hyaline fibrin thrombi,
○ thrombocytopenia,
○ microangiopathic hemolytic anemia,
○ fever,
○ renal failure,
○ fluctuations in level of consciousness,
○ and evanescent focal neurologic deficits.
What is diagnostic of TTP?
The presence of hyaline thrombi in arterioles capillaries, and venules without any inflammatory changes in the vessel wall is diagnostic.
What can help to confirm the clinical suspicion of TTP?
The presence of a severe Coombs-negative hemolytic anemia with schistocytes in the peripheral blood coupled with thrombocytopenia, and minimal activation of the coagulation system
The classic pentad of TTP consists of:
○ hemolytic anemia with fragmentation of erythrocytes and signs of intravascular hemolysis,
○ thrombocytopenia,
○ diffuse and nonfocal neurologic findings,
○ decreased renal function
○ and fever.
● These signs and symptoms occur variably depending on the number and sites of the arterial lesions.
What is due to a deficiency in the activity of a specific metalloproteinase called ADAMTS 13?
TTP
What is a normal plasma constituent that cleaves the ultra-high-molecular-weight forms of WWF secreted by endothelial cells to yield the heterogeneous set of multimers normally present in plasma?
ADAMTS 13
The treatment of acute TTP has focused on the use of
exchange transfusion or intensive plasmapheresis coupled with infusion of fresh frozen plasma
● Therapy may remove abnormal forms of VWF, lower the concentration of ADAMTS 13 inhibitors, and replenish the deficient ADAMTS enzyme.
● Overall mortality has been markedly reduced, and the majority of patients with TTP recover from this formerly fatal disorder.
Hemolytic-Uremic Syndrome
● HUS is a disease of infancy and early childhood that closely resembles TTP.
● Patients present with fever, thrombocytopenia, microangiopathic hemolytic anemia, hypertension, and varying degrees of acute renal failure.
● In many cases, onset is preceded by a minor febrile illness, and an infectious or immune complex-mediated cause has been proposed.
● In contrast to TTP, the disorder remains localized to the kidney, where hyaline thrombi are seen in the afferent arterioles and glomerular capillaries.
● No therapy is proven effective; however, with dialysis for acute renal failure, the initial mortality is only 5% in children but may be higher in adults.
Henoch-Schonlein Purpura
● Henoch-Schonlein, or anaphylactoid, purpura is a distinct, self-limited type of vasculitis that occurs in children and young adults.
● Patients have acute inflammatory reactions in capillaries, mesangial tissues, and small arterioles that leads to increased vascular permeability, exudation and hemorrhage.
● Vessel lesions contain lgA and complement components. The syndrome may be preceded by an upper respiratory infection or streptococcal pharyngitis or be associated with food or drug allergies.
● Patients develop a purpuric or urticarial rash on the extensor surfaces of the arms and legs as well as hematuria from focal glomerulonephritis.
● Despite the hemorrhagic features, all coagulation tests are normal.
● Glucocorticoids provide symptomatic relief of the joint and abdominal pains but doesn’t alter the course of the illness.
Acquired vessel wall abnormalities
● Acute febrile illnesses may cause capillary fragility and skin bleeding.
● Immune complexes containing viral antigens or the viruses themselves may damage endothelial cells.
● Thrombocytopenia is also a frequent finding in acute infectious disorders and may contribute to skin bleeding.
● In addition, whenever the platelet count is <10,000/uL, gaps develop between endothelial cells, which allow the diapedesis of red cells into the dermis, forming petechiae.
● Drugs such as the sulfonamides, penicillin, and allopurinol may cause vascular inflammation, resulting in maculopapular or urticarial rashes.
● Some of these mechanisms are additive, and drug reactions in thrombocytopenic individuals cause an intensely hemorrhagic rash.
