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N5315 Advanced Pathophysiology

Disorders of Hemostasis

Coagulopathy versus Thrombocytopenia

A coagulopathy is a defect in the coagulation process which results in the prolongation of

the PT and/or PTT. In most instances the individual with a coagulopathy will be at an
increased risk of bleeding. In some instances (this is rare), there is no increased risk of
bleeding. This is the case when an individual has a deficiency of Hageman Factor (Factor
XII).

Bleeding which occurs as a result of a coagulopathy manifests differently than a bleed

which results from a thrombocytopenia. Clinical manifestations of a bleed from a
coagulopathy include:
• joint bleeding
• tissue hematomas
• large, spontaneous, centrally located ecchymosis
• bleeding after trauma, surgery or an injury tends to be delayed

A thrombocytopenia is a decrease in the total number of platelets. This has numerous

etiologies. Bleeding which occurs as a result of a thrombocytopenia manifests differently
than a bleed which results from a coagulopathy. Clinical manifestations of a bleed from a
thrombocytopenia include:
• Mucosal bleeding such as:
• Epistaxis
• Oral bleeding
• GI or GU bleeding (in the absences of malignancy)
• Hemoptysis
• Heavy menses
• Bleeding occurs immediately after a trauma or injury
• Petechiae may be present.

The differences in the clinical manifestations of a coagulopathy and a thrombocytopenia

should be used to help you identify the defect and determine the etiology of the bleed.
These clinical manifestations, as do any clinical manifestations, help to guide your
evaluation and management of the patients for which you provide care.
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Alterations of Platelets
Thrombocythemia and thrombocytosis both indicate that there is an increased number of
platelets. This can occur due to bone marrow disorders or after a splenectomy. The spleen
stores some platelets and after it is resected the individual will have a higher platelet
count.

Thrombocytopenia is the term used to describe a low number of platelets. The risk of
bleeding from a thrombocytopenia is directly associated to its severity. In most instances
a platelet count above 50,000 is enough to maintain hemostasis. As platelets drop below
that level the individual begins to have some signs of bleeding. The most severe scenario
occurs when the count is less than 10,000. At this level the person can have spontaneous
bleeds. The most worrisome would be an intracranial bleed. Be familiar with the
parameters you have seen on your slide.
• Risk of bleeding
• Platelet counts >50,000: adequate for hemostasis in most instances
• Platelet counts 30,000-50,000: these individuals will rarely develop
purpura even with trauma
• Platelet counts 10,000-30,000: These individuals are usually asymptomatic
but are at risk for excessive bleeding with trauma
• Platelet counts of < 10,000: Experience spontaneous bleeding and display
petechiae

General rules as they apply to Thrombocytopenia

• A Platelet count >50,000 is usually indicated for invasive procedures.
• A Platelet count of above 80,000 to 100,000 is required by most
surgeons and anesthesiologists for surgery.
Common causes of thrombocytopenia include:
• Hemodilution which tends to occur post-operatively and has a nadir of 2-4 days.
A nadir refers to the lowest point.
• Splenomegaly which is seen in some cancer patients and patients with cirrhosis.
The spleen sequesters platelets.
• HIV, bone marrow failure
• Hemolysis
• Medications cause a lot of issues and thrombocytopenia is one of them. On this
slide you see a list of medications which can cause thrombocytopenia.
• Sulfonamides
• Vancomycin
• Quinine –remember tonic water
• Linezolid (Zyvox)
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• Heparin
• Abciximab (Reopro)
• Eptifibatide (Integrilin)
• Tirofibab (Aggrastat)
• Rifampin (Rifadin)
• Piperacillin
• Beta Lactam antibiotics (PCN, Cephalosporins)
• Valporic acid (Depakote)
• Carbamazepine (Tegretol)
• Phenytoin (Dilantin)

Primary Immune Thrombocytopenic Purpura is also known as idiopathic

thrombocytopenic purpura. It is an acquired thrombocytopenia which results from an
immune mediated destruction of the platelets. There is a secondary form of ITP and in
this instance there is an etiology identified for the cause of ITP. Primary ITP refers to an
isolated thrombocytopenia in the absence of another etiology such as SLE, CML,
Antiphospholipid syndrome, or medications. It is not a very common disorder. It occurs
more commonly in women. Children tend to experience an acute form of ITP which
resolves in 1-2 months. Acute ITP is usually secondary to viral infections, SLE, or drug
allergies. Chronic ITP tends to be idiopathic in nature (or primary) and is progressive.

Etiologies for secondary ITP include:

• Preceding viral infection: HIV, VZV, CMV, HCV
• Disease states (as above) cause secondary ITP

Process of platelet destruction begins with the phagocytosis of platelets by macrophages.

The macrophages then present the digested platelet peptides to the CD4 cells. The CD4
cells believe these peptides are antigens and initiate the immune response. IgG antibodies
then bind to platelets most often on the platelet membrane glycoproteins such as
GPIIb/IIIa and ultimately platelets are destroyed.

Neonatal thrombocytopenia may occur because of a mother with ITP being pregnant. The
IgG antibodies cross the placenta, coat the fetus’ platelets and potentially cause platelet
destruction. An alloimmune response from a mother without ITP may occur and cause
intrauterine thrombocytopenia. When the fetus’ platelet count drops below 20,000, there
is a high risk of intracranial hemorrhage.

Clinical manifestations of ITP include:

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• Presentation can vary

• Petechiae, purpura, and easy bruising are expected.
• Epistaxis, gingival bleeding, and menorrhagia are common.
• Overt gastrointestinal bleeding and gross hematuria are rare.
• Intracranial hemorrhage, a potentially fatal bleeding complication, is so
uncommon that there is no reliable estimate of its frequency.
• The clinical manifestations of thrombocytopenia also vary with age. Older
patients may have more severe bleeding manifestations, such as
gastrointestinal bleeding and possibly intracranial hemorrhage because of
comorbidities such as hypertension.

Thrombotic Thrombocytopenic Purpura (TTP)

Characteristically TTP results in severe thrombocytopenia and thrombotic
microangiopathy. The thrombotic microangiopathy occurs when platelets aggregate
together and cause occlusion in the arterioles and capillary beds in the microcirculation.
This aggregation of platelets leads to platelet consumption and organ ischemia especially
of the brain, heart and kidneys.

TTP is a rare disease. There are two forms - familial and acquired. Children tend to be
afflicted more often with the familial form, which also tends to be more chronic in its
presentation. They will experience predictable recurring episodes at approximately 3-
week intervals. Familial TTP is not as common as acute TTP and tends to be responsive
to treatment. Acquired TTP tends to be more acute in onset and severe in nature. It is
more common in females in their 30’s and is rare in infants and adults.

Etiologies include: autoimmune, familial, drugs (antiplatelet agents, quinine, mitomycin,

cisplatin, bleomycin), HIV, Cancers, and it may occur in post-surgical patients.

The pathogenesis includes the following steps:

• ADAMTS13 is a protease that is responsible for the breakdown of von
Willebrand factor.
• Persons with TTP have large amounts of vWF in their plasma and lack
ADAMTS13 protease.
• In congenital forms of the disease there is a mutation in the gene responsible for
making ADAMTS13, leading to a deficiency of this protease.
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• The increased levels of vWF leads to platelet aggregation, microthrombi in

organs, causing organ failure. The thrombi are mainly made of platelets (lacking
RBCs and fibrin).
• Antibody to ADAMTS13 has been isolated in most people with acquired TTP.
• Other factors
o Plasminogen activator inhibitor- levels are increased. Normal function is
to inhibit fibrinolytic compound.
Clinical Presentation includes:
• Altered mental status, seizures, hemiplegia, paresthesias, visual changes, aphasia.
They do not necessarily have to have neurologic symptoms.
• Fatigue with anemia, microangiopathic anemia occurs as a result of RBC Lysis
while traveling through small vessels which are rich in platelets
• Petechiae, pallor, jaundice
• Fever
• Dark urine from hemoglobinuria
• N/V/D and abdominal pain. GI symptoms are common.
• Chest pain, heart failure, cardiogenic shock, sudden death
• Dyspnea
• Thrombocytopenia, a normal PT/PTT, normal or high fibrinogen levels, elevated
creatinine and BUN, elevated LDH, elevated bilirubin
• Blood smear will show schistocytes which are fragmented red blood cells.

Disorders of Coagulation
As you can see in this picture Hemophilia A is labeled in green and is pointed to factor
VIII. Likewise, you can see also in green that hemophilia B results in a deficiency of
factor IX.

Hemophilia A is a sex linked recessive disease which results in a deficiency of factor

VIII. A mutation in the F8 gene leads to the development of hemophilia A.

Hemophilia A affects 1 in 4,000-5,000 males. The most common sites of bleeding in

adults are:
• Knees, elbows and ankles
• GI bleeding is common as well.
• Spontaneous bleeding is indicative of more severe disease.
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• Bleeding only after injury/trauma or surgery indicates milder disease.

Diagnostic Testing for a person with hemophilia A would reveal

• Normal platelets
• A normal PT
• An abnormally prolonged aPTT
• A decreased factor VIII level

The characteristics of Hemophilia B (Christmas Disease) are very similar to hemophilia

A, but the deficiency is related to factor IX. All other characteristics are essentially the
same, except that it occurs less commonly than Hemophilia Type A.
• Sex Linked recessive disease, secondary to a mutation in the F9 gene.
• Deficiency in factor IX
• Affects 1 in every 20,000-30,000 males
• Most common sites of bleeding in adults are into the joints.
• Knees, elbows and ankles
• GI bleeding is common as well.
• Spontaneous bleeding is indicative of more severe disease.
• Bleeding only after injury/trauma or surgery indicates milder disease.
• Diagnostic Testing
• Normal platelets
• Normal PT
• Abnormally prolonged aPTT
• Decreased factor IX level

Hemophilia A and B in children is typically diagnosed when they start to crawl, pull up
and stand. They become injured and experience easy bruising, swelling, joint redness and
mouth bleeding. Often boys can be circumcised without excessive bleeding, but this does
not mean that is will not or does not happen. By ages 3-4, the majority of children with
hemophilia have experienced an episode of excessive bleeding. Recurrent bleeding
spontaneous or otherwise is a lifelong problem.

Disseminated Intravascular Coagulation (DIC)

DIC is a complication of underlying disease that leads to the activation of both the
coagulation cascade and fibrinolytic cascade. Disease states which trigger DIC include:
• Malignancy
• Sepsis / infection
• Obstetrical complications
• Trauma/ extensive surgeries
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• ARDS, rhabdomyolysis
• Venomous Snake Bites
• Shock states
• Acidemia, hypoxemia
• Trauma (TBI, Burns)
• Fulminant liver failure
• Severe pancreatitis
• Transfusion reactions
• Recreational drug use

Pathophysiology of DIC
The igniting event causes endothelial damage. The endothelial damage exposes the
subendothelial tissue factor and activates the inflammatory cascade. The exposed TF
activates the coagulation cascade.
The activation of the coagulation system leads to a widespread and systemic intravascular
fibrin deposition. While this is happening the fibrinolytic system is working to break
down the fibrin. The fibrin degradation products (which are present in massive amounts)
adhere to platelets and prevent platelet adhesion. Eventually the products of coagulation
are consumed, resulting in bleeding. Organ failure may ensue due to micro-thrombi.

Clinical Presentation includes:

• Diffuse bleeding
• Bleeding from wounds, venipuncture sites
• Petechiae
• Ecchymosis, hematuria, hematemesis
• Stroke, PE, necrotic skin lesions
• Hemorrhaging into closed compartments
• “Indicators of multisystem failure include changes in level of consciousness,
behavior, and mentation; confusion; seizure activity; oliguria; hematuria; hypoxia;
hypotension; hemoptysis; chest pain; and tachycardia. Symmetrical cyanosis of
the fingers and toes (“ blue finger/ toe syndrome”) and, in some instances, of the
nose and breasts may be present.” Direct quote from the textbook

Diagnostic test results will reveal a prolonged PT/PTT, low fibrinogen level, elevated d-
dimer and a platelet count less than 100,000.
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Thromboembolic Disorders
A thrombus is a clot attached to a vessel wall. It is composed of fibrin and blood cells.
Thrombi can be arterial or venous in nature. Arterial thrombi form in areas of high
arterial blood flow such as the left atrium of the heart. They are composed mainly of
fibrin and platelets and are a common complication of atrial fibrillation. A venous
thrombus forms in the deep veins (areas of low venous blood flow, stasis) and is referred
to as Deep Vein Thrombosis (DVT). They are composed mainly of RBCs, fibrin and
only a few platelets.

The Triad of Virchow is a combination of factors that puts a person at risk for venous
thrombosis. If these factors are present, the person is at a greater risk for developing a
thrombosis. The factors include an injury to blood vessels, abnormalities in blood flow
(turbulent blood flow caused by sickle cell anemia, hyperviscosity of blood), and
hypercoagulable states (states that promote stasis of blood, i.e. orthopedic surgery, acute
MI, CHF, limb paralysis, bedrest). Vascular injury may occur from atherosclerosis,
hypertension, turbulent blood flow, radiation, exogeneous chemicals such as smoking,
bacterial toxins or endotoxins, or immunologic mechanisms. Platelets become activated
in areas of venous stasis and turbulent blood flow, thus leading to clot formation.

An embolus occurs when a clot breaks loose and travels elsewhere in the body in the
direction of blood flow. For example, an arterial thrombus from the left atrium can break
loose and travel via the arterial system to carotid arteries to the brain and cause a stroke.
A venous thrombus can break loose from a DVT and will travel to the lungs and cause a
pulmonary embolus.

Drugs which increase the risk of Thromboembolus are as listed:

• Estrogen
• Tamoxifen
• Cancer Chemotherapy
• L-aspraginase
• Mitomycin
• Steroids
• Growth factors
• Protease inhibitors

Hypercoagulable Disorders
Thrombophilias can be inherited or acquired. You should suspect a thrombophilia in the
following scenarios:
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• Recurrent thromboembolism
• VTE in a person younger than 40
• A familial history of venous thromboembolism
• Thrombosis in unusual sites such as the mesenteric vein, renal vein, hepatic and
cerebral thrombosis

Thrombophilias are usually associated with venous thrombosis; however, protein C,

protein S, antithrombin deficiencies and lupus anticoagulants have been associated with
arterial thrombosis.

Types of Hereditary Hypercoagulable Disorders

• Factor V Leiden Mutation
• Most common cause of inherited thrombophilia in Caucasians
• The mutation causes Factor Va to be resistant to activated protein C (APC),
thus causing it to not be broken down by APC leading to an excess of
thrombin and a thrombophilic state
• Protein S Deficiency
• Protein S helps to activate protein C (APC) which inactivates factor Va and
VIIIa. A deficiency in protein S will then lead to a hypercoagulable state.
• I want to discuss protein S in general.
• Protein S naturally circulates in a free form and a bound form. In
normal physiology it binds to complement and only the free form is
available to be used by the body. During times of inflammation,
remember that there is an increased amount of complement
circulating. The increased amount of complement binds more
protein S. This results in less free protein S and causes a
hypercoagulable state; therefore, these individuals are at an
increased risk for developing clots.
• Protein C deficiency
• Protein C is activated by protein S to form APC which inactivates Factor Va
and VIIIa, thus controlling the clotting process. In a deficiency this process
does not happen and it causes the person to be in a hypercoagulable state.
• This deficiency is a result of an autosomal dominant gene mutation in the
PROC gene.