Thrombotic Thrombocytopenic Purpura, Congenital

Alternative Names

  • TTP
  • Microangiopathic Hemolytic Anemia
  • Thrombotic Microangiopathy, Familial
  • Upshaw-Schulman Syndrome
  • USS
  • Schulman-Upshaw Syndrome
  • Upshaw Factor, Deficiency of
  • Microangiopathic Hemolytic Anemia, Congenital
  • Thrombotic Thrombocytopenic Purpura, Familial
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WHO-ICD-10 version:2010

Diseases of the musculoskeletal system and connective tissue

Systemic connective tissue disorders

OMIM Number

274150

Mode of Inheritance

Autosomal recessive

Gene Map Locus

9q34

Description

hrombotic thrombocytopenic purpura (TTP) is a blood disorder characterized by the classic pentad of thrombocytopenia, microangiopathic hemolytic anemia, renal failure, neurologic dysfunction, and fever. Microvascular platelet aggregation is the physiological cause of TTP. The platelet aggregation causes formation of thrombi, as well as thrombocytopenia. Symptoms of TTP at first may be general, including fever, malaise, headache and diarrhea. Spontaneous bleeding and bruising (purpura) is also noticed. Thrombocytopenia and hemolysis may occur as early as during early infancy. Later, the affected patient may show symptoms like jaundice, transient paralysis, numbness, convulsions, and/or kidney impairment.

TTP is suspected based on the clinical symptoms. Confirmation of the diagnosis involves studying the blood count, renal function, and markers of hemolysis. Plasma infusion is the most commonly used treatment strategy to control the disease. Along with the plasma infusion, corticosteroids, and hepatitis B vaccination also need to be administered. Sometimes, blood thinning drugs, like aspirin may also be administered.

Molecular Genetics

TTP is caused due to aggregation of the von Willebrand Factor (vWF) on the surface of platelets, resulting in the sticking together of these platelets. This aggregation of the vWF is due to the non-functioning of the vWF Cleaving Protease (VWFCP). The function of the protease is to cleave the polymeric form of the VWF to monomeric units. The polymeric forms are more susceptible to aggregation. Mutations in the gene coding for the VWFCP, also known as ADAMTS13 (A Disintegrin-Like and Metalloprotease with Thrombospondin Type 1 Motif, 13), result in loss of function or reduced function of the protease, resulting in platelet aggregation.

Epidemiology in the Arab World

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Other Reports

Kuwait

In a retrospective study on ITP in Kuwait, Zaki et al. (1990) studied the admissions due to the disease in a regional hospital in Kuwait over a 6-year period. In this period, 60 children were admitted, giving an annual incidence of 12.5 in 100,000 in this population. Zaki et al. (1990) opined that this high incidence was probably due to viral infections. Treatment was by administering corticosteroids in 33 patients, while four other patients received intravenous gamma globulin. No therapy was provided for the remaining 23 patients. Spelenectomy was performed in two patients, one of whom died 2-years later as a result of septicemia. Zaki et al. (1990), on the basis of the results of the study, suggested that conservative management be adopted in mild cases of ITP, and active management be reserved only for patients presenting with severe forms of the disease.

Oman

Al Azzawi and Jayaprakash (2004) reported the use of large amounts of blood products in the management of a case of TTP. This Omani female patient, 23 years old, was referred with anemia, thrombocytopenia, episodes of generalized convulsions and loss of consciousness, and as the diagnosis of TTP was considered, she was managed with platelets and packed cell transfusions, antibiotics and prednisolone, and by the third day she received 15ml/kg of fresh frozen plasma followed by intravenous immunoglobulin (400mg/kg/day). As the diagnosis of TTP was confirmed by hematological and biochemical investigations, peripheral blood film, and bone marrow aspirate examination, she was started on 11 sessions during 13 days of aggressive plasma exchange therapy. The replacement fluid was fresh frozen plasma (FFP) in the first six sessions, followed by cryoprecipitate poor plasma (CPP) in the remaining sessions. Improvement was seen from the sixth day. This was followed up by 15ml/kg of CPP for a week. She was then discharged on 10mg of prednisolone daily and was advised on regular blood count checking. She was admitted with a relapse after eight months, and received plasma exchange with FFP for three sessions which was replaced by CPP. She showed improvement from the ninth day. Afterwards, she received eight units of packed red cells but as she developed non hemolytic transfusion reaction, washed red cell preparations were used in the other four transfusions. The third relapse was with low platelet count, and was 30 months after the first episode. Management was by daily infusions of CPP (15ml/kg daily) as plasma exchange facility was unavailable. She improved within three days and was discharged on 10mg of prednisolone daily and regular blood count checking. After fifty months of the first presentation, she presented with multiple bruises and low platelet count, and this time she did not respond to treatment which included 15ml/kg CPP infusion for two days followed by plasma exchange with CPP as replacement fluid, oral prednisolone, methyl prednisolone infusion, intravenous immunoglobulin and vincristine along with intravenous diazepam and phenytoin for the convulsions. Resistance to plasma exchange was considered, and plasma exchange sessions were tapered until they were discontinued and intravenous infusions of 5mg/kg cyclosporin A were started with marked improvement seen from the third day. After 40 days of hospital admission, she was discharged with regular follow up and was put on 200 mg of cyclosporin A, 10 mg of prednisolone, and 300 mg of aspirin. Her serology for hepatitis B and C, HIV 1,2, and 0 were negative and she did not develop red cell antibodies. Her regular liver function tests continued to be normal. Al Azzawi and Jayaprakash (2004) pointed out that this patient during her course of illness had received blood components derived from 858 donors and that her successful management reflected the competence and quality of the blood transfusion service in Oman.

Palestine

Alqadah et al. (1993) reported two Palestinian sisters with TTP associated with pregnancy. The sisters were born to non-consanguineous parents. The elder of these had onset of symptoms during the induction of labor of her first pregnancy. Although the baby was born healthy, the mother was febrile, jaundiced, and thrombocytopenic. The anemia and thrombocytopenia persisted after the delivery and did not respond to steroid therapy. Two months later, she went abroad for treatment. Peripheral blood smear there showed spherocytes, fragmented, and nucleated RBCs. Increased megakaryocytes were seen in the bone marrow examination. She was diagnosed with TTP and was put on medications and plasma exchange. Although her condition improved temporarily, she relapsed as soon as plasma exchange was stopped. In the next one year period, she underwent four relapses; each resolving completely upon plasma infusion. She did not have any more pregnancies. Her sister had the onset of her symptoms in the 23rd week of gestation of her first pregnancy. She presented with epistaxis and spontaneous skin bruises. She was found to have generalized purpuric rash and skin bruises. She was also found to be anemic and thrombocytopenic, and peripheral blood smear showed neutrophil leucocytosis, and fragmented and nucleated RBCs. Bone marrow exam was normal. Urinalysis revealed >300 RBCs per high power field. She was diagnosed with TTP and put on medications and plasma exchange. Vaginal delivery was induced in the 34th week of gestation due to intrauterine growth retardation. However, the baby died 3 days later. The placenta showed multiple vascular infarcts. The plasma infusions were stopped 4-months later, and no relapses were noted. Four other sisters of these patients had normal pregnancies. Analysis of the HLA types of the family showed no correlation between the HLA pattern and development of TTP.

Qatar

[See: Palestine > Alqadah et al, 1993].

Yemen

Savasan et al. (2001) reported a patient who had thrombocytopenia and microangiopathic hemolysis in early infancy that was responsive to plasma infusion, but who was thought to have normal ADAMTS13 activity. This patient is a female and she was born to first cousins parents of Yemenite background. Savasan et al. (2003) reinvestigated this case of reportedly normal levels of VWF-cleaving protease activity despite the presence of features that were characteristic of congenital TTP, or Schulman-Upshaw syndrome. Using a different method for analyzing plasma VWF-cleaving protease activity, they found that the patient had less than 0.1 U/L ADAMTS13 protease activity, whereas the parents were both partially deficient. Sequence analysis showed that the patient was homozygous for a 2-nucleotide (TT) deletion at the end of exon 15 (corresponding to positions 1783-1784 of the ADAMTS13 cDNA), resulting in a frameshift after his594, followed by a predicted 18-amino acid extension and premature termination. Savasan et al. (2003) concluded that hereditary TTP always results from genetic deficiency of ADAMTS13, since gene mutations had been identified in all patients studied at the molecular level.

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