# Presentation: 438978

## Definition of Hemophilia

- Deficiency characterized by interruption of clot formation
- Hemophilia A  (Classic)
-  decreased factor VIII
- Hemophilia B (Christmas Disease)
-  decreased factor IX

## Coagulation Cascade

- Casella JF, *Oski’s Pediatrics: Principles and Practices, 3rd Ed., 1999*

## Coagulant-Anticoagulant Scheme

- Casella JF, *Oski’s Pediatrics: Principles and Practices, 3rd Ed., 1999*

## Incidence of Hemophilia

- Sex-linked inheritance pattern
- 1 in 5000 live male births in U.S.
- 4:1 ratio Hemophilia A to Hemophilia B
- Many (~ 1/3) cases are new mutations

## Hemophilia - Classification 

-  Mild       		5-30%	Activity
-  Moderate		2-5%	Activity
-  Severe		< 1%	Activity

## Hemophilia - Classification

*Symptoms*
- _Mild_ -
- Hemorrhage usually only after severe trauma or surgery
- _Moderate_ -
- Hemorrhage more frequent after moderate trauma
- _Severe_ -
- Hemorrhage frequently after minor or unrecognized trauma

## Complications of Hemophilia

- Joint disease
- Deep soft tissue bleeding
- Neurovascular compromise

## Complications of Hemophilia

-  Infections
-  Inhibitor formation
-  Psychosocial
-  Financial

## Philosophy of Care

- Normalization of life style and prevention of disability
- Rx still “on-demand” in most cases, but prophylactic treatment should be considered
- Home therapy whenever possible

## Evaluation of the patient - General

- Personal History
- Family History
- Medications
- Physical exam
- Consider circumstances of the bleed
- Presence of pain usually enough to initiate therapy
- Avoid I.M. injections, NSAIDs contraindicated

## Joint Bleeds - General

- Most common complication
- Often spontaneous
- Target joints
- Early treatment desirable
- Predictable progression once anatomical abnormality occurs

## Joint Bleeds - Evaluation 

- Consider circumstances of bleed (spontaneous vs traumatic)
- Presence of pain usually enough to initiate therapy
- Physical exam
- X-rays of limited value

## Joint Bleed - Treatment

- Factor replacement  (40-60%)
- Immobilization and cold packs may help initially
- Mobilization as soon as feasible
- Physical therapy if indicated (restore normal forces to joint)
- Prophylaxis in resistant cases
- Should see response in 6-12 hrs in average bleed

## Hematomas

- More common in infants
- Treatment dictated by site and extent
- Treat closed spaces aggressively (e.g. throat, hand, wrist, nerve compressions)
- Blood counts often best indicator of extent

## Hematuria

- Treatment controversial
- Often resolves spontaneously
- Treatment may be indicated in some cases (steroids, factor replacement)
- Therapeutic misadventures have occurred (Amicar)

## GI Bleeding

- Can be due to bleeding into the wall of the intestines
- Requires immediate evaluation
- Often due to the common sources of bleeding

## Lacerations

- Pressure
- Factor replacement, especially with   sutures
- Epsilon amino caproic acid (Amicar) or tranexamic acid may be helpful with mouth bleeds

## Slide 18

## Tooth Extraction

- Treat before (50% or greater, depending on extent of procedure)
- Consider DDAVP for mild hemophiliac
- Epsilon amino caproic acid (Amicar) or tranexamic acid after

## CNS Bleeds (Head trauma)

- Most common cause of fatal bleeding
- May occur in delayed fashion
- Treat even minor head trauma in general
- 100% replacement, _before_ diagnostic procedures
- CT or MRI may be helpful
- When in doubt, or if any sign of objective head trauma (abrasion or external hematoma), _treat_

## Life-threatening and Critical Bleeds

- Central Nervous System
- Neck and Oropharynx
- Major fractures
- Multiple traumas
- Deep lacerations
- Compartment bleeds
- Gastrointestinal bleeds

## Infections

- HIV
- Hepatitis (A, B and C)
- Septic Arthritis

## General Approach to Treatment

- Prophylactic treatment
- Get a clot (provide replacement as needed)
- Suppress fibrinolysis
- Use adjunctive measures maximally
- Local pressure, closure of wounds
- Gelfoam (gelatin sponge), topical thrombin or fibrin glue, oxidized cellulose (Oxycel, Surgicel) , other local stimulants to coagulation
- DDAVP

## Treatment

- Hemophilia
- Mild 			DDAVP
-                                     Epsilon aminocaproic acid
- Moderate or 		Factor replacement
-    Severe                      Epsilon aminocaproic acid

## Factor Replacement - General

- Previously untreated patients - use recombinant factor when possible
- Surgery - any significant surgery usually requires factor replacement - keep levels > 50%, need to monitor
- Consider constant infusion
- Remember carriers can bleed

## Factor Replacement - Dosing

- Factor VIII (intermediate purity, monoclonal, recombinant)
- 1Unit/kg produces 2% increase in VIII activity  (1-1.5 % increase with IX)
- Use to next full vial

## Factor Replacement

- Factor VIII
- 		pharmacokinetics:
- 		  - first infusion of shorter duration (4-8 hrs),
- 			 - second longer, usually 8-12 hrs
- Factor IX
- 		pharmacokinetics:
- 	  - first infusion of shorter duration (2-6 hrs),
- 		  	 - second longer, usually 18-24 hrs

## Factor IX

- None in cryo
- FFP
- Vitamin K dependent concentrates
- Purified factor IX
- Recombinant factor IX
- Can also use continuous infusion

## Suggested Replacement Levels

- 						level		duration
- 	CNS 	  			100%            10-14 days
- 	Extensive soft tissue  	  	70%
- 	Joint				40-60%	   1-4 days
- 	Surgery			  	>50%	   	   2-7 days
- 						>20-30%	   3-7 days
- 	Minor soft tissue		20-30%	   1-2 days

## DDAVP

- Only if efficacy established for that patient, (mild bleeds)
- Watch fluids (hyponatremia)
- Chest pain can occur (vasospasm)
- Repeated use leads to decreased effectiveness (tachyphylaxis)

## DDAVP for Dental Procedures in Mild Hemophilia

## Inhibitors

- Three varieties (low titer 1-5 bethesda units, intermediate 5-10, high >10)
- 10-15% of patients
- Recurrence the rule with high titer patient, with higher and higher levels
- Poor response to treatment often the first sign

## Treatment of Inhibitors 

- Activated factor IX
- FEIBA
- VIIa
- Porcine factor VIII
- High doses of VIII
- Immunosuppression

## Factor VIIa for Surgical Procedures	

## Preventive

- Padded cribs
- Avoid platelet antagonists (e.g., aspirin)
- No contact sports
- Helmets
- Immunization (Hepatitis A and B)
- Choice of lifestyle

## Emergencies

- Have a medical alert bracelet
- Know emergency resources
- Treat if in doubt

## What does the HTC do?

- Evaluation
- Laboratory Services
- Treatment Plan
- Coordination
- Counseling
- Education
- Referral

## Advantages of Comprehensive Care

- One-stop Shopping
- Coordinated Care
- Decreased Expense
- Patient Oriented
- Advocacy
- Decreased Mortality

## Conclusions and Final Thoughts

- Comprehensive care is a proven method for the care of hemophilia that reduces morbidity and mortality (Soucie et al., 2000)
- Treatment of hemophiliacs requires a multidisciplinary approach – Pharmacy plays a major role in quality of life for hemophiliacs
- Further research into cost-effective management of problems in hemophiliacs is warranted

## Who Supports Comprehensive Care

- Federal Government (MCHB and CDC)
- State of Maryland (DHMH)
- HFM

## ITP

- James F. Casella, M.D.
- Chief, Pediatric Hematology
- The Johns Hopkins University School of Medicine

## Idiopathic (Immune) Thrombocytopenic Purpura	

- Sometimes referred to as _immune_ or _autoimmune_ thrombocytopenic purpura  (ITP or ATP)
- Most commonly encountered acquired quantitative platelet disorder of childhood
- Overall incidence of ITP is 1:10,000/yr
-               ~ 1⁄2 of cases in children

**Notes:**
Read from slide

## Etiology and Pathogenesis

-  Evidence for an immunologic basis
- Rapid destruction of autologous or heterologous platelets
- Passive transmission by serum
- Increased PAIgG (Platelet-associated IgG)
- Demonstration of specific antiplatelet antibodies
- Transplacental transfer of “passive” disease

**Notes:**
The immunologic basis of ITP is well accepted, based on a number of lines of evidence:

Both autologous and heterologous platelets are rapidly removed from the circulation
Passive transmission of the disease by serum (or the IgG fraction) of blood has been demonstrated
Increased amounts of  immunoglobulin bound to platelets can be demonstrated in most cases of ITP
While some of this PAIgG may be nonspecific, specific antiplatelet antibodies can be demonstrated in many cases
Finally, the disease can be passively transmitted from mother to child by transplacental passage of antibody 

## Etiology and Pathogenesis

- Destruction of platelets in ITP
- Spleen the major site of destruction
- Less important contribution from the reticuloendothelial system of the liver, bone marrow, and lungs.

**Notes:**
In ITP, the spleen represents the major site of platelet destruction

With usually less important participation of the reticuloendothelial system of the liver, bone marrow and lungs

## Acute ITP

- Often preceded by a viral illness
- 	Viral antigens may trigger antibodies that cross-react with the platelet membrane    (e.g. varicella)

**Notes:**
What triggers ITP is not always clear:

Acute ITP often appears to have been triggered by a viral illness

In specific cases, viral antigens appear to trigger antibodies that cross react with platelet antigens, perhaps most clearly with varicella

## Chronic ITP

- Often occurs in the setting of other known autoimmune illnesses
- Specific anti-glycoprotein IIb/IIIa antibodies often demonstrated

**Notes:**
Chronic ITP often occurs in the setting of other known autoimmune diseases, and this is probably pathophysiologically important

Specific antibodies, particularly anti-glycoprotein IIB/IIIA antibodies can be demonstrated in many cases

## Acute and Chronic ITP

- Not all platelet-associated IgG (PAIgG) in ITP is directed against specific platelet antigens
- Other serum proteins (eg albumin) associated with platelet membranes in increased amounts
- Decreased production of platelets in otherwise classic cases of ITP
- ? decreased production and increased destruction in some cases

**Notes:**
There are several other points of interest pertinent to the pathophysiology of ITP
First, it is important to recognize that  much of the platelet-associated IgG (PAIgG) in ITP is not directed against specific platelet antigens, that is, it is not specific anti-platelet antibody
This idea was first supported by the observation that other serum proteins (eg albumin) are  associated with platelet membranes in increased amounts
Finally, decreased production of platelets has been demonstrated in otherwise classic cases of ITP, suggesting that both  decreased production and increased destruction may play a role in some cases

## ITP - Clinical Features	

**Notes:**
Turning to the clinical features of ITP, Acute and Chronic ITP offer an interesting contrast, and they can often be distinguished on initial presentation
In Acute ITP, as we discussed earlier, preceding viral  illnesses are common	-   In chronic ITP, antecedent illnesses are less common 
 In Acute ITP, the onset of purpuric symptoms tends to be abrupt, whereas it is more insidious  in chronic ITP	
 Acute ITP  occurs predominately  in early childhood; Chronic ITP is more common in children > 10 years of age	
Acute ITP shows an equal incidence in both sexes; chronic ITP is more common in females 	
Finally, Acute ITP tends to occur in previously healthy children; In chronic ITP, other immunoregulatory abnormalities are much more common

## Acute and chronic ITP

- Purpura and mucosal bleeding most prominent symptoms
- Children generally appear well, except for purpura
- Large submucous hemorrhages in the mouth associated with increased risk of bleeding
- Hepatomegaly, splenomegaly and lymphadenopathy notably absent
- GI and renal hemorrhage may occur
- * Central nervous system bleeding the most feared complication

**Notes:**
The following features are common to both Acute and Chroinic ITP:

Purpura and mucosal bleeding usually the most prominent symptoms
Children generally appear well, except for the presence of purpuric lesions
Large submucous hemorrhages in the mouth, and are generally felt to associated with increased risk of bleeding
On the other hand, hepatomegaly, splenomegaly and lymphadenopathy are notably absent, and their presence should instigate a search for other associated illnesses 
Gastrointestinal and renal hemorrhage may occur, however,
Central nervous system bleeding is the most feared complication of ITP, occurring in approximately 1% of cases, usually early in the course of the illness.  This is really the major reason for considering treatment in ITP, as we will discuss later

## Laboratory Diagnosis of ITP

- Platelet counts vary from normal to undetectable,
- (tend to be lower in acute ITP than in chronic ITP)
- Remainder of the CBC should be normal
- (Anemia secondary to bleeding may be seen)
- Careful review of the peripheral blood smear should be performed
- Eosinophilia and atypical lymphocytosis may be seen

**Notes:**
To turn to the laboratory diagnosis of ITP:

Platelet counts vary from normal (in compensated states) to undetectable, and tend to be lower in acute ITP than in chronic ITP.  
Remainder of the CBC should be normal, However, Anemia secondary to bleeding may be seen
Careful review of the peripheral blood smear should be performed
In addition, Eosinophilia and atypical lymphocytosis may be seen

## Laboratory Diagnosis of ITP 

- Need to rule out other abnormalities, including:
- immature white blood cells
- red cell morphology consistent with microangiopathic hemolysis
- (Thrombotic Thrombocytopenic Purpura)
- spherocytes
- (Evan’s syndrome)

**Notes:**
A careful review of the peripheral smear is important for several reasons, including ruling out the presence of abnormal blasts;  diagnostic findings such as the presence of atypical lymphocytes can also be helpful

On rare occasions, other hematologic diseases with serious consequences, such as TTP, may present with severe thrombocytopenia, and can be diagnosed early with recognition of typical signs of microangiopathic hemolytic anemia on the peripheral blood smear

The presence of spherocytes may also be a clue to the presence of other immunological abnormalities, such as autoimmune hemolytic anemia, which, when it occurs in association with ITP, is sometimes called Evan’s syndrome, and indicates a high likelihood of chronic ITP 

## Laboratory Diagnosis of ITP

- PAIgG on the platelet surface (ie, direct test) usually positive
- Patient's serum may or may not increase the amount of IgG on the surface of control platelets (i.e., indirect test)
- PT and aPTT should be normal
- Bone marrow aspirates show increased megakaryocytes
- There is no definitive test for ITP

**Notes:**
In all forms of ITP, PAIgG on the platelet surface, called the direct test, is usually positive
The patient's serum may or may not increase the amount of IgG on the surface of control platelets (i.e., indirect test)
The PT and aPTT should be normal
Bone marrow aspirates, when performed, show normal of increased numbers of megakaryocytes
However, it is important to recognize that there is no definitive test for ITP

## Laboratory Diagnosis of ITP

-  ITP is a diagnosis of exclusion

**Notes:**
In essence, the diagnosis of ITP remains one of exclusion

## When Should You do a Bone Marrow?

- When there are signs and symptoms of possible bone marrow disease
- Abnormally low or high white blood cell count
- Immature forms on peripheral smear
- Unexplained or severe anemia
- Macrocytosis
- Organomegaly or lymphadenopathy
- _Not_ when the thrombocytopenia is isolated

**Notes:**
This brings us to the question, when should one do a bone marrow for ITP

The simplest answer to this is “when there are signs and symptoms of possible bone marrow disease”

For example, an
Abnormally low or high white blood cell count
Immature forms on peripheral smear
or unexplained or severe anemia
Macrocytosis, suggestive of an underlying bone marrow dysfunction syndrome, 
Organomegaly or lymphadenopathy suggestive of a myeloproliferative disorder, or perhaps an abnormal thumb or other morphological abnormality suggestive of Fanconi’s syndrome 
A bone marrow need Not  be done when the thrombocytopenia is isolated

## Isolated Thrombocytopenia

- What is the risk of leukemia?

**Notes:**
In reality, several studies have shown that the primary reason that most practitioners do a bone marrow is to rule out the possibility of leukemia

Hence, answering the question “what is the risk of leukemia”may be the best way to address the need for a bone marrow in typical cases of ITP

## Isolated thrombocytopenia in ALL

**Notes:**
Several studies have looked at this:

In 1985, McIntosh reported 218 patients with leukemia from Toronto Sick Children’s, and pointed out that none of them had isolated thrombocytopenia, suggesting that isolated thrombocytopenia was quite uncommon as a presenting symptom in acute leukemia

Dubansky later confirmed this by surveying 2339 patients with leukemia in the POG working group, where he found no instances of true isolated thrombocytopenia

Conversely, Jones showed that, of 41 patients with isolated thrombocytopenia, none turned out to have leukemia
This was also demonstrated with larger groups, 127 patients, by Halperin, and 332 patients by Calpin

	* Of Calpin’s patients, 1 with typical findings of ITP had marrow aplasia.  

	Of those with atypical findings (135 patients), 3 had leukemia, 7 had marrow aplasia
Thus, it appears that the simultaneous occurrence of leukemia and isolated thrombocytopenia, without other suggestive physical findings or laboratory abnormalities,  is a rare event

Thus, it appears that the simultaneous occurrence of leukemia and isolated thrombocytopenia, without other suggestive physical findings or laboratory abnormalities,  is a rare event

## ITP - Clinical Course and prognosis

- Frequently benign in young children
- Excellent prognosis:
- >50% of untreated children recover within four weeks
- >80% spontaneously recover within six months
- Resolution of the thrombocytopenia occurs in a variety of patterns
- Improvement of symptoms often precedes a detectable rise in the platelet count.

**Notes:**
Fortunately, the Clinical course of ITP is typically benign, particularly in young children
Overall, the prognosis is excellent, with 
>50% of untreated children recovering within four weeks
>and 80% spontaneously recovering within six months
Resolution of the thrombocytopenia occurs in a variety of patterns, from abrupt and complete, to a more saw-tooth recovery pattern, with multiple ups and downs, to a slow, continuous recovery pattern
The observation that improvement of symptoms often precedes a detectable rise in the platelet count is frequently made, with or without treatment.

## ITP - Clinical Course and prognosis 

- Generally not considered chronic unless symptoms > than 6 months
- Relapses common in chronic ITP
- Acute ITP tends not to recur, but relapses reported (~3%)

**Notes:**
ITP is generally not considered chronic unless symptoms are present for greater than 6 months
Relapses are very common in chronic ITP
Acute ITP tends not to recur, but relapses reported in up to 3% of patients, who appear to have more than one episode of acute ITP, without other signs of chronicity, sometimes separated by as many as ten years

## Treatment of ITP

- Background
- Incidence of serious complications of ITP is very low
- Mortality and morbidity most often associated with intracranial hemorrhage
- Given the low incidence of intracranial hemorrhage, no prospective, randomized trials to truly estimate the likelihood of prevention

**Notes:**
Any discussion of treatment should take into account the following background information:
First, the incidence of serious complications of ITP is very low
Second, as I said previously, most of the mortality and morbidity in ITP is  associated with intracranial hemorrhage

Also, Given the low incidence of intracranial hemorrhage, no prospective, randomized trials to truly estimate the likelihood of prevention are available, nor are any likely to be done

## Rx of ITP - General Principles

- Goal of Rx: reduce the likelihood of bleeding during periods of maximal risk
- Waiting period usually warranted before treating in mild cases (platelet count >20,000/mm3, no bleeding other than purpura)
- Platelet counts < 20,000/mm3 or extensive mucosal bullae suggest a higher risk for internal hemorrhage and Rx should be considered
- If serious complications are present or suspected, or if a protective environment cannot be guaranteed, Rx should be initiated

**Notes:**
Therefore, the goal of Rx for most practitioners is to reduce the likelihood of bleeding during periods of maximal risk
Given the high spontaneous remission rate for acute ITP, a waiting period is usually warranted before treating in mild cases, that is, when the platelet count >20,000/mm3, and there is no bleeding other than purpura
Platelet counts < 20,000/mm3 and extensive mucosal hemorrhage such as bullae indicate higher risk for internal hemorrhage and Rx should be considered
Finally, if serious complications are present or suspected, or if a protective environment cannot be guaranteed, Rx should be initiated

## ITP - Treatment Options

- Corticosteroids
- Historically, the most commonly used therapy
- Effectiveness still debated; the following statements are generally considered to be true:
- Steroids at least transiently increase the platelet count in most patients
- Even if the platelet count is not increased, a lessening of bleeding symptoms may occur
- Steroids do not change the natural history of the disease

**Notes:**

Now, to turn to a discussion of specific treatment options,  we will begin with corticosteroids, which are historically, the most commonly used therapy

The effectiveness of streroids is still debated; however, the following statements are generally considered to be true:
Steroids at least transiently increase the platelet count in most patients
Even if the platelet count is not increased, a lessening of bleeding symptoms may occur
Steroids do not change the natural history of the disease, that is, they  do not induce a true remission or shorten the duration of the disease

## Prednisone for ITP

- Usually administered at an initial dosage of 2 mg/kg/day orally
- Higher or intravenous dosages up to 30 mg/kg/day of prednisolone for very short periods may be more effective.
- Important not to taper aggressively

**Notes:**
Steroids are usually administered at an initial dosage of 2 mg/kg/day of prednisone orally
Higher or intravenous dosages up to 30 mg/kg/day of prednisolone for very short periods have been advocated, and may be more effective.  
It is very important not to taper aggressively, however, and relapses are commonly seen when steroids are tapered too fast

## Intravenous -globulin (IVIgG)

- Useful modality in the treatment of ITP
- Mechanism of action not entirely clear
- Best evidence suggests reticuloendothelial blockade
- Reduces splenic clearance of sensitized RBCs
- Upregulation of inhibitory Fc Receptors (Animal models)
- Anti-idiotypic or anti-Fc receptor antibodies
- Modulation of T- or B-cell function postulated
- Clearance of infection or antigenemia may play a role

**Notes:**
IVIgG is now recognized as a very useful modality in the treatment of ITP
The mechanism of action  for IVIgG is not entirely clear
However, the best evidence to date suggests that it may act by causing reticuloendothelial blockade
Notably, there is reduced splenic clearance of sensitized RBCs after administration, suggesting that the effect is not specific for platelets; it has even been suggested that sensitization of the patients own red cells might be a mechanism for how IVIgG causes reticuloendothelial blockade, and I will show you how this might work in a minute
Recent and intriquing animal modes suggest that upregulation of inhibitory Fc Receptors in the spleen may be the primary mechanism for clearance of antibodies, at least in mice
Anti-idiotypic or anti-Fc receptor antibodies have also been demonstrated in some lots of IVIgG,
Modulation of T- or B-cell function postulated, and
It has been speculated that clearance of infection or antigenemia may play a role  -  This may be a consideration at times, when infection is suspected as a cause of the thrombocytopenia, or as a trigger for the ITP

## Intravenous -globulin (IVIgG)

- Treatment varies from 0.5-2 g/kg over 1 to 5 days (Most commonly used dose is 1 g/kg, single administration)
- Responses usually rapid and transitory - should not be expected in all patients
- Up to 34% of patients may experience transient complications (severe headache, nausea, aseptic meningitis)
- Some risk of transmission of infection; appears to be quite safe
- Extremely expensive

**Notes:**
Treatment regimens for IVIgG vary from 0.5-2 g/kg over 1 to 5 days, with 1 g/kg in a single administration the most commonly used dose
Responses are usually rapid and transitory - they should not be expected in all patients, but can last for several weeks.  With most regimens, greater than 80% of patients respond
It is important to recognize that up to 34% of patients may experience transient complications, including severe headache, nausea, and even an aseptic meningitis, which can be quite troublesome   
As with all blood products, there is some risk of transmission of infection; however, in general, the product appears to be quite safe
One of the major drawbacks of IVIgG is that it is extremely expensive, approximately $30-40/gram.  Therefore, one dose for an adolescent can run into the thousands of dollars  

## Anti-D Immunoglobulin

- Relatively new, but useful therapy for ITP
- Mechanism of action incompletely understood
- Hypothesis: antibody-coated red cells compete with antibody-coated  platelets for destruction in the RE-system
- No response in Rh-negative  individuals
- Splenectomized individuals may respond suboptimally, but responses seen

**Notes:**
Anti-D, or WinRho, represents a relatively new, but useful therapy for ITP
Mechanism of action is again incompletely understood, 
but it is hypothesized that antibody-coated red cells compete with antibody-coated  platelets for destruction in the RE-system
No response in Rh-negative  individuals
Also, Splenectomized individuals may respond suboptimally, but responses can be seen

## Anti-D immunoglobulin 

- Dose varies from 25g/kg/dose on two consecutive days to 50-100 g/kg x 1
- Can be infused within 1/2 hour
- I.M. use also been reported
- Response rates similar to that of IVIgG
-  (Slightly longer delay in response reported; may be dose related)
- Major toxicity a predictable fall in Hgb (mean decrease 1.3 g/dl)

**Notes:**
Dose of Anti-D vary from 25g/kg/dose on two consecutive days to 50-100 g/kg in a single administration
The agent can be infused in less than 1/2 hour
I.M. use has also been reported
Response rates appear to be similar to that of IVIgG
 (Slightly longer delay in response reported; may be dose related)
The major toxicity of Anti-D is a predictable fall in Hgb (mean decrease 1.3 g/dl)
Severe anemia appears to be rare
It is generally not recommended for patients with significant anemia

## Advantages of Anti-D vs IVIgG

- Ease of use
- Outstanding safety record of anti-D for other indications
- Significantly lower protein load and expense
- Smaller donor pool

**Notes:**
One of the biggest advantages of anti-D is its ease of use,
In addition to its outstanding safety record for another indication, the prevention of Rh sensitization in pregnant women
Significantly lower protein load and expense
Another advantage of IVIgG is that the donor pools of patients used to make Anti-D are much smaller than those used for IVIgG, in the hundreds vs tens thousands for IVIgG;  This may substantially reduce the risk for transmission of infection with Anti-D vs IVIgG

All of this is leading to much more widespread use of Anti-D, often as the treatment of first choice for ITP

As with all plasma-derived products, there is a risk of transmission of infection or allergic reactions, and this should be considered in its use

## Mechanisms of IVIgG and Anti-D

**Notes:**
Some of the most common question we get about Anti-D and IVIgG concern their mechanisms of action:  The scheme shown in this slide illustrates how they might function in causing reticuloendothelial blockade:

In panel A, splenic macrophages are shown ingesting platelets sensitized by Immunoglobulin, by recognizing Fc receptors

In panel B, clearance of the platelets is blocked by providing IVIgG in excess;  the Fc receptors of the splenic macrophages recognize the immunoglobulins, blocking clearance of the  platelets

In panel C, Some of the IVIgG is binding to RBC’s, sensitizing them, and increasing the competitition for sensitized platelets

In panel D, RBC’s are directly sensitized by anti-D, causing splenic blockade at much lower levels of Immunoglobulin 

## ITP - Blanchette et al. 1993

- 53 children (7 mos - 11.3 yrs)
- IVIgG (1g/kg/day x 2), p.o. prednisone 		(4 mg/kg/day), or no treatment (control)
- IVIgG > prednisone > control for plts > 20,000
- (1 day vs 2days vs 4 days)
- IVIgG > prednisone > control for plts > 50,000
- (2 day vs 4 days vs 16 days)
- No differences in chronic ITP or side effects

## Blanchette et al. 1993

## Blanchette et al. 1993

## ITP - Blanchette et al. 1994

- 146 children (6 mos - 18 yrs)
- IVIgG (1g/kg/day x 2 _or_ 0.8 g/kg x 1), p.o. prednisone (4 mg/kg/day), or I.V. Anti-D (Winrho) (25 u/kg/day x 2)
- IVIgG > prednisone > anti-D for plts > 20,000
- IVIgG > prednisone > anti-D for plts > 50,000
- 0.8 g/kg IVIgG best overall
- No differences in chronic ITP or side effects

## Blanchette et al. 1994

## Blanchette et al. 1994

## Platelet transfusions 

- Generally avoided because of the shortened survival of transfused platelets
- May be effective in immediately reducing serious bleeding

**Notes:**
Platelet transfusions are generally avoided because of the shortened survival of transfused platelets
However, they may be effective in immediately reducing serious bleeding, and should be used in cases of true emergency, such as intracranial hemorrhage

## Splenectomy

- Effective in resolving thrombocytopenia in approximately two thirds of patients
- Generally used only in emergencies or in extremely resistant cases

**Notes:**
Splenectomy is effective in resolving thrombocytopenia in approximately two thirds of patients
Due to the significant risk of post-splenectomy sepsis, splenectomy is usually performed only in emergencies or in extremely resistant cases

## Other therapeutic approaches for ITP

- Vinca-loaded platelets or vincristine infusions
- Other immunosuppressive agents,
- azathioprine
- cyclosporine
- cyclophosphamide
- Miscellaneous agents
- interferon
- ascorbic acid
- danazol
- protein A adsorption columns

**Notes:**
In my mind, what we have discussed to this point represents conventional therapy

the following slide shows a partial list of other agents that are  used in the treatment of ITP - 

for the purposes of this talk, I will mention only that these therapies all have significant toxicities, and in general, are effective in only a small fraction of the patients with ITP 

## Who needs therapy?

- Platelet count less than ? 5,000/mm3, ?10,000/mm3, ?20,000/mm3
- Active mucosal bleeding
- Suspected internal bleeding
- Prolonged thrombocytopenia

**Notes:**
This leaves us with the question, then, of who needs therapy

Is it the patient with a platelet count of <5,000/mm3, ?10,000/mm3, or ?20,000/mm3.  Thresholds will vary for different practitioners, and a minority withhold therapy at any platelet count

We generally feel that platelet counts below 20,000 indicate a higher risk for serious bleeding, and treatment should be considered

Certainly, most consider treatment if there active mucosal bleeding, including bullae

If there is suspected internal bleeding

Or in cases of  prolonged severe thrombocytopenia

## Surveys

- 1986 - 3 y.o. with platelets of 10,000/mm3 and epistaxis
- ~50% of respondents suggested treatment
- 1997 - 720 members of ASPHO
-  490 respondents
-  370 questionnaires analyzed

**Notes:**
Two surveys of note have looked at practice patterns of hematologists in treating ITP

The first, in 1986, looked at the response to a 3 y.o. with platelets of 10,000/mm3 and epistaxis
~50% of respondents suggested treatment, usually with corticosteroids

More recently, in 1997, Buchanan and his colleagues surveyed - 720 members of ASPHO, asking a similar question

There were
 490 respondents
 with 370 questionnaires analyzed

## Survey by Buchanan, et al., 1998

- Scenario:
- A) 5 y.o. with platelets of 3,000/mm3 , purpura only
- B) 5 y.o. with platelets of 3,000/mm3 , more severe bleeding
-  (epistaxis, mucosal bullae, Hgb of 9.7 gm/dL)

**Notes:**
The participants were presented with two scenarios:

The first, a 
A) 5 y.o. with platelets of 3,000/mm3 , purpura only

The second, a

B) 5 y.o. with platelets of 3,000/mm3 , and more severe bleeding
 (epistaxis, mucosal bullae, Hgb of 9.7 gm/dL)

## Survey by Buchanan, et al., 1998

- Results:
- Treatment                  	 A	  B
-    No treatment		16%	   1%
-    Steroids		19%	 11%
-    IVIgG			45%	 60%
-    Anti-D			10%	   5%
-    Steroids & IVIgG 	  2%    15%

**Notes:**
The responses to these questions are shown in your handouts:

As you can see, more practitioners elected to treat than in the previous survey

84 percent suggested using some form of treatment, even in the milder patient, with  only 1% withholding treatment in the face of more severe bleeding symptoms

IVIgG was the most commonly recommended treatment, and preferred for more serious bleeding over steroids and Anti-D

The low frequency of use of Anti-D probably reflects the fact that Anti-D is a relatively new form of therapy

## Survey by Buchanan, et al., 1998

- Results:
**Hospitalization****	****	****A****	****B**
-   Always			18%	61%
-   Usually			23%	24%
-   Sometimes		29%	12%
-   Never   			30%	  3%
**Bone marrow**
-   With steroids		77%
-   No steroids		  9%

**Notes:**
The tendency to hospitalize and do bone marrows is shown on the next slide

Note that a significant number of practitioners (30%) never hospitalize their patients despite low platelet counts, even if there is purpura in the absence of serious hemorrhage

Only 3% did not consider admission in the face of more serious signs of hemorrhage

77% said that they would do a bone marrow if they were going to give steroids; only 9%  if they were going to avoid steroids

This is to avoid masking the presence of leukemia by giving steroids, which can have very serious consequences in the diagnosis and treatment of leukemia ;

Note that they chose to do this, even though the risk of leukemia is almost non-existent - In our practice, we do treat children with steroids without a bone marrow, but I would not recommend this for general pediatricians in general 

## Differential Diagnosis

- Immune
- Drug-Induced Immune Thrombocytopenia
- Posttransfusion Purpura
- Alloimmune Thrombocytopenia

**Notes:**
The diagnosis of ITP is a distinctive clinical entity, and in general, there is little confusion about diagnosis

There is, however, a differential diagnosis for both immune and non-immune causes of thrombocytopenia which can occasionally be confused with ITP

Time will preclude a thorough discussion of differential diagnosis, but I will point out that I have included this in your handout for further consideration

I should mention, though,  that drug-induced immune thrombocytopenia is almost identical to ITP in its presentation and has a similar mechanism - in this case, the platelets recover within days of withdrawing the offending agent

A thorough history for potential offending agents and even foodstuffs such as quinine should be obtained in every  case of ITP

## Differential Diagnosis

- Nonimmune
- Infectious Thrombocytopenia
- Inherited Thrombocytopenias
- Microangiopathic Causes of Thrombocytopenia
- Nonimmune Drug-Induced
- Miscellaneous
- Sequestration, Infiltration, Rheumatologic, Cyanotic CHD disease, Chromosomal defects, Metabolic illnesses, Severe liver disease, hypothermia, anoxia, or iron deficiency, Folate or B12 deficiency, Large vessel catheters, Cardiopulmonary bypass, Cardiac prostheses, Rejection phenomenon, Severe allergic reactions, Myeloproliferative and myelodysplastic disorders, Aplastic anemia

**Notes:**
Among the Nonimmune causes of ITP, I will just mention that infections, particularly herpesviruses like EBV, can cause thrombocytopenia in two ways

the first is a direct result of infection, and usually due to decreased production, with or with out increased destruction

The second is a post-infectious phenomenon due to the immune response to the virus, which constitutes a true ITP-like phenomenon

It is sometimes important to be able to distinguish these two mechanisms 

Finally, if you are going to make a mistake in diagnosis, it will probably be in mistaking an inherited cause of thrombocytopenia or an early aplastic anemia for ITP

## Nonimmune Causes of Thrombocytopenia 

- Inherited Thrombocytopenias
- TAR
- Amegakaryocytic thrombocytopenia
- Wiskott-Aldrich
- Bernard-Soulier
- May-Hegglin anomaly
- Ebstein anomaly
- Hermansky-Pudlak syndrome
- Autosomal dominant, recessive and sex-linked recessive
-    thrombocytopenia

## Research at JHH

- Lehmann, Casella, Buchanan
- Decision analytic approach to treatment of ITP – NIH TMH network
- Study of the decision to treat
- Analysis of center to center variation
- Assessment of provider and patient preferences and perception of risk

## Summary - ITP

- Common disorder
- Acute and chronic forms
- Low overall morbidity and mortality
- Dx of exclusion
- Routine bone marrows unnecessary
- Newer treatment modalities have helped simplify Rx

**Notes:**
So, in summary, ITP is a common disorder,
that occurs in acute and chronic forms
While the overall morbidity and mortality of ITP remains low, there is still a finite risk of serious and even life-threatening hemorrhage
ITP remains a Dx of exclusion
Routine bone marrows are presently not felt to be necessary in all cases
Finally, newer treatment modalities and perhaps better therapeutic agents based on the mechanism of platelet destruction will help to simplify Rx

## Drug-Induced Immune Thrombocytopenia

- Characteristics
- onset of thrombocytopenia tends to be abrupt
- (within hrs of ingestion or administration of the drug)
- ceases with clearance of the drug
- tends to recur with repeated administration of the drug
- rechallenge very dangerous
- in vitro testing available

## Drug-Induced Immune Thrombocytopenia

- Mechanisms
- Specific platelet antigen---drug (ie, hapten) complex
- Absorption of antigen-antibody complexes onto the platelet surface
-  (ie, “innocent bystander” phenomenon)
- True autoantibodies

## Drugs Convincingly Associated with Immune Thrombocytopenia

- penicillins 			digoxin
- quinine 			quinidine
- cimetidine 			stibophen
- benzodiazepine 		novobiocin
- heparin 			trimethoprim-sulfamethoxasole
- allylisopropylacetylurea (Sedormid)
- *  Many other agents have the potential for causing immune-mediated thrombocytopenia

## Nonimmune Causes of Thrombocytopenia

- Non-immune drug-induced
- valproic acid
- chloramphenicol
- thiazide diuretics
- alcohol
- chemotherapeutic agents
- anti-convulsants
- antibiotics
- ionizing radiation

## Posttransfusion Purpura

- Infrequent problem, usually adults - severe thrombocytopenia  after erythrocyte transfusions
- Thrombocytopenia typically abrupt,  ~1 week after transfusion
- Affected patients typically HPA(1b,1b) (ie, PlA1 negative) women with Hx of 1 or more pregnancies, transfused with blood from a HPA(1a,1a) or HPA(1a,1b) (ie, PlA1 positive) donor
- Possibly secondary to passive absorption of soluble HPA 1a antigen from the donor's plasma to recipient's platelets, but pathophysiology may be more complex

## Nonimmune Causes of Thrombocytopenia

- Infectious Thrombocytopenia
- viral infections (active infection or postinfectious)
- varicella, Epstein-Barr virus, cytomegalovirus, other herpesviruses, infuenza, scarlatina, measles, mumps, rubella and HIV
- Other infectious agents
- toxoplasmosis, erlichiosis, RMSF, hepatitis, malaria, syphilis, tuberculosis, overwhelming bacterial or rickettsial sepsis

## Nonimmune Causes of Thrombocytopenia

- Microangiopathic
- HUS
- TTP
- DIC
- Hemangiomas

## Nonimmune Causes of Thrombocytopenia

- Miscellaneous Thrombocytopenias
- Sequestration (eg, hypersplenism or sickle cell disease)
- Infiltrative (eg, Gaucher's disease)
- Rheumatologic (eg, Felty's syndrome)
- Cyanotic congenital heart disease with polycythemia
- Chromosomal Defects
- Severe liver disease
- Severe hypothermia or anoxia
- Severe iron deficiency
- Folate or vitamin B12 deficiency

## Nonimmune Causes of Thrombocytopenia

- Miscellaneous Thrombocytopenias  (Con’t)
- 	Placement of large vessel catheters
- 	Cardiopulmonary bypass
- 	Cardiac prostheses
- 	Rejection phenomenon
- 	Severe allergic reactions
- 	Metabolic abnormalities (e.g. aminoacidopathies)
- 	Myeloproliferative and myelodysplastic disorders
- 	Aplastic anemia

## Infections Associated with Viral Illnesses

- Rubella			Varicella
- Measles			Mumps
- RMSF				CMV
- EBV				Other herpesviruses
- Hepatitis			Influenza
- Tuberculosis			Scarlatina
- Erlichiosis			HIV
- Toxoplasmosis		Malaria
- Syphilis			Overwhelming bacterial or rickettsial 					sepsis