Inherited and Acquired Coagulation Disorders

Question 1

Grading of hemophilias

Answer 1

Severe: <1% factor

Moderate: 1%-4% factor

Mild: >4% factor

Question 2

Hemophilia A is a deficiency in ____.

Hemophilia B is a deficiency in ____.

Answer 2

Hemophilia A is a deficiency in Factor VIII.

Hemophilia B is a deficiency in Factor IX.

Question 3

Why is it that hemophilia A and B are truly identical in phenotype?

Answer 3

Because factor XIII and IX have to complex together in the coagulation cascade. Both hemophilias are essentially a deficiency in the XIII-IX complex, aka, the tenase complex.

Question 4

Genetics of hemophilia A and B

Answer 4

Both hemophilia A and B are X-linked recessive Mendelian diseases

As it happens, most female cases of hemophilia A are thought to be due to unfavorable lyonization rather than homozygosity.

Question 5

Clinical presentation of hemophilia A

Answer 5

• Hemarthroses (deep bleeding into joints)
  
  • Chronic disability due to swelling, deformity, severe pain, limitation of motion, and contractures that can be corrected only by joint replacement
• Gastrointestinal or genitourinary bleeding
  
  • Less common
• Intracerebral hemorrhage
  
  • Very rare but very serious

Question 6

Because factor VIII is part of the ___ pathway of coagulation, the ___ in a patient with hemophilia A is prolonged, whereas the ___ time is normal.

Answer 6

Because factor VIII is part of the intrinsic pathway of coagulation, the partial thromboplastin time (PTT) in a patient with hemophilia A is prolonged, whereas the prothrombin time (PT) is normal.

Question 7

Treating hemophilia A

Answer 7

• Infusions of either recombinant factor VIII or highly purified plasma-derived factor VIII prepared from human donor plasma
  
  • However, patients are less likely to develop immune resistance to plasma-derived factor VIII
• Both are equally effective and free of viral pathogens
• The recombinant product costs two to three times as much as the plasma concentrates
• Factor VIII has a half-life of 8-12 hours, so 2 infusions per day are required
• Isolated hemorrhages like joint hemorrhage may be treated by raising VIII to 30% reference with a single infusion

Question 8

Limiting factor with most hemophilia treatment

Answer 8

Cost

Prophylactic treatment of children with factor VIII deficiency costs over $100,000 per year.

Question 9

Desmopressin

Answer 9

Releases vWF from its stores within endothelial cells. This results in a significant increase in plasma levels of factor VIII, which binds and is stabilized by vWF

As a general rule, when given daily for up to 3 days, desmopressin treatment raises factor VIII levels three- to four-fold.

Question 10

Treating hemophilia A patients who have developed anamnestic anti-factor VIII

Answer 10

• Porcine factor VIII infusion
• Recombinant factor VIIa (bypass factor VIII and the intrinsic pathway)
• Bispecific IgG against factor IX and factor X (mimicking factor VIIIa)

Question 11

Treating hemophilia B

Answer 11

• Recombinant factor IX
• ultrapure plasma-derived factor IX
• Half-life of about 24 hours, so only once-a-day infusions
  
  • However, twice as much must be given to achieve the same bioavailability due to its different volume of distribution
• Treatments for alloantibodies against factor IX are similar to those for hemophilia A with alloantibodies against factor VIII
  
  • Unfortunately, as hemophilia B is less prevalent, there are fewer novel treatments for this disease (no bispecific antibodies or progress on gene therapy)

Question 12

von Willebrand disease

Answer 12

• Most prevalent bleeding disorder ( 1 in 90 in the US )
• Very mild, overwhelmingly asymptomatic in general population
• Unlike hemophilias:
  
  • Inherited autosomal dominant
  • Bleeding primarily from mucous membranes
  • Association with purpura
  • Bleeding time is prolonged

Question 13

___ have lower levels of plasma vWF and are commonly misdiagnosed as having von Willebrand disease.

Answer 13

Humans with group O blood have lower levels of plasma vWF and are commonly misdiagnosed as having von Willebrand disease.

Question 14

Diagnosing von Willebrand’s disease

Answer 14

• Factor VIII activity is measured with the PTT assay
• vWF antigen is measured with an immunologic assay that detects both normal and mutant vWF proteins
• The ristocetin cofactor assay provides a functional assessment of vWF protein
  
  • ‘Dead’ platelet test
• Western blot for vWF MW
  
  • Also used to diagnose TTP and IATP

Question 15

Rule of thumb for bleeding disorders

Answer 15

If it’s just internal bleeding, probably hemophilia A or B

If it’s just mucosal bleeding or purpura, probably vWD type I or II.

If it’s both, probably vWD type III

Question 16

Type I, IIA, IIB, and III vWD

Answer 16

• Type I: Heterozygous, most prevalent (70%), 15-60% normal vWF
• Type II: Normal levels vWF and factor VIII, but impaired function (low ristocetin cofactor activity)
  
  • Type IIA: Heterozygous. Defective multimerization of vWF. Impaired ability to tether platelets to endothelium and one another.
  • Type IIB: Heterozygous. vWF affinity for platelet glycoproteins is too high and impairs multimerization. Clearance of multimers from plasma and mild thrombocytopenia. Unusually sensitive to ristocetin agglutination.
  • Type IIN: Homozygous, autosomal recessive. N-terminal mutations that abolish vWF binding to factor VIII. Normal ristocetin cofactor activity, but no circulating factor VIII. Similar in phenotype to hemophilia A.
• Type III: Homozygous, rare, 0% vWF, effectively 0% factor VIII function

Question 17

vWD therapy

Answer 17

• Intravenous infusion of factor VIII concentrates, which are enriched in vWF
• Patients with less severe disease are often treated quite effectively with desmopressin, a vasopressin analog, which triggers the release into the plasma of vWF protein stored in endothelial cells.
  
  • Desmopressin is contraindicated in type 2B von Willebrand disease because it induces severe thrombocytopenia.

Question 18

All clotting factor deficiencies except ___ may be diagnosed by a panel of factor exclusion serum tests.

Answer 18

All clotting factor deficiencies except factor XIII may be diagnosed by a panel of factor exclusion serum tests.

Question 19

Chaotropic agent

Answer 19

A molecule in water solution that can disrupt the hydrogen bonding network between water molecules.

This has an effect in the stability of the native state of other molecules in the solution, mainly macromolecules (proteins, nucleic acids) by weakening the hydrophobic effect.

Ex, urea

Question 20

Testing for factor XIII deficiency

Answer 20

Deficiency of factor XIII can be demonstrated by testing the stability of the fibrin clot in a chaotropic solution such as 5 M urea

Question 21

___ is a clotting disorder encountered primarily among Ashkenazi Jewish populations.

Answer 21

Factor XI deficiency is a clotting disorder encountered primarily among Ashkenazi Jewish populations.

Individuals with factor XI deficiency, even when severe, seldom bleed abnormally unless challenged by trauma or major surgery. Because factor XI has a relatively long half-life, patients can be effectively treated with infusions of fresh frozen plasma.

Question 22

Where is vitamin K found?

Answer 22

Vitamin K is a fat-soluble vitamin found primarily in leafy green vegetables but also in meat and dairy products.

Some vitamin K is also synthesized by gut flora.

Question 23

Vitamin K cycle

Answer 23

Question 24

In which patients do you worry about nutritional vitamin K deficiency?

Answer 24

Patients who are not eating and who are receiving broad-spectrum antibiotics are at risk for vitamin K deficiency. This scenario is commonly encountered in hospitalized patients and often is not diagnosed until clinically significant bleeding develops.

Less often, vitamin K deficiency is caused by obstructive liver disease or by disorders of the intestinal mucosa that lead to chronic malabsorption.

Question 25

Hemorrhagic disease of the newborn

Answer 25

Arises because plasma levels of vitamin K–dependent clotting factors are relatively low at birth, the gastrointestinal tract of the newborn is relatively sterile, and mother’s milk contains very little vitamin K. The risk is enhanced if the mother has been taking antibiotics or anticonvulsant drugs.

This complication is now rarely encountered, due to the routine administration of vitamin K to newborns.

Question 26

Diagnosing vitamin K deficiency

Answer 26

• Markedly prolonged prothrombin time (PT)​
  
  • Due to impairment of prothrombin, factor VII, factor X
• Partial thromboplastin time (PTT) is also prolonged to a lesser extent
  
  • Due to impairment of prothrombin, factor IX, factor X
• A mismatch of functional impairment of prothrombin, factor VII, factor IX, X with immunological assays showing their presence at normal levels

Question 27

Treatment of vitamin K deficiency

Answer 27

Parenteral supplementation of vitamin K. The prothrombin time should reach normal levels within about 12 hours of initiating therapy.

Patients with severe bleeding should receive not only vitamin K but also Kcentra, a mixture of prothrombin and factors VII, IX, and X that is purified from human plasma.

Fresh plasma transfusion is another possibility.

Question 28

Which coagulation factors does the liver produce

Answer 28

It is the only source of the vitamin K-dependent factors and is the major, but not only, source of factor VIII.

Also responsible for most fibrinogen production.

Question 29

Clinical characteristics of liver disease with respsect to coagulation

Answer 29

• Prothrombin time is prolonged
• Partial thromboplastin time is prolonged
• Thrombin time may also be prolonged if dysfibrinogenemia is present
• Often compounded by thrombocytopenia caused either by congestive splenomegaly (in patients with cirrhosis) or suppression of platelet production (in patients with alcoholism)
• Patients with impaired liver function fail to clear activated clotting factors from the circulation and are also at higher risk for DIC

Question 30

In patients with liver disease, abnormal bleeding is primarily from ___

Answer 30

In patients with liver disease, abnormal bleeding is primarily from the gastrointestinal tract.

This is mostly due to comorbidity rather than anything inherent about the effects on the clotting system. For example, patients with cirrhosis may have esophageal varices, whereas patients with alcoholism often have not only hepatic cirrhosis but also alcohol-induced gastric erosions.

Question 31

Treating coagulation disorder secondary to liver disease

Answer 31

• Treat the underlying liver disease
• Beware occult GI bleeds
• Supplement with vitamin K, particularly if they have obstructive liver disease, and consider Kcentra if factor function is low
• Extensive thrombocytopenia can be corrected by platelet tranfusion

Question 32

Pathophysiology of disseminated intravascular coagulation at its core

Answer 32

Release of tissue factor or the exposure of blood to endotoxin or other procoagulants, such as substances derived from cancer cells, in sufficient amounts to activate blood coagulation systemically, thereby overwhelming normal hemostatic regulatory mechanisms.

Question 33

Hallmark blood characteristics of DIC

Answer 33

Coagulation cascade is ignited to such a degree that coagulation factors are consumed along with platelets

Accompanied by secondary fibrinolysis due to activation of plasmin, which may digest any fibrin that is formed, resulting in high levels of circulating fibrin breakdown products, like D-dimers.

May be associated with microangiopathic hemoltyic anemia.

Question 34

___ is the most common trigger of DIC among medical or surgical inpatients

Answer 34

Sepsis is the most common trigger of DIC among medical or surgical inpatients

Question 35

Obstetrical DIC

Answer 35

In many of these patients, DIC is induced by the release of fetal cells or fluid into the maternal circulation. Obstetrical DIC usually resolves promptly with surgical correction of the problem.

Question 36

Spectrum of DIC symptoms

Answer 36

Question 37

Treatment of DIC

Answer 37

1. Treat underlying illness (often IV antibiotics for sepsis)
2. Administration of platelets and frozen plasma, sometimes coagulation factor concentrates
3. If thrombosis is present, careful tritation of heparin may be effective
4. Close monitoring is crucial - the clinical status of patients with DIC can deteriorate rapidly

Question 38

Antiphospholipid syndrome

Answer 38

Individuals who develop antiphospholipid antibodies often have a slightly prolonged prothrombin time and a significantly prolonged partial thromboplastin time but are at risk of thrombosis rather than bleeding.