Brian R. Odum, DO

Resident Physician

University of Missouri-Columbia

Department of Pathology and Anatomical Sciences

Patient Presentation

A 13 year old male without significant

past medical history was transferred to

the pediatric intensive care unit at our

institution from an outside hospital for

further management of new onset

intraparenchymal brain hemorrhage.

History of Present Illness

He had been in his usual state of health until five weeks prior to admission when he began experiencing intermittent epistaxis and noted an associated petechial rash and several ecchymoses

Approximately three weeks after the onset of these symptoms, the patient fell while skate boarding, striking the back of his head against concrete At the time of the injury he denied loss of consciousness,

nausea, vomiting, or significant headache

In the days following the fall, he reported persistent intermittent frontal headaches unresponsive to acetaminophen and non-steroidal anti-inflammatory medications.

Outside Hospital

He was found to be anemic

and thrombocytopenic

Hemoglobin: 6.0 g/dL

Platelet count: Undetectable

Imaging

CT scan: two

intraparenchymal

hemorrhages

○ left frontal lobe

○ right temporal lobe

On Admission

Complete blood count revealed a Hgb: 5.6 g/dL,

WBC: 10.3x103/µL ○ normal differential

Plt: 5x103/ µL.

Peripheral smear revealed Severe normochromic normocytic anemia

Mild reticulocytosis without schistocytosis

Severe thrombocytopenia

Bone marrow biopsy Mildly hypercellular, normoblastic bone marrow

Increased megakaryocytes

No evidence of hematologic malignancy

Bacterial blood cultures negative

Serology for ehrlichia negative

Diagnosis

Immune Thrombocytopenia (ITP)

Having excluded hypoplastic, infectious, and

neoplastic etiologies for thrombocytopenia

Initial Treatment

IVIg

○ 1 gm/kg

Initiated almost immediately

Bolus platelet transfusion

○ 2 apheresis units

Clinical Course 2nd Hospital Day

Increasing intracranial hemorrhage (ICH)

intravenous corticosteroid was added to his regimen ○ Methylprednisolone

1.8g every 24 hours

Slightly abnormal coagulation test results ○ PT 16.3s

○ PTT 31.3s

○ INR 1.2

Received a total of 4 doses of intravenous recombinant factor VII ○ rVIIa

4 mg every 3 hours

Despite this, his ICH continued to worsen

Clinical Course

3rd Hospital Day IVIG discontinued in favor of

corticosteroids

Received a third unit of apheresis platelets via bolus infusion.

These measures continued to fail to produce significant rise in platelet count ○ Maximum uncorrected increment

2x103/µL

○ Maximum corrected count increment 1104 m2/µL

Low-dose continuous platelet infusion (platelet drip) initiated ○ Transfusion rate: ½ apheresis unit

every 3 hrs

4th Hospital Day He began showing some

evidence (albeit intermittent) of rising platelet counts ○ Maximum platelet count

25x103/µL

Hemorrhage stabilized

Infusion of intravenous rVIIa discontinued

Methylpredinsolone taper begun

5th and 6th Hospital Days Ongoing platelet drip

Platelet count continued to fluctuate ○ Range of 4x103/µL to 21x103/µL

ICH remained stable

Clinical Course

7th Hospital Day Splenic artery embolization

Platelet drip continued

8th Hospital Day Platelet count rose as high as

40x103/µL ○ Radiologic assessment of

embolization showed 70-80 % of the spleen to be embolized

Methylprednisolone taper was continued.

9th Hospital Day Treatment regimen continued

Platelet count continued to rise ○ Reaching 121x103/µL

10th Hospital Day Open Splenectomy

Platelet drip was discontinued following surgery

Madoff D C et al. Radiographics 2005;25:S191-S211

Splenic Artery Embolization

Pre-embolization Post-embolization

Splenectomy O = megakaryocyte

Splenectomy

Viable Infarcted

Clinical Course

14th Hospital Day Platelet count rose to a high of 141x103/µL

15th Hospital Day Platelet count rose to 172x103/µL

Platelet drip discontinued ○ decline in platelet count to 41x103/µL

16th Hospital Day Platelet count gradually decreases

○ Low of 14x103/µL

17th Hospital Day Platelet drip re-initiated

○ Platelet count gradually increases to 32x103/µL

11th Hospital Day Platelet count dropped to

41x103/µL in the morning

Continued to decline throughout the day ○ Low of 11x103/µL

Platelet drip re-initiated ○ Platelet count rose to 29x103/µL.

12th Hospital Day Platelet count remained stable

○ mid to high 20x103/µL range

13th Hospital Day Platelet counts again fell

○ possibly in response to continued methylprednisolone taper

No increase in ICH and no overt bleeding

Platelet drip was increased ○ one full unit every four hours

Corticosteroid dose was increased

Clinical Course

Days 18-24 Platelet drip continued

Platelet count fluctuates ○ Peaks at 104x103/µL

○ Danazol (started day 23) 300 mg bid

25th Hospital Day Platelet drip discontinued

○ decline in platelet count to 14x103/µL

26th Hospital Day Platelet count drops

continuously to 3x103/µL ○ Epistaxis

○ Bleeding from incisions

Aminocaproic acid started ○ 3,000 mg q6h

Platelet drip re-initiated

27th and 28th Hospital Days Platelet count rose

incrementally ○ 15x103/µL to 20 x103/µL

range

29th Hospital Day Platelet drip continued

Azothioprine added ○ 50 mg daily

30th Hospital Day No changes

Platelet count increased to 104 x103/µL

31st Hospital Day Platelet drip discontinued

Platelet count decreased to 13x103/µL

Clinical Course

32nd Hospital Day Platelet drip re-initiated

33rd and 34th Hospital Days Platelet count increased to

63x103/µL

35th Hospital Day Platelet drip discontinued

Platelet count decreased to 9x103/µL

Days 36-40 Condition remained stable

Platelet count remained stable

○ 10x103/µL-13x103/µL

41st Day

Discharged!!!! Platelet count 13x103/µL

Platelet Count in Relation to Platelet Drip

Total Platelet Use

Apheresis Platelets

12 units over the course of his

hospitalization

Platelet Drip

193 platelet aliquots over the course of his

hospitalization

Immune Thrombocytopenia (ITP)

acquired autoimmune disease characterized by isolated thrombocytopenia (<100x103/µL) in the absence of a known underlying etiology

Previously known as Idiopathic Thrombocytopenic Purpura Nomenclature changed in light of consensus

opinion of an International Working Group on ITP(1)

○ Patients rarely show signs of bleeding (purpura)

○ Research points toward an autoimmune pathogenesis

Immune Thrombocytopenia (ITP)

Pathogenesis

Conventional theories of pathogenesis have

centered on increased autoantibody-mediated

destruction of platelets via the mononuclear

phagocyte (reticuloendothelial) system

Evolving theories of pathogenesis are more

complex

○ inhibition of platelet production(2,3)

○ T-cell mediated platelet destruction(4)

Additional research into potential genetic

mechanisms is underway(5)

Immune Thrombocytopenia (ITP)

Diagnosis(6)

ITP is a diagnosis of exclusion

Other etiologies of thrombocytopenia must be ruled out

Work-up(6)

History

Physical exam

Complete blood count

Peripheral blood smear

Bone marrow biopsy

Immune Thrombocytopenia (ITP)

Clinical Features Onset

○ Adults Insidious onset

Chronic course

○ Children Acute onset

- Often following a viral illness

Generally short-lived

Symptoms ○ Variable

Absent to minimal bleeding/bruising versus widespread hemorrhage from the GI tract, skin, and/or mucosal surfaces

Intracranial hemorrhage (ICH) is a rare, potentially life-threatening, complication(7)

Immune Thrombocytopenia (ITP)

Treatment(8) Medical

○ First line Corticosteroids

Intravenous immunoglobulin (IVIg)

Rh immunoglobulin (Rhogam, Winro)

- Only effective in Rh+ patients

○ Second line Additional immunotherapy

- azathioprine, cyclosporine A, cyclophosphamide, rituximab, danazol, dapsone, mycophenolate mofetil, thrombopoeitin receptor agonists, or vinca alkaloids

Interventional ○ Splenic artery embolization

Surgical ○ Splenectomy

Platelet Transfusion in ITP

Controversial topic

No absolute contraindication

Generally ineffective(9,10)

Transfused platelets are vulnerable to the same destructive mechanisms as native platelets

Rarely results in significant post-transfusion increments

Potentially useful in the setting of life-threatening hemorrhage

Platelet Transfusion in ITP

Conventional wisdom regarding platelet

transfusion in ITP has recently been

challenged

Some studies have shown significant post-

transfusion increments in ITP patients(11)

Platelet transfusion, when given

concurrently with immunosupression, may

effectively control bleeding(12)

Our Patient

Platelet transfusion was initiated in an attempt to stabilize the ICH, while hopefully increasing platelet count to a level where splenectomy would be a safe option Plt goal = 50x103/µL

○ *per surgeon request

Initial bolus platelet infusions were ineffective ○ Maximum uncorrected increment 2x103/µL

○ Maximum corrected count increment 1104 m2/µL

Platelet drip started with three initial goals 1. Provide a steady stream of platelets in the hopes that some

would reach the bleeding sites and stabilize the ICH

2. Minimize donor exposure in a patient requiring serial transfusions

3. Manage platelet supply in the blood bank of a hospital that is a level 1 trauma center and has an active cardiothoracic/vascular surgery service

Our Patient

Platelet drip in combination with immunosuppression worked! ICH stabilized

Platelet count increased, allowing for a safe surgery

Platelet count rose in excess of the stated goal (50x103/µL) Peaks ranged from 73x103/µL to 172x103/µL

○ Remained elevated as long as the platelet drip continued

Platelet count plummeted when the drip was stopped Bottomed out at 3x103/µL to 9x103/µL

Significant recovery occurred only when the drip was re-initiated

Our Patient: Response to Platelet Drip

Our Patient

Why did the platelet drip work? Perhaps duration of platelet transfusion is more

important than volume of platelets transfused ○ PLADO study(13)

In the setting of prophylactic platelet transfusion for patients with hypo-proliferative thrombocytopenia, there was no significant difference in bleeding risk, regardless of the dose of platelets transfused.

- Low

- Intermediate

- High

○ Platelet drip use has been proposed for prophylactic and therapeutic use in thrombocytopenic patients with non-immunologic platelet refractoriness(14,15)

Efficacy confined to isolated case reports

Conclusions

In ITP patients with severe persistent thrombocytopenia despite aggressive medical therapy, alternative treatments should be considered Especially in the presence of clinically significant or

potentially life-threatening bleeding

Conventional wisdom regarding platelet transfusion in ITP should be reconsidered

The use of platelet drip in patients with ITP resistant to conventional therapy needs further investigation

○ Randomized, controlled, prospective trials are needed to validate platelet drip as a potential treatment modality

Long Term Follow-Up

@ 1 week Platelet count 15-16x103/µL

Epistaxis

@ 2 months Platelet count 185x103/µL

@ 2.5 months MRSA abscess at site of

surgical excision

@ 5 months Platelet count 635x103/µL

@ 8 months Platelet count 100x103/µL

○ Likely chronic ITP

○ Interval development of psychiatric symptoms Self-mutilation and

insomnia

@ 11 months Platelet count 123x103/µL

@ 13 months Platelet count 105x103/µL

Began danazol wean

@15.5 months Danazol stopped

@16 months Platelet count 67x103/µL

Continued azothiaprine

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JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN. Standardization of Terminology, Definitions and Outcome Criteria in Immune Thrombocytopenic Purpura of Adults and Children: Report from an International Working Group. Blood 2009; 113.11: 2386-93.

2. Chang, M. Immune Thrombocytopenic Purpura (ITP) Plasma and Purified ITP Monoclonal Autoantibodies Inhibit Megakaryocytopoiesis in Vitro. Blood 2003; 102.3: 887-95.

3. McMillan, R. Suppression of in Vitro Megakaryocyte Production by Antiplatelet Autoantibodies from Adult Patients with Chronic ITP. Blood 2003; 103.4: 1364-9.

4. Olsson B, Andersson PO, Jernås M, Jacobsson S, Carlsson B, Carlsson LMS, Wadenvik H. T-cell-mediated Cytotoxicity toward Platelets in Chronic Idiopathic Thrombocytopenic Purpura. Nat Med 2003; 9.9: 1123-4.

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6. Neylon AJ, Saunders PWG, Howard MR, Proctor SJ, Taylor PRA. Clinically Significant Newly Presenting Autoimmune Thrombocytopenic Purpura in Adults: A Prospective Study of a Population-based Cohort of 245 Patients. Br J Haem 2003; 122.6: 966-74.

7. Roganovic J, Kalinyak K. Intracranial Hemorrhage in Children with Idiopathic Thrombocytopenic Purpura. Pediatr Int 2006; 48.5: 517.

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BH, Cines DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J, Kuter DJ. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168-86.

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